Synthesis, Structure-activity Relationship, and Biological Activity of
Benzimidazole-quinoline: A Review to Aid in the Design of a New Drug

Vimal      Datt; Salahuddin; Avijit      Mazumder; Rajnish      Kumar; Himanshu      Singh; Ranjeet   Kumar   Yadav; Km      Shabana; Mohammad      Shahar Yar; Mohamed   Jawed   Ahsan
doi:10.2174/1570180820666230207160338
Abstract

Heterocyclic compounds are fundamental building blocks for developing novel bioactive compounds. Due to their extensive uses in both industrial and synthetic organic chemistry, quinoline and benzimidazole have recently become important heterocycles. Clinical trials have investigated quinoline and benzimidazole analogues to treat a variety of illnesses, including cancer, bacterial and fungal infection, DNA damage, etc. Medicinal chemists are paying attention to nitrogen-containing hybrid heterocyclic compounds that have a wide range of therapeutical potential with lesser adverse effects. Many efforts have been made to find new and more efficient ways to synthesize these molecules. However, microbial resistance is becoming a major threat to the scientific community; hence, the necessity for the discovery and development of novel antimicrobial drugs with novel modes of action is becoming highly significant. One strategy to overcome this problem is to produce hybrid molecules by combining two or more bioactive heterocyclic moieties in a single molecular platform. Based on established research data on quinoline- bearing benzimidazole derivatives, it can be concluded that both moieties are used for the synthesis of promising therapeutically active agents. This present review comprises the synthetic approaches of biologically active quinolines containing benzimidazole derivatives with their structure-activity relationship studies to provide an overview of the work done on quinoline derivatives to the medicinal chemist for future research.
« Previous Next »
Graphical Abstract

[1]
Weyesa, A.; Mulugeta, E. Recent advances in the synthesis of biologically and pharmaceutically active quinoline and its analogues: a review. RSC Advances,  2020, 10(35), 20784-20793.
 [http://dx.doi.org/10.1039/D0RA03763J] [PMID:  35517753]

[2]
Jain, S.; Chandra, V.; Kumar Jain, P.; Pathak, K.; Pathak, D.; Vaidya, A. Comprehensive review on current developments of quinoline-based anticancer agents. Arab. J. Chem.,  2019, 12(8), 4920-4946.
 [http://dx.doi.org/10.1016/j.arabjc.2016.10.009]

[3]
Matada, B.S.; Pattanashettar, R.; Yernale, N.G. A comprehensive review on the biological interest of quinoline and its derivatives. Bioorg. Med. Chem.,  2021, 32, 115973.
 [http://dx.doi.org/10.1016/j.bmc.2020.115973] [PMID:  33444846]

[4]
Panda, P.; Chakroborty, S. Navigating the synthesis of quinoline hybrid molecules as promising anticancer agents. ChemistrySelect,  2020, 5(33), 10187-10199.
 [http://dx.doi.org/10.1002/slct.202002790]

[5]
Sultana, R.; Tippanna, R.R. A novel and different approach for the synthesis of quinoline derivatives starting directly from nitroarenes and their evaluation as anti-cancer agents. Int. J. Chem.,  2020, 12(1), 99.
 [http://dx.doi.org/10.5539/ijc.v12n1p99]

[6]
Karnik, K.S.; Sarkate, A.P.; Tiwari, S.V.; Azad, R.; Burra, P.V.L.S.; Wakte, P.S. Computational and Synthetic approach with Biological Evaluation of Substituted Quinoline derivatives as small molecule L858R/T790M/C797S triple mutant EGFR inhibitors targeting resistance in Non-Small Cell Lung Cancer (NSCLC). Bioorg. Chem.,  2021, 107, 104612.
 [http://dx.doi.org/10.1016/j.bioorg.2020.104612] [PMID:  33476869]

[7]
Bharadwaj, S.S.; Poojary, B.; Madan Kumar, S.; Byrappa, K.; Nagananda, G.S.; Chaitanya, A.K.; Zaveri, K.; Yarla, N.S.; Shiralgi, Y.; Kudva, A.K.; Dhananjaya, B.L. Design, synthesis and pharmacological studies of some new quinoline Schiff bases and 2,5-(disubstituted-[1,3,4])-oxadiazoles. New J. Chem.,  2017, 41(16), 8568-8585.
 [http://dx.doi.org/10.1039/C6NJ03913H]

[8]
Atukuri, D. S, V.; R, S.; L, V.; R, P.; M M, R. Identification of quinoline-chalcones and heterocyclic chalcone-appended quinolines as broad-spectrum pharmacological agents. Bioorg. Chem.,  2020, 105(105), 104419.
 [http://dx.doi.org/10.1016/j.bioorg.2020.104419] [PMID:  33142228]

[9]
Ökten, S. Aydın, A.; Koçyiğit, Ü.M.; Çakmak, O.; Erkan, S.; Andac, C.A.; Taslimi, P.; Gülçin, İ. Quinoline-based promising anticancer and antibacterial agents, and some metabolic enzyme inhibitors. Arch. Pharm. (Weinheim),  2020, 353(9), 2000086.
 [http://dx.doi.org/10.1002/ardp.202000086] [PMID:  32537757]

[10]
Solomon, V.R.; Lee, H. Quinoline as a privileged scaffold in cancer drug discovery. Curr. Med. Chem.,  2011, 18(10), 1488-1508.
 [http://dx.doi.org/10.2174/092986711795328382] [PMID:  21428893]

[11]
Narwal, S.; Kumar, S.; Verma, P.K. Synthesis and therapeutic potential of quinoline derivatives. Res. Chem. Intermed.,  2017, 43(5), 2765-2798.
 [http://dx.doi.org/10.1007/s11164-016-2794-2]

[12]
Pradeep, M.A.; Kumar, N.R.; Swaroop, D.K.; Reddy, N.S.; Sirisha, K.; Kumar, C.G.; Babu, N.J.; Ganapathi, T.; Narsaiah, B. Design and synthesis of novel pyrimidine/hexahydroquinazoline-fused pyrazolo[3,4- b]pyridine derivatives, their biological evaluation and docking studies #. ChemistrySelect,  2019, 4(1), 138-144.
 [http://dx.doi.org/10.1002/slct.201803078]

[13]
Vogel, S.; Barbic, M.; Jürgenliemk, G.; Heilmann, J. Synthesis, cytotoxicity, anti-oxidative and anti-inflammatory activity of chalcones and influence of A-ring modifications on the pharmacological effect. Eur. J. Med. Chem.,  2010, 45(6), 2206-2213.
 [http://dx.doi.org/10.1016/j.ejmech.2010.01.060] [PMID:  20153559]

[14]
Martynenko, Y.; Antypenko, O.; Nosulenko, I.; Berest, G.; Kovalenko, S. Directed search of anti-inflammatory agents among (3hquinazoline- 4-ylidene)hydrazides of n-protected amino acids and their heterocyclization products. Antiinflamm. Antiallergy Agents Med. Chem.,  2020, 19(1), 61-73.
 [http://dx.doi.org/10.2174/1871523018666190115092215] [PMID:  30648525]

[15]
López, S.N.; Castelli, M.V.; Zacchino, S.A.; Domínguez, J.N.; Lobo, G.; Charris-Charris, J.; Cortés, J.C.G.; Ribas, J.C.; Devia, C.; Rodríguez, A.M.; Enriz, R.D. in vitro antifungal evaluation and structure-activity relationships of a new series of chalcone derivatives and synthetic analogues, with inhibitory properties against polymers of the fungal cell wall. Bioorg. Med. Chem.,  2001, 9(8), 1999-2013.
 [http://dx.doi.org/10.1016/S0968-0896(01)00116-X] [PMID:  11504637]

[16]
Musiol, R.; Serda, M.; Hensel-Bielowka, S.; Polanski, J. Quinoline-based antifungals. Curr. Med. Chem.,  2010, 17(18), 1960-1973.
 [http://dx.doi.org/10.2174/092986710791163966] [PMID:  20377510]

[17]
Neelarapu, R.; Maignan, J.R.; Lichorowic, C.L.; Monastyrskyi, A.; Mutka, T.S.; LaCrue, A.N.; Blake, L.D.; Casandra, D.; Mashkouri, S.; Burrows, J.N.; Willis, P.A.; Kyle, D.E.; Manetsch, R. Design and synthesis of orally bioavailable piperazine substituted 4(1 h)-quinolones with potent antimalarial activity: structure-activity and structure-property relationship studies. J. Med. Chem.,  2018, 61(4), 1450-1473.
 [http://dx.doi.org/10.1021/acs.jmedchem.7b00738] [PMID:  29215279]

[18]
Nasveld, P.; Kitchener, S. Treatment of acute vivax malaria with tafenoquine. Trans. R. Soc. Trop. Med. Hyg.,  2005, 99(1), 2-5.
 [http://dx.doi.org/10.1016/j.trstmh.2004.01.013] [PMID:  15550254]

[19]
Al-Salem, H.S.A.; Hegazy, G.H.; El-Taher, K.E.H.; El-Messery, S.M.; Al-Obaid, A.M.; El-Subbagh, H.I. Synthesis, anticonvulsant activity and molecular modeling study of some new hydrazinecarbothioamide, benzenesulfonohydrazide, and phenacylacetohydrazide analogues of 4(3H)-quinazolinone. Bioorg. Med. Chem. Lett.,  2015, 25(7), 1490-1499.
 [http://dx.doi.org/10.1016/j.bmcl.2015.02.025] [PMID:  25754489]

[20]
Muruganantham, N.; Sivakumar, R.; Anbalagan, N.; Gunasekaran, V.; Leonard, J.T. Synthesis, anticonvulsant and antihypertensive activities of 8-substituted quinoline derivatives. Biol. Pharm. Bull.,  2004, 27(10), 1683-1687.
 [http://dx.doi.org/10.1248/bpb.27.1683] [PMID:  15467220]

[21]
Kumar, H.; Devaraji, V.; Joshi, R.; Jadhao, M.; Ahirkar, P.; Prasath, R.; Bhavana, P.; Ghosh, S.K. Antihypertensive activity of a quinoline appended chalcone derivative and its site specific binding interaction with a relevant target carrier protein. RSC Advances,  2015, 5(80), 65496-65513.
 [http://dx.doi.org/10.1039/C5RA08778C]

[22]
Rahman, M.U.; Rathore, A.; Siddiqui, A.A.; Parveen, G.; Yar, M.S. Synthesis and characterization of quinazoline derivatives: search for hybrid molecule as diuretic and antihypertensive agents. J. Enzyme Inhib. Med. Chem.,  2014, 29(5), 733-743.
 [http://dx.doi.org/10.3109/14756366.2013.845820] [PMID:  24156743]

[23]
Modh, R.P.; De Clercq, E.; Pannecouque, C.; Chikhalia, K.H. Design, synthesis, antimicrobial activity and anti-HIV activity evaluation of novel hybrid quinazoline-triazine derivatives. J. Enzyme Inhib. Med. Chem.,  2014, 29(1), 100-108.
 [http://dx.doi.org/10.3109/14756366.2012.755622] [PMID:  23327639]

[24]
Sharma, H.; Patil, S.; Sanchez, T.W.; Neamati, N.; Schinazi, R.F.; Buolamwini, J.K. Synthesis, biological evaluation and 3D-QSAR studies of 3-keto salicylic acid chalcones and related amides as novel HIV-1 integrase inhibitors. Bioorg. Med. Chem.,  2011, 19(6), 2030-2045.
 [http://dx.doi.org/10.1016/j.bmc.2011.01.047] [PMID:  21371895]

[25]
Kaur, R.; Kumar, K. Synthetic and medicinal perspective of quinolines as antiviral agents. Eur. J. Med. Chem.,  2021, 215, 113220.
 [http://dx.doi.org/10.1016/j.ejmech.2021.113220] [PMID:  33609889]

[26]
De la Guardia, C.; Stephens, D.; Dang, H.; Quijada, M.; Larionov, O.; Lleonart, R. Antiviral activity of novel quinoline derivatives against dengue virus serotype 2. Molecules,  2018, 23(3), 672.
 [http://dx.doi.org/10.3390/molecules23030672] [PMID:  29547522]

[27]
Li, E.; Lin, Q.; Meng, Y.; Zhang, L.; Song, P.; Li, N.; Xin, J.; Yang, P.; Bao, C.; Zhang, D.; Zhang, Y.; Wang, J.; Zhang, Q.; Liu, H. 2,4-Disubstituted quinazolines targeting breast cancer cells via EGFR-PI3K. Eur. J. Med. Chem.,  2019, 172, 36-47.
 [http://dx.doi.org/10.1016/j.ejmech.2019.03.030] [PMID:  30939352]

[28]
Solyanik, G.I. Quinazoline compounds for antitumor treatment. Exp. Oncol.,  2019, 41(1), 3-6.
 [http://dx.doi.org/10.32471/exp-oncology.2312-8852.vol-41-no-1.12414] [PMID:  30932417]

[29]
Sashidhara, K.V.; Kumar, A.; Kumar, M.; Sarkar, J.; Sinha, S. Synthesis and in vitro evaluation of novel coumarin-chalcone hybrids as potential anticancer agents. Bioorg. Med. Chem. Lett.,  2010, 20(24), 7205-7211.
 [http://dx.doi.org/10.1016/j.bmcl.2010.10.116] [PMID:  21071221]

[30]
Lilienkampf, A.; Mao, J.; Wan, B.; Wang, Y.; Franzblau, S.G.; Kozikowski, A.P. Structure-activity relationships for a series of quinoline-based compounds active against replicating and nonreplicating Mycobacterium tuberculosis. J. Med. Chem.,  2009, 52(7), 2109-2118.
 [http://dx.doi.org/10.1021/jm900003c] [PMID:  19271749]

[31]
Lin, Y.M.; Zhou, Y.; Flavin, M.T.; Zhou, L.M.; Nie, W.; Chen, F.C. Chalcones and flavonoids as anti-tuberculosis agents. Bioorg. Med. Chem.,  2002, 10(8), 2795-2802.
 [http://dx.doi.org/10.1016/S0968-0896(02)00094-9] [PMID:  12057669]

[32]
Mahamoud, A.; Chevalier, J.; Davin-Regli, A.; Barbe, J.; Pagès, J.M. Quinoline derivatives as promising inhibitors of antibiotic efflux pump in multidrug resistant Enterobacter aerogenes isolates. Curr. Drug Targets,  2006, 7(7), 843-847.
 [http://dx.doi.org/10.2174/138945006777709557] [PMID:  16842215]

[33]
Viana, G.S.B.; Bandeira, M.A.M.; Matos, F.J.A. Analgesic and antiinflammatory effects of chalcones isolated from Myracrodruon urundeuva Allemão. Phytomedicine,  2003, 10(2-3), 189-195.
 [http://dx.doi.org/10.1078/094471103321659924] [PMID:  12725575]

[34]
Saini, S.; Dhiman, N.; Mittal, A.; Kumar, G. Synthesis and antioxidant activity of the 2-methyl benzimidazole. J. Drug Deliv. Ther.,  2016, 6(3), 100-102.
 [http://dx.doi.org/10.22270/jddt.v6i3.1234]

[35]
Gurvinder, S.; Maninderjit, K.; Mohan, C. Benzimidazoles: The latest information on biological activities. Int. Res. J. Pharm.,  2013, 4(1), 82-87.

[36]
Walia, R.; Naaz, S.F.; Iqbal, K.; Lamba, H.S. Benzimidazole derivatives-An overview. Int. J. Res. Pharm. Chem.,  2011, 1(3), 565-574.

[37]
Tiglani, D. Salahuddin; Mazumder, A.; Yar, M.S.; Kumar, R.; Ahsan, M.J. Benzimidazole-quinoline hybrid scaffold as promising pharmacological agents: A review. Polycycl. Aromat. Compd.,  2021, 0(0), 1-23.
 [http://dx.doi.org/10.1080/10406638.2021.1942933]

[38]
Madawali, I.M.E.N. G.; Kalyane, Navanath. V.; Shivakumar, B. A review on substituted benzimidazoles: Biologically active compounds. Am. J. PharmTech Res.,  2019, 9(3), 256-274.
 [http://dx.doi.org/10.46624/ajptr.2019.v9.i3.021]

[39]
Faheem, M.; Rathaur, A.; Pandey, A.; Kumar Singh, V.; Tiwari, A.K. A review on the modern synthetic approach of benzimidazole candidate. ChemistrySelect,  2020, 5(13), 3981-3994.
 [http://dx.doi.org/10.1002/slct.201904832]

[40]
Tarı, Ö.; Gümüş, F.; Açık, L.; Aydın, B. Synthesis, characterization and DNA binding studies of platinum(II) complexes with benzimidazole derivative ligands. Bioorg. Chem.,  2017, 74, 272-283.
 [http://dx.doi.org/10.1016/j.bioorg.2017.08.015] [PMID:  28881255]

[41]
Goud, N.S.; Kumar, P.; Bharath, R.D. Recent developments of target-based benzimidazole derivatives as potential anticancer agents. Heterocycles - Synthesis Biological Activities; Intech Open, 2020, pp. 1-18.
 [http://dx.doi.org/10.5772/intechopen.90758]

[42]
Çevik, U.A. Synthesis and evaluation of new benzimidazole derivatives with hydrazone moiety as anticancer agents. Turk. J. Biochem.,  2018, 1-7.

[43]
Darwish, S.A.Z.; Elbayaa, R.Y.; Ashour, H.M.A.; Khalil, M.A.; Badawey, E.A.M. Potential anticancer agents: Design, synthesis of new pyrido[1,2-a]benzimidazoles and related derivatives linked to alkylating fragments. Med. Chem. (Los Angeles),  2018, 8(4), 86-95.
 [http://dx.doi.org/10.4172/2161-0444.1000498]

[44]
Zhang, Y.; Xu, J.; Li, Y.; Yao, H.; Wu, X. Design, synthesis and pharmacological evaluation of novel NO-releasing benzimidazole hybrids as potential antihypertensive candidate. Chem. Biol. Drug Des.,  2015, 85(5), 541-548.
 [http://dx.doi.org/10.1111/cbdd.12442] [PMID:  25283264]

[45]
Sharma, M.C.; Sharma, S.; Sahu, N.K.; Kohli, D.V. 3D QSAR kNN-MFA studies on 6-substituted benzimidazoles derivatives as nonpeptide angiotensin II receptor antagonists: A rational approach to antihypertensive agents. J. Saudi Chem. Soc.,  2013, 17(2), 167-176.
 [http://dx.doi.org/10.1016/j.jscs.2011.03.005]

[46]
Florio, R.; Veschi, S.; di Giacomo, V.; Pagotto, S.; Carradori, S.; Verginelli, F.; Cirilli, R.; Casulli, A.; Grassadonia, A.; Tinari, N.; Cataldi, A.; Amoroso, R.; Cama, A.; De Lellis, L. The benzimidazole-based anthelmintic parbendazole: A repurposed drug candidate that synergizes with gemcitabine in pancreatic cancer. Cancers (Basel),  2019, 11(12), 2042.
 [http://dx.doi.org/10.3390/cancers11122042] [PMID:  31861153]

[47]
Sreena, K.; Ratheesh, R.; Rachana, M.; Poornima, M.S.C. Synthesis and anthelmintic activity of benzimidazole derivatives. Hygeia,  2009, 1(1), 21-22.

[48]
Gaba, M.; Gaba, P.; Uppal, D.; Dhingra, N.; Bahia, M.S.; Silakari, O.; Mohan, C. Benzimidazole derivatives: search for GI-friendly anti-inflammatory analgesic agents. Acta Pharm. Sin. B,  2015, 5(4), 337-342.
 [http://dx.doi.org/10.1016/j.apsb.2015.05.003] [PMID:  26579464]

[49]
Gaba, M.; Singh, S.; Mohan, C. Benzimidazole: An emerging scaffold for analgesic and anti-inflammatory agents. Eur. J. Med. Chem.,  2014, 76, 494-505.
 [http://dx.doi.org/10.1016/j.ejmech.2014.01.030] [PMID:  24602792]

[50]
Achar, K.C.S.; Hosamani, K.M.; Seetharamareddy, H.R. In vivo analgesic and anti-inflammatory activities of newly synthesized benzimidazole derivatives. Eur. J. Med. Chem.,  2010, 45(5), 2048-2054.
 [http://dx.doi.org/10.1016/j.ejmech.2010.01.029] [PMID:  20133024]

[51]
Pérez-Villanueva, J.; Santos, R.; Hernández-Campos, A.; Giulianotti, M.A.; Castillo, R.; Medina-Franco, J.L. Towards a systematic characterization of the antiprotozoal activity landscape of benzimidazole derivatives. Bioorg. Med. Chem.,  2010, 18(21), 7380-7391.
 [http://dx.doi.org/10.1016/j.bmc.2010.09.019] [PMID:  20888242]

[52]
Torres-Gómez, H.; Hernández-Núñez, E.; León-Rivera, I.; Guerrero-Alvarez, J.; Cedillo-Rivera, R.; Moo-Puc, R.; Argotte-Ramos, R.; Carmen Rodríguez-Gutiérrez, M.; Chan-Bacab, M.J.; Navarrete-Vázquez, G. Design, synthesis and in vitro antiprotozoal activity of benzimidazole-pentamidine hybrids. Bioorg. Med. Chem. Lett.,  2008, 18(11), 3147-3151.
 [http://dx.doi.org/10.1016/j.bmcl.2008.05.009] [PMID:  18486471]

[53]
Patel, V.M.; Patel, N.B.; Chan-Bacab, M.J.; Rivera, G. N -Mannich bases of benzimidazole as a potent antitubercular and antiprotozoal agents: Their synthesis and computational studies. Synth. Commun.,  2020, 50(6), 858-878.
 [http://dx.doi.org/10.1080/00397911.2020.1725057]

[54]
Shaikh, I.N.; Hosamani, K.M.; Kurjogi, M.M. Design, synthesis, and evaluation of new α-aminonitrile-based benzimidazole biomolecules as potent antimicrobial and antitubercular agents. Arch. Pharm. (Weinheim),  2018, 351(2), 1700205.
 [http://dx.doi.org/10.1002/ardp.201700205] [PMID:  29356105]

[55]
Kanwal, A.; Ahmad, M.; Aslam, S.; Naqvi, S.A.R.; Saif, M.J. Recent advances in antiviral benzimidazole derivatives: A mini review. Pharm. Chem. J.,  2019, 53(3), 179-187.
 [http://dx.doi.org/10.1007/s11094-019-01976-3]

[56]
Tonelli, M.; Novelli, F.; Tasso, B.; Vazzana, I.; Sparatore, A.; Boido, V.; Sparatore, F.; La Colla, P.; Sanna, G.; Giliberti, G.; Busonera, B.; Farci, P.; Ibba, C.; Loddo, R. Antiviral activity of benzimidazole derivatives. III. Novel anti-CVB-5, anti-RSV and anti-Sb-1 agents. Bioorg. Med. Chem.,  2014, 22(17), 4893-4909.
 [http://dx.doi.org/10.1016/j.bmc.2014.06.043] [PMID:  25082514]

[57]
Padhy, G.K.; Panda, J.; Raul, S.K.; Behera, A.K. Synthesis of some new benzimidazole acid hydrazide derivatives as antibacterial agents. Indian J. Heterocycl. Chem.,  2018, 28(4), 447-451.

[58]
Gullapelli, K.; Brahmeshwari, G.; Ravichander, M.; Kusuma, U. Synthesis, antibacterial and molecular docking studies of new benzimidazole derivatives. Egypt. J. Basic Appl. Sci.,  2017, 4(4), 303-309.
 [http://dx.doi.org/10.1016/j.ejbas.2017.09.002]

[59]
Sahoo, B.M.; Banik, B.K. Mazaharunnisa; Rao, N.S.; Raju, B. Microwave assisted green synthesis of benzimidazole derivatives and evaluation of their anticonvulsant activity. Curr. Microw. Chem.,  2019, 6(1), 23-29.
 [http://dx.doi.org/10.2174/2213335606666190429124745]

[60]
Siddiqui, N.; Alam, M.S.; Ali, R.; Yar, M.S.; Alam, O. Synthesis of new benzimidazole and phenylhydrazinecarbothiomide hybrids and their anticonvulsant activity. Med. Chem. Res.,  2016, 25(7), 1390-1402.
 [http://dx.doi.org/10.1007/s00044-016-1570-6]

[61]
Tahlan, S.; Kumar, S.; Kakkar, S.; Narasimhan, B. Benzimidazole scaffolds as promising antiproliferative agents: A review. BMC Chem.,  2019, 13(1), 66.
 [http://dx.doi.org/10.1186/s13065-019-0579-6] [PMID:  31384813]

[62]
da Silva, R.B.; Lange Coelho, F.; Rodembusch, F.S.; Schwab, R.S.; Schneider, J.M.F.M.; da Silveira Rampon, D.; Schneider, P.H. Straightforward synthesis of photoactive chalcogen functionalized benzimidazo[1,2- a]quinolines. New J. Chem.,  2019, 43(29), 11596-11603.
 [http://dx.doi.org/10.1039/C9NJ01948K]

[63]
Perin, N.; Škulj, S.; Martin-Kleiner, I.; Kralj, M.; Hranjec, M. Synthesis and antiproliferative activity of novel 2-substituted n -methylated benzimidazoles and tetracyclic benzimidazo [1,2- a]quinolines. Polycycl. Aromat. Compd.,  2020, 40(2), 343-354.
 [http://dx.doi.org/10.1080/10406638.2018.1441877]

[64]
Mantu, D.; Antoci, V.; Moldoveanu, C.; Zbancioc, G.; Mangalagiu, I.I. Hybrid imidazole (benzimidazole)/pyridine (quinoline) derivatives and evaluation of their anticancer and antimycobacterial activity. J. Enzyme Inhib. Med. Chem.,  2016, 31(sup2), 96-103.
 [http://dx.doi.org/10.1080/14756366.2016.1190711] [PMID: 27250919]

[65]
Yadav, S.; Narasimhan, B. kaur, H. Perspectives of benzimidazole derivatives as anticancer agents in the new era. Anticancer. Agents Med. Chem.,  2016, 16(11), 1403-1425.
 [http://dx.doi.org/10.2174/1871520616666151103113412] [PMID:  26526461]

[66]
Perin, N.; Martin-Kleiner, I.; Nhili, R.; Laine, W.; David-Cordonnier, M.H.; Vugrek, O.; Karminski-Zamola, G.; Kralj, M.; Hranjec, M. Biological activity and DNA binding studies of 2-substituted benzimidazo[1,2-a]quinolines bearing different amino side chains. MedChemComm,  2013, 4(12), 1537-1550.
 [http://dx.doi.org/10.1039/c3md00193h]

[67]
Kuang, W.B.; Huang, R.Z.; Qin, J.L.; Lu, X.; Qin, Q.P.; Zou, B.Q.; Chen, Z.F.; Liang, H.; Zhang, Y. Design, synthesis and pharmacological evaluation of new 3-(1H-benzimidazol-2-yl)quinolin-2(1H)-one derivatives as potential antitumor agents. Eur. J. Med. Chem.,  2018, 157, 139-150.
 [http://dx.doi.org/10.1016/j.ejmech.2018.07.066] [PMID:  30092368]

[68]
Perin, N.; Uzelac, L.; Piantanida, I.; Karminski-Zamola, G.; Kralj, M.; Hranjec, M. Novel biologically active nitro and amino substituted benzimidazo[1,2-a]quinolines. Bioorg. Med. Chem.,  2011, 19(21), 6329-6339.
 [http://dx.doi.org/10.1016/j.bmc.2011.09.002] [PMID:  21964184]

[69]
Zhi, S.; Li, Y.; Qiang, J.; Hu, J.; Song, W.; Zhao, J. Synthesis and anticancer evaluation of benzo-N-heterocycles transition metal complexes against esophageal cancer cell lines. J. Inorg. Biochem.,  2019, 201(September), 110816.
 [http://dx.doi.org/10.1016/j.jinorgbio.2019.110816] [PMID:  31518868]

[70]
Li, S.; Zhao, J.; Yuan, B.; Wang, X.; Zhang, J.; Yue, L.; Hou, H.; Hu, J.; Chen, S. Crystal structure, DNA interaction and in vitro anticancer activity of Cu(II) and Pt(II) compounds based on benzimidazole-quinoline derivative. Polyhedron,  2020, 179, 114369.
 [http://dx.doi.org/10.1016/j.poly.2020.114369]

[71]
Hamaguchi, W.; Masuda, N.; Isomura, M.; Miyamoto, S.; Kikuchi, S.; Amano, Y.; Honbou, K.; Mihara, T.; Watanabe, T. Design and synthesis of novel benzimidazole derivatives as phosphodiesterase 10A inhibitors with reduced CYP1A2 inhibition. Bioorg. Med. Chem.,  2013, 21(24), 7612-7623.
 [http://dx.doi.org/10.1016/j.bmc.2013.10.035] [PMID:  24238902]

[72]
Perin, N. Alić J.; Liekens, S.; Van Aerschot, A.; Vervaeke, P.; Gadakh, B.; Hranjec, M. Different positions of amide side chains on the benzimidazo[1,2- a]quinoline skeleton strongly influence biological activity. New J. Chem.,  2018, 42(9), 7096-7104.
 [http://dx.doi.org/10.1039/C8NJ00416A]

[73]
Zhang, Q.W.; Ye, Z.D.; Shen, C.; Tie, H.X.; Wang, L.; Shi, L. Synthesis of novel 6,7-dimethoxy-4-anilinoquinolines as potent c-Met inhibitors. J. Enzyme Inhib. Med. Chem.,  2019, 34(1), 124-133.
 [http://dx.doi.org/10.1080/14756366.2018.1533822] [PMID:  30422010]

[74]
Pragathi, Y.J.; Veronica, D.; Anitha, K.; Rao, M.V.B.; Raju, R.R. Synthesis and biological evaluation of chalcone derivatives of 1,2,4-thiadiazol-benzo[d]imidazol-2-yl)quinolin-2(1H)-one as anticancer agents. Chem. Data Collect.,  2020, 30, 100556.
 [http://dx.doi.org/10.1016/j.cdc.2020.100556]

[75]
Gaikwad, N.B.; Bansode, S.; Biradar, S.; Ban, M.; Srinivas, N.; Godugu, C.; Yaddanapudi, V.M. New 3-(1 H -benzo[ d]imidazol-2-yl)quinolin-2(1 H)-one-based triazole derivatives: Design, synthesis, and biological evaluation as antiproliferative and apoptosis-inducing agents. Arch. Pharm. (Weinheim),  2021, 354(11), 2100074.
 [http://dx.doi.org/10.1002/ardp.202100074] [PMID:  34346099]

[76]
Baig, M.F.; Shaik, S.P.; Nayak, V.L.; Alarifi, A.; Kamal, A. Iodine-catalyzed Csp3-H functionalization of methylhetarenes: One-pot synthesis and cytotoxic evaluation of heteroarenyl-benzimidazoles and benzothiazole. Bioorg. Med. Chem. Lett.,  2017, 27(17), 4039-4043.
 [http://dx.doi.org/10.1016/j.bmcl.2017.07.051] [PMID:  28789894]

[77]
Meščić, Macan, A.; Perin, N.; Jakopec, S.; Mioč, M.; Stojković, M.R.; Kralj, M.; Hranjec, M.; Raić-Malić, S. Synthesis, antiproliferative activity and DNA/RNA-binding properties of mono- and bis-(1,2,3-triazolyl)-appended benzimidazo[1,2-a]quinoline derivatives. Eur. J. Med. Chem.,  2020, 185, 111845.
 [http://dx.doi.org/10.1016/j.ejmech.2019.111845] [PMID:  31718941]

[78]
Shi, L.; Wu, T.T.; Wang, Z.; Xue, J.Y.; Xu, Y.G. Discovery of N-(2-phenyl-1H-benzo[d]imidazol-5-yl)quinolin-4-amine derivatives as novel VEGFR-2 kinase inhibitors. Eur. J. Med. Chem.,  2014, 84, 698-707.
 [http://dx.doi.org/10.1016/j.ejmech.2014.07.071] [PMID:  25064347]

[79]
Almansour, A.I.; Arumugam, N.; Suresh Kumar, R.; Mahalingam, S.M.; Sau, S.; Bianchini, G.; Menéndez, J.C.; Altaf, M. Ghabbour, H.A. Design, synthesis and antiproliferative activity of decarbonyl luotonin analogues. Eur. J. Med. Chem.,  2017, 138, 932-941.
 [http://dx.doi.org/10.1016/j.ejmech.2017.07.027] [PMID:  28753517]

[80]
Hranjec, M. Pavlović, G.; Marjanović, M.; Kralj, M.; Karminski-Zamola, G. Benzimidazole derivatives related to 2,3-acrylonitriles, benzimidazo[1,2-a]quinolines and fluorenes: Synthesis, antitumor evaluation in vitro and crystal structure determination. Eur. J. Med. Chem.,  2010, 45(6), 2405-2417.
 [http://dx.doi.org/10.1016/j.ejmech.2010.02.022] [PMID:  20207049]

[81]
Hranjec, M.; Kralj, M.; Piantanida, I. Sedić, M.; Šuman, L.; Pavelić, K.; Karminski-Zamola, G. Novel cyano- and amidino-substituted derivatives of styryl-2-benzimidazoles and benzimidazo[1,2-a]quinolines. Synthesis, photochemical synthesis, DNA binding, and antitumor evaluation, part 3. J. Med. Chem.,  2007, 50(23), 5696-5711.
 [http://dx.doi.org/10.1021/jm070876h] [PMID:  17935309]

[82]
Ni, Z.J.; Barsanti, P.; Brammeier, N.; Diebes, A.; Poon, D.J.; Ng, S.; Pecchi, S.; Pfister, K.; Renhowe, P.A.; Ramurthy, S.; Wagman, A.S.; Bussiere, D.E.; Le, V.; Zhou, Y.; Jansen, J.M.; Ma, S.; Gesner, T.G. 4-(Aminoalkylamino)-3-benzimidazole-quinolinones as potent CHK-1 inhibitors. Bioorg. Med. Chem. Lett.,  2006, 16(12), 3121-3124.
 [http://dx.doi.org/10.1016/j.bmcl.2006.03.059] [PMID:  16603354]

[83]
Effendi, N.; Mishiro, K.; Takarada, T.; Yamada, D.; Nishii, R.; Shiba, K.; Kinuya, S.; Odani, A.; Ogawa, K. Design, synthesis, and biological evaluation of radioiodinated benzo[d]imidazole-quinoline derivatives for platelet-derived growth factor receptor β (PDGFRβ) imaging. Bioorg. Med. Chem.,  2019, 27(2), 383-393.
 [http://dx.doi.org/10.1016/j.bmc.2018.12.016] [PMID:  30563725]

[84]
Manjuraj, T.; Krishnamurthy, G.; Bodke, Y.D.; Bhojya Naik, H.S. Metal complexes of quinolin-8-yl [(5-methoxy-1H-benzimidazol-2-yl)sulfanyl]acetate: Spectral, XRD, thermal, cytotoxic, molecular docking and biological evaluation. J. Mol. Struct.,  2017, 1148, 231-237.
 [http://dx.doi.org/10.1016/j.molstruc.2017.07.020]

[85]
Garudachari, B.; Satyanarayana, M.N.; Thippeswamy, B.; Shivakumar, C.K.; Shivananda, K.N.; Hegde, G.; Isloor, A.M. Synthesis, characterization and antimicrobial studies of some new quinoline incorporated benzimidazole derivatives. Eur. J. Med. Chem.,  2012, 54, 900-906.
 [http://dx.doi.org/10.1016/j.ejmech.2012.05.027] [PMID:  22732060]

[86]
Uttarwar, R.B.; Nawale, R.B.; Shamkuwar, P.B. Synthesis and pharmacological screening of derivatives of benzimidazole linked with quinoline and tetrazole. J. Chem. Pharm. Res.,  2013, 5(4), 41-46.

[87]
Zhang, L.; Addla, D.; Ponmani, J.; Wang, A.; Xie, D.; Wang, Y.N.; Zhang, S.L.; Geng, R.X.; Cai, G.X.; Li, S.; Zhou, C.H. Discovery of membrane active benzimidazole quinolones-based topoisomerase inhibitors as potential DNA-binding antimicrobial agents. Eur. J. Med. Chem.,  2016, 111, 160-182.
 [http://dx.doi.org/10.1016/j.ejmech.2016.01.052] [PMID:  26871658]

[88]
Shivakumar, B.; Madawali, I.M.; Hugar, S.; Kalyane, N.V. Synthesis and evaluation of 2-chloro-3-[3-(6-methyl-1h-benzimidazol-2-yl)-4, 5-dihydro-1h-pyrazol-5-yl] quinolines as potent antimicrobial agents. Am. J. Pharm. Health Res.,  2018, 6(12), 33-43.
 [http://dx.doi.org/10.46624/ajphr.2018.v6.i12.004]

[89]
Sangani, C.B.; Jardosh, H.H.; Patel, M.P.; Patel, R.G. Microwave-assisted synthesis of pyrido[1,2-a]benzimidazole derivatives of β-aryloxyquinoline and their antimicrobial and antituberculosis activities. Med. Chem. Res.,  2013, 22(6), 3035-3047.
 [http://dx.doi.org/10.1007/s00044-012-0322-5]

[90]
Gowda, J.; Khader, A.M.A.; Kalluraya, B.; Hidayathulla, S. Synthesis, characterization and antibacterial activity of benzimidazole derivatives carrying quinoline moiety. Indian J. Chem. - Sect. B Org. Med. Chem.,  2011, 50(10), 1491-1495.

[91]
El-Gohary, N.S.; Shaaban, M.I. Synthesis, antimicrobial, antiquorum-sensing and antitumor activities of new benzimidazole analogs. Eur. J. Med. Chem.,  2017, 137, 439-449.
 [http://dx.doi.org/10.1016/j.ejmech.2017.05.064] [PMID:  28623814]

[92]
El Faydy, M.; Dahaieh, N.; Ounine, K.; Lakhrissi, B.; Warad, I.; Tüzün, B.; Zarrouk, A. Synthesis, identification, antibacterial activity, ADME/T and 1BNA-docking investigations of 8-quinolinol analogs bearing a benzimidazole moiety. Arab. J. Sci. Eng., 2021.
 [http://dx.doi.org/10.1007/s13369-021-05749-7]

[93]
Wang, Y.N.; Bheemanaboina, R.R.Y.; Gao, W.W.; Kang, J.; Cai, G.X.; Zhou, C.H. Discovery of benzimidazole-quinolone hybrids as new cleaving agents toward drug-resistant Pseudomonas aeruginosa DNA. ChemMedChem,  2018, 13(10), 1004-1017.
 [http://dx.doi.org/10.1002/cmdc.201700739] [PMID:  29512892]

[94]
Rajakumar, P.; Raja, R.; Selvam, S.; Rengasamy, R.; Nagaraj, S. Synthesis and antibacterial activity of some novel imidazole-based dicationic quinolinophanes. Bioorg. Med. Chem. Lett.,  2009, 19(13), 3466-3470.
 [http://dx.doi.org/10.1016/j.bmcl.2009.05.019] [PMID:  19477639]

[95]
Mungra, D.C.; Patel, M.P.; Patel, R.G. Microwave-assisted synthesis of some new tetrazolo[1,5-a]quinoline-based benzimidazoles catalyzed by p-TsOH and investigation of their antimicrobial activity. Med. Chem. Res.,  2011, 20(6), 782-789.
 [http://dx.doi.org/10.1007/s00044-010-9388-0]

[96]
Villa, P.; Arumugam, N.; Almansour, A.I.; Suresh Kumar, R.; Mahalingam, S.M.; Maruoka, K.; Thangamani, S. Benzimidazole tethered pyrrolo[3,4-b]quinoline with broad-spectrum activity against fungal pathogens. Bioorg. Med. Chem. Lett.,  2019, 29(5), 729-733.
 [http://dx.doi.org/10.1016/j.bmcl.2019.01.006] [PMID:  30655213]

[97]
Ukrainets, I.V.; Bezuglyi, P.A.; Gorokhova, O.V.; Treskach, V.I.A.V.T. 4-Hydroxy-2-quinolones, synthesis and biological properties of 1-r-3-(2- benzimidazolyl)-4-hydroxy-2-quinolones. Plenum Publ. Corp.,  1993, 1, 105-108.

[98]
Ukrainets, I.V.; Taran, S.G.; Gorokhova, O.V.; Marusenko, N.A.; Turov, A.V. 4-Hydroxy-2-quinolones. 32. Synthesis and antithyroid activity of thio analogs of 1H-2-oxo-3-(2-Benzimidazolyl)-4-hydroxyquinoline. Chem. Heterocycl. Compd.,  1997, 33(5), 600-604.
 [http://dx.doi.org/10.1007/BF02291946]

[99]
Ukrainets, I.V.; Grinevich, L.A.; Tkach, A.A.; Gorokhova, O.V.; Kravchenko, V.N.; Sim, G. 4-hydroxy-2-quinolones. 191.* synthesis, tautomerism and biological activity of benzimidazol-2-ylamides of 1-r-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids. Chem. Heterocycl. Compd.,  2011, 46(11), 1364-1370.
 [http://dx.doi.org/10.1007/s10593-011-0673-8]

[100]
Li, Q.; Xing, S.; Chen, Y.; Liao, Q.; Xiong, B.; He, S.; Lu, W.; Liu, Y.; Yang, H.; Li, Q.; Feng, F.; Liu, W.; Chen, Y.; Sun, H. Discovery and biological evaluation of a novel highly potent selective butyrylcholinsterase inhibitor. J. Med. Chem.,  2020, 63(17), 10030-10044.
 [http://dx.doi.org/10.1021/acs.jmedchem.0c01129] [PMID:  32787113]

[101]
Baartzes, N.; Jordaan, A.; Warner, D.F.; Combrinck, J.; Taylor, D.; Chibale, K.; Smith, G.S. Antimicrobial evaluation of neutral and cationic iridium(III) and rhodium(III) aminoquinoline-benzimidazole hybrid complexes. Eur. J. Med. Chem.,  2020, 206, 112694.
 [http://dx.doi.org/10.1016/j.ejmech.2020.112694] [PMID:  32861176]

[102]
Baartzes, N.; Stringer, T.; Seldon, R.; Warner, D.F.; Taylor, D.; Wittlin, S.; Chibale, K.; Smith, G.S. Bioisosteric ferrocenyl aminoquinoline-benzimidazole hybrids: Antimicrobial evaluation and mechanistic insights. Eur. J. Med. Chem.,  2019, 180, 121-133.
 [http://dx.doi.org/10.1016/j.ejmech.2019.06.069] [PMID:  31301563]

[103]
Kumar, R.; Abdullah, M.M. Synthesis, characterization and anticonvulsant potential of 2,5-disubstituted 1,3,4-oxadiazole analogues. Asian J. Chem.,  2019, 31(6), 1389-1397.
 [http://dx.doi.org/10.14233/ajchem.2019.22061]

[104]
Bharadwaj, S.S.; Poojary, B.; Nandish, S.K.M.; Kengaiah, J.; Kirana, M.P.; Shankar, M.K.; Das, A.J.; Kulal, A.; Sannaningaiah, D. Efficient synthesis and in silico studies of the benzimidazole hybrid scaffold with the quinolinyloxadiazole skeleton with potential α-glucosidase inhibitory, anticoagulant, and antiplatelet activities for type-ii diabetes mellitus management and treating thrombotic disorders. ACS Omega,  2018, 3(10), 12562-12574.
 [http://dx.doi.org/10.1021/acsomega.8b01476] [PMID:  30411010]

[105]
El-Feky, S.A.; Thabet, H.K.; Ubeid, M.T. Synthesis, molecular modeling and anti-inflammatory screening of novel fluorinated quinoline incorporated benzimidazole derivatives using the Pfitzinger reaction. J. Fluor. Chem.,  2014, 161, 87-94.
 [http://dx.doi.org/10.1016/j.jfluchem.2014.02.012]

[106]
CN101553470AGuillemont, J.E.G.; Dorange, I.; Marcel, K.J.L.; Koul, A.  Antibacterial Quinoline Derivatives 2009.

[107]
No inventor listed. Quinoline derivatives for use in the treatment of inflammatory disease. European Patent 2974729, 2016.

[108]
Guillemont, J.E.G.; Motte, M.M.S.; Lancois, D.F.A.; Balemans, W.M.A. Antibacterail quinoline derivatives. U.S. Patent 9133167, 2015.

[109]
Andries, K.J.L.M.; Koul, A.; Guillemont, J.E.G.; Motte, M.M.S. Quinoline derivatives as antibacterial agents. U.S. Patent 0030017, 2013.

[110]
Gibson, K.H. Quinoline derivatives as inhibitors of MEK Enzymes. U.S. Patent 6809106, 2004.

[111]
Guile, S.D.; Ebden, M. Quinoline derivatives for the treament of inflammatory disease. International Patent 114002, 2008.

[112]
Arthur, S.G.M.; Hertel, C.; Nettekoven, M.H.; Richter, H.; Roche, O.; Sarimiento, R.M.R.; Schuler, F. Quinoline derivatives as H3R inverse agonists. U.S. Patent 7534891, 2009.

[113]
Andrew, P.C.; Craig, M.C.; Dong, H. Compounds and methods for the targeted degradation of rapidly accelerated fibrosarcoma polypeptides. Australian Patent 382436, 2021.

[114]
Liu, X.; Han, Y.; Yang, L. Benzimidazole Compound and Prepafration Method thereof. U.S. Patent 10787420, 2020.

[115]
Bourque, E.M.J.; Renato, S. Cxcr4 Inhibitors and Uses thereof. 
          	U. S. Patent 0322671, 2019.

[116]
Bartberger, M.D.; Nagasree, C.; Gao, H. Benzimidazole derivatives and their uses. Canadian Patent 3079081, 2019.

[117]
Adak, V.S.; Awate, P.B.; Bhagat, V.C. Synthesis of benzimidazole derivatives against M. tb. Australian Patent 104192, 2018.

[118]
Czardybon, W.; Michal, K.B. Novel benzimidazole derivatives as kinase inhibitors. U.S. Patent 033696, 2015.

[119]
Chappie, T.A.; Verhoest, P.R. Azabenzimidazole Compounds. U.S. Patent 032206, 2015.

[120]
Poss, M.A. Indole and benzimidazole-substituted quinoline derivatives. U.S. Patent 5616591, 1997.

[121]
Dieter, D.; Theodor, P. Yellow to blue dyestuffs of the benzobenzimidazo( 1,2-a)-quinoline series, process for their manufacture, and their use. U.S. Patent 4077961, 1978.
Rights & Permissions Print Cite
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/1570180820666230207160338	Print ISSN 1570-1808
Publisher Name Bentham Science Publisher	Online ISSN 1875-628X
Letters in Drug Design & Discovery

Synthesis, Structure-activity Relationship, and Biological Activity of Benzimidazole-quinoline: A Review to Aid in the Design of a New Drug

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Abstract
