artemisinin: the white gold for treatment of malaria’s rampant …€¦ · ashu chaudhary1*,...

Chemical Science Review and Letters ISSN 2278-6783

Chem Sci Rev Lett 2017, 6(21), 319-364 Article CS292048011 319

Research Article

Artemisinin: The White Gold for Treatment of Malaria’s Rampant Growth

Ashu Chaudhary1*, Anshul Singh

1 and Shama Khan

2

1Department of Chemistry, Kurukshetra University, Kurukshetra-136 119, India

2Department of Chemistry, Banasthali University, Banasthali-304 022, India

Introduction

Malaria, a parasitic infection keeps on taking a tremendous toll on human wellbeing, especially in tropical zones [1]. It

is brought about by the Plasmodium parasite and kills around 1–3 million individuals and reasons ailment in 300–500

million individuals annually [2]. Shockingly, mortality from malaria gives off an impression of being expanding in

the most elevated danger gathering, African kids (Figure 1) [3].

Malaria, the most crushing malady is brought about by numerous strains of plasmodium like P. falciparum, P.

vivax, P. malarae and P. ovale. P.falciparum is the most lethal gene among these [4,5]. So to battle this issue, the

utilization of spraying materials like dichlorodiphenyltrichloroethane (DDT) came into action for the vector control

[6-8]. However, due to frequent use of DDT, anopheles became resistant against this chemical. Along these lines there

turned into a need to grow new antimalarials. Prior, numerous prescriptions were utilized like Quinine [9,10],

chloroquine [11,12], amodiaquine, mefloquine, primaquine, and so forth [13]. All things considered, their utilization

was stopped because of some predicament. The crisis was in consequence of resistance to chloroquine and other

antimalarial drugs [14-17]. In the mid 1970's, another antimalarial drug artemisinin was found by You-You Tu [18].

The medication contained an endoperoxide linkage which is vital for antimalarial activity [19-23]. In the year 2006

WHO had prescribed the utilization of Artemisinin Combination Therapy (which was the utilization of two

medications in combination) [24,25]. Owing to the incessant utilization of artemisinin, in the year 2008, the first

resistance against this medication was accounted for [26,27]. On record of this, there is a steady need for new

antimalarials despite the ever-present and regularly rising resistance of parasites to as of now accessible medications,

whether utilized as a part of monotherapy or in combination.

Abstract Malaria is a perilous parasitic disease that occurs by the

parasites transmitted to the human blood through the bite of

female Anopheles mosquito. It is estimated that 250 to 500

million cases have been reported each year, imposing a

stark human and economic encumbrance on households,

communities, and countries. Majority of these deaths are

caused by infection with Plasmodium falciparum and are

common among children and pregnant women in the

developing world. Malaria is a leading health problem in

the parts of Asia, Latin America, the Middle East, Eastern

Europe and the Pacific. In India, epidemics of malaria have

been frequently reported from areas that were earlier not

associated with malaria. Unfortunately, mortality during

severe or complicated malaria still exceeds 10% to 30%.

Due to increasing resistance among malaria parasites to

chemotherapeutic agents, dissolution of malaria control

programs, and increasing international travel, the incidence

of malaria is increasing worldwide. Malaria’s cost to the

social well-being is gigantic as this mosquito-borne disease

typically strikes its victims not once but repeatedly. This

article presents a detailed survey of drugs emerging out as

potent antimalarials.

Keywords: DDT, Plasmodium falciparum,

Artemisinin, combinational therapy, Sporozoites,

Natural products

*Correspondence Author: Ashu Chaudhary

Email: [email protected]



Figure 1 Mortality rate due to malaria

Malaria: an infectious disease

Around the globe, malaria is the most critical parasitic malady of people, and kills a bigger number of children

worldwide than some other irresistible illness [28]. It is brought about by distinctive strains of plasmodium however

the most deadly among these is Plasmodium falciparum. The principal reason of its lethality is that it reproduces

rapidly in the blood. This implies disease levels can develop rapidly; if a man contaminated with P. falciparum does

not get analyzed and treated inside of a couple of days of feeling wiped out, the contamination can advance to a point

where the ailment turns out to be extremely serious. Another purpose behind its lethality is that when P. falciparum

contaminates RBC’s, it causes their shape to change, and makes them "sticky". This stickiness causes the red blood

cells to wind up stopped in the blood vessels driving into significant organs, in a procedure known as sequestration.

Sequestration makes blockages of these veins, diminishing blood stream and bringing about oxygen hardship. At the

point when this procedure happens in the blood vessels in the brain, the result is known as cerebral malaria, portrayed

by hindered cognizance, trance state and even demise. It is this pathology which is connected with most instances of

severe malaria, and reasons the most number of deaths. The manifestations of malaria incorporate recurrent fever and

shuddering, agony in the joints, migraine, weakness, and rehashed vomiting. In serious cases, shakings and kidney

failures can come about. Inconveniences of P. falciparum incorporate intense anemia and cerebral malaria. In a few

patients who apparently recuperate, another episode of malaria may happen if the treatment does not totally clear the

parasite from the blood and liver.

Lifecycle of Plasmodium

Plasmodium requires a female anopheles vector and a human body as a host to accomplish its life cycle (Figure 2).

During the erythrocyte stage, some P. falciparum merozoites form into male and female gametocytes. Gametocyte

generation likely has a versatile premise: it expands when conditions for asexual reproduction of the parasite intensify

(e.g. upon introduction to immunological anxiety and/or antimalarial chemotherapy). A female Anopheles mosquito

conveying malaria creating parasites nourishes on a human and infuses the parasites as sporozoites into the circulation

system. The sporozoite goes to the liver and attack liver cells. More than 5-16 days, the sporozoites develop, gap, and

create countless haploid structures, called merozoites, per liver cell. Some malaria parasite species stay lethargic for

broadened periods in the liver, bringing about backslides weeks or months after the fact. The merozoites leave the

liver cells and re-enter the circulatory system, starting a cycle of intrusion of red blood cells, asexual replication, and

arrival of recently shaped merozoites from the red platelets repeatedly over 1-3 days. This multiplication can bring

about a huge number of parasite-infected cells in the host circulation system, prompting ailment and entanglements of

malaria that can keep going for quite a long time if not treated. A percentage of the merozoite-tainted platelets leave



the cycle of asexual multiplication. Rather than repeating, the some of the merozoites get converted into sexual forms

of the parasite, called male and female gametocyte, that flow in the blood stream. At the point when a mosquito

nibbles an infected human, it ingests the gametocytes. In the mosquito gut, the tainted human platelets burst,

discharging the gametocytes, which form further into adult sex cells called gametes.

Figure 2 Life cycle of Plasmodium

These gametes of male and female then fuses together to form diploid zygotes, which turns into effectively

moving ookinetes that tunnel into the mosquito midgut wall and structure oocysts. Development and division of each

oocyst produces a large number of dynamic haploid structures called sporozoites. Following 8-15 days, the oocyst

blasts, discharging sporozoites into the body pit of the mosquito, from which they go to and attack the mosquito

salivary organs. The cycle of human disease re-begins when the mosquito takes a blood feast, infusing the sporozoites

from its salivary organs into the human circulation system [29].

DDT Hindrance

During the 20th century, significant decrease was achieved in the malaria done with aggressive vector control. Vector

control is one of the foremost components of the WHO Global Strategy for Malaria Control, with an objective to

break the transmission of malarial parasites by employing indoor residual spraying or pyrethroid- Impregnated

materials (bed nets and/or curtains). The first, involving A. gambiae s.s., was observed in 1967 in Bobo Dioulasso

(Burkina Faso) and attributed to the use of DDT against cotton pests (1±3, J. Hamon et al., unpublished data, 1968).

Later, it was also witnessed amongst A. arabiensis from Senegal. Resistance from DDT can be either due to a specific

detoxification mechanism (glutathione-S-transferase) or by a nerve insensitivity ensuing from a modification of the

target site (sodium channel). The latter, governed by the kdr gene, reduces both the knockdown and lethal effects of

DDT [30,31].

Biomagnfication is another reason for interrupted use of DDT. It is defined as a process in which certain

substances such as pesticides or heavy metals move up the food chain, making their way into rivers or lakes, where

they are eaten by aquatic organisms such as fish, which in turn are eaten by large birds, animals or humans. The

substances become concentrated in tissues or internal organs as they move up the chain, now termed as

Bioaccumulants with the gradual increase in their concentration due to their slow rate of being metabolized or

excreted.

Challenges Faced in Antimalarial Drug Discovery

By virtue of increment in fatalities on account of malaria, the quick emergence of new medication continued

enrooting [32,,33]. Here we discuss some of the antimalarials of the past time and the new emerging ones with their

adverse effects due to which their use were halted. Table 1 shows the date of introduction of these antimalarials with

their first reported resistance.



Table 1 Date of introduction of different antimalarials with their first reported resistance.

Antimalarial drug Introduction date First reported resistance

Quinine 1632 1910

chloroquine 1945 1957

Proguanil 1948 1949

Sulfadoxine + Pyrimethamine 1967 1967

Mefloquine 1977 1982

Halofantrine 1988 1993

Atovaquone 1996 1996

Artemisinin 1971 1980

Artesunate 1975 2008

Artesunate + Mefloquine 2000 2009

Here is the discussion of some of the antimalarial drugs:

(1) Quinine: Quinine is an alkaloid derived from bark of cinchona tree which acts as a blood schizonticidal and

feeble gametocide against Plasmodium vivax and Plasmodium malariae. As an alkaloid, it gets accumulated into

the food vacuoles of Plasmodium species, especially Plasmodium falciparum thereby inhibiting the hemozoin

biocrystallization, and thus facilitating an aggregation of cytotoxic heme. Owing to some of the demerits its use

came to an end. Use of quinine is characterised by a frequently experienced syndrome called cinchonism with

symptoms such as tinnitus (a hearing impairment), rashes, vertigo, nausea, vomiting and abdominal pain.

However in some cases Neurological effects are reported due to the drug's neurotoxic properties [34].

(2) Chloroquine: It’s action has been found to be limited to the stages of parasites life cycle that are actively

degrading hemoglobin as it has a remarkable effect on trophozoites and gametocytes but no effect on schizonts

and merozoites [35].

(3) Proguanil: Proguanil (chloroguanide) is a biguanide; a synthetic derivative of pyrimidine. It inhibits the malarial

dihydrofolate reductase enzyme [36] and thus has a most prominent effect on the primary tissue stages of P.

falciparum, P. vivax and P. ovale. However it has a weak blood schizonticidal activity and has no known effect

against hypnozoites, therefore is not used in the prevention of relapse. There are very few side effects to

proguanil, with slight hair loss and mouth ulcers being occasionally reported following prophylactic use.

(4) Sulphonamides: Sulphonamides act on the schizont stages of the erythrocytic (asexual) cycle and its efficiency

increase combining with pyrimethamine as it produces synergistic effect adequate enough to cure sensitive strains

of malaria. However, Sulfonamides causes severe skin reactions and therefore are not recommended for

chemoprophylaxis [37].

(5) Mefloquine: Mefloquine [38,39] acts by forming toxic heme complexes that damages the parasitic food vacuoles

and thus is a very effective blood schizonticide with a long half life. It produces severe side effects such as

nausea, diarrhea, abdominal pain and dizziness.

(6) Halofantrine: Halofantrine is not effective against exo-erythrocytic (hepatic) schizonts but exerts action at the

erythrocytic stage of the life cycle (trophozoite and schizont. It interferes with the neutralization of a toxic

metabolite involved in the digestion of hemoglobin within the plasmodium as this toxic metabolite if accumulates

breaks down the internal cell membranes resulting in the death of the parasite. Most commonly reported side

effects are diarrhea, vomiting, coughing, nausea, headache and fever [40].

(7) Atovaquone: Atovaquone is a chemical compound that belongs to the class of naphthoquinones. Malarone

formed by the combination of Atovaquone with proguanil is commercially available for the treatment of malaria

[41,42]. Malaron is indicated for the prophylaxis of P. falciparum malaria, together with the areas where

chloroquine resistance has been conveyed. Some of the side effects of malaron that were reported are renal

impairment, vomiting, diarrhea, relapse of infection, hepatotoxicity etc.

(8) Artemisinin: It is a sesquiterpene lactone with a chemically rare peroxide bridge linkage. It acts primarily on the

trophozite phase, thus inhibiting progression of the disease [43]. Some of its adverse effects are nausea, vomiting,

headaches, abnormal bleeding, itching etc.

(9) Artesunate: Artesunate is a hemisuccinatederivative of the active metabolite dihydroartemisinin [44]. Its effect is

mediated through a reduction in the gametocyte transmission and is generally reported to be safe and well-

tolerated.

https://en.wikipedia.org/wiki/Alkaloid

https://en.wikipedia.org/wiki/Schizont

https://en.wikipedia.org/wiki/Gamete

https://en.wikipedia.org/wiki/Plasmodium_vivax

https://en.wikipedia.org/wiki/Plasmodium_malariae

https://en.wikipedia.org/wiki/Vacuole

https://en.wikipedia.org/wiki/Plasmodium_falciparum

https://en.wikipedia.org/wiki/Hemozoin

https://en.wikipedia.org/wiki/Biocrystallization

https://en.wikipedia.org/wiki/Cytotoxic

https://en.wikipedia.org/wiki/Cinchonism

https://en.wikipedia.org/wiki/Tinnitus

https://en.wikipedia.org/wiki/Vertigo_(medical)

https://en.wikipedia.org/wiki/Neurotoxic

https://en.wikipedia.org/wiki/Proguanil

https://en.wikipedia.org/wiki/Biguanide

https://en.wikipedia.org/wiki/Hypnozoite

https://en.wikipedia.org/wiki/Sesquiterpene_lactone

https://en.wikipedia.org/wiki/Artesunate

https://en.wikipedia.org/w/index.php?title=Hemisuccinate&action=edit&redlink=1



O

O

H

H

OO

O

O

O

H

H

OO

O

OOH

O

O

NOH

NCl

NH N

N

NHOH

CF3

CF3

1 Quinine 2 Chloroquine

5 Mefloquine 6 Halofantrine

F3C

N

Cl

Cl

N

N OCH3

OCH3

NHS

NH2

O O

4 Sulphadoxine

Cl

NH NH NH CH3

NH NH CH3

3 Proguanil

Cl

O

O

OH

H

H

7 Atovaquone

H

8 Artemisinin 9 Artesunate

Artemisinin : An Emerging Sesquiterpene Lactone In Medicinal Field

Artemisia annua also known as sweet warmwood or qinghao is a sesquiterpene lactone bearing an endoperoxide

linkage which is believed to be responsible for its antimalarial action [45]. Earlier it was used to treat hemorrhoids by

Chinese herbal medicine practitioners for at least 2000 years. It is a natural product with low toxicity [46]. In the year

1980, first resistance had been reported against artemisinin. The World Health Organization (WHO) in year 2004

recommended that artemisinin-based combination therapy (ACT) should be the norm for the treatment of falciparum

malaria in most endemic countries [47]. Nowadays, the most recent single drugs approved for malarial treatment are

artemisinin derivatives [48].

Mechanism of action

Within the parasitic host hemoglobin is degraded by a series of protease enzymes to release peptides and amino acids

which are required for development and to create space inside its digestive vacuole. All through this process a build

up of hematin occurs which is potentially toxic to the parasite. To elude this kind of toxicity, the parasite has

established a mechanism where hematin undergoes biomineralization forming insoluble non-toxic hemozoin (malaria

pigment) [49]. A carboncentered radical, formed from an oxy radical via an intramolecular 1s-hydrogen atom shift, is

important for antimalarial activity [50]. Highly reactive free radicals formed by the cleavage of the peroxide bridge

in presence of ferrous ion (Fe2+

) from haem rapidly gets rearranged into more stable carbon-centered radicals [51-

53]. It has been suggested that these artemisinin-derived free radicals chemically modify and inhibit a variety of

parasite molecules, resulting into parasite's death [54].

Resistance developed against artemisinin

After the 9 years of discovery of artemisinin, parasites started developing resistance against it. It was observed that

PfATP6 is a target of artemisinin antimalarials; and single amino acid mutation in the enzyme can mediate resistance



to this important group of compounds. This has been confirmed in an independent series of experiments that use yeast

expressing this Ca2+

ATPase. Artemisinins selectively and reproducibly inhibit the yeast growth by their action on

PfATP6, as well as provides information on the effects of mutations in PfATP6 on drug sensitivity [55].

Commencement of Artemisinin Combination Therapy

In the year 2001 there was a change in the guidelines of WHO inorder to recommend artemisinin-based combination

therapies (ACTs) as first-line malaria treatment because of their high efficacy and ability to limit the development of

further resistance [56-59]. According to this therapy, the two artemisinin derivatives are used together. For instance,

Swiss pharmaceutical giant Novartis for its antimalarial treatment used Coartem, an artemisinin-based combination

therapy (ACT) which contains both artemether 12 and lumefantrine 13. World health organization (WHO)

recommends artesunate 9 and artemether 12 drugs in combination with other antimalarial drugs for treatment of

severe malaria. This approach worked very efficiently and has offered advantages such as reduced treatment time,

diminished parasite recrudescence, and lower probability of resistance development.

Semisynthetic Derivatives of Artemisinin as Potent Antimalarials First generation artemisinin derivatives, their scope and limitations

China has extensively employed Artemisinin 8 for the treatment of malaria, however poor oil and water solvency and

additionally poor ingestion through gastrointestinal tract was its constraining element. A considerable measure of

consideration has been put so far to combine better analogs of artemisinin that can have upgraded bioavailability. To

conquer this issue Chinese worker made a few subsidiaries of 8 and evaluated them for their antimalarial viability

[60]. They decreased the lactone moiety of parent particle to hemiacetal to synthesize dihydroartemisinin 10 [61].

This compound was despite the fact that having better oil and water dissolvability, yet endured the issue of

neurotoxicity and relative shakiness under acidic conditions. In order to reduce its danger and expand its steadiness it

was changed over into its relating ethyl and methyl ether derivatives arteether 11 [62] and artemether 12 [63]

individually, the first generation analogues of 8. Both of these compounds were found several times more active both

in vitro and in vivo against multi-drug resistant malaria in comparison to 8 and are at present the drugs of choice for

treatment of complicated malaria. Aremisinin derivatives 11 and 12 are principally used in India and in Netherlands

(Artemotil, Emal) however the more dominant substance is 12(Paluther, Artenam, Artemos) [64]. At present, the only

artemisinin-based combination therapy available and manufactured under Good Manufacturing Practice (GMP)

standards involves the application of 12 with lumefantrine (13) (Coartem or Riamet). Moreover, a formulation for

small children (Pediatric Coartem) is still under clinical development [65]. Even though this combination is far too

expensive and unaffordable for most of the malarial patients, yet it is believed to be effective and well tolerated [66-

68].

Another modification of dihydroartemisinin which was developed by Chinese workers was artesunic acid 14

which is another first generation artemisinin derivative, in which the hemiacetal OH group is acetylated with succinic

acid [69] 9, its sodium salt is an unstable drug as the succinic ester linkage gets rapidly cleaved, releasing

dihydroartemisinin as the active agent. Because of the free carboxylate, artesunate is a water-soluble drug that can be

administered via the i.v. route. This is of particular importance for the treatment of severe malaria tropica in which the

condition of the patients prohibits any other route of administration. A study on children with complicated malaria

conducted in India indicated the supremacy of 9 over 1 [70]. In a recent study conducted in various regions of Asia,

revealed that intravenous artesunate is considerably superior to the standard intravenous quinine for the treatment of

adult severe malaria [71].

Currently available artesunate preparations for parenteral application originated from China or Vietnam and are

now unable to meet western quality standards. Phase II and III studies were to commence in 2006 in a joint project by

the University of Tubingen in Germany (P. G. Kremsner), an industrial partner, and the Walter Reed Army Institute

of Research, with the aim of bringing an intravenous artesunate preparation to the market in 2009, to be manufactured

according to western drug regulations [72]. In addition to i.v. application, artesunate can also be administered via the

i.m., rectal, or oral routes. In a recent study made on severe malaria in childrens, presented out the fact that rectally

administered artesunate 9 was found to be as effective as i.m. applied artemether 12 and thus can prove out to be

useful in settings in which parenteral therapy cannot be given [73].



Artemisinin-based combination therapy (ACT), which is now used as the standard therapy for the treatment of

malaria in many countries, comprises artesunate as the main artemisinin combination partner. Combinations with

numerous antimalarials are used, most of which are problematic due to unmatched pharmacokinetic profiles or

widespread resistance against the non-artemisinin component of the combination. In particular, the combination of

artesunate 9 with mefloquine 5 is most widely used in Asia [74-76].

The efficacy of sodium artesunate, however, is weakened by its poor stability in aqueous solution due to the facile

hydrolysis of the ester linkage and short plasma half-life (20-30 min) [77]. A new series of water-soluble derivatives

have been reported by Lin et al. in which the solubilizing group, carboxylate, is on a moiety that is joined to

dihydroartemisinin by ether, rather than an ester, linkage. One of these derivatives, artelinic acid 14, is not only

considerably more stable than artesunic acid in weakly alkaline solution but is also more active against P. berghii in

mice. Its sodium salt, sodium artelinate 15 possesses comparable antimalarial activity both in vivo as well as in vitro

to artemether or arteether. Sodium artelinate was not only found stable in aqueous solution but also has a much longer

plasma half-life (1.5-3 h) [78]. Because of its encouraging chemical and biological properties, sodium artelinate was

subjected to preclinical testing. In an animal model, intravenous sodium artelinate was shown to be superior to

artesunate [79]. However further development of sodium artelinate has been discontinued in favor of sodium

artesunate because of its higher neurotoxicity [80, 81].

Second generation artemisinin derivatives, a need for better antimalarials

Neurotoxicity [82] was the serious issue associated with all the first generation artemisinin derivatives due to their

short plasma half-life and biotransformation to neurotoxic dihydroartemisinin 10, hence lot of work has been done for

the development of second generation artemisinins that can have reduced toxicity and increased bioavailability.

Methyl and ethyl residues of the first-generation semisynthetic artemisinins, 11 and 12 have been replaced by

numerous other residues. Most variations have been carried out at position 10, where the exocyclic oxygen atom is

replaced by carbon substituents to remove the metabolically sensitive acetal substructure. Alkyl, aryl, hetroalkyl and

heteroaryl residues have been placed at this position. Some substituents have even been used for the formation of

dimers that carry two dihydroartemisinin substructures.



Artemisinin based monomers

C-10 acetal analogs of artemisinin

Lin et al. [83] (1987) carried out structure activity relationship for various water soluble derivatives of DHA 17a-c)

by joining various alkyl groups containing free carboxylate group via ether linkage rather than ester linkage as in case

of artesunic acid 16 to insure better stability in aqueous solution.

Lin et al. [84] (1989) have synthesized various optically active ether derivatives of artemisinin in order to search

for new hydrolytically stable and less toxic analogs. He synthesized both water soluble 18a-d and oil soluble

derivatives 19a-e, out of which compound 19a-d showed very promising in vitro antimalarial activity against P.

falciparum both in Sierra Leone (IC50 = 0.44 to 2.15 ng/mL) and Indochina strains (IC50 = 0.015 to 0.480 ng/mL).

Compound 19c also showed very good in vivo activity against P. berghei in mice.

In the year 1992 Lin et al. [85] searched for more and more hydrophilic derivatives of dihydroartemisinin and

thus prepared various sugar analogs 20a-d, together with a trimethylsilylated analog 21 which exhibited much better

activity as compared to artemisinin.

Venugopalan et al. [86] (1995) prepared several ether derivatives in search for compounds having better

therapeutic index, good solubility and bioavailability. Compound 22, 23 and 24 were found as most active derivatives

of this series when tested against multidrug resistant P. yoelii nigeriensis.



Lin et al. [87] (1995) showed that α-alkylbenzylic ethers of dihydroartemisinin 25a-d have much better activity in

vitro in comparison to artemether, arteether and artesunate against two clones of human malaria, P. falciparum D-6

(Sierra Leone I clone) and W-2 (Indochina clone). In this study he demonstrated the role of steric factors and

lipophilicity in antimalarial activity.

P. M. O’Neill et al. [88] (1996), synthesized several mechanism based benzamino 26a-e and alkylamino 27a-b

ethers of artemisinin by taking into account of the fact, that the food vacuole has a slightly acidic pH and therefore the

introduction of a basic alkyl chain would assist in accumulation of drug inside the parasite. Lin et al. [89] (1997)

synthesized several analogs of DHA 28a-e exhibiting higher efficacy and longer half-life than artelinic acid.

Compound 28d was observed to be the most active compound of the series.

P. M. O’Neill et al. [90] (2001) have synthesized C-10 phenoxy derivatives of artemisinin 29a-g and 30a-g in

both α and β series respectively. The C-10-phenoxy derivatives were tested in vitro against the K-1 chloroquine-

resistant strain of P. falciparum. The phenoxy derivatives were also tested against the chloroquine sensitive HB3

strain. The most potent β-isomers, the phenyl 29a, and 4-fluorophenyl 29c were tested in vivo against P berghei and

were found more active than arteether.



Delhaes et al. [91] (2000) reported a new series of dihydroartemisinin derivatives 31a-c containing a ferrocene

nucleus. These compounds showed in vitro activity comparable to that of artemisinin against P. falciparum.

Haynes et al. [92] (2002) reported various C-10 ether and ester derivatives of DHA. They also first of all reported

a convenient synthesis of β-artesunate 32 via base catalyzed esterification. Novel esters derivatives 33a-e was

prepared using Mitsunobu and Schmidt reaction procedures. Coupling reaction using DCC or normal acylation

conditions were also reported for the synthesis of various esters. Synthesis of various lipophilic ethers 34a-e was

reported using either BF3.Et2O or TMSOTf as acid catalyst, out of which steroidal ester 35 not only showed good

antimalarial activity but also very good antiparasitic activity. Mitsunobu and Schmidt reactions were also utilized for

the synthesis of ethers as well.

Singh et al. [93] have also reported the synthesis of hydrolytically stable derivatives of artemisinin 36a-d and 37

by the incorporation of various alkyl chains. Among these compounds 36a-d and 37 were found to have activity

comparable to β-arteether. Hemisuccinates 38a-d showed activity comparable to artesunic acid.



Several workers synthesized various nitrogen containing ethers of DHA that have shown potential antimalarial

activity. Liu et al. [94] synthesized carbamate derivative 39 and assessed its cytotoxicity. Singh et al. [95] (2006)

recently reported synthesis and in vivo antimalarial assessment of highly lipophilic ether derivatives 40a-e of

dihydroartemisinin. He showed that in contrary to arteether where -isomer is more active α-isomers were far more

active than -isomers. He also synthesized various ester derivatives of DHA, 41a-f. Several of these derivatives

showed better activity profile in comparison to arteether.

Posner and coworkers reported various nitrogen containing C-10 acetals (42-46) [96-99].



Jung’s [100] deoxoartelinic acid 47 was more potent than artelinic acid 14 against both chloroquine-resistant and

chloroquine-sensitive strains of P. falciparum. When tested in malaria-infected mice, deoxo 47 was completely

curative. Chemical stability studies under simulated stomach conditions indicated that 47 possessed a significantly

longer half life than its acetal-containing analog 14 [t1/2 258.7 and 13.1 h for 32 and artelinic acid, respectively].

Deoxo 47 was also 4 times more soluble in water than artemisinin 8, revealing its potential as a drug candidate.

Antimalarially active C10-heteroaryl derivatives 48 were prepared by Posner and coworkers [101]. Friedel–Crafts

chemistry afforded C10-furan 48a,b and -pyrrole 48c derivatives in high yields. Fifty percent inhibition of

chloroquine-sensitive P. falciparum parasites occurred at 1.4, 5.2, and 4.6 nM for 48a, 48b, and 48c, respectively.

When P. berghei-infected mice were treated subcutaneously, C10-heteroaryl compounds 48 were more efficacious

than both 8 and 2.

O’Neill and coworkers [102] recently disclosed a new library of C10- pyrrole Mannich base trioxanes 49. As with

their previous work, they aimed to achieve the pharmacological benefits of nitrogen-containing artemisinins. Mannich

conditions provided aminomethyl pyrroles 49 in good yields. In vitro antimalarial activity against chloroquine-

sensitive P. falciparum was promising for these compounds (IC50¼ 2.5, 3.5, and 6.5 nM for 49a, 49b, and 49c,

respectively). In addition, Mannich bases 49 lacked toxicity, with therapeutic indices ranging well within the safety

profile of the artemisinin family. Compounds 49 displayed 100% parasitemia suppression in P. berghei-infected mice.



O

O

H

H

O

O

NR

49a, X=O, R=H49b, X=O, R=Me49c, X=NMe, R=Me

N X

49

Posner and coworkers [103] disclosed a highly efficacious fluorinecontaining C10-alkyl derivative. Amide

coupling with 4-fluoroaniline afforded fluoroanilide 50a in excellent yield. Adhering to the WHO

recommended ACT protocol,3 fluoroanilide 50a (6.8 mg kg-1

) was combined with mefloquine (20 mg kg-1

)

to achieve 99% parasitemia suppression on day 3 post infection and a complete cure of P. berghei infected

mice using only a single oral dose.

O

O

H

H

O

O

50a, R= 4-F50b, R=3-SMe

O NH

R

C-10 carba analogs of artemisinin

Several analogs of artemisinin have been prepared by the replacement of oxygen at C-10 with alkyl or aryl residues.

These deoxoartemisinin [104] 51 analogs were being designed to be more chemically robust towards acidic

hydrolysis due to lack of C-10 acetal functionality together with the fact that these compounds on oxidative

dealkylation would not lead to neurotoxic dihydroartemisinin. Several approaches have been made in made in this

regard; Jung et al. [105] (1990) first time reported the synthesis and antimalarial activity of 10β-n-

butyldeoxoartemisinin. It was found to have in vivo antimalarial activity comparable to that of artemisinin. Haynes et

al. [106] (1992) also reported the synthesis of 12α and 12β alkyldeoxoartemisnins using artemisinic acid as starting

material. Ziffer et al. [107] (1995) have reported synthesis of various 10β-alkyldeoxoartemisinin 53a-d. 10β-

allyldeoxoartemisinin 53b was converted into several promising derivatives, of which 10β-n-propyldeoxoartemisinin

53d was having in vitro antimalarial activity approx. equal to that of arteether against W-2 and D-6 clones of P.

falciparum. Ma et al. [108] (2000) utilized 10β- allyldeoxoartemisinin for the synthesis of various potent carba

analogs 54a-d. Several of these compounds showed better activity than artemisinin.



Jung et al. [109] reported the synthesis of 12-(3’-hydroxy-n-propyl) deoxoartemisinin 55a-b from artemisinic

acid. Compound 55a showed 5 times more activity than Sulphadoxine in vitro against chloroquine-resistant P.

falciparum.

McChesney et al. [110] reported the synthesis of another series of deoxo-artemisinin analogues having prototype

56a-c from artemisinic acid.

Vroman et al. [111] (1997) gave a new synthetic method for the synthesis of 9-alkyl-12-deoxoartemisinin.

Compounds 57a and 57b prepared by this method were reported to be highly potent antimalarials.

Jung et al. [112] (1998) also reported the synthesis and stability of various water soluble carba anlogs 58a-c of

artemisinin.

58a: n=158b: n=358c: n=4

O

O

H

H

O

O

COOHn

O

O

H

H

O

O

R

59a: R=H59b: R=Me59c: R=Ph

O

O

H

H

O

O

O

F/CF3 O

O

H

H

O

O

O

F/CF3

O60a: 2-fluoro phenyl60b: 3-fluoro phenyl60c: 4-fluoro phenyl60d: 2-trifluoromethylphenyl60e: 4-trifluoromethylphenyl

61a: 2-fluoro phenyl61b: 3-fluoro phenyl61c: 4-fluoro phenyl61d: 3-trifluoromethylphenyl

61e: 4-trifluoromethylphenyl

O

O

H

H

O

O

N NR

62a: R=p-Cl

62b: R=m-CF3

62c: R=p-H

62d: R=p-NO2

62e: R=p-F

O

O

H

H

O

O

HO

O

O

H

H

O

O

HO

63a 63b

Posner and coworkers [113] (1998) reported various aromatic analogs of 10-deoxoartemisinin. Posner and

coworkers [114] (1999) also reported the chemo selective synthesis of 10-deoxoartemisinin analogues 59a-c which

showed good in vitro antimalarial activity. He also reported the synthesis and antimalarial assessment of several

orally active derivatives of artemisinin family in this report.

P. M. O’Neill et al. [115] (1999) reported the synthesis of carba analogs of first generation 1,2,4-trioxane

artemether 60a-e and 61a-e which showed potent antimalarial activity.



O

O

H

H

O

O

O

O

H

H

O

O

COOH

64 65

O

O

H

H

O

O

R

66a: R=H

66b: R=C6H5

66c: R=p-FC6H4

66d: R=p-MeOC6H4

66e: R=p-3,4-Cl2C6H3

O

O

H

H

O

O

R

67a: R=CF3

67b: R=C4H9

Hindley et al. [116] (2002) reported the synthesis of carba amino derivatives of artemisinin 62a-e out of which

compound 22 showed ED90 less than 10 mg/kg against P. yoelii in mice.

Wang et al. [117] reported the synthesis of 2-hydroxy-naphthyl carba analogs of artemisinin. The C-10 naphthyl

substituted derivative 63a and 63b exhibited antimalarial activities similar to that of artemisinin in vivo.

68a: R=

68b: R=

68c: R=

O

O

H

H

O

O

R

69

OMe

MeO

MeO

OMe

MeO

OMe

OMe

OMe

NMe

O

O

H

H

O

O

COOH

O

O

H

H

O

O

CF3R

70a: R=OMe

70b: R=OEt

70c: R=OCH2CH=CH2

70d: R=OCH2CH2OH

70e: R=OCH2CF3

68d: R =68e: R =

Jung et al. [118] (2002) reported water soluble, hydrolytically stable (+) deoxoartelinic acid 65 from 64 and

assessed its antimalarial activity. Avery et al. [119] reported the synthesis and antimalarial activity of novel

substituted deoxoartemisnin 66a-e.

Chorki et al. [120] (2002) for the first time reported synthesis of C-10α trifluoromethyl deoxoartemisinins 67a

and 67b. Haynes et al. [121] reported stereo selective preparation of 10α and 10β aryl derivatives of artemisinin of

prototypes like 68a-e and 69.

Bonnet-Delphon and co-workers [122] (2004) tried to increase the metabolic and chemical stability of arteether

and DHA by the incorporation of C-10 CF3 group, thereby, making CF3 analogues of arteether 70a-e 45 times more

stable than arteether itself under “simulated stomach acid conditions”.

Liu et al. [123] reported synthesis and cytotoxicity of various carba analogs 71a-c, 72a-c and 73a-c.

O

O

H

H

O

O

O

NR

O

O

H

H

O

O

O

OR

O

O

H

H

O

O

O

R

71a: R=C2H5

71b: R=C4H9

71c: R=C6H13

72a: R=C2H5

72b: R=C12H25

72c: R=C18H37

73a: R=C2H5

73b: R=C12H25

73c: R=C18H37H



C-10 aza analogs of artemisinin

Lin et al. [124] first time reported the synthesis and antimalarial activity of C-10 aza analogs of artemisinin 74a-e.

These compounds showed very good in vitro antimalarial activity but poor in vivo antimalarial activity.

Yang et al. [125] then reported synthesis and antimalarial assessment of aniline substituted aza analogs of

artemisinin 75a-j.

Haynes et al. [126] (2005) carried out detailed structure activity relationship of C-10 aza analogs of artemisinin

76a-e, 77a-f and 78a-e. Out of these compound 77f (artemisone) was chosen for clinical trials on account of its better

pharmacokinetic and activity profile.

C-10 thio analogs of artemisinin

Venogopalan et al. (1995) have synthesized several C-10 thioether analogs of prototype 79 of artemisinin by treating

DHA with various thiols in the presence of BF3.Et2O to furnish α and isomers which were separated. These

thioethers were found active both in P. berghei (K-173)-infected mice and in P. yoelii nigeriensis (NS) infected mice

via subcutaneous and oral route.



Azaartemisnins

Avery et al. [127] (1995) gave a synthetic methodology for the synthesis of 11-aza-9-desmethylartemisins 80a-f and

assessed their antimalarial activity Torok et al. [128] (1995) developed semisynthetic method for preparation N-alkyl

-11-azaartemisinins 81a-f and screened them for antimalarial activity. One of the compounds in them showed much

better activity than artemisinin in vivo. Mekonnen et al. [129] have also synthesized several analogs of artemisinin of

prototype 82. Haynes et al. [130] (2007) carried out detailed thermal stability and in vitro efficacy study of various N-

sulfonyl derivatives of 11-azaartemisinin of prototype 83.

80a: R=CH3

80b: R=CH2CH2CH3

80c: R=CH2COOH

80d: R=CH2C6H5

80e: R=CH2CH2C6H5

80f: R=CH2CH2CH2C6H5

N

O

H

H

O

O

O

R N

O

H

H

O

O

O

R

81a: R=H

81b: R=CH2CH=CH2

81c: R=CH2CH(CH3)2

81d: R=CH3

81e: R=CH2C6H5

81f: R=CH2CHO

N

O

H

H

O

O

OR O

82a: R=CH3

82b: R=C6H5

N

O

H

H

O

O

O

S

R

OO

83a: R=CH3

83b: R=

83c:R=

83d: R=

N

N

Artemisinin Hybrids

Egan, J.T and coworkers [131] synthesized artesunate–indolo[2,3-b]quinoline hybrid. The hybrid prepared showed

increased antimalarial activity and beta-haematin inhibition, as well as low cytotoxicity.

O

O

H

O

OH

H

O

O

N

O

H

N

H

N

N

H

CH3

HH

84

Artemisinin ether and ester derivatives

Bhakuni, R.S and coworkers [132] have synthesised various ether 85a-e and ester 86a-c derivatives of

dihydroartemisinin which show better activity than arteether and artemisinin.



O

O

OH

O

O

R

85

O

O O

O

MeO

OMe

OO

S

85a, R=

85b, R=

85c, R=

85d, R=

85e, R=

O

O

O

O

O

R

NO2

NO2

O

O

86a, R=

86b, R=

86c, R=

86

Artemisinin based dimers

The first report of artemisinin based dimmer and it antimalarial activity comes from Chinese group, who isolated the

compound 87 as self dimer of dihydroartemisinin formed during the course of acetal formation reaction under acidic

conditions. This compound has been mentioned in literature by various other workers as well [133].

Physical properties and antimalarial activity of dimers of dihydroartemisinin 88-90 with intercalating succinyl

group their have also been reported by several groups [134].



Venugopalan et al. [135] (1995) synthesized various ring contracted dimmers of artemisinin 91 and 92 and

assessed them for antimalarial activity.

Posner et al. [136] (1997) reported the antimalarial and antiproliferative activity of various artemisinin based

dimers 93a-c.

O

O

H

H

O

O

O

O

O

H

H

O

O

OR

93a: R=OCH3CH2O

93b: R=(CH2)2CH2CH3

93c: R=S-S

O

O

H

H

O

O

O

O

H

H

O

O

LINKER

94a:

94b:

94c:

94d:

O O

10 10

O O10 10

MeO OMe

10 10

O10 10

LINKER

Posner et al. [137] (1999) reported the antimalarial, antiproliferative and antitumor activity of artemisinin derived

chemically robust trioxane dimers 94. He in his ongoing research developed varieties of artemisinin derived dimers

94a-d and assessed them for their antimalarial and anticancer activity.

Ekthawatchai et al. [138] reported the antimalarial activity of various prototype dimers 95 and 96 of artemisinin

formed upon nucleophilic addition to artemisitene.

Jung et al. [139] also synthesized various artemisinin based dimers 97 and 98. Jeyadevan et al. [140] carried out

synthesis and antimalarial assessment of C-10 non acetal dimers of artemisinin 99.

O

O

H

H

O

O

O

O

H

H

O

O

S

97a: n=097b: n=2

(O)n

O

O

H

H

O

O

98a: n=098b: n=2

OO

H

H

OO

S Sn(O) (O)n

O

O

H

H

O

O

O

O

H

H

O

O

OP

O

OOR

99a: R=Me99b: R=Ph



Grellepois et al. [141] synthesized various artemisinin based dimers having prototype 100 via self cross

metathesis reaction using Grubbs catalyst [103].

P. M. O’Neill [142] synthesized a series of artemisinin dimmers of prototype 101, 102 and 103 by incorporating a

metabolically stable C-10 carba-linkage which shows remarkable activity against P. falciparum malaria.

O

O

H

O

OH

H OHO

O

O

H

P

OMe

O

OO

O

O

H

O

OH

H OHO

O

O

H

P

OPh

O

OO

101 102

OO

H

O

O

H

H O

HO

O

O

H

103

HN

O

Posner et al. reported the synthesis of two-carbon-linked artemisinin-derived dimmers of prototype 104 and 105

[143]. He also synthesized new artemisinin-derived 2-carbon-linked trioxane dimmer 106 [144]. He in his ongoing

research developed three-carbon-linked trioxane dimer esters 107 and 108 and assessed them for their antimalarial

activity [145].

Synthetic Peroxides as Potent Antimalarials 1,2 Dioxanes

Yingzhaosu A 109, a natural product endoperoxide with antimalarial properties was disengaged from Chinese herb,



Yingzhao, Artabotrys uncinatus [146], yet its scarcity in nature and troublesome total synthesis [147] has prompted

the development of its different fundamentally more simpler synthetic analogs. Roche’s group [148] reported several

analogs of 109 incorporating its 2,3 dioxabicyclo[3.3.1]nonane core which were synthesized from the enantiomers of

carvone. Endoperoxide 110b, the core structure of 109, has been reported to have fragile antimalarial activity in vivo.

Substitution of the methyl group at position 4 with n-alkyl chains of 9-11 carbon iotas that 110c prompts an increment

in its size; while analogs with shorter or more chains were found to be less dynamic. As represented by 110d,

compounds containing polar functional groups, for example, alcohols, acids esters, or amines at position 4 indicated

slight or no activity, despite the fact that reduction of the ketone group at position 7 to the more polar alcohol 110e

did not influence action altogether. As displayed by 110f, substitution of the undecyl chain in 110c with a styryl group

nullified antimalarial action. On the other hand, analogs of 110f, including quinoline 110g, and particularly 110a, the

2,4-di (trifluoromethyl) styryl derivatives, has great antimalarial profiles.

Albeit 110a is less intense than the semisynthetic artemisinin in vitro, while in vivo it is just 3-fold less dynamic

than artemether [149]. Further alluring properties of 110a is that it incorporates a chemically more steady 1,2-dioxane

(endoperoxide) as opposed to the 1,2,4-trioxane in artemisinin, and also a lower rate of recrudescence and a prolonged

plasma half-life than in either of the artemether or arteether. From these information, 110a (arteflene) was chosen as

the clinical candidate, and it advanced to Phase II clinical trials in semi-immune African patients with mellow P.

falciparum malaria. In these trials, the medication was given orally as a lipid suspension, yet the outcomes were

conflicting and the compound was dissipated [150].

OO

HO

OHO O CF3

CF3O

O

O

O

O O

O OO

OHO

OO

OO

O O O

ON

CF3

F3C

109 110a 110b 110c 110d

110e 110f 110g

OH

A short and effective union of 4,8-dimethyl-4-phenylsulfonylmethyl-2,3 dioxabicyclo[3.3.1]nonanes from the

enantiomers of limonene or R-(-)- carveol managed another series 111 of analogs of yingzhaosu 109 with an

assortment of substituents at C-8. In respect to benzyl ether 111a, action deteriorated considerably for the more polar

carbinol 111c, a pattern that was somewhat turned around by acetylation to form 111d. Fascinatingly, the less polar

olefin, a dehydration product of 111c, and its completely saturated hydrogenation product, were less active than 111c.

Albeit 111b was irrelevantly less intense than its diastereomer 111a in vitro, however it was altogether more dynamic

than 111b and just slightly less dynamic than artemisinin when administered orally.

O

O

OO

S

O

O

OO

SO

O

O

O

O

O

OHO

S O

O

O

O

OAcO

S O

O

111a 111b 111c 111d



Posner's group recounted the mechanism-based configuration of a series of conveniently synthesized symmetrical

bicyclo[3.2.2]nonane 97 and bicyclo[2.2.2]octane 113 endoperoxides. As outlined by sulfone 112b, seven

heterocyclic analogs of 112a comprising sulfur, oxygen or nitrogen molecules were prepared; nevertheless, these

were all an order of magnitude less powerful than their carbocyclic simple 112a despite the fact that they are reduced

by ferrous ion to form reactive carbon centered radicals and epoxides [151]. Varieties of dioxanes have been

synthesized so far and have been evaluated for their antimalarial action yet none of them have demonstrated robust

antimalarial action.

OO

H3CO OCH3

SO

OH3CO OCH3

O O

F F

112a 112b 113

O

O

Vennerstrom et al. [152] reported the synthesis of 1,2-dioxolanes [153] 114a and 114b.These dioxolanes were

obtained as single diastereomers and assigned a cis configuration based on the stereochemistry. They exhibit very

weak antimalarial properties, which was credited to their reaction with ferrous ion to form inactive diol reaction

products.

1,2,4 trioxanes

These classes of compounds have been known in literature subsequent to 1957, when Payne and Smith as a matter of

first importance combined first synthetic trioxane [154]. Later on a few specialists created different strategies for the

synthesis of distinctive sorts of trioxanes only from synthetic point of view. It was strictly when the exposure of the

way that it is really the endoperoxide linkage of artemisinin in type of 1,2,4-trioxane, which is in charge of its

antimalarial action substantial accentuation has been made towards the synthesis and bio-assessment of different sorts

of synthetic trioxanes. The bicyclic trioxanone [155] 115 was synthesized from 2-methyl-2-cyclopenten-1-ol as in six

stages. Bicyclic trioxane [156] 116 (2,3,5-trioxabicyclo[2.2.3]nonane), readily exposed as the pharmacophoric core of

artemisinin, was prepared from 6-tetrahydrooxepanol as starting material and have just marginal antimalarial action.

The epimeric 1,2,4-trioxanes 117a and 117b were prepared by the photooxygenation reaction. Compound 117a was

only an order of magnitude less powerful than artemisinin, though 117b was entirely less intense than artemisinin.

Jefford et al. demonstrated the substitution of the bridgehead C-3 methyl group by C-3 phenyl group in 113a which

enhances its antimalarial potency by 6-fold [157]. Based on these realities Posner et al. [158] synthesized different

substituted C-3 phenyl analogs of prototype 118. Some of these compounds 118a-e have been demonstrated to exhibit

promising in vivo activity. Trioxane alcohol 118b, acetate trioxane 118c are stronger to artemisinin though water

soluble carboxylic acid derivative 118d was found to be less dynamic than artemisinin.



In extension of their work, Posner et al. [159] synthesized carboxyphenyl trioxanes 119a and 119b which were

more soluble in water at pH 7.4 than artesunate. These compounds were less adequate than their less lipophilic but

rather more commendably prepared parent compound 118. A substantial number of derivatives of artemisinin such as

1,2,4-trioxanes, including ethers, carboxylate esters, phosphate esters, carbamates and sulfonates have been

synthesized by Posner et al. A portion of the compounds discovered dynamic in vitro was likewise tried in vivo in

mice model. Taking into account their antimalarial strength in mice, two trioxanes 120 and 121 were chosen for

organic assessment in Aotus monkeys contaminated with multidrug-resistant (MDR) P. falciparum. The activity

information acknowledges that both 120 and 121 are as convincing as arteether against multidrug-resistant (MDR) P.

falciparum in Aotus monkeys [160].

Spiro ring-fused trioxane 122 was prepared beginning with (-) - isopulegol. This trioxane was just marginally less

intense than artemisinin. The analog in which the spirocyclopentane ring was superseded with geminal methyl

substituents was 9-fold less powerful than 122 [161].

1,4-Endoperoxides, formed from photooxygenation of 1,4-diaryl-1,3-cyclopentadienes, reacted with aldehydes or

ketones in reactions catalyzed by Me3SiOTf to create an immense series of cis-combined cyclopenteno-1,2,4-

trioxanes, examplified by 123a (Fenozan B07) [162]. Several such analogs 123b-f were prepared and surveyed for

their antimalarial action [163]. Among these cis-fused cyclopenteno-1,2,4-trioxanes, 123a (Fenozan B07) has the

most assuring action profile and was decided for further development [164].



Spiro trioxanes 124 and 125 and their analogs were synthesized by photooxygenation of the corresponding allylic

alcohols followed by peroxyacetalization reactions with aldehydes or ketones. Griesbeck et al. [165] synthesized the

antimalarial 1,2,4-trioxanes by means of photooxygenation of chiral allylic alcohol 4-methyl-3-penten-2-ol after

ensuing BF3 catalyzed peroxyacetalization with aldehydes or ketones that gave four monocyclic and spirobicyclic

1,2,4-trioxanes, of which 124 was the most powerful. O’Neill et al. [166] (2001) reported Co(II)-mediated

regioselective Mukaiyama hydroperoxysilylation of 2-alkyl- or 2-aryl-prop-2-en-1-ols furnished peroxysilyl alcohols

which on treatement with aldehydes or ketones provides various spiro trioxanes. Trioxane 125, the best of these, was

only an order of magnitude less compelling than artemisinin.

Singh (1990) reported a new and convenient O2-mediated synthesis of 6-arylvinyl-1,2,4- trioxanes [167]. The key

steps of this method involves the preparation of β-hydroxyhydroperoxides by photooxygenation of suitably

substituted allylic alcohols which are then elaborated into 1, 2, 4-trioxanes by acid catalyzed condensation with

various ketones or aldehydes. This method being safe has been now used for the preparation of trioxanes on the

multigram scale.

Singh et al. [168] have prepared several in vivo potent spiro 1, 2, 4-trioxanes of different prototypes and were the

first to report the antimalarial potency of these trioxanes. In the preliminary study on 6-arylvinyl-1,2,4-trioxanes,

compounds 126-132 revealed promising activity by intra peritoneal (i.p.) route against chloroquine-sensitive P.

berghei in mice but these compounds failed to exhibit any remarkable activity against chloroquine-resistant P. yoelii

in mice. Among geraniol derived 6-arylalkylvinyl trioxanes, compound 130 showed 100% survival rate at 96 mg/kg

against MDR P. yoelii in mice by p.o and i.m. routes. Although no in vitro data was presented for these trioxanes but

their in vivo data disclosed that the order of efficacy was spiroadamantane > spirocyclopentane > spirocyclohexane.

Introduction of a methyl group at the carbon atom bearing the α-arylvinyl group eradicated the antimalarial activity.

Singh et al. have further prepared a number of highly lipophilic synthetic trioxanes 132a-g, amino functionalized

trioxanes 133a-d and trioxane quinoline hybrids (trioxaquines) 134a-f. Compound 132a and 132b presented 100%

survival at 12 mg/kg and 24 mg/kg dose respectively, by oral route against multidrug resistant (MDR) P. falciparum

in swiss mice. Water soluble trioxanes 132e is active by both oral and i.m. route at 72 mg/kg dose and has been

selected for clinical trials on account of its improved pharmacokinetic profile. Among amino derivatives compound

133d showed 80% survival rate at 24mg/kg dose by oral route against MDR P. yoelii in mice, while the trioxaquines

134a-e were found to have poor activity.



OO

O

OO

O

OO

O

OO

OOO

OHO

O

132c132a 132b 132d

OO

O

O

OO

132e 132f

OO

O

COOEt

132g OO

O

133d

133a 133b 133c

NH

OO

ONH

OO

ONH

OO

ONH

MeO CF3

OO

ONH

N Cl

NHn OO

ONH

N Cl

NHn

134a: n=2134b: n=3134c: n=4

134d: n=2134e: n=3134f: n=4

Woerpel et al. [169] reported the synthesis of 1,2,4-trioxane by the treatment of γ,δ-unsaturated ketones with

hydrogen peroxide and acid. The formation of 1,2,4-trioxanes occurred most efficiently with acyclic aliphatic γ,δ-

enones with trisubstituted alkenes. The formation of trioxanes 135, 136, and 137 with the corresponding yields of

95%, 67% and 88% respectively revealed that the ketoalkenes with short alkyl side-chains underwent the

transformation most effectively,. The synthesis of trioxanes 138 and 139 demonstrated that increasing the chain

length and introduction of functional groups leads to longer reaction times and decreased yields (25% and 27%)

respectively. Compound 136 was found to be more potent among other trioxanes in the series with the yield of about

95%.

O

OO

HMe

MeMeO

OO

HMe

MeO

OO

HMe

MeO

OO

HMe

MeO

OO

HMe

Me

Me

Me OBn

136 136 137 138 139

Posner et al. [170] reported the better efficacy of monomeric trioxane in combination with mefloquin as ACT in

comparison with combination of artemether with the same. All three of the new trioxane fluorinated amides 142, 142a

and 142b along with mefloquin hydrochloride protracts the average survival time much more than monotherapy using

trioxolane which is in phase II clinical trials. Monomeric trioxane fluoroanilide 142b, at a single oral dose of only 6.8

mg/Kg in addition with 20 mg/Kg of mefloquin hydrochloride was found to be the most efficacious at prolonging

survival. On comparing 142b with 140, compound 140 exhibited only 19.8 days survival which was 30 days in case

of 142b.

O

O

H

H

O

O

OMe

140

O

O

H

H

O

O

O

O

H

H

O

O

O NHCH2 F

141

O

O

H

H

O

O

O NH(CH2)n F

142a,n=1142b,n=0(artefanilide)



Vennerstrom et al. [171] compared the antimalarial properties of weak base and neutral synthetic ozonides. First

generation antimalarial peroxide such as the semisynthetic artemisinins, artemether artesunate and artelinic acid and

the synthetic peroxides arteflene and fenozan Bo7 are all neutral or acidic compounds. More recently, the discovery

of artemisone, trioxaquine PA1103/SAR116242 and OZ277 illustrated that both semisynthetic artemisinins and

synthetic peroxides with weak base functional groups have high antimalarial efficacy and are under clinical trials.

Amino ozonide OZ209 (143) has substantially better antimalarial activity than OZ277, but it inhibits several CYP450

isoforms and has a less than ideal therapeutic index. Here five types of ozonides were synthesized namely acidic

amide, weak base amides, oxaamides, aryl amides and ureas. Out of these only three compounds showed better

potency i.e.144, 145, 146.

OO

O O

OO

NH2O

OO

O O

OO

HNO

HN

O

O

NH

OO

O O

OO

HNONH

O

O

NH2

143 144

146145

OO

O O

OO

HNON

O

NH

Singh et al. [172] earlier reported a series of phenyl vinyl substituted amino trioxanes. Unfortunately, they

showed only moderate antimalarial activity. Recently, they reported another series in which phenyl group is replaced

by naphthyl, phenanthrenyl and fluorenyl which have a major improvement on oral antimalarial activity. All the

trioxanes reported here [147(a-i), 148 (a-i), 149(a-i), 150(a-i)] provided 100% protection at 96 mg/Kg × 4 days.

Among all the trioxanes synthesized, 2 naphthalene- based trioxanes were found to be more promising than 1-

naphthalene and 3-phenanthrene based compounds while fluorene based trioxanes being the least promising. Among

all the compounds in this series, 2- naphthalene based trioxanes 148c and 148i are the most active (Table 2).

O

OO

NHR

Ar

147a-i148a-i149a-i150a-i

Robert et al. [173] reported the synthesis, characterization and antimalarial evaluation of a new series of potential

antimalarial molecules, named trioxaferroquines. These trioxaferroquines are hybrid antimalarial drugs enclosing a

1,2,4-trioxane covalently linked to ferroquine (Fq), a synthetic ferrocenylquinoline derivative. The first generation of

trioxaquines was already highly active against chloroquine-resistant strains of Plasmodium falciparum. The

antimalarial activities of trioxaferroquines were evaluated and then compared with the activity of trioxaferrocenes.



Table 2 Trioxanes with antimalarial activity Compound Ar R Yield%

147a 1-naphthyl Phenyl 87

147b 1-naphthyl 4-fluorophenyl 78

147c 1-naphthyl 4-chlorophenyl 58

147d 1-naphthyl 3,5-dichlorophenyl 54

147e 1-naphthyl 4-methylphenyl 64

147f 1-naphthyl 4-methoxyphenyl 55

147g 1-naphthyl 2-biphenyl 61

147h 1-naphthyl 3-trifluoromethyl phenyl 48

147i 1-naphthyl 4-trifluoromethyl phenyl 81

148a 2-naphthyl Phenyl 87

148b 2-naphthyl 4-fluorophenyl 66

148c 2-naphthyl 4-chlorophenyl 46

148d 2-naphthyl 3,5-dichlorophenyl 46

148e 2-naphthyl 4-methylphenyl 62

148f 2-naphthyl 4-methoxyphenyl 47

148g 2-naphthyl 2-biphenyl 55

148h 2-naphthyl 3-trifluoromethyl phenyl 60

148i 2-naphthyl 4-trifluoromethyl phenyl 68

149a 2-fluorenyl Phenyl 54

149b 2-fluorenyl 4-fluorophenyl 66

149c 2-fluorenyl 4-chlorophenyl 58

149d 2-fluorenyl 3,5-dichlorophenyl 65

149e 2-fluorenyl 4-methylphenyl 72

149f 2-fluorenyl 4-methoxyphenyl 59

149g 2-fluorenyl 2-biphenyl 64

149h 2-fluorenyl 3-trifluoromethyl phenyl 65

149i 2-fluorenyl 4-trifluoromethyl phenyl 58

150a 3-phenanthrenyl Phenyl 67

150b 3-phenanthrenyl 4-fluorophenyl 82

150c 3-phenanthrenyl 4-chlorophenyl 63

150d 3-phenanthrenyl 3,5-dichlorophenyl 78

150e 3-phenanthrenyl 4-methylphenyl 74

150f 3-phenanthrenyl 4-methoxyphenyl 65

150g 3-phenanthrenyl 2-biphenyl 54

150h 3-phenanthrenyl 3-trifluoromethyl phenyl 72

150i 3-phenanthrenyl 4-trifluoromethyl phenyl 56



Trioxaferroquines 151-154 all displayed IC50 values in the range 16-43 nM, adjacent to the values reported for

trioxaquine PA1103 (24 and 10 nM against FcB1 and FcM29, respectively). In fact, these hybrid compounds are

highly active, like artemisinin and Fq and unlike chloroquine. In addition, all the corresponding trioxaferrocenes 155-

157, lacking the quinoline fragment, are weak inhibitors of Plasmodium growth (IC50 > 150-200 nM against both

FcB1 and FcM29). The IC50 value was 235 nM for trioxaferrocene 155 compared to 20 nM for trioxaferroquine 151,

and 334 nM for trioxaferrocene 156 compared to 43 nM for trioxaferroquine 152. Results drawn from the in vivo

antimalarial activity clearly indicates that the compound 151 is the most efficient trioxaferroquine with IC50 = 20 and

17 nM against FcB1 and FcM29, respectively.

Posner et al. [174] prepared sixteen new anilide derivatives of the natural trioxane artemisinin and then evaluated

their antimalarial efficacy using Plasmodium berghei infected mice. Out of these 16 new anilides were administered

orally as 6 mg/kg dose combined with 18 mg/kg mefloquine hydrochloride, and only sulfide 3-arteSanilide 161d was

robserved to be completely remediable on day 30 after infection, as all mice in this group had no detectable

parasitemia, and gained as much weight as the uninfected control mice.

O

O

H

O

O

O NHAr

161b-q

Trioxane Ar Calculated Log P

161a 4-FPh (4-artefanilide) 4.96

161b 3-FPh (3-artefanilide) 4.96

161c 4-MeSPh (4-arteSanilide) 5.44

161d 3-MeSPh (3-arteSanilide) 5.44

161e 2-MeSPh (4-arteSanilide) 5.44

161f 3,5-(MeS)2Ph [3,5 arteSSanilide] 6.07

161g 3-(S)-MeS(O)Ph 3.55

161h 3-(R)-MeS(O)Ph 3.55

161i 4-MeS(O)2Ph 3.65

161j 3-MeS(O)2Ph 3.65

161k 2-MeS(O)2Ph 3.65

161l 3-n-PrSPh 6.22

161m 3-n-PrS(O)2Ph 5.32

161n 2-n-PrS(O)2Ph 5.34

161o 2-Cl-4-MeS(O)2Ph 3.61

161p 3-MeOPh 4.66

161q 4-n-HexOPh 6.82

Singh et al. [175] have synthesized a new series of bile acid-based trioxanes 162a−d, 163a−d, 164a−d, 165a,

165b, and 165d which heve been evaluated for their antimalarial activity against multidrug-resistant Plasmodium

yoelii in Swiss mice via oral route. The antimalarial activity of these trioxanes displayed a strong dependence on the

length of the side-chain; as it was detected that shortening the length of side- chain leads to increase in the

antimalarial activity. Both the fractions (less polar and more polar) corresponding to trioxanes 162a−d, 163a−d,

164a−d, 165a, 165b, and 165d were initially screened for antimalarial activity by oral route against multidrug-

resistant Plasmodium yoelii nigeriensis in Swiss mice at a dose of 96 mg/kg × 4 days using Peter’s procedure and

among these 14 Trioxanes which showed 100% protection at 96 mg/kg × 4 days were further screened at lower doses.

Trioxane 162a−d (more polar isomer) with full length bile acid side chain showed reduced antimalarial activity;



however none of these trioxanes exhibited 100% clearance of parasitemia on day 4 at 96 mg/kg. Among trioxane

163a−d (more polar isomer), with side chain shorter by one carbon, trioxane 163a−c showed 100% clearance of

parasitemia on day 4 at 96 mg/kg and two of them (163a and 163b) provided 60% protection to the treated mice.

Trioxane 164a−d (more polar isomer) with side chain length shorter by another two carbons, showed high-order

antimalarial activity. Trioxanes 164a−c provided 100% protection both at 96 mg/kg and 48 mg/kg. These trioxanes

provided 60−80% protection at 24 mg/kg. While trioxanes 165a, 165b, and 165d (more polar isomer), with no carbon

side chain, were the most active compounds of this series. All these three trioxanes showed 100% protection at 96, 48,

and 24 mg/kg. The positive control used in these studies is β-arteether which provided 100% protection at 48 mg/kg

and 20% protection at 24 mg/kg comparatively all the directly above mentioned three trioxanes showed 100%

protection at 24 mg/kg and were twice as active as β-arteether.

Yadav et al. [176] synthesized 3,3-spiroanellated 5-aryl, 6-arylvinyl-substituted 1,2,4-trioxanes 166-190 and

evaluated their antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice via oral

route at doses ranging from 96 mg/kg to 24 mg/kg in 4 days. Out of these compounds, compound 169, showed 20%

protection at 48 mg/kg × 4 days, while at 24 mg/kg × 4 days, 98.58% suppression of parasitaemia taking place on day

4 was observed and provided poor protection in terms of survival of the treated mice. Compound 182 showed 80%

protection at 96 mg/kg × 4 days dose, while only 89.43% clampdown of parasitaemia on day 4 was observed at 48

mg/kg × 4 days dose. Compound 181 was identified as the most active compound of the series, which was found to be

two times as active as β-arteether.

RO

O

O

R

RO

O

O

R

RO

O

O

R

166,R=H167,R=chloro168,R=methyl169,R=Bromo170,R=fluoro

180,R=H181,R=chloro182,R=methyl183,R=bromo184,R=fluoro

185,R=H186,R=chloro187,R=methyl188,R=methoxy189,R=bromo190,R=fluoro



1,2,4,5-tetraoxanes

O. Terent’ev et al. [177] reported the synthesis of bridged 1,2,4,5- tetraoxanes (191a-191l) using a facile,

experimentally simple, and selective method centered on the reaction of hydrogen peroxide with diketones catalyzed

by strong acids such as H2SO4, HClO4, HBF4, or BF3. The yields so obtained vary from 44% to 77%. (Table 3)

O

O

O

O

191a

O

O

O

O191b

O

O

O

O

191c

O

O

O

O

NC

191d

O

O

O

O

EtO

O

191e

O

OO

O

191f

O

O

O

O

191g

O

O

O

O

191h

O

O

O

O

191i

O

O

O

O

191j

OMe

O

O

O

O

191k

O2N

OO OO

191l

Table 3 Yield obtained by O. Terent’ev et al.177

during the synthesis of bridged 1,2,4,5-tetraoxanes (191a-191l).

COMPOUNDS YIELD OBTAINED ( % )

191a 77

191b 73

191c 62

191d 47

191e 55

191f 67

191g 69

191h 75

191i 77

191j 54

191k 58

191l 48

Vennerstrom et al. [178] reported the synthesis of an unsaturated dispiro 1,2,4,5-tetraoxane formed by per

oxidation of (+) – dihydrocarvone which was then converted into four structurally diverse derivatives (compounds

192-193). It was observed that as the polarity of tetraoxane series increases, in vitro potency against plasmodium

falciparum [179] decreases. It has been reported earlier that 1, 4, 10, 13-tetraalkyl substituted tetraoxanes have

relatively high in vivo antimalarial activities but due to their lipophilicity, they have little scope in offering more polar

derivaties. Out of these synthesized tetraoxanes, 192 were found to be the most effective and 194 was the least due to

high polar or hydrophilic diamino trioxane.

O O

OO

X

X

192, X= CH2

193, X= O

O O

OO

NH2

H2N

194

O O

OO

N

N

OH

194

O O

OO

N

N

Ph

Ph

195



O’Neill et al. [180] synthesized a new 1,2,4,5-tetraoxane RKA182(196) which clearly demonstrated supremacy

over mefloquine, artesunate, and artemisinin with all measured IC50 values below 5 nm. Compound (196) displayed

79% retrieval after 4 h in the infected blood.

O O

OO

O

N

N NCH3

196

In the following year they also synthesized a new series of tetraoxane inorder to eliminate any kind of potential

metabolic liability which arises due to the amide linkage present in the lead candidate RKA182.The key intermediate

of the synthesis was compound 197. All the compounds (198-214) displayed outstanding activities in the low

nanomolar range against 3D7 and K1 strains and proved to be superior in potency to chloroquine and artesunate and

similar to RKA182 (Table 4). Analogues 206 and 207 showed a remarkable 25-fold better potency than artesunate

against the chloroquine- resistant K1 strain of P. falciparum. Four of these compounds (201, 205, 213 and 214) were

further assessed using Peter’s test to determine oral in vivo ED50 and ED90 values against P. berghei. These four

compounds displayed high potency and two of the compounds 213 and 214 were found to be more potent than

artesunate in terms of ED90 in the mouse model of malaria. When dealing with turnover number compound 208 was

found to be more metabolically stable than RKA182.

O O

OO

OO O

OO

N

R1

R2

197 198-214

Table 4 New series of tetraoxanes synthesized by O’Neill et al.180

that displayed excellent activities in the low

nanomolar range against 3D7 and K1 strains.

Analogues Amine side chain (R1,R

2)

198 R1,R

2=(CH2)4O

199 R1,R

2=( CH2)4

200 R1=H,R

2=CH( CH2)4CF2

201 R1=H,R

2=CH( CH2)4O

202 R1=H,R

2=CH( CH2)4NCH3

203 R1,R

2= N(CH2))4SO2 N-Oxide

204 R1,R

2=(CH2)5

205 R1,R

2=(CH2)4CF2

206 R1,R

2=(CH2)4CHN(CH2)5

207 R1=H,R

2=CH( CH2)5

208 R1,R

2=(CH2)4CHNH2

209 R1=H,R

2=CH( CH2)2

210 R1=H,R

2=C( CH2)3

211 2-Oxopiperazinyl

212 R1,R

2=(CH2)4CHNHCOOC(CH3)3

213 Hydrochloride salt

214 Ditosylate salt

Lopes et al. [181] synthesized a new series of hybrid compounds by combining either a 1,2,4-trioxane or 1,2,4,5-

tetraoxane and 8-aminoquinoline moieties which were then tested for their antimalarial activities. These compounds

exhibited high potency in comparison to their trioxane counter part. Amide linker between the 2 moieties effectively

cleares the patent blood stage of infection caused by P. berghei in the mice. Hybrids such as 215, 216, 217 and 218

were screened for their activity against erythrocyte stage. All hybrids were observed to inhibit the growth of parasites



with IC50 values ranging from 21 to 45nm suggesting that linkers in these hybrids do not significantly affect the

antiplasmodial activity.

O O

OO HN

NH

O N

O

O O

OO HN

NH

N

O215 216

O O

OO HN

NH

O N

O217

O O

OO HN

NH

N

O218

Hybrid 215 was found to be most promising among all the hybrids and also more efficient than primaquine in

erythrocytic effect, lever effect, metabolic susceptibility and antimalarial activity.

Moreira and O’Neill et al. [182] reported a class of falcipain inhibitors: peptidomimetic pyrimidine nitriles.

Pyrimidine tetraoxane hybrids (219a-e) heve been found to exhibit influential activity against three strains of

Plasmodium falciparum. They have recently reported tetraoxane−peptide vinyl sulfone hybrids, however these

hybrids showed inhibitory effect at a low nanomolar concentrations.

O O

OO

X NH

N

R1

N

N

CN

R2

219

219a,R1=CH2CH(CH3)2, R2=5-Br,X=CO

219b,R1=CH2CH(CH2)4,R2=5-Br,X=CO

219c,R1=CH2CH(CH3)2,R2=5-Cl,X=CO

219d,R1=CH2CH(CH3)2,R2=5-H,X=CO

219e,R1=CH2CH(CH3)2, R2=6-Cl,X=CO

Moreover on making the comparison with the control clearly indicates in vivo decrease in parasitemia and an

increase in survival of mice infected with Plasmodium berghei. All tested compounds combines good blood stage

activity along with significant effects on liver stage parasitemia, an utmost welcome feature for any new class of

antimalarial drug.

Recent Leads from Natural Products Chalcones

Licochalcone A 220 isolated from Chinese licorice root [183], has been used as a traditional treatment for a number of

disorders. It is found to be active against chloroquine sensitive and resistant strains of P. falciparum and in vivo

against P. yoelii infected mice [184]. An analog of licochalcone A, 2,4-dimethoxy-4’-butoxy chalcone 221, is active

when introduced orally, and is much less toxic than the 220 [185].

O

Me

MeOH

OMe

HO

220

O

O

OCH3

OCH3

221

Awasthi and Bhasin et al. [186] have reported in vitro antimalarial potential of chalcone derivatives. Chalcones

are aromatic ketones and key biosynthetic intermediates for combinatorial assembly of different heterocyclic



scaffolds. A small number of effective chalcones were selected for their antimalarial interaction in combination with

artemisinin in vitro and evaluation of these combinations showed synergistic or additive interactions as these

chalcones are found to be active on the broad range of asexual stages of the parasite. Compound 222 in combination

with artemisinin exhibited synergistic antiplasmodial interaction in three of the four fixed-ratio combinations

evaluated and additive in the other. Similarly the combination of 223 and artemisinin displayed synergistic interaction

in two combinations and additive in rest of the two combinations while the interaction of artemisinin with 224 is

consistently found to be additive.

O

ClN

O

ClN

N N

O

ClNN

N222 223 224

Recently twenty-seven novel chalcone derivatives were synthesized using Claisen-Schmidt condensation and

their antimalarial activity against asexual blood stages of Plasmodium falciparum was determined. Out of these 27

chalcone derivatives, eight of them (225, 226, 227, 228, 229, 230, 231, 232) were forwarded for further screening.

Among these compound 228 containing benzimidazole substituent was found to be most active with IC50 value of

about 1.1 µg⁄mL. Further in this series, three of the compounds 225, 226, and 227 having pyrrolidine, morpholine, and

1, 2, 4-triazole substituents have also exhibited intense effect on parasites, with IC50 value of 2.37, 2.95, and 3.38

µg⁄mL respectively, while piperidine, pyrrole, imidazole, and benzotriazole substituents showed moderate

antiplasmodial activity with IC50 between 5.98 and 7.22 µg⁄mL. Compound 229 and compound 230 with N-methyl

piperazine and benzotriazole substituents on ring B displayed feeble activity with IC50 10.1 and 12.73 µg⁄mL

respectively. The compound 231 and compound 232 containing pyrrolidine and benzotriazole substituents showed

good activity with IC50 2.9 and 3.5 µg⁄mL respectively, while rest of compounds showed moderate activity with IC50

range from 7.34 to 4.96 µg⁄mL where piperidine substituent was found to be least active.



Quinoline and Isoquinoline alkaloids

Twelve of the 2-substituted quinoline alkaloids were isolated from Galipea longiflora (family Rutaceae) and among

them 2-(n-pentyl) quinoline 233 was found to be effective against the mice infected with P. vinckei petteri at dose of

50 mg/kg/day [187]. On taking 233 as a lead molecule, synthesis and the antimalarial activity of some related

compounds of prototype 234 and 235 have also been reported [188]. The aporphine alkaloid (-)- roemrefidine 236 that

is isolated from Sparattanthelium amazonum (family Hernandiaceae) showed activity against chloroquine resistant

and chloroquine sensitive strains of P. falciparum, with IC50 values of 0.58 and 0.71 M respectively. Compound 236

showed ED50 value of 5.98 mg/kg/day against P. berghei infected mice whereas chloroquine showed ED50 value of

0.98 mg/kg/day in the same model [189]. Naphthylisoquinoline alkaloids 237-240 have been identified as the active

principles of the African antimalarial medicinal plants Ancistrocladus abbreviatus, A. barteri (family

Ancistrocladaceae), and Triphyophyllum peltatum (Dioncophyllaceae) exhibiting in vitro activity against the K1

(multi-drug resistant) and NF-54 (CQ-sensitive) strains of P. falciparum [190], as well as P. berghei. [191]. Advance

studies have shown that dioncopeltine A 237 suppressed parasitaemia almost completely, while dioncophylline C 240

cured P. berghei infected mice completely after oral treatment at 50 mg/kg/day for 4 days without perceptible toxic

effects. However it was observed that when 240 was delivered directly to the circulatory system via a mini osmotic

pump a more rapid clearance of parasitaemia was detected which clearly indicated that compound 240 have some

bioavailability problems [192].

Four benzyl tetrahydroisoquinoline 241-245 and one benzyl isoquinoline alkaloid 245 isolated from Hernandia

voyronii (family Hernandiaceae) showed moderate in vitro antimalarial activity (IC50 = 1.68 to 3.38 g/ml) against the

CQ-resistant P. falciparum strain. In rodent’s studies, 241 and 243 showed 31.8% and 15% suppression of

parasitaemia respectively against the CQ-resistant strain (N67) of P. yoelii in mice at 10 mg/kg/day for 4 days. In a

chloroquine combination studies, 242 and 243 showed synergism while 241 had simple additive effects. On the other

hand, 244 showed antagonism and 245 potentiated the antiplasmodial activity of chloroquine in vivo [193].



Indolequinoline alkaloids

Cryptolepine 246 is an indolequinoline alkaloid isolated from the roots of Cryptolepis sanguinolenta (family

Periplocaceae) that exhibits in vitro activity against a multi-drug resistant strain of P. falciparum (K1) [194] with IC50

= 0.031g/ml and in vivo activity against rodent malaria when given orally [195].

-Carboline alkaloids

An alkaloid named Manzamine A 247 present in several marine sponge species was found to inhibit the growth of P.

berghei in mice. Compound 247 exhibited inhibition of more than 90% of the asexual erythrocytic stages of P.

berghei after a single i.p. injection into the infected mice. A significant aspect of treatment with compound 247 is its

ability to prolong the survival of highly parasitemic mice as 40% mice were able to survive beyond 60 days after the

single injection [196].

Sesquiterpene isonitriles

The initial report of isonitrile compounds, isolated from marine organisms, that have significant antimalarial activity

is that of axisonitrile-(3) 248 from the sponge Acanthella klethra [197]. Compound 248 has IC50 values of 142 µg/ml

and 16.5 µg/ml for CQ-sensitive (D6) and CQ-resistant (W2) strains of P. falciparum respectively [198]. Further

analyses of marine sources led to the isolation of a series of diterpene isonitriles and isocyanates from the sponge

Cymbastela hopper [199]. Two of the compounds 249a and 249b have IC50 values of 4.7 µg/mL and 3.2 µg/mL

respectively against chloroquine resistant strains (D6) of P. falciparum. While against chloroquine sensitive strains

(W2) of P. falciparum IC50 values were 4.3 µg/mL and 2.5 µg/mL respectively. As with the other isonitrile natural

products, Kalihinol A 250 has in vitro activity in the nanomolar range and is also found to be quite selective [200].

The isonitrile compound 250 seems to act on heme detoxification process. Schmalz et al. have synthesized several

analogues so as to evaluate the antimalarial potential of this class of compounds and have shown that they exhibit

moderate in vitro antimalarial activity against P. falciparum [201]. Singh et al. have synthesized several isonitriles

and tested them against P. falciparum (in vitro) and multi-drug resistant P. yoelii in mice model (in vivo) [202].

Compound 251 was found to be the most active compound of the series as it showed in vitro activity (MIC = 0.40

g/ml) and 99.8% suppression of parasitaemia on day 4 at 25 mg/kg and survival of about 20% of the treated mice

beyond 28th day.



Amino steroids

Sarachine 252 is an amino steroid that has been isolated from the leaves of Saraca punctata. The compound shows a

strong in vitro antiplasmodial activity with an IC50 of 25 nM [203].

Quinazolone alkaloids

The roots of Dichroa febrifuga (family Saxifragaceae) have been used for centuries in China to treat malaria fevers.

Febrifugine 253 and isofebrifugine 254 isolated from D. febrifuga and have attracted considerable attention as

antimalarial agents. In mice, febrifugine significantly reduced mortality as the drug seemed to potentiate the

production of nitric oxide in acute immune responses [204, 205].

Xanthones

These are secondary plant metabolites which exhibits antimalarial activity due to their ability to inhibit heme

polymerization [209]. They are found almost exclusively in the members of two families of plants, Guttiferae and

Gentianaceae as well as in certain fungi, ferns and lichens [206] Rufigallol 255, a hydroxylated anthraquinone, was

the first compound of this class, which was found to exhibit antimalarial activity and is active against CQ-sensitive P.

falciparum (D6) [207, 208] Exiphone 256, the structural analogue of rufigallol showed in vitro activity with an IC50 of

4.1µM against CQ-sensitive strain (D6) of P. falciparum. Combination studies have shown that 255 potentiated the

antimalarial activity of 256.

Naphthoquinones

Diospyrin 257, a Naphthoquinones isolated from Diospyros montana (family Ebenaceae) and its semisynthetic

derivatives have been investigated for their antiprotozoal effects. Tetrahydroxy 258 and tetraacetoxy 259 derivatives

are 100-fold more active than diospyrin against the multidrug resistant P. falciparum K1. These compounds are found

to be as active as chloroquine with an IC50 of 0.215 μM [210].



Amidoxime Derivatives

Hoang et al. [211] developed M34 prodrugs which revealed higher in vitro activity than M64 drugs. However, a

broader range of modulations are allowed by the M34 bis-C-alkylamidine structure as it enables the synthesis of

1,2,4-oxadiazole derivatives, which is not possible for M64. M34 antiplasmodial activity is found to be much superior

as compared to the neutral compounds 260, 261–267, and 270. Contrary to the previous compounds, the

methylsulfonate derivative 268 and, to a lesser extent, the thiadiazolone 269 were the only compounds to have in vitro

antimalarial activities occurring in the same nanomolar range as the parent alkylamidine M34. The in vivo

antimalarial activities of their compounds were investigated against the Plasmodium vinckei petteri strain (279BY) in

female Swiss mice. These compounds were then introduced into the mice either intraperitoneally (ip) or orally (po)

once daily for four consecutive days (days 1–4 post-infection). After administration done intraperitoneally (ip), no

antimalarial effect could be detected. However, with the thiadiazolone 269, parasitemia was reduced to 50% as

compared to the control and also parasitemia cleared out completely with the methylsulfonate derivative 268 (ED50 ip

= 7 mg/kg). Since the compounds 268 and 269 exert their antimalarial activity at the equivalent nanomolar range (in

vitro) or with the same ED50 ip (in vivo) as bis-cationic bis-alkylamidines, these prodrug candidates were probably

well converted into M34 drug either by chemical way or eventually by enzymatic systems differing from cytochrome

P450 reductases. In C-alkylamidine series, the oxadiazolone 270 and the O-methylsulfonate 268 exhibited effective

antimalarial activities when given orally. These prodrug candidates may be proficiently changed into active drugs as

they bring a reduction in parasitemia within two log of concentration and the wide-ranging clearance of the blood

parasite after one daily dose for 4 days.

N N

NH2 NH2

HO OH

260 261, R1=CONH2

262, R1=CN

NO

NN

ON

R1R1

N N

NH2 NH2

RO OR

263, R1= COCH3

264, R1=COC6H5

265, R1=CONHC6H5

266, R1=CONHC2H5

267, R1=CH3

269, X=S270, X=O

NX

HNNH

XN

OO

268, R1=SO2CH3

Chiral Triamines

Chiral triamines (TPI 762) are the new antimalarial compounds which are reported by Nefzi et al. [212]. These were

synthesized from resin bound reduced acylated dipeptides. However these compounds are less active upto 10 times

than the standard drugs such as chloroquine and Artemisinin.

NH

HN R3HN

R1

R2

TPI 762



1,2,4-Trioxepanes

Dhavale and Lombardo et al. [213] have recently reported the synthesis of new enantiomerically pure 1,2,4-

trioxepanes 271a,b and 272a,b which are being synthesized from D-glucose. On evaluation of in vitro antimalarial

activity, the adamantyl derivative 272b displayed IC50 values in the low micromolar range, chiefly against the W2

chloroquine-resistant Plasmodium falciparum strain (IC50 = 0.15 ± 0.12 μM).

O

O

O

O

OO

R1

R2

O

O

O

O

OO

R1

R2

271a: R1=n-Bu, R2=H

271b: R1=H, R2=n-Bu

272a: R1=n-Bu, R2=H

272b: R1=H, R2=n-Bu

Diterpenoid dimers

Yue et al. [214] reported the synthesis of diterpenoid dimers (273-277) which exhibited moderate antimalarial

activities with low micromolar IC50 values.

OO OO

O

O

O

O273

OO OO

R1R1

OO OO

R1R1

274 275

OO

R2

R1

HOO

R2

R1

276 277

O

O

R1=HO

OR2=



9-anilinoacridine triazines

A new series of hybrid 9-anilinoacridine triazines are synthesized by Kumar et al. [215] using the low priced

chemicals 6,9-dichloro-2-methoxy acridine and cyanuric chloride. The series of new hybrid 9-anilinoacridine triazines

were than evaluated in vitro for their antimalarial activity against CQ-sensitive 3D7 strain of Plasmodium falciparum

and their cytotoxicity were determined on VERO cell line. Among all the evaluated compounds, two of them i.e.

compounds 284 (IC50 = 4.21 nM) and 289 (IC50 = 4.27 nM) displayed two times greater potency than CQ (IC50 = 8.15

nM). Most of the compounds displayed fairly high selectivity index. The compounds 280 and 296 exhibited >96.59%

and 98.73% suppression, respectively, orally against N-67 strain of Plasmodium yoelii in swiss mice at dose 100

mg/kg for four days.

N

HN

HN

N

N

N

R1

R2

Cl

OCH3

278-299

Compound R1 R

2

278 Aniline N-Methyl piperazine

279 Aniline N-Ethylpiperazine

280 Aniline 4-(2-Aminoethyl)morpholine

281 Aniline 4-(3-Aminopropyl)morpholine

282 Aniline N,N-Dimethylethylenediamine

283 Aniline N,N-Diethylethylenediamine

284 Aniline N,N-Dimethylpropylenediamine

285 Aniline n-Butylamine

286 Aniline Cyclopentylamine

287 Aniline 2-Amino-1-ethanol

288 Aniline 3-Amino-1-propanol

289 Aniline Hydrazine

290 Aniline Ammonia

291 p-Fluoro-aniline N-Methyl piperazine

292 p-Fluoro-aniline N-Ethylpiperazine

293 p-Fluoro-aniline N,N-Dimethylethylenediamine

294 p-Fluoro-aniline N,N-Diethylethylenediamine

295 p-Fluoro-aniline N,N-Dimethylpropylenediamine

296 p-Fluoro-aniline 4-(2-Aminoethyl)morpholine

297 p-Fluoro-aniline 4-(3-Aminopropyl)morpholine

298 p-Fluoro-aniline Ammonia

299 p-Fluoro-aniline Methylamine

Conclusion

The fundamental problem with antimalarial chemotherapy is the rise of parasites imperviousness to contemporary

medications. Parasites impervious to the recent antimalarial drugs have been accounted for in different parts of the

world. So there is a necessity for interpreting the genome in charge of resistance. The combination therapy can be

superior in the range where resistance against single medication is accounted for. Another procedure is to discover

antimalarial agents whose component of activity is totally unique in relation to those medications effectively

accessible. Along these lines there is a sincere requirement to screen substantial number of plants and marine samples



to discover new potential antimalarial specialists with novel structures, diverse methods of activity and to expand on

the new lead structures.

Acknowledgements

The authors (Ashu Chaudhary and Anshul Singh) wish to express gratitude to the Council of Scientific and Industrial

Research (CSIR), New Delhi, India and University Grants Commission (UGC), New Delhi for financial assistance in

the form of JRF vide letter no. 09/105(0221)/2015-EMR-I and major research project vide letter no. F. No.42-

231/2013 (SR), respectively.

References

[1] Y. Zhang, M. Anderson, J.L. Weisman, M. Lu, C.J. Choy, V.A. Boyd, J. Price, M. Sigal, J. Clark, M.

Connelly, F. Zhu, W.A. Guiguemde, C. Jeffries, L. Yang, A. Lemoff, A.P. Liou, T.R.Webb, J.L. DeRisi, R.K.

Guy, ACS Med. Chem. Lett., 2010, 1, 460–465.

[2] D. Chaturvedi, A.Goswami, P.P. Saikia, C.N.Barua, P.G. Rao, Chem. Soc. Rev., 2010, 39, 435–454.

[3] P.J.Rosenthal, J. Exp. Biol., 2003, 206, 3735-3744.

[4] S. Meshnick, M. Dobson, Antimalarial Chemotherapy: Mechanism of action, resistance and new directions in

drug discovery. Humana: Totowa, New Jersy, 2001.

[5] H. Hussain, S. Specht, S.R. Sarite, M. Saeftel, A. Hoerauf, B.Schulz, K. Krohn, J. Med. Chem., 2011, 54,

4913–4917.

[6] H. Ranson, B. Jensen, X. Wang, L. Prapanthadara, J.Hemingway, F.H. Collins, Insect Mol Biol., 2000, 9,

499–507.

[7] B.M. Greenwood, A. David, D.A. Fidock, D. E. Kyle, S.H.I. Kappe, P.L. Alonso, F.H. Collins, P.E. Duffy, J.

Clin. Invest., 2008, 118, 1266-76.

[8] F. Curtis, A.E.P. Mnzava, Bull. World Health Organ., 2000, 78, 1389–1400.

[9] P.A. Winstanley, S.A. Ward, R.W. Snow, Microbes Infect., 2002, 4, 157-164.

[10] P. Bacon, D.J. Spalton, S.E. Smith, Br. J. Ophthalmol.,1988, 72, 219-224.

[11] L.H. Carvalno, A.U. Krettli, Mem.Inst.Oswaldo Cruz., 1991, 86, 181-184.

[12] R. Meshnick, M.J. Dobson, The History of Antimalarial Drugs In: Antimalarial Chemotherapy: Mechanisms

of Action, Resistance, and new Direction in Drug Discovery. Humana : Totowa, New Jersy, 2001; pp. 15-25.

[13] J. Achan, A.O. Talisuna, A. Erhart, A.Yeka, J.K. Tibenderana, F.N. Baliraine, P.J. Rosenthal, U.D.

Alessandro, Malar. J., 2011, 10, 144.

[14] C.P. Sanchez, J.E. McLean, W. Stein, M. Lanzer, Biochem. J., 2004, 43, 16365-16373.

[15] S.J. Burgess, A. Selzer, J.X. Kelly, M.J. Smilkstein, M.K. Riscoe, D.H. Peyton, J. Med. Chem., 2006, 49,

5623-5625.

[16] N.K. Baro, P.S. Callaghan, P.D. Roepe, Biochem. J., 2013, 52, 4242−4249.

[17] A.M. Lannang, G.N. Louh, D. Lontsi, S. Specht, S.R. Sarite, U. Florke, H. Hussain, A. Hoerauf, K. Krohn, J.

Antibiot., 2008, 61, 518-23.

[18] F. Liao, Molecules., 2009, 14, 5362-5366.

[19] P.M. O’Neill, G.H. Posner, J. Med. Chem., 2004, 47, 2946.

[20] G.H. Posner, D. Chang Ho Oh. Wang, L. Gerena, W.K. Milhous, S.R. Meshnick, W. Asawamahasadka, J.

Med. Chem., 1994, 37, 1256-1258.

[21] H.J. Woerdenbag, T. Moskal, N. Pras, T.M. Malingre, J. Nat. Prod., I993, 56, 849-856.

[22] W. Asawamahasakda, I. Ittarat, Y.M. Pu, H. Ziffer, S.R. Meshnick, Antimicrob. Agents Chemother., 1994,

38, 1854-1858.

[23] M.D.P.Crespo, T.D. Avery, E. Hanssen, E. Fox, T.V. Robinson, P. Valente, D.K. Taylor, L. Tilley,

Antimicrob. Agents Chemother., 2008, 52, 98–109.

[24] A.N.O. Dodoo, C. Fogg, A. Asiimwe, E.T. Nartey, A. Kodua, O. Tenkorang, D. Ofori-Adjei, Malar. J., 2009,

8,1475-2875.

[25] S. Yeung, W. Pongtavornpinyo, I.M. Hastings, A.J. Mills, N. J.; White, Am. J. Trop. Med. Hyg. 2004,

71,179–186.



[26] A.M. Dondorp, F. Nosten, P. Yi, D. Das, A.P. Phyo, J. Tarning, K.M. Lwin, F. Ariey, W. Hanpithakpong,

S.J. Lee, P. Ringwald, K. Silamut, M. Imwong, K. Chotivanich, P. Lim, T. Herdman, S.S. An, S. Yeung, P.

Singhasivanon, N.P. Day, N. Lindegardh, D. Socheat, N.J.White, N. Engl. J. Med., 2009, 361,455-67.

[27] R.M. Fairhurst, G.M.L.V Nayyar, J.G. Breman, R. Hallett, J.L. Vennerstrom, S. Duong, P. Ringwald, T.E.

Wellems, C.V. Plowe, A.M. Dondorp, Am. J. Trop. Med. Hyg., 2012, 87, 231–241.

[28] P. Grellier, D. Depoix, J. Schrével, I. Florent, Parasite, 2008, 15, 219-225.

[29] M.A. Biamonte, J. Wanner, G. Le Roch Karine, Bioorg. Med. Chem. Lett., 2013, 23, 2829–2843.

[30] F. Chandre, F. Darrier, L. Manga, M. Akogbeto, O. Faye, J. Mouchet, P. Guillet, Bull. World Health Organ.,

1999, 77, 230-234.

[31] T.G.E. Davies, L.M. Field, P.N.R. Usherwood, M.S. Williamson, IUBMB Life., 2007, 59, 151–162.

[32] R. Sharma, A.S. Lawrenson, N.E. Fisher, A.J. Warman, A.E. Shone, A. Hill, A. Mbekeani, C. Pidathala, R.K.

Amewu, S. Leung, P. Gibbons, D.W. Hong, P. Stocks, G.L. Nixon, J. Chadwick, J. Shearer, I. Gowers, D.

Cronk, S.P. Parel, P.M. O'Neill, S.A. Ward, G.A. Biagini, N.G. Berry, J. Med. Chem. 2012, 55, 3144−3154.

[33] S.V. Miert, S. Hostyn, B.U.W. Maes, K. Cimanga, Reto Brun, M. Kaiser, P. Matyus, R. Dommisse, G.

Lemiere, A. Vlietinck, L. Pieters, J. Nat. Prod. 2005, 68, 674-677.

[34] D.A. Dias, S. Urban, U. Roessner, Metabolites. 2012, 2, 303-336.

[35] A.F.G. Slater, Pharmacol. Ther., 1993, 57, 203-235.

[36] F. Ryley, Brit. J. Pharmacol., 1953, 8, 424.

[37] A. Robert, F. Benoit-Vical, O. Dechy-Cabaret, B. Meunier, Pure Appl. Chem., 2001,73, 1173– 1188.

[38] M. Schmidt, H. Sun, P. Rogne, G.K.E. Scriba, C. Griesinger, L.T. Kuhn, U.M. Reinscheid,. J. Am. Chem.

Soc., 2012, 134, 3080−3083.

[39] J.M. Karle, I.L. Karle, Antimicrob. Agents Chemother., 2002, 46, 1529−1534.

[40] A.B.S.Sidhu, A.C. Uhlemann, S.G. Valderramos, J.C. Valderramos, S. Krishna, D.A. Fidock, J. Infect. Dis.,

2006, 194, 528–535.

[41] P.D. Radloff, J. Philips, M. Nkeyi, P.G. Kremsner, D. Hutchinson, Lancelet., 1996, 347, 1511– 1514.

[42] I.K. Srivastava, A.B. Vaidya, Antimicrob. Agents Chemother., 1999, 43, 1334–1339.

[43] S. Krishnaa, A.C. Uhlemanna, R.K. Haynesb, Drug Resist., 2004, 7, 233–244.

[44] C. Wongsrichanalai, S.R. Meshnick, Emerg. Infect. Diseases., 2008, 14, 216-219.

[45] Y. Liu, Z. Liu, J. Shi, H. Chen, B. Mi, P. Li, P. Gong, Molecules, 2013, 18, 2864-2877.

[46] W. Nosoongnoen, J. Pratuangdejkul, K. Sathirakul, A. Jacob, M. Conti, S. Sylvain Loric, J.M. Launayabd, P.

Manivetab, Phys. Chem. Chem. Phys., 2008, 10, 5083–5093.

[47] M. Hommel, J. Biol., 2008, 7.

[48] J. Golenser, J.H. Waknine, M. Krugliak, N.H. Hunt, G.E. Grau, Int. J. Parasitol. , 2006, 36, 1427- 1441.

[49] P.M. O’Neill, V.E. Victoria E. Barton. S.A. Ward, Molecules, 2010, 15, 1705-1721.

[50] G.H. Posner, J.N. Cumming, P. Ploypradith, C.H. Oh, J. Am. Chem. Soc., 1995, 117, 5885-5886.

[51] S.R. Meshnick, Int. J. Parasitol., 2002, 32, 1655–1660.

[52] G.H. Posner, D. Wang, J.N. Cumming, C. Ho, A.N. French, A.L. Bodley, T.A. Shapiro, J. Med. Chem., 1995,

38, 11838- 2273.

[53] A.E. Mercer, J.L. Maggs, X.M. Sun, G.M. Cohen, J. Chadwick, P.M. O’Neill, B.K. Park, J. Biol. Chem.,

2007, 282, 9372–9382.

[54] D.Y. Wang, Y.L. Wu, Chem. Commun., 2000, 2193–2194.

[55] A. Afonso, P. Hunt, S. Cheesman, A.C. Alves, C.V. Cunha, V. do Rosario, P. Cravo, Antimicrob. Agents

Chemother., 2006, 50, 480–489.

[56] P.E. Duffy, T.K. Mutabingwa, The Lancet., 2006, 367, 2037-2039.

[57] N.M. Douglas, N.M. Anstey, B.J. Angus, F. Nosten, R.N. Price, Lancet Infect. Dis., 2010, 10, 405– 416.

[58] G. Holmgren, J. Hamrin, J. Svard, A. Martensson, J.P. Gil, A. Bjorkman, Infect. Genet. Evol., 2007, 7, 562–

569.

[59] S. Yeung, W. Pongtavornpinyo, I.M. Hastings, A.J. Mills, N.J.White, Am. J. Trop. Med. Hyg. 2004, 71, 179–

186.

[60] China cooperative research group on Qinghaosu and its derivatives as antimalarials. The chemistry and

synthesis of Qinghaosu derivatives.J. Tradit. Chinese Med. 1982, 2, 9.

[61] (a) A.J. Lin, D.L. Klayman, W.K. Milhous, J. Med. Chem., 1987, 30, 2147.

(b) J. Liu, M. Ni, J. Fan, Y. Tu, Z. Wu, Y. Qu, W. Chou, Acta Chim. Sinica, 1979, 37, 129.

http://www.sciencedirect.com/science/article/pii/016372589390056J

http://www.sciencedirect.com/science/article/pii/S0140673696906716





http://www.sciencedirect.com/science/journal/01406736/347/9014






http://www.sciencedirect.com/science/journal/00207519/36/14







http://europepmc.org/search;jsessionid=NMNKacTDDZeAOM8lPc7G.3?page=1&query=AUTH:%22Holmgren+G%22

http://europepmc.org/search;jsessionid=NMNKacTDDZeAOM8lPc7G.3?page=1&query=AUTH:%22Hamrin+J%22

http://europepmc.org/search;jsessionid=NMNKacTDDZeAOM8lPc7G.3?page=1&query=AUTH:%22Sv%C3%A4rd+J%22

http://europepmc.org/search;jsessionid=NMNKacTDDZeAOM8lPc7G.3?page=1&query=AUTH:%22M%C3%A5rtensson+A%22

http://europepmc.org/search;jsessionid=NMNKacTDDZeAOM8lPc7G.3?page=1&query=AUTH:%22Gil+JP%22

http://europepmc.org/search;jsessionid=NMNKacTDDZeAOM8lPc7G.3?page=1&query=AUTH:%22Bj%C3%B6rkman+A%22

http://www.ncbi.nlm.nih.gov/pubmed/?term=Yeung%20S%5BAuthor%5D&cauthor=true&cauthor_uid=15331836

http://www.ncbi.nlm.nih.gov/pubmed/?term=Pongtavornpinyo%20W%5BAuthor%5D&cauthor=true&cauthor_uid=15331836

http://www.ncbi.nlm.nih.gov/pubmed/?term=Hastings%20IM%5BAuthor%5D&cauthor=true&cauthor_uid=15331836

http://www.ncbi.nlm.nih.gov/pubmed/?term=Mills%20AJ%5BAuthor%5D&cauthor=true&cauthor_uid=15331836

http://www.ncbi.nlm.nih.gov/pubmed/?term=White%20NJ%5BAuthor%5D&cauthor=true&cauthor_uid=15331836



[62] H.-M. Waki, M.-Y. Zhu, J. Li, Y.-L. Qian, G.-D. Li, Acta Pharm. Sinica, 1988, 9, 160.

[63] Y. Li, P.L. Yu, Y.X. Chen, L.Q. Li, Y.Z. Gai, D.S. Wang, Y.P. Zheng, Acta Pharmaceut. Sinica., 1981, 16,

429.

[64] C.J. Woodrow, R.K. Haynes, S. Krishna, Postgrad. Med. J., 2005, 81, 71.

[65] I. Bathurst, C. Hentschel, Trends Parasitol., 2006, 22, 301.

[66] W.H. Wernsdorfer, Expert Rev. Anti-Infect. Ther., 2004, 2, 89.

[67] A.A. Omari, C. Gamble, P. Garner, Trop. Med. Int. Health., 2004, 9, 192.

[68] A.A. Omari, C. Gamble, P. Garner, Cochrane Database Syst. Rev., 2005, 4, 1.

[69] Q.C. Yang, W. Shi, R. Li, J. Gan, J. Tradit. Chin. Med., 1982, 2, 99.

[70] A.K.Mohanty, B.K. Rath, R. Mohanty, A.K. Samal, K. Mishra, Indian J. Pediatr., 2004, 71, 291.

[71] A. Dondorp, F. Nosten, K. Stepniewska, N. Day, N. White, Lancet, 2005, 366, 717.

[72] P.G. Kremsner, S. Winkler, C. Brandts, W. Graninger, U. Bienzle, Am. J. Trop. Med. Hyg., 1993, 49, 650–

654.

[73] H.A. Karunajeewa, J. Reeder, K. Lorry, E. Dadod, J. Hamzah, M. Page-Sharp, G.M. Chiswell, K.F. Ilett,

T.M.E. Davis, Antimicrob. Agents Chemother., 2006, 50, 968.

[74] H. Bukirwa, L. Orton, Cochrane Database Syst. Rev., 2005, 19, 1.

[75] M. Adjuik, A. Babiker, P. Garner, P. Olliaro, W. Taylor, N. White, Lancet, 2004, 363, 9.

[76] V.I. Carrara, S. Sirilak, J. Thonglairuam, C. Rojanawatsirivet, S. Proux, V. Gilbos, A. Brockman, E.A.

Ashley, R. McGready, S. Krudsood, S. Leemingsawat, S. Looareesuwan, P. Singhasivanon, N. White, F.

Nosten, PLOS Med. 2006, 3, 856.

[77] S. Krishna, T. Planche, T. Agbenyega, Antimicrob. Agents Chemother., 2001, 45, 509.

[78] M. Shrimali, A.K. Bhattacharya, D.C. Jain, R.S. Bhakuni, R.P. Sharma, Indian J. Chem., Sect. B: Org. Chem.

Incl. Med. Chem.,1998, 37, 1161.

[79] Q.G. Li, P. Lee, E. Wong, L.H. Xie, D.E. Kyle, G.S. Dow, Parasitology.,2003, 126, 283.

[80] Q. Li, L.H. Xie, Y. Si, E. Wong, R. Upadhyay, D. Yanez, P.J. Weina, Int. J. Toxicol., 2005, 24, 241.

[81] Xie, L. H.; Johnson, T. O.; Weina, P. J.; Haeberle, A.; Upadhyay, R.; Wong, E.; Li, Q. Int. J. Toxicol., 2005,

24, 251.

[82] T.M.E. Davis, T. Q. Binh, K.F. Ilett, K.T. Batty, H.L. Phuçng, G.M. Chiswell, V.D.B. Phuong, C. Agus,

Antimicrob. Agents Chemother., 2003, 47, 368.

[83] A.J. Lin, D.L. Klayman, W.K. Milhous, J. Med. Chem., 1987, 30, 2147.

[84] A.J. Lin, M. Lee, D.L. Klayman, J. Med. Chem., 1989, 32, 1249.

[85] A.J. Lin, L.-q. Li, S.L. Anderson, D.L. Klayman, J. Med. Chem., 1992, 35, 1639.

[86] B. Venugopalan, P.J. Karnik, C.P. Bapat, D.K. Chatterjee, N. Iyer, D. Lepcha, Eur J. Med. Chem., 1995, 30,

697.

[87] A.J. Lin, R.E. Miller, J. Med. Chem., 1995, 38, 764.

[88] P.M. O’Neill, L.P. Bishop, R.C. Storr, S.R. Hawley, J.L. Maggs, S.A. Ward, B.K. Park, J. Med. Chem., 1996,

39, 4511.

[89] A.J. Lin, A.B. Zikry, D.E. Kylen, J. Med. Chem., 1997, 40, 1396.

[90] P.M. O’Neill, A. Miller, L.P.D. Bishop, S. Hindley, J.L. Maggs, S.A. Ward, S.M.S. Roberts, F. Scheimann,

A.V. Stachutski, G.H. Posner, B.K. Park, J. Med. Chem., 2001, 44, 58.

[91] L. Delhas, C. Biot, L. Berry, L.A. Maciejewski, J.S. Brocard, D. Dive, Bioorg. Med. Chem., 2000, 8, 2739.

[92] R.K. Haynes, H.W. Chan, M.K. Cheung, W.L. Lam, M.K. Soo, H.W. Tsang, A. Voerste, I.D. Williams, Eur.

J. Org. Chem., 2002, 2002, 113.

[93] C. Singh, R. Kanchan, S.K. Puri, Indian Patent, 2000, 212DEL 2000.

[94] Y. Liu, W. Xiao, M.K. Wong, C.M. Che, Org. Lett., 2007, 9, 4107.

[95] C. Singh, S. Chaudhary, S.K. Puri, J. Med. Chem., 2006, 49, 7227.

[96] R.D. Slack, A.M. Jacobinea, G.H. Posner, Med. Chem. Commun., 2012, 3, 281.

[97] P.M. O’Neill, L.P. Bishop, R.C. Storr, S.R. Hawley, J.L. Maggs, S.A. Ward, B.K. Park, J. Med. Chem., 1996,

39, 4511–4514.

[98] S. Hindley, S.A. Ward, R.C. Storr, N.L. Searle, P.G. Bray, B.K. Park, J. Davies, P.M. O’Neill, J. Med.

Chem., 2002, 45, 1052–1063.

[99] Y. Li, Z.S. Yang, H. Zhang, B.J. Cao, F.D. Wang, Y. Zhang, Y.L. Shi, J.D. Yang, B.A. Wu, Bioorg. Med.

Chem., 2003, 11, 4363–4368.



[100] M. Jung, K. Lee, H. Kendrick, B.L. Robinson, S. L. Croft, J.Med. Chem., 2002, 45, 4940–4944.

[101] G.H. Posner, M.H. Parker, J. Northrop, J.S. Elias, P. Ploypradith, S. Xie, T.A. Shapiro, J. Med. Chem., 1999,

42, 300–304.

[102] B. Pacorel, S.C. Leung, A.V. Stachulski, J. Davies, L. Vivas, H. Lander, S.A. Ward, M. Kaiser, R. Brun, P.M.

O’Neill, J. Med. Chem., 2010, 53, 633–640.

[103] L.E. Woodard, W. Chang, X. Chen, J.O. Liu, T.A. Shaprio, G.H. Posner, J. Med. Chem., 2009, 52, 7458–

7462.

[104] M. Jung, X. Li, D.A. Bustos, H.N. Elsohly, J.D. McChesney, W.K. Milhous, J. Med. Chem., 1990, 33, 1516.

[105] M. Jung, D.A. Bustus, H.N. ElSohly, J.D. McChesney, Synlett, 1990, 743.

[106] R.K. Haynes, S. Vonwiller, Synlett., 1992, 481.

[107] H. Ziffer, Y.M. Pu, J Med. Chem., 1995, 38, 613.

[108] J. Ma, E. Katz, D.E. Kyle, H. Ziffer, J. Med. Chem., 2000, 43, 4228.

[109] M. Jung, D. Yu, D. Bustos, H.N. Elsohly, J.D. McChesney, Bioorg. Med. Chem. Lett., 1991, 1, 741.

[110] J.D. McChesney, A.C.C. Frietas, H.N. Elsohly, M. Jung, Heterocycles, 1994, 39, 23-29.

[111] J.A. Vroman, I. A. Khan, M.A. Avery, Tetrahedron Lett., 1997, 38, 6173.

[112] M. Jung, S. Lee, Bioorg. Med. Chem. Lett., 1998, 8, 1003.

[113] S.H. Woo, M.H. Parker, P. Ploypradith, J. Northtrop, G.H. Posner, Tetrahedron Lett., 1998, 39, 1533.

[114] H. O’Dowd, P. Ploypradith, S. Xie, T.A. Shapiro, G.H. Posner, Tetrahedron, 1999, 55, 3625.

[115] P.M. O’Neill, N.L. Searle, K.W. Kan, R.C. Storr, J.L. Maggs, S.A. Ward, K. Raynes, B. Kevin, J. Med.

Chem., 1999, 42, 5487.

[116] S. Hindley, S.A. Ward, R.C. Storr, N.L. Searle, P.G. Bray, B.K. Park, J. Davies, P.M. O’Neill, J. Med.

Chem., 2002, 45, 1052.

[117] D.Y. Wang, Y.K. Wu, Y.L. Wu, Y. Li, F. Shan, J. Chem. Soc., Perkin Trans., 1999, 1, 1827.

[118] M. Jung, K. Lee, H. Kendrick, B.L. Robinson, S.L. Croft, J. Med. Chem., 2002, 45, 4940.

[119] M.A. Avery, M. Alvim-Gaston, J.A. Vroman, B. Wu, A. Ager, W. Peters, B.L. Robinson, W. Charman, J.

Med. Chem., 2002, 45, 4321.

[120] F. Chorki, F. Grellepois, B. Crousse, V.D. Hoang, N.V. Hung, D. Bonnet-Delphon, J.P. Bengue, Org. Lett.,

2002, 4, 757.

[121] R.K. Haynes, H.W. Chan, M.K. Cheung, S.T. Chung, W.L. Lam, H.W. Tsang, A. Voerste, I.D. Williams,

Eur. J. Org. Chem., 2003, 2098.

[122] F. Grellepois, F. Chorki, M. Ourevitch, S. Charneau, P. Grellier, K.A. McIntosh, W.N. Charman, B. Pradines,

B. Crousse, D. Bonnet-delpon, J.P. Begue, J. Med. Chem., 2004, 47, 1423.

[123] Y. Liu, V.K.W. Wong, B.C.B. Ko, M.K. Wong, C.M. Che, Org. Lett., 2005, 7, 1561.

[124] A.J. Lin, L.Q. Li, D.L. Klayman, C.F. George, J.L. Flippen-Anderson, J. Med. Chem., 1990, 33, 2610.

[125] Y.H. Yang, Y. Li, Y.S. Shi, J.D. Yang, B.A. Wu, Bioorg. Med. Chem. Lett., 1995, 5, 1791.

[126] R.K.Haynes, B. Fugmann, J. Stetter, K. Rieckmann, H.D. Heilmann, H.W. Chan, M.K. Cheung, W.L. Lam,

H.N. Wong, S.L. Croft, L. Vivas, L. Rattray, L. Stewart, W. Peters, B.L. Robinson, M.D. Edstein, B.

Kotecka, D.E. Kyle, B. Beckermann, M. Gerisch, M. Radtke, G. Schmuck, W. Steinke, U. Wollborn, K.

Schmeer, A. Romer, Angew. Chem. Int. Ed., 2006, 17, 2082.

[127] M.A. Avery, J.D. Bonk, W.K.M. Chong, S. Mehrotra, R. Miller, W. Milhous, D.K. Goins, S. Venkatesan, C.

Wyandt, I. Khan, B.A. Avery, J. Med Chem., 1995, 38, 5038.

[128] D.S. Torok, H. Ziffer, Tetrahedron Lett., 1995, 36, 829.

[129] B. Mekonnen, E. Weiss, E. Katz, J. Ma, H. Ziffer, D.E. Kyle, Bioorg.Med. Chem., 2000, 8, 1111- 6.

[130] R.K. Haynes, H.N. Wong, K.W. Lee, C.M. Lung, L.Y. Shek, I.D. Williams, S.L.Croft, L. Vivas, L. Rattray,

L. Stewart, V.K.W. Wong, B.C.B. Ko, Chem. Med. Chem., 2007, 2, 1464.

[131] N. Wang, K.J. Wicht, E. Shaban, T.A. Ngoc, M.Q. Wang, I. Hayashi, M. Hossain, Y. Takemasa, M. Kaiser,

I.T. Sayed, T.J. Egan, T. Inokuchi, Med. Chem. Commun., 2014, 5, 927.

[132] R. Gaur, H.S. Cheema, Y. Kumar, S.P. Singh, D.K. Yadav, M.P. Darokar, F. Khan, R.S. Bhakuni, RSC Adv.,

2015, 5, 47959.

[133] H.J.Woerdenbag, T.A. Moskal, N. Pras, T.M. Malingre, F. El-Feraly, H.H. Kampinga, A.W.T. Konings, J.

Nat. Prod., 1993, 56, 849.

[134] X.D. Luo, H.J.C. Yeh, A. Brossi, J.L. Flippen-Anderson, R. Gilardi, Helv.Chim. Acta, 1984, 67, 1515-1522.

http://www.ncbi.nlm.nih.gov/pubmed/?term=Jung%20M%5BAuthor%5D&cauthor=true&cauthor_uid=12383020

http://www.ncbi.nlm.nih.gov/pubmed/?term=Lee%20K%5BAuthor%5D&cauthor=true&cauthor_uid=12383020

http://www.ncbi.nlm.nih.gov/pubmed/?term=Kendrick%20H%5BAuthor%5D&cauthor=true&cauthor_uid=12383020

http://www.ncbi.nlm.nih.gov/pubmed/?term=Robinson%20BL%5BAuthor%5D&cauthor=true&cauthor_uid=12383020

http://www.ncbi.nlm.nih.gov/pubmed/?term=Croft%20SL%5BAuthor%5D&cauthor=true&cauthor_uid=12383020

http://pubs.rsc.org/en/results?searchtext=Author%3ANing%20Wang

http://pubs.rsc.org/en/results?searchtext=Author%3AKathryn%20J.%20Wicht

http://pubs.rsc.org/en/results?searchtext=Author%3AElkhabiry%20Shaban

http://pubs.rsc.org/en/results?searchtext=Author%3ATran%20Anh%20Ngoc

http://pubs.rsc.org/en/results?searchtext=Author%3AMing-Qi%20Wang

http://pubs.rsc.org/en/results?searchtext=Author%3AIkuya%20Hayashi

http://pubs.rsc.org/en/results?searchtext=Author%3AMd.%20Imran%20Hossain

http://pubs.rsc.org/en/results?searchtext=Author%3AYoshihiko%20Takemasa

http://pubs.rsc.org/en/results?searchtext=Author%3AMarcel%20Kaiser

http://pubs.rsc.org/en/results?searchtext=Author%3AIbrahim%20El%20Tantawy%20El%20Sayed

http://pubs.rsc.org/en/results?searchtext=Author%3ATimothy%20J.%20Egan

http://pubs.rsc.org/en/results?searchtext=Author%3ATsutomu%20Inokuchi



[135] B. Venugopalan, C.P. Bapat, P.J. Karnik, D.K. Chatterjee, N. Iyer, D. Lepcha, J. Med. Chem., 1995, 38,

1922-7.

[136] G.H. Posner, P. Ploypradith, W. Hapangama, D. Wang, J.N. Cumming, P. Dolan, T.W. Kensler, D.

Klinedinst, T.A. Shapiro, Q.Y. Zheng, C.K. Murray, L.G. Pilkington, L.R. Jayasinghe, J.F. Bray, R.

Daughenbaugh, Bioorg. Med. Chem., 1997, 5, 1257-65.

[137] G.H. Posner, P. Ploypradith, M.H. Parker, H. O’Dowd, S.H. Woo, J. Med. Chem., 1999, 42, 4275-80.

[138] S. Ekthawatchai, S. Kamchonwongpaisan, P. Kongsaeree, B. Tarnchompoo, Y. Thebtaranonth, Y.

Yuthavong, J. Med. Chem., 2001, 44, 4688-95.

[139] M. Jung, S. Lee, J. Ham, K. Lee, H. Kim, S.K. Kim, J. Med. Chem., 2003, 46, 987-94.

[140] J.P. Jeyadevan, P.G. Bray, J. Chadwick, A.E. Mercer, A. Byrne, S.A. Ward, B.K. Park, D.P. Williams, R.

Cosstick, J. Davies, A.P. Higson, E. Irving, G.H. Posner, P.M. O’Neill, J. Med. Chem., 2004, 47, 1290.

[141] F. Grellepois, B. Crousse, D. Bonnet-Delpon, J.P. Begue,Org. Lett., 2005, 7, 5219.

[142] J. Chadwick, A.E. Mercer, B.K. Park, R. Cosstick, P.M. O’Neill, Bioorg. Med. Chem., 2009, 1325–1338.

[143] B.T. Mott, A. Tripathi, M.A. Siegler, C.D. Moore, D.J. Sullivan, G.H. Posner, J. Med. Chem. 2013, 56,

2630−2641.

[144] R.C. Conyers, J.R. Mazzone, M.A. Siegler, A.K. Tripathi, D.J. Sullivan, B.T. Mott, G.H. Posner, Bioorg.

Med. Chem. Lett., 2014, 24, 1285–1289.

[145] R.C.Conyers, J.R. Mazzone, A.K. Tripathi, D.J. Sullivan, G.H. Posner, Bioorg. Med. Chem. Lett., 15, 25,

245–248.

[146] X.T. Liang, D.Q. Yu, W.L. Wu, H.C. Deng, Huaxue Xuebao, 1979, 37, 215.

[147] A.M. Szpilman, E.E. Korshin, H. Rozenberg, M.D. Bachi, J. Org. Chem., 2005, 70, 3618.

[148] W. Hofheinz, H. Burgin, E. Gocke, C. Jaquet, R. Masciadri, G. Schmid, H. Stohler, H. Urwyler, Trop. Med.

Parasitol., 1994, 45, 261.

[149] L.A. Salako, R. Guiguemde, M.L. Mittelholzer, L. Haller, F. Sorenson, D. Sturchler, Trop Med Parasitol.,

1996, 45, 284.

[150] M.D. Bachi, E.E. Korshin, R. Hoos, A.M. Szpilman, P. Ploypradith, S. Xie, T.A. Shapiro, G.H. Posner, J.

Med. Chem., 2003, 46, 2516-33.

[151] G.H. Posner, L. Gonzalez, J.N. Cumming, D. Klinedinst, T.A. Shapiro, Tetrahedron, 1997, 53, 37-50.

[152] X. Wang, Y. Dong, S. Wittlin, S.A. Charman, F.C.K. Chiu, J. Chollet, K. Katneni, J. Mannila, J. Morizzi, E.

Ryan, C. Scheurer, J. Steuten, J.S.Tomas, C. Snyder, J.L.Vennerstrom, J. Med. Chem., 2013, 56, 2547−2555.

[153] A. Ramirez, K.A.Woerpel, Org. Lett., 2005, 7, 4617-4620.

[154] G.B. Payne, C.W. Smith, J. Org. Chem., 1957, 22, 1682.

[155] P.R. Story, J.R. Burgess, J. Am. Chem. Soc., 1967, 89, 5726.

[156] D.A. Casteel, S.P. Peri, L. Gerena, Bioorg. Med. Chem. Lett., 1993, 3, 1707-10.

[157] C.W. Jefford, J.A. Velarde, G. Bernardinelli, D.H. Bray. D.C. Warhurst, W.K. Milhous, Helv. Chim. Acta,

1993, 76, 2775-88.

[158] G.H. Posner, C.H. Oh W.K. Milhous, Tetrahedron Lett., 1991, 32, 4235-8.

[159] G.H. Posner, H.B. Jeon, P. Ploypradith, I. Paik, K. Borstnik, S. Xie, T.A. Shapiro, J. Med. Chem., 1998, 41,

940-51.

[160] G.H. Posner, C.H. Oh, W.K. Milhous, J. Med. Chem., 1992, 35, 2459-67.

[161] C.W. Jefford, D. Misra, J.C. Rossier, P. Kamalaprija, U. Burger, J. Mareda, G. Bernardinelli, W. Peters, B.L.

Robinson, W.K. Milhous, F. Zhang, D.K. Gosser, S.R. Meshnick, Perspectives in medicinal chemistry. Basel:

VCH; 1993.

[162] C.W. Jefford, J. Boukouvalas, S. Kohmoto, J. Chem. Soc. Chem. Commun., 1984, 523-524.

[163] C.W. Jefford, J.C. Rossier, W.K. Milhous, Heterocycles, 2000, 52, 1345.

[164] W. Peters, B.L. Robinson, J.C. Rossier, C.W. Jefford, Ann. Trop. Med. Parasitol., 1993, 87, 1-7.

[165] A.G. Griesbeck, T.T. El-Idreesy, M. Fiege, R. Brun, R. Org. Lett., 2002, 4, 4193-5.

[166] P.M. O’Neill, M. Pugh, J. Davies, S.A. Ward, B.K. Park, Tetrahedron Lett., 2001, 42, 4569.

[167] C. Singh, Tetrahedron Lett., 1990, 31, 6901.

[168] C. Singh, U. Sharma, G. Saxena, S.K. Puri, Bioorg. Med. Chem. Lett., 2007, 17, 4097.

[169] A.P. Ramirez, A.M. Thomas, K. A. Woerpel, Org. Lett., 2009, 11, 507-510.

[170] L.E. Woodard, W. Chang, X. Chen, J.O. Liu, T.A. Shapiro, G.H. Posner, J. Med. Chem., 2009, 52, 7458–

7462.



[171] Y. Tang, S. Wittlin, S.A. Charman, J. Chollet, F.C.K. Chiu, J. Morizzi, L.M. Johnson, S.J. Tomas,

C. Scheurer, C. Snyder, L. Zhou, Y. Dong, W.N. Charman, H. Matile, H. Urwyler, A. Dorn, J.L.

Vennerstrom, Bioorg. Med. Chem. Lett., 2010, 20, 563–566.

[172] C. Singh, M. Hassam, N.K. Naikade, V.P. Verma, A.S. Singh, S.K. Puri, J. Med. Chem., 2010, 53, 7587–

7598.

[173] F.O. Bellot, F. Cosledan, L. Vendier, J. Brocard, B. Meunier, A. Robert, J. Med. Chem., 2010, 53, 4103–

4109.

[174] R.D. Slack, B.T. Mott, L.E. Woodard, A. Tripathi, D. Sullivan, E. Nenortas, S.C.T. Girdwood, T.A. Shapiro,

G.H. Posner, J. Med. Chem., 2012, 55, 291−296.

[175] C. Singh, M. Hassam, N.K. Naikade, V.P. Verma, A.S. Singh, S.K.P. Puri, P.R. Maulik, R. Ruchir Kant, J.

Med. Chem., 2012, 55, 10662−10673.

[176] R. Maurya, A. Soni, D. Anand, M. Ravi, K.S.R. Raju, I. Taneja, N.K. Naikade, S. K. Puri, Wahajuddin, S.

Kanojiya, P.P. Yadav, ACS Med. Chem. Lett., 2013, 4, 165−169.

[177] A.O.Terent’ev, D.A. Borisov, V.V. Chernyshev, G.I. Nikishin, J. Org. Chem., 2009, 74, 3335– 3340.

[178] Y. Dong, K.J. McCullough, S. Wittlin, J. Chollet, J.L. Vennerstrom, Bioorg. Med. Chem. Lett., 2010, 178,

6359–6361.

[179] L. Laurence Florens, M.P.Washburn, J.D. Raine, R.M. Anthony, M. Grainger, J.D. Haynes, J.K. Moch, N.

Muster, J.B. Sacci, D.L. Tabb, A.A. Witney, D. Wolters, Y. Yimin Wu, M.J. Gardner, A.A. Holder, R.E.

Sinden, J.R. Yates, D.J. Carucc, Nature, 2002, 419, 520-526.

[180] P.M. O’Neill, R.K. Amewu, G.L. Nixon, F.B. Garah, M. Mungthin, J. Chadwick, A.E. Shone, L. Vivas, H.

Lander, V. Barton, S. Muangnoicharoen, P.G. Bray, J. Davies, B.K. Park, S. Wittlin, R. Brun, M. Preschel, K.

Zhang, S.A. Ward, Angew. Chem. Int. Ed., 2010, 49, 5693–569.

[181] D. Miranda, R. Capela, I.S. Albuquerque, P. Meireles, I. Paiva, F. Nogueira, R. Amewu, J. Gut, P.J.

Rosenthal, R. Oliveira, M.M. Mota, R. Moreira, F. Marti, M. Prud ncio, P.M. O’Neill, F. Lopes, ACS Med.

Chem. Lett., 2014, 5, 108−112.

[182] R. Oliveira, R.C. Guedes, P. Meireles, I. Albu uer ue, L.M. Gon alves, E. Pires, M.R. Bronze, J. Jiri Gut,

P.J. Rosenthal, M. Miguel Prud ncio, R. Moreira, P.M. O’Neill, F. Lopes, J. Med. Chem., 2014, 57,

4916−4923.

[183] M. Chen, T.G. Theander, S.B. Christensen, L. Hviid, L. Zhai, A. Kharazmi, Antimicrob. Agents Chemother.,

1994, 38, 1470.

[184] P.D. Radloff, J. Philipps, M. Nkeyi, D. Hutchinson, P.G. Kremsner, Lancet, 1996, 347, 1511-4.

[185] M. Chen, S.B. Christensen, L. Zhai, M.H. Rasmussen, T.G. Theander, S. Frokjaer, B. Steffansen, J. Davidsen,

A. Kharazmi, J. Infect. Dis., 1997, 176, 1327-1333.

[186] N. Yadav, S.K. Dixit, A. Bhattacharya, L.C. Mishra, M. Sharma, S.K. Awasthi, V.K. Bhasin, Chem. Biol.

Drug Des., 2012, 80, 340–347.

[187] J.C. Gantier, A. Fournet, M.H. Munos, R. Hocquemiller, Planta Med., 1996, 62, 285.

[188] X. Franck, A. Fournet, E. Prina, R. Mahieux, R. Hocquemiller, B. Figadere, Bioorg. Med. Chem. Lett., 2004,

14, 3635.

[189] V. Munoz, M. Sauvain, P. Mollinedu, J. Collapa, I. Rojas, A. Gimenez, A. Balentin, M. Mallie, Planta Med.,

1999, 65, 448.

[190] G. Francois, G. Bringmann, J.D. Phillipson, L.A. Assi, C. Dochez, M. Rubenacker, C. Schneider, M. Wery,

D.C. Warhurst, G.C. Kirby, Phytochemistry, 1994, 35, 1461.

[191] G. Francois, G. Bringmann, C. Dochez, C. Schneider, G. Timperman, L.A. Assi, Ethanopharmacol., 1995, 46,

115.

[192] G. Francois, G. Timperman, W. Eling, L.A. Assi, J. Holenz, G. Brigmann, Antimicrob. Agents Chemother.,

1997, 41, 2533.

[193] P. Rasoanaivo, S. Ratsimamanga-Urverg, H. Rafatro, D. Ramanitrahasimbola, G. Palazzino, C. Galeffi, M.

Nicoletti, Planta Med., 1998, 64, 58.

[194] G.C. Kirby, A. Paine, D.C. Warhurst, B.K. Noamese, J.D. Phillipson, Phytother. Res., 1995, 9, 359.

[195] C.W. Wright, J. Addae-Kyereme, A.G. Breen, J.E. Brown, M.F. Cox, S.L. Croft, Y. Gokcek, H. Kendrick,

R.M. Phillips, P.L. Pollet, J. Med. Chem., 2001, 44, 3187.

[196] K.H. Ang Kenny, M.J. Holmes, T. Higa, M.T. Hamann, A.K. Kara Ursula, Antimicrob. Agents Chemother.,

2000, 44, 1645.

http://www.sciencedirect.com/science/article/pii/S0960894X09016588

























[197] A.D. Wright, G.M. Konig, C.K. Angerhofer, P. Greenidge, A. Linden, R. Desqueyroux- Faundez, J. Nat.

Prod. 1996, 59, 710.

[198] C.K. Angerhofer, G.M. Konig, A.D. Wright, O. Sticher, J.M. Pezzuto, J. Nat. Prod., 1992, 55, 1787.

[199] G.M. Konig, A.D. Wright, C.K. Angerholfer, J. Org. Chem., 1996, 61, 3259.

[200] H. Miyaoka, M. Shimomura, H. Kimura, Y. Wataya, Tetrahedron 1998, 54, 13467.

[201] O. Schwarz, R. Brun, J.W. Bats, H.G. Schmalz, Tetrahedron Lett., 2002, 43, 1009.

[202] C. Singh, N.C. Srivastav, S.K. Puri, Bioorg. Med. Chem., 2002, 12, 2277.

[203] C. Moretti, M. Sauvain, C. Lavaud, G. Massiot, J.A. Bravo, V. Munoz, J. Nat. Prod., 1998, 61, 1390.

[204] J.B. Koepfli, J.F. Mead, J. A. Jr. Brockman, J. Am. Chem. Soc., 1949, 71, 1048.

[205] K. Muratu, F. Takano, S. Fushiya, Y. Oshima, Biochem. Pharmacol. 1999, 58, 1593.

[206] K.A. Hostettmann, M. Hostettmann, Xanthones. In Methods in plant biochemistry, J.Harborne, B. Ed.;

Academic Press : London, 1989.

[207] R.W. Winter, K.A. Cornell, L.L. Johnson, L.M. Isabelle, D.J. Hinrichs, M.K. Riscoe, Bioorg. Med. Chem.

Lett. 1995, 5, 1927.

[208] R.W. Winter, K.A. Cornell, L.L. Johnson, M. Ignatuschchenko, D.J. Hinrichs, M.K. Riscoe, Antimoicrob.

Agents Chemother., 1996, 40, 1408.

[209] J.X. Kelly, R.W. Winter, M.K. Riscoe, D.H. Peyton, J. Inorg. Biochem., 2001, 86, 617.

[210] G. Francois, T. Steenackers, L.A. Assi, W. Steglich, K. Lamottke, J. Holenz, G. Brigmann, Parasitol. Res.,

1999, 85, 582.

[211] M. Ouattara, S. Wein, S. Denoyelle, S. Ortial, T. Durand, R. Escale, H. Vial, Y.V. Hoang, Bioorg. Med.

Chem. Lett., 2009, 19, 624–626.

[212] A. Dellai, J. Appel, A. Bouraoui, S. Croft, A. Nefzi, Bioorg. Med. Chem. Lett., 2013, 23, 4579– 4582.

[213] D.P. Sonawane, Y. Corbett, D.D. Dhavale, D. Taramelli, C. Trombini, A. Quintavalla, M.D. Lombardo, Org.

Lett., 2015, 17, 4074−4077.

[214] H. Zhang, J. Liu, L.S. Gan, S. Dalal, M.B. Casserac, J.M. Yue, Org. Biomol. Chem., 2015, 5, 107045-

107053.

[215] A. Kumar, K. Srivastava, S.R. Kumar, S.K. Puri, P.M.S. Chauhan, Bioorg. Med. Chem. Lett., 2009, 19,

6996–6999.

Publication History

Received 29th Jan 2017

Revised 11th Feb 2017

Accepted 12th Feb 2017

Online 28th Feb 2017

© 2017, by the Authors. The articles published from this journal are distributed to

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commons.org/licenses/by/3.0/). Therefore, upon proper citation of the original

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artemisinin: the white gold for treatment of malaria’s rampant …€¦ · ashu chaudhary1*,...

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