a new generation of 7-chloro-4-aminoquinoline antimalarials€¦ · 184 systematic reviews in...

182 Systematic Reviews in Pharmacy | July-December 2010 | Vol 1 | Issue 2

Introduction

Malaria, a life-threatening disease transmitted by Anopheles mosquitoes, is probably one of the oldest diseases known to mankind. In the 5th century BC, Hippocrates, the Greek physician, was the first to describe the manifestations of the disease. In the 7th

century AD, the Italians named the disease mal’aria meaning bad air, due to its association with ill-smelling vapors from the swamp near Rome. The first recorded treatment of malaria dates back to 1600

A new Generation of 7-Chloro-4-Aminoquinoline Antimalarials

Singh V, tyagi l, Singhal M1, Sharma CS2, Kori Ml3

Department of Pharmaceutical Chemistry, Geetanjali College of Pharmaceutical Studies, Udaipur, Rajasthan, 1Jaipur National University, Jaipur, Rajasthan, 2B. N. P. G. College, Udaipur, Rajasthan, 3IES School of Pharmacy, Bhopal, Madhya Pradesh, India

Review Article

Correspondence: Virendra Singh; E-mail: [email protected]

A R t I C l E I n f O

Article history: Received 21 October 2009 Accepted 27 October 2009 Available online 07 January 2011

Keywords: Malaria Plasmodium falciparum Antimalarial agents 4-aminoquinoline

A B S t R A C t

There is an urgent need to find new and cost-effective drug molecules for the treatment of malaria due to the rapid spread of resistance toward currently available drugs. Records of malaria date back to the earliest human civilizations when it was described as the distinct periodic fevers. Malaria is a serious infection with Plasmodium parasites, which are spread by the bite of Anopheles mosquitoes. For this reason, nearly all malaria control strategies target either the parasite or the mosquito. In spite of worldwide efforts, however, an eradication of malaria is far from being achieved. There are no fewer than 4 species of Plasmodium that infect people, each with thousands of genetic variants, and about —35 different species of malaria-transmitting mosquitoes. It is the complex diversity of the parasites, the mosquitoes, the local ecologies, socioeconomic conditions, and human responses to disease that conspire to make malaria notoriously hard to control. There is no single prescription which can successfully control malaria in all areas. Plasmodium falciparum is generally slow to develop resistance to the 4-aminoquinoline-containing drug. Antimalarial drug resistance is worsening, with the geographic spread of resistance widening to previously unaffected areas and a remorseless increase both in the prevalence and degree of drug resistance. The unavoidable spread of drug resistance and until the development of an effective antimalarial vaccine, the search for effective, safe, and affordable drugs for falciparum malaria is one of the most pressing health priorities worldwide. This article reviews the newly synthesized 7-chloro-4-aminoquinolines as effective antimalarial agents.

AD when the bark of the Cinchona tree was first used by the native Peruvian Indians to treat the intermittent fevers associated with this illness.[1] It was not until 1889 that Alphonse Laveran discovered the protozoal (single-celled parasite) cause of malaria and not until 1897 that Ronald Ross demonstrated that the Anopheles mosquito was the vector for the disease.[2] His pioneering work on establishing the main features of the parasitic life cycle earned Ross the Nobel Prize in Medicine in 1902.

Malaria is the most common parasitic disease in tropical and subtropical regions, and 40% of the worldwide population lives in a malaria endemic area. World Health Organization estimated that a quantum of people living in areas at risk of malarial transmission is alarming, and approximately 1.0–3.0 million die due to nonavailability of proper treatment.[3,4] Malaria is caused by protozoan parasites of the genus Plasmodium, and the four species, namely, P. falciparum, P. vivax, P. malariae, and P. ovale are responsible for the spread of the disease in humans. In the past, quinoline-derived compounds were extensively studied for the development of new therapeutic agents that led to the development of some molecules, namely, pamaquine and mepacrine. The best compound that emerged from this endeavor is chloroquine (CQ), which was discovered in the 1940s.[5] During the past six decades, CQ and other aminoquinolines have been the frontline antimalarial agents

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183Systematic Reviews in Pharmacy | July-December 2010 | Vol 1 | Issue 2

because of their therapeutic efficacy and lower cost.[6] However, the development of resistance has severely limited the choice of available antimalarial drugs, which clearly highlights the urgent need of novel chemotherapeutic agents for the treatment of malaria. The structure–activity relationship studies on 4-aminoquinoline antimalarial compounds suggest that the 7-chloro-4-aminoquinoline nucleus is obligatory for the antimalarial activity, particularly, the inhibition of β-hematin formation, and accumulation of the drug at the target site.[7-9] It has been reported that when the 7-chloro group is replaced by an electron donor group like -NH2, -OCH3, and so on or an electron-withdrawing group like NO2, the antimalarial activity is reduced due either to an increase or a decrease in the pKa of quinoline nitrogen atom. This suggests that 7-chloro is most suited for the antiplasmodial activity of 4-aminoquinoline classes of compounds.[10,11] The importance of the 4-aminopyridine substructure for hematin binding and antimalarial activity was also supported by experimental and molecular modeling.[12]

Considering increasing resistance to available agents, there is a broad consensus that there is a need to develop new antimalarial drugs. Antimalarial drug development can follow several strategies, ranging from minor modifications of existing agents to the design of novel agents that act against new targets. Increasingly available agents are being combined to improve antimalarial regimens. The following groups of newer 7-chloro-4-aminoquinoline antimalarials have been reported, from which some new molecules have been reported to be of superior activity than the chloroquine and/or amodiaquine and and/or both.

Group 1 Isoquine and Related Amodiaquine Analogs

O’Neill et al. synthesized and evaluated a new series of 4-aminoquinolines, which they obtained by interchanging the 3′ hydroxyl and the 4′ Mannich side-chain function of amodiaquine.[13]

The preparation of isoquine and its analogs from commercially available starting materials involves a two-step procedure according to a method originally utilized by Burkhalter et al.[14] [Figure 1]. Thus, step 1 involves a Mannich reaction of the 3-hydroxyacetanilide to provide the Mannich product. Stage 2 of the sequence involves hydrolysis of the amide function to provide the corresponding Mannich-substituted 3-aminophenol that is subsequently coupled

with 4, 7-dichloroquinoline to provide target molecules shown in Table 1.

Antimalarial Activity

The in vitro antimalarial activity of the synthesized compounds (1–10) against chloroquine-sensitive HB3 strain and highly chloroquine resistant K1 strain of P. falciparum has been reported by O’Neill et al.[15] along with that of chloroquine and amodiaquine [Table 1]. It is reported that compounds 1, 3, 4, 8, and 10 show activity below 20 nm and the most potent compounds are 1 (isoquine) and 8 (piperidinyl analogs) against the HB3 strain, while compounds 1, 3, 6, 8, and 9 show excellent activity against the K1 strain; compound 1 is as potent as amodiaquine while about 20 times more potent than chloroquine diphosphate against the K1 strain.

Group 2 Compounds with thiazolidin-4-One nucleus at the terminal Side Chain

Solomon et al. synthesized and reported a new series of side-chain modified 4-aminoquinolines and evaluated for antimalarial activity.[16]

The 4-aminoquinoline derivatives of 2-substituted thiazolidin-4-ones and [1, 3] thiazinan-4-ones (Table 2, 1–30) are reported and they are obtained from the appropriate amine (a1, a2, and a3), substituted aldehyde (b1, b2, and b3), and mercapto acid (c1, c2, and c3) in the presence of N,N-dicyclohexylcarbodiimide (DCC) in tetrahydrofuran (THF, anhy.) at room temperature. The target compounds (1–30) were prepared as outlined in Figure 2.


The antimalarial activity (in vitro) of the synthesized compounds (1–30) against the NF-54 strain of P. falciparum compared to chloroquine has been reported by Solomon et al. [Table 2]. All the compounds (1–30)

figure 1: Synthesis of compounds (1–10)

Table 1: Compounds (1–10) with an antimalarial activity (IC50)

Compounds Substituents IC50 (nM)

R1 R2 HB3 K1

1 Ethyl Ethyl 12.65 17.632 H tert-Butyl 30.03 32.753 Methyl Methyl 14.76 18.654 n-Propyl n-Propyl 19.78 30.635 tert-Butyl tert-Butyl 51.88 37.216 -(CH2)4- 28.37 21.757 -(CH2)2O(CH2)2- 97.20 112.378 -(CH2)5- 9.07 20.289 H Isopropyl 20.22 26.2210 H Ethyl 16.24 32.42Chloroquine 14.98 183.82Amodiaquine 9.60 15.08

Singh, et al.: A new generation of 7-chloro-4-aminoquinoline antimalarials


possess an antiplasmodial activity (in vitro) while many of the compounds (3, 8, 9, and 16) possess a superior activity than chloroquine.

Group 3 Quinolizidinyl and Quinolizidinylalkyl derivatives

Sparatore et al. synthesized a set of quinolizidinyl and quinolizidinylalkyl derivatives of 4-amino-7-chloroquinoline and reported an activity (in vitro) against CQ-sensitive (D-10) and CQ-resistant (W-2) strains of P. falciparum.[17] The target compounds (1–10) were prepared as outlined in Figure 3a-c.


The antimalarial activity (in vitro) of the synthesized compounds (1–10) against D-10 (CQ-S) and W-2 (CQ-R) strains of P. falciparum compared to chloroquine has been reported by Sparatore et al. [Table 3]. With only one exception (compound 10), all reported compounds exhibited a high degree of activity and these compounds were 0.17- to 1.32-fold as active as chloroquine on the D-10 (CQ-S) strain.

Compounds (5, 8, 1, and 2) are 6.9- to 10.1-fold more active than chloroquine while compounds (3, 4, and 9) are 2.1–5.6 times more active than chloroquine against the W-2 (CQ-R) strain.

Group 4 Compounds with Modification in the 3,5-Diaminobenzyl Alcohol

Delarue et al. synthesized a new series of 4-anilinoquinolines with two proton-accepting side chains and reported an antimalarial activity of the synthesized compounds.[18] The outlines of the synthesis of the reported compounds [Figure 4a] (Table 4, 2–66) are given in Figure 4, b, and c.


The antimalarial activity (in vitro) of the synthesized compounds (1–66) against the CQ-resistant strain FcB1R reported by Delarue et al. is given in Table 4. Most of the compounds (among 52–60) are more efficient than amodiaquine while compounds 2, 8, 27, 28, and 31 also show good results.

Group 5 Alkyl Substituents in the 5′-Position of the 4′-Hydroxyanilino n-terminal of the Side Chain

Raynes et al. synthesized 4-aminoquinoline Mannich base derivatives and reported their antimalarial activity.[19] Here the 3′-diethylamino function of amodiaquine (AQ) is replaced by a 3′-tert-butylamino group and aliphatic hydrocarbon entities are incorporated into the 5′-position of the 4′-hydroxyanilino side chain. Structures of all the designed compounds are shown in Table 5 and the outline of the synthesis of the reported compounds (1–7) is given in Figure 5.

Table 2: Compounds (1–30) with an antimalarial activity (IC50)

Compound n A R IC50 (μM)

1 1 A1 H 2.144 ± 0.152 1 A1 4-Chlorophenyl 0.980 ± 0.073 1 A1 2,6-Dichlorophenyl 0.039 ± 0.014 1 A2 H 1.678 ± 0.075 1 A3 H 2.917 ± 0.136 1 A3 4-Chlorophenyl 4.070 ± 0.177 1 A3 2,6-Dichlorophenyl 3.271 ± 0.778 1 A4 H 0.065 ± 0.019 1 A4 4-Chlorophenyl 0.013 ± 0.0110 1 A4 2, 6-Dichlorophenyl 0.291 ± 0.0311 2 A1 H 1.650 ± 0.0412 2 A1 4-Chlorophenyl 1.040 ± 0.0813 2 A1 2, 6-Dichlorophenyl 0.138 ± 0.0214 2 A2 H 2.327 ± 0.0515 2 A3 H 1.810 ± 0.5416 2 A3 4-Chlorophenyl 0.014 ± 0.0117 2 A3 2,6-Dichlorophenyl 6.154 ± 0.00318 2 A4 H 0.429 ± 0.0219 2 A4 4-Chlorophenyl 1.031 ± 0.0520 2 A4 2,6-Dichlorophenyl 2.193 ± 0.1021 3 A1 H 2.647 ± 0.0322 3 A1 4-Chlorophenyl 1.980 ± 0.0423 3 A1 2,6-Dichlorophenyl 3.031 ± 0.1024 3 A2 H 1.286 ± 0.0825 3 A3 H 1.812 ± 0.0526 3 A3 4-Chlorophenyl 0.271 ± 0.0227 3 A3 2,6-Dichlorophenyl 7.153 ± 0.8128 3 A4 H 1.510 ± 0.0729 3 A4 4-Chlorophenyl 1.272 ± 0.1730 3 A4 2,6-Dichlorophenyl 3.074 ± 0.17Chloroquine 0.106 ± 0.01

*IC50 = 50 inhibitory concentration values (μM) against the NF-54 strain of P. falciparum.

figure 2: Synthesis of compounds (1–30)



Table 3: Antimalarial activity of compounds (1–10)

Compound D-10 (CQ-S)IC50 (nM)

Ratio IC50CQ/

Compound

W-2 (CQ-R)

IC50 (nM)

Ratio IC50CQ/

Compound

1 24.73 ± 15.64 1.11 23.34 ± 8.10

9.42

2 24.20 ± 14.58 1.32 21.27 ± 7.65

9.69

3 102.46 ± 29.55 0.17 106.57 ± 14.38

2.12

4 71.74 ± 23.78 0.23 73.83 ± 32.70

3.42

5 26.36 ± 15.29 0.87 41.87 ± 1986

6.93

6 26.08 ± 11.07 1.03 181.57 ± 61.10

1.67

7 45.96 ± 21.87 0.60 384.40 ± 136.75

0.88

8 33.68 ± 11.33 0.45 31.90 ± 9.15

7.44

9 31.34 ± 8.15 1.17 94.97 ± 31.03

4.22

10 ≥5030.00 0.006 ≥3968.00 0.03Chloroquine 24.68 ± 15.75 1.00 276.53 ±

149.351.00

figure 3: (a) Synthesis of compounds (1–4)

figure 3: (b) Synthesis of compounds (5–9)

figure 3: (c) Synthesis of Compound (10)

figure 4: (a) Synthesis of Compounds (1-24)

figure 4: (b) Synthesis of Compounds (25-36)


The antimalarial activity (in vitro) of the synthesized compounds

(Table 5, 1–7) against the chloroquine-sensitive HB3 strain and



Table 4: Compounds (1–66) with an Antimalarials activity (IC50)

Compound A n NRR’ X IC50 (nM)

1 - - - - 278.9 ± 83.02 A1 1 4-Methylpiperidine - 77.7 ± 52.33 A1 2 4-Methylpiperidine - 135.5 ± 23.54 A1 4 4-Methylpiperidine - 465.0 ± 47.05 A1 5 4-Methylpiperidine - 304.5 ± 21.56 A1 7 4-Methylpiperidine - 308.5 ± 43.57 A1 1 4-Methylpiperidine - 86.0 ± 5.08 A1 1 Piperidine - 44.5 ± 9.79 A1 1 N-Methylpiperidine - 344 ± 3210 A1 1 Morpholine - >100011 A1 1 4-Hydroxypiperidine - 1050 ± 51012 A1 1 Pyrrolidine - 44.0 ± 5.813 A1 1 Thiazolidine - 588.0 ± 41.014 A1 1 tert-Butylamine - 50.9 ± 10.615 A1 1 Diethyl-amine - 41.6 ± 6.116 A1 1 Benzylamine - 192.7 ± 57.617 A1 1 4-Chloro-benzylamine - 855 ± 22518 A1 1 1,2,3,4-Tetrahydroisoquinoline - 1450 ± 35019 A1 1 3-Aminopyrazole - 806.5 ± 86.520 A1 1 Cl - >100021 A1 1 Pyridinium chloride - 927 ± 3722 A1 1 OH - >100023 A1 0 Phenyl - >100024 A1 0 H - 359.8 ± 7.825 A2 1 - Piperidine 54.0 ± 12.626 A2 2 - Piperidine 78.3 ± 38.327 A2 4 - Piperidine 15.5 ± 4.228 A2 5 - Piperidine 27.4 ± 10.329 A2 7 - Piperidine 165 ± 59.030 A2 4 - Pyrrolidine 23.0 ± 3.531 A2 4 - Morpholine 14.1 ± 1.532 A2 4 - N-methylpiperazine 65.1 ± 7.233 A2 4 - Diethyl-amine 141.1 ± 5.734 A2 4 - Br 151.1 ± 22.735 A2 0 - Phenyl 75.5 ± 14.1



36 A2 0 - Quinol-4-yl 25.6 ± 5.237 - - - - 281.7 ± 35.338 A3 - N,N-Dimethyl-ethane-1,2-diamine - 15.5 ± 2.939 A3 - N,N-Dimethyl-propane-1,3-diamine - 134 ± 240 A3 - N,N,N’-Trimethyl-ethane-1,2-diamine - 5.0 ± 0.841 A3 - 2-Pyrrolidin-1-yl-ethylamine - 10.2 ± 1.342 A3 - 2-Pyrrolidin-1-yl-ethylamine - 6.6 ± 1.643 A3 - 2-Pyrrolidin-1-yl-ethylamine - 7.9 ± 0.7 44 A3 - Diethylamine - 8.2 ± 1.445 A3 - tert-Butylamine - 3.7 ± 1.846 A3 - Piperidine - 10.2 ± 3.647 A3 - Pyrrolidine - 6.9 ± 3.348 A3 - N-Methylpiperazine - 7.5 ± 3.149 A3 - Morpholine - 9.5 ± 3.450 A3 - 4-Hydroxypiperidine - 6.5 ± 2.051 A3 - N-(2-Hydroxyethyl)-piperazine - 11.5 ± 0.652 A3 - N-Phenylpiperazine - 5.5 ± 0.653 A3 - N-Benzylpiperazine - 13.0 ± 4.754 A3 - N-(Diphenylmethyl)-piperazine - 12.5 ± 3.255 A3 - N-(4-Chlorobenzyl)-piperazine - 11.5 ± 0.356 A3 - N-(4-Methoxybenzyl)-piperazine - 11.0 ± 1.4 57 A3 - N-(4-Nitrobenzyl)-piperazine - 13.2 ± 0.5 58 A3 - N-(4-Diethylaminobenzyl)-piperazine 11.9 ± 0.659 A3 - N-(4-Cyanobenzyl)-piperazine - 13.3 ± 0.560 A3 - N-Piperonylpiperazine - 6.9 ± 2.661 A3 - Phenylamine - 21.2 ± 1.562 A3 - Benzylamine - 8.5 ± 5.763 A3 - C,C-Diphenyl-methylamine - 9.1 ± 1.264 A3 - 4-Chloro-benzylamine - 4.6 ± 0.265 A3 - 4-Methoxy-benzylamine - 4.4 ± 0.166 A3 - 4-Trifluoromethyl-benzylamine - 5.5 ± 0.1Chloroquine 126 ± 26Amodiaquine 7.4 ± 2.7

Table 5: Compounds with an antimalarial activity (IC50)

Compound R IC50 (nM)

HB3 K1

1 Methyl 2.99 ± 1.25 11.2 ± 2.12 Ethyl 2.97 ± 1.5 7.90 ± 1.823 Propyl 0.98 ± 0.2 1.83 ± 0.424 Isopropyl 1.24 ± 0.32 1.87 ± 0.565 sec-Butyl 1.97 ± 0.31 5.77 ± 0.236 tert-Butyl 8.35 ± 2.30 21.2 ± 4.27 Cyclohexyl 6.80 ± 1.64 14.5 ± 1.2Chloroquine 19 ± 3 182 ± 17Amodiaquine 2.47 ± 0.50 13.2 ± 2.5tert-Butylamodiaquine 1.47 ± 0.40 3.43 ± 0.53

figure 4: (c) Synthesis of Compounds (37-66)

chloroquine-resistant K1 strain of P. falciparum has been reported by Raynes and coauthors. They reported that the introduction of large nonplanar substituents, such as a N-tert-butyl (compound 6) or cyclohexyl (compound 7) group, substantially decreased the antimalarial activity, while alkyl groups which contained a 3-carbon backbone with only one branch (with compounds 3-5) gave an optimum antimalarial activity.

Group 6 tebuquine Analogs

O’Neill et al. synthesized some novel tebuquine analogs and

reported their antimalarial activity. These novel tebuquine analogs



Table 6: Compounds with an antimalarial activity (IC50)

Compound R R1 R2IC50(nM)

HB3 K1

Chloroquine 9.75 ± 2.7

250 ± 7.1

Amodiaquine 3.7 ± 0.8

27.2 ± 4.3

Tebuquine OH H tert-Butyl 0.9 ± 0.3

20.8 ± 1.4

Amotebuquine OH Ethyl Ethyl 24.2 ± 1.8

42.1 ± 3.6

Fluorotebuquine (1) F H tert-Butyl 61.6 ± 4.1

74.3 ± 1.4

Fluoroamotebuquine (2) F Ethyl Ethyl 104.1 ± 4.7

101.3 ± 6.8

Dehydroxytebuquine (3) H H tert-Butyl 56.6 ± 1.8

74.2 ± 3.2

are designed by replacing the 4-hydroxyl function of tebuquine with either fluorine or hydrogen and with tert-butyl or diethylamino substitution in the side chain (1–3). Structures of all the designed compounds are shown in the Table 6 and the outline of the synthesis of the reported compounds (1–3) is given in Figure 6a-b.


As per the report of O’Neill et al. (Table 6), fluorotebuquine (1) and fluoroamotebuquine (2) are more potent than chloroquine against the chloroquine-resistant K1 strain of the parasite while dehydroxytebuquine (3) is significantly less potent than tebuquine or amodiaquine in the HB3 strain of the parasite.

Conclusion

The development of resistance has severely limited the choice of available antimalarial drugs, which clearly indicates the urgent need for novel chemotherapeutic agents for the treatment of malaria. As reviewed here, many novel 7-chloro-4-aminoquinoline antimalarials are found with a superior activity and few of them may even come into the market for antimalarial therapy in the near future. The 7-chloro-4-aminoquinoline may be a good lead for developing novel antimalarial agents for various resistant strains of malarial parasites.

References

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figure 5: Synthesis of Compounds (1-7)

figure 6: (a) Synthesis of Fluorotebuquine and Fluoroamotebuquine

figure 6: (b) Synthesis of Dehydroxytebuquine



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19. Raynes KJ, Stocks PA, O’Neill PM, Park BK, Ward SA. New 4-aminoquinoline Mannich base antimalarials. 1. Effect of an alkyl substituent in the 5’-position of the 4’-hydroxyanilino side chain. J Med Chem 1999;42:2747-51.

Source of Support:Nil,Conflict of Interest:Nonedeclared.


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