QUINOLINE: A DIVERSE THERAPEUTIC AGENT

QUINOLINE: A DIVERSE THERAPEUTIC AGENT

Anjali *, Dharampal Pathak and Divya Singh

Department of Pharmaceutical Chemistry, Delhi Pharmaceutical Sciences and Research University, Pushp Vihar  Sec-3, New  Delhi-110033,  India.

ABSTRACT: Quinoline and its derivatives are diverse pharmacological agents. They play a vital role in the development of new therapeutic agents. Many new therapeutic agents have been developed by using quinoline nucleus. Hence quinoline and its derivatives constitute an important class of heterocyclic compounds for the new drug development. Quinoline is also known as 1-azanapthalene and many researchers have synthesized large number of quinoline derivatives. Different synthetic routes have been developed by these researchers for the synthesis of quinoline derivatives. These derivatives have also been evaluated for the relevant biological activity by in vitro as well as in vivo methods. The present review focuses on detailed work done so far on the quinoline and its derivatives in the search of new therapeutic agents. The review covers the synthesis as well as biological activities of quinoline derivatives such as antimalarial, anticancer, antibacterial, anthelmintic, antiviral, antiprotozoal, antifungal, anti-inflammatory, analgesic, cardiovascular, reproductive, central nervous system activity, hypoglycemic and miscellaneous activity.

Antimalarial, Anticancer, Antibacterial, Anthelmintic, Antiviral, Antifungal

INTRODUCTION: Quinoline  a  nitrogen  containing  heterocyclic  compound  is  known  for  its  diverse  therapeutic potential .  The  derivatives   of quinoline  have  been  synthesized  by  many  routes  in   the  search  of  potent  therapeutic  agents.  Quinoline  has  a  molecular   formula  C₉H₇N  and  molecular  weight  of  129.16 ¹.  Quinoline  was  first  extracted  from  coal  tar  in  1934  by  Friedel  Ferdinand  Runge.  Coal tar remains the principal source of commercial quinoline.  Quinolones  are  synthesized  from  simple  anilines  using  a  number  of  named  reactios  for  example combes synthesis, Conrad limpach synthesis, Doebner  reaction, Doebner miller reaction, Gould Jacobs reaction and Skraup synthesis ².

Various new methods have been developed which employed metallic or organometellic reagents such as CuCN, LiCl ³ Ruthenium(III) chloride RuCl3.nH2O/3PPh3 ⁴ Ytterbium (III) triflate Yb(OTf)3 ⁵, Tungsten vinylidene complex W(CO)5(THF) ⁶, Boron trifluoride etherate BF3.OEt2 ^{7, 8}, Benzotriazoleiminiumsalts etc. ⁹ for the synthesis of quinoline derivatives.

Moreover  quinoline  also  occurs  in  plants  in  the  form  of  alkaloids  which  is  used  for  the  design of  many  synthetic  compounds  with  diverse  pharmacological  activities.  Many  natural  compounds  with  quinoline  skeleton  are  used  as  medicine  or  as  lead  compound  for  design  and  development  of  novel  and  potent  molecules. For  example  quinine was  isolated  from  the  bark  of  cinchone  trees and  has  been  employed  as  an  antimalarial  agent. Quinoline has also been found to possess antimalarial, anticancer, antibacterial, anticonvulsant, cardiotonic, antifungal, anthelmintic, anti-inflammatory and analgesic activity.

Biological activities:

Antimalarial activity

• Analogues of ferrochloroquine by Chibale et al. In 2000 also showed antimalarial activity.  In  these  analogues   carbon  chain  of  chloroquine  is  replaced  by  ferrocenyl  group ¹⁰.

n = 2-6

R = H, CONHBn

• A series of  7-chloroquinolinyl  thioureas   were  synthesized  by  Mahajan  et  in  2007  as  potential  antimalarials ^{11, 12}.

R = (CH₂)₂OH, (CH₂)₃N(Et)₂, (CH₂)₃N(Me)₂, (CH2)₂NH₂

R' = H, C₆H₅, CH₂C₆H₅, COOC₂H₅

• Few 4-aminoquinoline triazines synthesized by Kumar et al. in 2008 showed antimmalarial activity against chloroquine sensitive strain 3D7 of falciparum in an in-vitro model ¹³.

R1 = p-Fluoroaniline, Piperidine

R2 = Piperidine, Cyclohexylamine

• Few pyrimidine quinoline hybrids were synthesized by Acharya et al. in 2008 evaluated as antimalarial agent against chloroquine susceptible strain of Falciparum ^{14, 15}.
• 

• A series of ureido-4-quinolinamides synthesized by Modapa et al. in 2009sowed antimalarial effect at MIC OF 0.25mg/ml against chloroquine sensitive Plasmodium falciparum strain¹⁶.

R = Me, Ph, CH₂Cl, 2-ClC₆H₅, 3-ClC₆H₅,2-Furyl , R' = F, Cl, Br, CF₃

• Few chloroquinolyl derivatives were synthesized by Kovi et al. in 2009 as potent antimalarials at submicromolar levels ¹⁷.
• 

• Some derivatives with 4-anilinoquinoline ring developed by Singh et al. in 2011 showed good degree of activity against chloroquine sensitive falciparum stain as well as against rodent malaria parasite. P.yoeii ¹⁸.

R = H, Phenyl, Butyl, Isopropyl, n-Butyl

• A series of tetrazole derivatives of 4-aminoquinoline were synthesized by Pandey et al. in 2013 and screened for their antimalarial activity against both chloroquine sensitive 3D7 and chloroquine resistant K1 strains of falciparum as well as for cytotoxicity against VERO cell lines ¹⁹.
• 

Anticancer activity:

• A series of 4-anilinoquinolines synthesized by Assefa et al. in 2003 have been found to be tyrosine kynase inhibitors ²⁰.

R = 3'-Br, 3'-Cl, 3'-CF3, 3'-CN,   R1 = R2 = OMe, OEt

• Certain derivatives of amido-anilinoquinolines developed by Scott et al. in 2009 showed antitumor activity by inhibiting CSF-1R kinase ²¹.
• 

R = F, Cl, Br, CH₃

Few 4-hydroxyquinolines synthesized by Mai et al. in 2009 as histone acetyltransferase (HAT) inhibitors ²²

R1 = OH, OEt, R2 = CH₃, C₅H₁₁, C₁₀H₂₁, C₁₅H₃₁

Novel derivatives of 3-cyanoquinolines were developed by Miller et al. in 2009 and evaluated as inhibitors of insulin like growth factors receptors (IGH-1R) for treatment of cancer ²³.

R1 = Substituted-2-thioimidazole,

R2 = Substituted nitrogen heterocyclic

• Potent quinoline carboxylic acids have been developed by Chen et al. in 2009 and found to be act by inhibiting insulin like growth factors ²⁴.
•         

R1 = OH, H, COOH, F, Cl, NH₂,

R2 = OH, OMe, COOH

• Some quinoline derivatives synthesized by Wang et al. in 2011 as c- Met kinase inhibitors with IC₅₀ less than 1nM. It produces the inhibition of c-Met phosphorylation in c-Met dependent cell lines ²⁵.
• 

• A series of 6,7,8-substituted thiosemacarbazones of 2-chloro-3-formylquinoline derivatives developed by Merganakop et al. in 2012 with anticancer activity. The compounds had a better drug store and clog P values ²⁶.

R1 = R2 = R3 = H, CH₃, OCH₃

• A novel series of 6,8-disubstituted derivatives of quinoline and 1,2,3,4-tetrahydroquinoline synthesized by Salih et al. in 2013 found to be   as potent anticancer agent.6,8-dibromo-1,2,3,4-tetrahydroquinoline and 6,8-dimetoxy quinoline showed significant anticancer activities against the tumors cell lines ²⁷.
• 

• Certain derivatives of 6H-indolo[2,3-b] quinoline substituted at C-2,C-9 or N-6with O-L-daunosamine or L-acosamine connected with the chromophore via an alkoxy alkyl linker  were synthesized by Katarzyna et al in 2013 and found to be effective multidrug resistance in cancer treatment. All derivatives showed cytotoxicity against A549, MCF-7 and Hs294T. as well as multidrug resistance in colorectal adenocarcinolma LoVo/DX. Uterine sarcoma MES-SA/DX5 and promyelocytic leukemia. Compounds also induceG₂M or G0/G1 phasse cell cycle arrest in the JurkatT-cell leukemia cells ²⁸.
• 

2IQ, n=2          2IQ, n=5

2IQ, n=5          6IQ, n=5

9IQ, n=2          9IQ, n=5

9IQ, =5

6IQ, n=2

6IQ, n=5

Antibacterial activity:

• A series of phenoxy, phenylthio and benzyloxy substituted quinolones were synthesized by Ma et el. in 2009 with a good degree of antibacterial activity ²⁹.
• 

R1 = Ethyl, Cyclopropyl, FCH₂CH₂, R₂ = Substituted phenyl

Few 3-benzyl-6-bromo-2-methoxy quinoline derivatives synthesized by Upadhayaya et al. in 2009 through molecular modeling techniques found to be active against Mycobacterium tuberculosis H37Rv strain ³⁰.

R1 = Imidazolyl, Pyrazolyl, 1-(3-Trifluoromethyl-phenyl)-piperazinyl, 6-Amino-chromen-2-one

• Certain 7-chloroquinoline derivatives developed by De souza et al. in 2009 were found to be effective against multi drug resistant tuberculosis ³¹.
• 

n = 8-10

• A series of quinoline based compounds bearing an isoxazole containing side chain were developed by Lileinkampf et al. in 2009 and found to be active against Mycobacterium tuberculosis ³².
• 

• Some novel quinoline have been designed by Eswaran et al. in 2010 as antibacterial agents using mefloquine as the lead, wherein active pharmacophores i.e. hydrazones, ureas, thoureas and pyrazoles have been attached at the fourth position ³³.

R = R1 = Alkyl, Aryl, Heteroaryl

A series of novel  quinoline-6-carboxamides and 2-chloroquinoline-4-carboxamides derivatives of quinoline were synthesized by Vijaykumar et al. in 2012 by the reaction of their analogous carboxylic acids with various amine derivatives and evaluated for their antibacterial activity against Escherchia coli and Staphyllococcus aureus ³⁴.

• Few substituted pyrroloquinoline derivatives developed by Farah et al in 2014 found to be potent antibacterial agents against strains of coli and S.aureus ³⁵.
• 

R=H, CH₃, Cl

• Novel flouroquinole derivatives were developed by Patel et al. in 2014 as active antibacterial agents by studying there in vitro activity as well as interaction with  topoisomerase II DNA gyrase enzymes by using molecular docking protocol ³⁶.
• 

Anthelmintic activity:

A novel series of substituted 2,4-arylquinolines were developed by Rossiter et al. in 2005 and found to have a good degree of activity against the nematode Haemoncus contortus. These derivatives also showed activity against levamisole, ivermectin and thiabendazole resistant strains of H. contortus ³⁷.

Antiviral activity:

• Some derivatives of mono and polysubstituted quinoline were synthesized by Fakhfakh et al. in 2003 and found to be active against HIV-1 ^{38, 39, 40}.
• 

R = C₂H₅, C₃H₇, C₁₂H₂₅

• Novel anilidoquinoline derivatives developed by Ghosh et al. in 2008 showed good degree of in vitro antiviral activity against Japanese encephalitis virus ⁴¹.
• 

• Certain quinoline derivatives synthesized by Chen et al. in 2009 showed activity by behaving as HIV-1 Tat-TAR interaction inhibitors ⁴².
• 

• Few desflouroquinoline derivatives developed by Massari et al. in 2009  found to be effective antiviral agents in the treatment of HIV infection ⁴³. .

Antiprotozoal activity:

• A novel series of Alkenyl and alkynyl derivatives of quinoline were synthesized by Fakhfakh et al. in 2003 and found to be active against the casual agents of cutaneous leishmaniasis, visceral leishmaniasis, African trypanosomiasis and Chagas’ disease ^{44, 45}.
• 

• Some derivatives of quinoline designed by Franck et al. showed activity against Trypanosoma cruzi ⁴⁶.
• 

• A few quinolones developed by Ma et al. showed activity against Trypanosoma cruzi ⁴⁷.

R₁ = Et, Pr, CH=CH₂

R₂ = COOH, COOMe, COOet, CONH₂

R₃ = R₄ = Substituted Phenyl

Antifungal activity:

• A series of tetrahydroquinoline derivatives were developed by Gholap et al. in 2007 and evaluated as a potent antifungal agent against fungi Candida albicans , Fusarium oxysporum and Mucor sp ⁴⁸.

R = 4-Cl, 4-F, 3-NO₂, 4-CH₃, 2-Cl, 3,4,5-(OCH₃)₃

• Few derivatives of quinoline were designed by Kharkar et al. in 2009 using terbenafine as lead as antifungal agents. The developed compounds contained different bulky aromatic rings in the side chain. These compounds were designed using Leap Frog Drug Design programme ⁴⁹.
• 

R = 4-Cl, 4-F, 3-NO₂, 4-CH₃, 2-Cl, 3,4,5-(OCH₃)₃

Some secondary amines containing 2-chloroquinoline synthesized by Kumar et al. in 2011 and evaluated to be active as antimycotic agent against Aspergillus niger, As.flavus, Monascus purpureus and Penicillium citrinum. These were non-azole antimycotic agent ⁵⁰.

X = F, Cl, Br, CH₃, NO₂, Dichloro

Y = H, CH₃

Antiinflammatory activity:

• A novel series of 2-(furan-2-yl)-4-phenoxyquinoline derivatives were synthesized by Chen et al. in 2006 and found to be as inhibitors of lysozyme and β-glucoronidase ^{51, 52}.
• 

R = H, CH3

• Few quinoline derivatives developed by Gilbert et al. in 2008 found to be as amino acetamide inhibitors of Aggecanase-2 for the treatment of osteoarthritis ^{53, 54}.
• 

R1 = H, F, NO₂, Cl

R=H, 4-Cl, 4-CH, 4-OCH

R1 = H, 4-OCH₃, 3-NO₂

R2 = Nitrogen Heterocyclic

Analgesic activity:

• Certain 4-substituted-7-trifluoromethyl quinoline derivatives have been synthesized by Abadi et al. in 2005 and showed a good degree of analgesic actrivity. The activity is attributed to their notric oxide releasing properties ⁵⁵.
• 

• Novel derivatives of quinoline were developed by Gomtsyan et al. as active analgesis agent and activity is attributed to antagonism at Vanilloid receptors ⁵⁶.
• 

• A series of quinoline derivatives designed by Manera et al. in 2007 found to active analgesic by acting as selective agonists at Cannaboid CB₂ receptors ⁵⁷.

Cardiovascular activity:

• A series of phenyl acetic acid based derivatives of quinoline were synthesized by Hu et al. in 2007 as agonist at liver X receptors. These agents have good binding affinity for LXRb and LXRa receptors ⁵⁸.
• 

X = CH₂Ph, COPh, CN, CONH₂, Y = CF₃, CH₃, Cl

• Few 4-thiopheny derivatives of quinoline developed by Cai et al. in 2007 as HMGCoA reductase inhibitors and also as hypocholestrolaemic agents ⁵⁹.
• 

R = 4-CH(CH3)2, 4-F, 3-OCH3; R1 = H, F

R2 = H, F, Cl or Substituted thiophenyl group;

R3 = H, F or Substituted thiophenyl group

• Certain tetrahydroquinolinamides synthesized by Ramos et al. in 2008 found to be as inhibitors of platelet aggregation ⁶⁰.
• 

R = 3-Cl, 3-Br, 3-OCH₃

• Some tetrahydroquinoline derivatives have been designed by Rano et al. in 2009 as cholesteryl ester transfer protein inhibitors ⁶¹.
• 

A novel series of biaryletheramide derivatives of quinoline were developed by Bernotas et al. in 2009 and showed activity as agonist of liver X receptor and are useful in conditions of dyslipidaemia. These agents also reverse the conditions of arteriosclerosis ⁶².

X = CF₃, Cl; Y = CH₂ Ph, NR1R2 = Methyl ester, Pyrrolidine, Piperidine, Morpholine

Reproductive system:

• A series of tetrahydroquinoline derivatives were synthesized by Wallace et al. in 2003 as selective estrogen receptor modulator ⁶³.
• 

R = H, 3-OH, 4-OH; X = CH₂, O

Novel quinolines developed by Bi et al. in 2004 as potent PDE5 inhibitors having utility in the treatment of erectile dysfunction ⁶⁴.

R1 = COOEt; R2 = H, CN; R3 = H, CF₃; R4 = H, Et

CNS activity:

• A series of quinoline derivatives have been developed by Smith et al. in 2009 having CNS activity as NK3 receptor antagonist ⁶⁵.
• 

Hypoglycemic activity:

• A series of quinoline carboxyguanides were designed by Edmont et al. in 2000 as hypoglycemic agents ⁶⁶.
• 

R = H, C(NH)NH₂

Miscellaneous activity:

Quinolines have been found to possess other activities as well.

• Some quinolines have been synthesized by Evans et al. in 2009 and found to be as PDE4 inhibitors which can be utilized in treatment of chronic obstructive pulmonary disorder ⁶⁷.
• 
• Some novel tetrahydroquinoline-6-yloxy propanes were designed by Shakya et al. in 2009 as β-3 agonists ⁶⁸.

Certain tacrine 8-hydroxyquinoline derivatives were developed by Bachiller et al in 2010 which showed activity against Alzeihmer’. Tacrine has cholinesterase inhibition action while8-hydroxyquinoline derivatives have metal-chelating, neuroprotective and anti-oxidant properties ⁶⁹.

Z = Alkyl chain;

Str-I: R1 = R2 = H

Str-II: R1 = CH3; R2 = H

Str-III: R1 = H; R2 = C

Few aminoalkoxyquinolines were synthesized by Wolkenberg et al. in 2011 as somatostatin receptor subtype-2 agonist which have utility in proliferative diabetic retinopathy and oxidative age related macular degeneration ⁷⁰.

R = Aromatic ring

CONCLUSION: Many researchers have synthesized quinoline and its fused heterocyclic derivatives. These observations have been guiding for the development of new quinoline derivatives that possess varied biological activities i.e. anticancer, antimycobacterial, antimicrobial, anticonvulsant, anti-inflammatory and cardiovascular activities. A lot of work have been done and more to go. Developments of newer quinolines have immense possibilities and scope for drug development scientist. We have presented a concise compilation of this work to aid in present knowledge and to help researchers to explore an interesting quinoline class.

ACKNOWLEDGEMENT: We are grateful to the director, Dr. D.P. Pathak for the valuable discussion and suggestions and to the college authorities of Delhi Pharmaceutical Sciences and Research University (DPSRU) for financial support.

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    Anjali, Pathak D and Singh D: Quinoline: A diverse therapeutic agent. Int J Pharm Sci Res 2016; 7(1): 1-13.doi: 10.13040/IJPSR.0975-8232.7 (1).1-13.

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