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Raut et al. World Journal of Pharmaceutical Research
www.wjpr.net Vol 9, Issue 8, 2020. 674
DIFFERENT BIOLOGICAL ACTIVITIES OF QUINOLINE
Kirti Raut*1, Rutuja Thombare
1, Pratik Zagade
1 and Nikhil Kumbhar
2
1Department of Pharmaceutical Chemistry, SGRS College of Pharmacy, Saswad, Pune.
2Department of Pharmaceutics, SGRS of Pharmacy, Saswad, Pune.
ABSTRACT
Quinoline and its fused heterocyclic derivatives tested with diverse
pharmacological activity constitute a crucial class of compounds for
new drug development. Therefore, many researchers have synthesized
these compounds as target structures and evaluated their biological
activities. The present review provides an in depth view of work done
so far on quinolines and its biological activities covering anticancer,
antimicrobial, anticonvulsant, antiinflamatory, antimycobacterial, and
cardiovascular activities.
INTRODUCTION
The quinoline ring system occurs in various natural products,
especially in alkaloids[1]
with interesting biological activities. Quinolline nucleus provides
variety of therapeutic activities, novel quinolone derivatives proved to be biologically active
comounds possessing several pharmacological activities. There are many therapeutic agents
with quinolone nucleus. Hence for the new drug development Quinoline and its derivatives
are important class of compounds. For the synthesis of Quinoline and its derivatives
numerous synthetic routes have been developed due to its wide range of pharmacological and
biological activities.
This review article covers Biological activities of Quinoline derivatives such as anticancer,
anti-inflammatory, cardiovascular, central nervous system, hypoglycemic, antiviral,
antifungal and miscellaneous activities. Various natural products contain Quinoline nucleus
especially alkaloids. Quinine was obtained as the active ingredient from the bark of cinchona
trees and has been used for malaria.[2]
World Journal of Pharmaceutical Research SJIF Impact Factor 8.084
Volume 9, Issue 8, 674-689. Review Article ISSN 2277– 7105
Article Received on
31 May 2020,
Revised on 21 June 2020,
Accepted on 12 July 2020,
DOI: 10.20959/wjpr20208-18149
*Corresponding Author
Kirti Raut
Department of
Pharmaceutical Chemistry,
SGRS College of Pharmacy,
Saswad, Pune.
Raut et al. World Journal of Pharmaceutical Research
www.wjpr.net Vol 9, Issue 8, 2020. 675
KEYWORDS: Quinoline, Anticancer, Antimalarial, Cardiovascular activity, CNS effect,
Hypoglyacemic activity, Antiinflammmatory, Anticonvulsant, Analgesic, Antimicrobial.
ANTICANCER
Tuğba Kul Köprülü et. al.[3]
synthesized a variety of quinoline derivatives (3‐13) substituted
with phenyl, nitro, cyano, N‐oxide, and methoxy were tested in vitro for their biological
activity against cancer cell lines, including rat glioblastoma (C6), human cervical cancer cells
(HeLa), and human adenocarcinoma (HT29). 6-Bromo-5-nitroquinoline, and
6,8‐diphenylquinoline showed the best antiproliferative activity as compared with the
reference drug, 5‐fluorouracil (5‐FU), while the other compounds showed low
antiproliferative activity. The compond 6‐Bromo‐5‐nitroquinoline possesses lower cytotoxic
activity than 5‐FU in HT29 cell line. Due to its the apoptotic activity 6-Bromo-5-
nitroquinoline has the potential to cause cancer cell death.
N
6,8-diphenylquinoline
1
Rania Hamdy et. al.[4]
synthesized Target compounds via common aryl-substituted quinolin-
4-carbonyl-N-arylhydrazine-1-carbothioamide intermediate. Sub-micromolar anti-
proliferative activity in Bcl-2-expressing neoplastic cell lines were showed by some
quinolone-based oxadiazole analogues, and sub-micromolar IC50 activity within a Bcl2-Bim
peptide ELISA assay. Computational molecular modelling was further used to elucidate the
Bcl-2 targeted anticancer activity, offering possibilities to increase this work into the
planning of further potent and selective Bcl-2 inhibitory heteroaromatics with therapeutic
potential. In the study Bcl-2 protein has been Taken as anticancer drug target due to its
gatekeeper role in resisting programmed cancer cell death (apoptosis).
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Novel N-(4-acetyl-4,5-dihydro-5-(7,8,9-substituted-tetrazolo[1,5-a]-quinolin-4-yl)-1,3,4-
thiadiazol-2-yl)acetamide were synthesized by Sheetal Babu Marganakop et. al.[5]
and their in
vitro anticancer activity against two cell lines viz., human breast cancer cell line MCF7 and
human cervix cancer cell line HeLa were carried out. GI50, TGI, LC50 values were analysed.
Two of the compounds 4e and 4i with halogen substituent at 7th position of the target
molecules have shown potent activity against human cervix cancer cell line HeLa. DNA
cleavage studies revealed that most of these compounds show partial cleavage and few of
them show complete cleavage of DNA.
CARDIOVASCULAR
A series of 4-(amido-biarylether)-quinolines was prepared by R. C. Bernotas et al. as
potential LXR agonists. substitution with amide groups provided high affinity LXR ligands,
some with good potency and efficacy in functional assays of LXR activity. Novel amide had
a binding IC50 = 1.9 nM for LXRb and EC50 = 34 nM (96% efficacy relative to T0901317)
in an ABCA1 gene expression assay in mouse J774 cells, demonstrating that 4-(biarylether)-
quinolines with appropriate amide substitution are potent LXR agonists.[6]
A few phenyl
acetic acid based quinolones developed by Hu et al. also act as agonists at liver X receptors.
These agents have good binding affinity for LXRb and LXRa receptors.[7]
Tetrahydroquinolines which inhibit cholesteryl ester transfer protein was synthesis by Rano
et al.[8]
N
OR
CH2
R1
R2
R1=CF3 R=Morphine
R2=CH2
N
NH
COOH
R
R1
R1=CH2Ph
R=CF3
2 3
N+
OCF 3
OH
F3C
OCF 3CF2H
4
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CNS EFFECT
The neurokinin-3 (NK3) receptor is one of the tachykinin peptide receptor family. It is a
seven transmembrane G-protein coupled receptor and is preferentially activated by
neurokinin B (NKB). NK3 receptors are expressed in the mammalian CNS in cortical regions
and in basal ganglia structures implicated in psychiatric diseases. Quinoline based NK3
receptor antagonists[4,5]
with CNS activity have been developed by Smith et al.[9]
new SAR
studies within the established quinoline series of NK3 receptor antagonists has led to the
discovery of two promising new compounds which both produce excellent NK3 receptor
occupancy in gerbil brain.
N
NHO
NH2
F
N
NHO
F
NS
O
O
CH3CH3
5 6
HYPOGLYCEMIC ACTIVITY
The number of people su€ering from diabetes around the world increases day by day.
Predictions estimate from 110 million in 1994, numbers will reach 300 million in 2025.1
About 90% of cases are diabetes of type II (NIDDM), and recent therapies to treat this type of
diabetes require the use of oral hypoglycaemic drugs. Recent work4 showed clearly the
efficacy of some quinolones in inhibiting the activity of the ATP-K+ channel of the b cell
pancreatic membrane, inducing the production of insulin. These quinolones act accordingto a
mechanism similar to sulfonylureas. Quinoline carboxyguanides[6]
prepared by Edmont et al.
are hypoglycaemic agents.[10]
N
O
Et
H3CONH
NH NH2R
NH
O
ClH
R=H, C(NH)NH2
7
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ANTIMALARIAL
Malaria is one of the most severe and widespread parasitic diseases because of its drug
resistance, prevalence and virulence, and. It has a devastating impact on public health in the
developing regions of the world (Butcher et al., 2000).[11]
Despite more than two decades of
research effort, no vaccine has been discovered for effective control of malaria. In addition,
increasing emergence of drug-resistant strains of Plasmodium falciparum has created a need
for silico studies. The docking studies of synthesized compounds on falcipain-2 showed their
binding conformation and vital interactions. Compound 7d and 7f might be used as cause to
develop selective falcipain2 inhibitors as they showed good inhibition of the enzyme in
enzyme assay studies.
Microwave assisted green syntheses and protein–ligand docking calculations on P.
falciparum UCHL3 protein, were carried out by Sarveswari and colleagues[12]
in 2015 for 4-
hydroxy-3-(3-arylacryloyl)quinolin-2(1H)-ones and 3-(4,5-dihydro-5-aryl-1-phenyl-1H-
pyrazol-3-yldevelopment of novel and effective antimalarial agents.
Mymoona Akhter et. al.[13]
synthesized 3-[(2-Chloroquinolin-3-yl) methylene]-5-
phenylfuran-2(3H)-one derivatives (6a–j and 7a–j) and antimalarial activity of this twenty
derivatives were evaluated. Among this three compounds 7d, 7f, and 7g showed excellent
activity (0.50–0.72 lg/mL). A preliminary structure– activity relationship analysis of the
series suggested that electropositive character is useful for antimalarial activity. Falcipain-2
was reccognised as potential target for the compounds by in silico studies. Structure–activity
relationship (SAR) studies have shown that replacement of the methoxy group with a chloro
group at the 6th position of the quinolone ring increases antimalarial activity.
8
Compound code R R1
7d OCH3 Cl
7f OCH3 2,4-di CH3
7g OCH3 3,4-di Cl
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Glans et al[14]
in their laboratory prepared 4-aminoquinoline derivatives, two chromium
arene-quinoline half sandwich complexes. Screening of compounds for their in vitro
antimalarial activity against both chloroquine-sensitive and chloroquine-resistant strains of
Plasmodium falciparum proved N1-(7-chloroquinolin-4-yl)-N2 -(2-
((dimethylamino)methyl)benzyl) ethane-1,2-diamine 11 (IC50 = 33.9nM), twice active
against malarial parasite than organic ligand alone (IC50 = 63.1 nM).
Antiinflammatory
Inflammation is the protective response of the immune system to infection or irritation
consist of cascade biochemical events. It involves immune system, local vascular system, and
various cells of the injured tissue to endorse repairing of the damaged tissues. However,
uncontrolled inflammation can lead to acute, chronic and systemic inflammatory disorders
like cardiovascular disease, autoimmune disease [e.g. rheumatoid arthritis, Inflammatory
bowel disease, multiple sclerosis etc.], periodontal disease, asthma, diabetes, chronic
obstructive pulmonary disease (COPD), as well as neurological disorders such as
Alzheimer’s disease and age related macular degeneration (AMD).[15]
Sujeet Kumar Gupta and Ashutosh Mishra synthesized series of newer 3-chloro-1-
(substituted)-4-(tetrazolo [1,5-a]quinolin-4-yl)azetidin-2-one derivatives (6a-l) was
synthesized starting with acetanilide. Initially, acetanilide reacts with Vilsmeier-Haack
reagent (DMF + POCl3) to form 2- chloro-3-formyl quinoline. The 2-chloro-3-formyl
quinoline was further reacted with p-toluenesulphonic acid and sodium azide which yielded
Tetrazolo [1,5-1] quinoline-4- carbaldehyde . Schiff base intermediates (5a-l) formed from
the reaction of formyl group with various substituted amines, which were further allowed to
react with chloroacetyl chloride to produce 3-chloro-1-(substituted)-4-(tetrazolo [1,5-
a]quinolin-4-yl) azetidin-2-one derivatives (6a-l). Anti-inflammatory activity of all the
synthesized compounds reported good.[16]
Anticonvulsant Activity
8-substituted quinolines series were synthesized and tested against seizures. Neurologic
deficit was evaluated by the rotarod test. In the synthesized derivatives, compounds with a 2-
hydroxypropyloxyquinoline moiety displayed excellent anticonvulsant. Compound(8-(3-(4-
phenylpiperazino)-2-hydroxypropyloxy)quinoline)[7]
was potent in both series as an
anticonvulsive agent.[17]
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N
O
OH
N
NC6H5
9
5-alkoxy-[1,2,4]triazolo[4,3-a]quinoline series of derivatives were synthesized using 4
hydroxyquinolin-2(1H)-one as the starting material. By the maximal electroshock test (MES)
and their neurotoxicities by the rotarod test the evaluation was done for anticonvulsant
activities. The results of these tests were found that 5-hexyloxy-[1,2,4]triazolo[4,3-
a]quinolone[8]
was the most potent anticonvulsant, with median effective dose (ED50) of 19.0
mg/kg and protective index (PI¼ TD50/ED50) values of 5.8 in the MES test.[18]
N
N
N
OC6H13
10
Jin, H-G et al. extended their work to synthesized a series of 7-alkoxy-4,5-dihydro-
[1,2,4]triazolo[4,3-a]quinoline-1(2H)-one derivatives and compound 7-benzyloxyl-4,5-
dihydro-[1,2,4]thiazolo [4,3-a]quinoline-1(2H)-one[9]
was among the most active with
(ED50) of 12.3 mg/kg.[19]
N
N
N
OR
R=Benzyloxy
11
ANALGESIC ACTIVITY
Anuruddha R. et. al.[20]
synthesized seventeen quinolone derivatives starting from 8-hydroxy
quinolone via aldol condensation of substituted benzaldehydes with quinoline chalcones.
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analgesic activity were performed on COX-2 protein. Compounds 2,4,12,14, and 15 showed
significant interaction in terms of hydrophobic attachment, hydrogen bonding and
vanderwaal interaction with COX-2 according to docking study.
R4
R3
R2
R1
N
O OHR5
12
Most active compounds R1
R2
R3
R4
R5
2 OH H OCH3 H H
4 OH H H OCH3 H
12 OH H OH H H
14 H OCH3 H Br H
15 OH H OH H OH
MISCELLANEOUS
Quinolines have been found to possess a number of other activities some of them are
Selective PDE4 inhibitor quinolones[10,11]
have been developed by Lunniss et al. with utility
in chronic obstructive pulmonary disorder.[21]
N
NH
SNH2
O
CH3
OCH3
F
O
O
CH3
N
NH
SNH2
O
CH3
CN
F
O
O
CH3
13 14
Bachiller et al. have developed some novel tacrine– 8-hydroxyquinoline hybrids[12]
with
activity against Alzheimer’s. Tacrine has cholinesterase inhibition action while 8-
hydroxyquinoline derivatives have metal-chelating, neuroprotective and anti-oxidant
properties.[22]
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NNH
R3
NHTacrine
R2
OH
R1
R3=Alkyl chain;
R1=R2=H
R1=CH3; R2=H
R1=H ; R2=Cl
15
Tetrahydroquinolin-6-yloxy propanes[13]
have been developed by Shakya et al. which are b-3
agonists.[23]
NH
OH
O
N
SO2Ar
H3CO
H3CO
16
Certain aminoalkoxyquinolines[14]
as somatostatin receptor subtype-2 agonists have been
reported by Wolkenberg et al. (2011) which have utility in proliferative diabetic retinopathy
and exudative age related macular degeneration.[24]
N
O
NH
CH3
CH3
R
Cl
R=Aromatic ring
17
Anthelmintics
Sharon Rossiter et. al.[25]
synthesized 2,4-Disubstituted quinolines with additional
substituents in positions 5–8 have been found to have anthelmintic properties. The
synthesized compounds showed potent anthelmintic properties against sheep nematode
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Haemonchus contortus. These arylquinolines maintain their activity against ivermectin,
levamisole-, and thiabendazole-resistant strains of H. contortus.
Robert J. Alaimo et. al.[26]
prepared A series of 2-arylimidazo[4,5-flquinolin-9-ols by a
multistep procedure from various 5-aminobenzimidazoles. These compounds showed a
significant degree of anthelmintic activity against the mouse tapeworm Hymenolepis nana. 2-
(2-furyl) was the most active compound reported.
N
R1
R2
OH
N
NH
R
18
R- 2-furyl, 2-Me-Ph, Ph
R1- Me, Ph. Cyclopentano
R2- Ph, Me, Cyclopentano
ANTIMICROBIAL
Infections caused by multidrug-resistance (MDR) bacteria, especially ―ESKAPE‖
pathogens[27,28]
, kill thousands of people worldwide per year, posing a greater health crisis to
human beings.[29]
However, we are losing the battle against never-ending resistance due to
the limits of efficacy and life-span of current antibiotics[30]
, which makes drifting back to pre-
antibiotic era possible.
Thirteen oxazino quinoline and six quinoline derivatives were designed, prepared, and
evaluated by Hai-Gen Fu[31]
for their antibacterial activities against Gram positive and Gram
negative strains. From the newly synthesized target compounds, quinolone coupled hybrid
exerted the promising effect with MIC values of 0.125–16 µg/mL against the most tested
Gram positive and Gram negative bacteria. Molecular-docking study showed that compound
5d might target both bacterial LptA and Top IV proteins, thereby displaying a broad-
spectrum activity against Gram positive and Gram negative organisms.
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N
OH
R
Cl
19
Eight quinoline-based hydroxyimidazolium hybrids were prepared and evaluated in vitro
against a panel of clinically important fungal and bacterial pathogens by Daniel Insuasty et.
al.[32]
Hybrid compounds showed remarkable antifungal activity against Cryptococcus
neoformans with a minimum inhibitory concentration (MIC) value of 15.6 µg/mL.
Sumesh Eswaran et. al.[33]
synthesized A new class of quinoline derivatives containing 1,2,4-
triazole moiety were synthesized from derivatives of 4-hydroxy-8-(trifluoromethyl)quinoline-
3-carbohydrazide through multi-step reactions. 4-hydroxy-8-(trifluoromethyl)quinoline-3-
carbohydrazide on treatment with substituted Isothiocyanates yielded quinoline-
thiosemicarbazides, which were conveniently cyclized to (5-mercapto-4H-triazol-3-yl)-
quinolin-4-ols in basic medium. These intermediates were then transformed to their
respective chloro derivatives by treatment with phosphorus oxychloride, which on further
reaction with different biologically active rare amines yielded the target compounds good
yield. The synthesized compounds showed good antibacterial and antifungal activity.
Two new series of 7-(trifluoromethyl)-4-hydroxy substituted quinoline carbohydrazide
derivatives and N-alkyl-3-(5-phenyl-1,3,4-oxadiazol-2-yl)-7- (trifluoromethyl) quinolin-4-
amine derivatives were synthesized by B. Garudachar et. al.[34]
Structures of compounds were
confirmed by spectral study. Compunds screened for there antibacterial activity against
Mycobacterium smegmatis and Pseudomonas aeruginosa. Antifungal activity was carried out
on the fungal stains Candida albicans and Penicillium chrysogenum. From this compounds
20 and 21 showed significant antimicrobial activity.
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N
OH
F
FF
NHN
O
CH3
O
N
NH
OH
N
O
N
F
FF
20 21
S
No Application No
Patent
No
Patent
Grant Date Title Applicant
1 537/DEL/1996 196774 23-02-2007
A novel [6,7-bis(2ethoxyethoxy)
Quinazolin-4-yl]-(3-
ethynylphenyl)amine
hydrochloride and a process
For preparing the same
Pfizer Products,
INC.
2 IN/PCT/2002/1890/MUM 200903 06-05-2006 Quinolinyl benzothiazalyl
ppargamma Modulator
Tularik Inc and
Japan Tobacco Inc,
3 IN/PCT/2002/1457/MUM 206226 19/04/2007 A QUINAZOLINE DERV Astrazeneca AB
4 IN/PCT/2001/878/CHE 209091 20-08-2007
Quinoline and quinoxaline
compounds
Of formula i and a stent device
Comprising the same
Aventis
Pharmaceuticals,
Inc
5 IN/PCT/2002/344/MUM 209328 24/08/2007 Quinazoline derivatives as vegf
Inhibitors Astrazeneca AB
6 339/MUMNP/2005 210956 16/10/2007
Quinolinecarboxylic acid
derivative
Or salts thereof
Wakunaga
Pharmaceutical Co
Limited
7 628/CHENP/2004 211857 13-11-2007 Quinoline Derivatives Of Formula
I
M/S. F. Hoffmann-
La Roche Ag
8 943/KOLNP/2005 212279 28-11-2007
A quinolinyl-pyrrolopyrazole
Compound and pharmaceutical
Composition thereof
Eli Lilly and
Company
9 IN/PCT/2001/879/CHE 212755 14-12-2007 Quinoline and quinoxaline
Compounds
Aventis
Pharmaceuticals
INC
10 3254/DELNP/2006 235051 24-06-2009 A quinazoline derivatives and a
Process for preparing the same Astrazeneca AB.
11 4627/DELNP/2005 239487 23-03-2010
Quinazoline compounds of
formula (i),pharmaceutical
composition and Process for
prepering the same
Astrazeneca AB
12 1955/KOLNP/2005 239547 24-03-2010
Quinazolines useful as modulators
of
Ion channels
Vertex
Pharmaceuticals
Incorporated
13 2040/KOLNP/2006 239691 30-03-2010 2-(HETERO) ARYL-Substituted
Tetrahydroquinoline Derivatives Merck Patent Gmbh
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CONCLUSION
Till now many researchers have synthesized Quinolline derivatives. Researchers from the
study conclude that Quinoline and its substituted derivatives possess different biological
activities i.e. anticancer, antimycobacterial, anticonvulsant, antiinflamatory, antimicrobial
and cardiovascular activities. newer quinolines development have immense possibilities and
scope for drug development scientist. We have presented a brief compilation of this work to
aid in present knowledge and to help researchers to explore an interesting Quinoline class.
Patent List.
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