Abstract
Benzimidazole (BI) and derivatives are interesting because several of these compounds have been found to have a diversity of biological activities with clinical applications. In view of their importance, the synthesis of BI and its derivatives is still considered as a challenge for synthetic chemists. Examples of compounds used in medicinal chemistry containing BI, as important nucleus, are Astemizole (antihistaminic), Omeprazole (antiulcerative) and Rabendazole (fungicide), some of these compounds have the 2- aminobenzimidazole (2ABI) as base nucleus. The structure of 2ABI derivatives contains a cyclic guanidine moiety, which is interesting because of its free lone pairs, labile hydrogen atoms and planar delocalized structure. The delocalized 10-π electron system and the extension of the electron conjugation with the exocyclic amino group, in 2ABI, making these heterocycles to have amphoteric character. The 2ABI has been used as building blocks for the synthesis of several BI derivatives as medicinally important molecules. On these bases, herein, we present a bibliographic review concerning the recent methodologies used in the synthesis of 2ABIs, including the substituted ones.
Keywords: 2-aminobenzimidazoles, 2-mercaptobenzimidazoles, 2-chlorobenzimidazoles, phenylcarbodiimides, o-phenylendiamines, phenylguanidines.
Graphical Abstract
(b) Srestha, N.; Banerjee, J.; Srivastava, S. A review on chemistry and biological significance of benzimidazole nucleus. IOSR J. Pharm., 2014, 4, 28-41.
(c) Yerragunta, V.; Patil, P.; Srujana, S.; Devi, R.; Srujana, G.R.; Divya, A. Benzimidazole derivatives and its biological importance: A review. PharmaTutor, 2014, 2, 109-113.
(d) Hamiduzzaman, M.; Mannan, S.J.; Dey, A.; and Rahman, A.S.M. Evaluation of analgesic, antipyretic, hypoglycemic and CNS depressant activity of 2-bromopopylamine hydrobromide, 3-bromopopyl ammonium bromide, ortho-amino aniline and benzimidazole-2-thiol in animal model. Der Pharm. Lett., 2014, 6, 47-53.
(e) Arulmurugan, S.; Kavitha, H.P.; Sathishkumar, S.; Arulmozhi, R. Biologically active benzimidazole derivatives. Mini Rev. Org. Chem., 2015, 12, 178-195.
[http://dx.doi.org/10.2174/1570193X1202150225153403]
(f) Naga, P.K.; Kumar, K.R. Green synthesis of benzimidazole derivatives: An overview of bulk drug synthesis. Int. J. Pharm. Tech. Res., 2015, 8, 60-68.
(g) Wang, Y-T.; Qin, Y-J.; Yang, N.; Zhang, Y-L.; Liu, C.H.; Zhu, H.L. Synthesis, biological evaluation, and molecular docking studies of novel 1-benzene acyl-2-(1-methylindol-3-yl)-benzimidazole derivatives as potential tubulin polymerization inhibitors. Eur. J. Med. Chem., 2015, 99, 125-137.
[http://dx.doi.org/10.1016/j.ejmech.2015.05.021] [PMID: 26070164]
(h) Fatmah, A. S. Evaluation of selected benzimidazole derivatives as potential antimicrobial agents. Molecules,, 2015, 20, 15206-15223.
(i) Maiti, B.; Chanda, K. Diversity oriented synthesis of benzimidazolebased biheterocyclic molecules by combinatorial approach: A critical review. RSC Adv, 2016, 6, 50384-50413.
[http://dx.doi.org/10.1039/C6RA06930D]
(j) Gaba, M.; Mohan, C.H. Development of drugs based on imidazole and benzimidazole bioactive heterocycles: Recent advances and future directions. Med. Chem. Res., 2016, 25, 173-210.
[http://dx.doi.org/10.1007/s00044-015-1495-5]
(k) Keri, R.S.; Rajappa, C.K.; Patil, S.A.; Nagaraja, B.M. Benzimidazolecore as an antimycobacterial agent. Pharmacol. Rep., 2016, 68, (6), 1254- 1265.
[http://dx.doi.org/10.1016/j.pharep.2016.08.002] [PMID: 27686965]
(l) Aishwarya, M.N.L.; Rao, E.A.; Babu, M.N. A Review on gastro-intestinal drug esomeprazole. Pharm. Tutor, 2017, 5, 19-26.
(m) Rajasekhar, S.; Maiti, B.; Balamurali, M.M.; Chanda, K. Synthesis and medicinal applications of benzimidazoles: An overview. Curr. Org. Synth, 2017, 14, 40-60.
[http://dx.doi.org/10.2174/1570179413666160818151932]
(n) Alaqueel, Sh.I. Synthetic approaches to benzimidazoles from ophenylenediamine: A literature review. J. Saudi Chem. Soc, 2017, 21, 229- 237.
[http://dx.doi.org/10.1016/j.jscs.2016.08.001]
[http://dx.doi.org/10.1177/030006059702500401] [PMID: 9283989]
(b) Ramalingan, C.; Balasubramanian, S.; Kabilan, S. A convenient synthesis of novel 1-[2-(benzimidazol-2-yl)ethoxy]-2,6-diarylpiperidin-4-ones. Synth. Commun., 2004, 34, 1105-1116.
[http://dx.doi.org/10.1081/SCC-120028643]
(b) Pittman, J.S. Effect of fenbendazole on shedding and embryonation of Ascaris suum eggs in naturally infected gestating sows; 2014.
[http://dx.doi.org/10.1016/j.bmcl.2004.04.005]
[http://dx.doi.org/10.1021/jm00150a028] [PMID: 4068010]
(b) Mor, M.; Bordi, F.; Silva, C.; Rivara, S.; Zuliani, V.; Vacondio, F.; Rivara, M.; Barocelli, E.; Bertoni, S.; Ballabeni, V.; Magnanini, F.; Impicciatore, M.; Plazzi, P.V. Synthesis, biological activity, QSAR and QSPR study of 2-aminobenzimidazole derivatives as potent H3-antagonists. Bioorg. Med. Chem., 2004, 12(4), 663-674.
[http://dx.doi.org/10.1016/j.bmc.2003.11.030] [PMID: 14759727]
[http://dx.doi.org/10.1002/(SICI)1521-4184(199807)331:7/8<249:AID-ARDP249>3.0.CO;2-B] [PMID: 9747181]
[http://dx.doi.org/10.1007/s00044-017-2036-1]
[http://dx.doi.org/10.1021/jm800318d] [PMID: 18690678]
[http://dx.doi.org/10.1016/j.antiviral.2004.04.007] [PMID: 15451177]
(b) Dayam, R.; Deng, J.; Neamati, N. HIV-1 integrase inhibitors: 2003-2004 update. Med. Res. Rev., 2006, 26(3), 271-309.
[http://dx.doi.org/10.1002/med.20054] [PMID: 16496343]
[http://dx.doi.org/10.1016/S0968-0896(02)00616-8] [PMID: 12628659]
(b) Carpenter, R.D.; Andrei, M.; Lau, E.Y.; Lightstone, F.C.; Liu, R.; Lam, K.S.; Kurth, M.J.; Kurth, M.J. Highly potent, water soluble benzimidazole antagonist for activated alpha 4 beta 1 integrin. J. Med. Chem., 2007, 50(23), 5863-5867.
[http://dx.doi.org/10.1021/jm070790o] [PMID: 17948981]
(c) Cindrić, M.; Jambon, S.; Harej, A.; Depauw, S.; David-Cordonnier, M-H.; Kraljević Pavelić, S.; Karminski-Zamola, G.; Hranjec, M. Novel amidino substituted benzimidazole and benzothiazole benzo[b]thieno-2-carboxamides exert strong antiproliferative and DNA binding properties. Eur. J. Med. Chem., 2017, 136, 468-479.
[http://dx.doi.org/10.1016/j.ejmech.2017.05.014] [PMID: 28525845]
(b) Zhong, M.; Bui, M.; Shen, W.; Baskaran, S.; Allen, D.A.; Elling, R.A.; Flanagan, W.M.; Fung, A.D.; Hanan, E.J.; Harris, S.J.; Heumann, S.A.; Hoch, U.; Ivy, S.H.N.; Jacobs, J.W.; Lam, S.; Lee, H.; McDowell, R.S.; Oslob, J.D.; Purkey, H.E.; Romanowski, M.J.; Silverman, J.A.; Tangonan, B.T.; Taverna, P.; Yang, W.; Yoburn, J.C.; Yu, Ch.H.; Zimmerman, K.M.; O’Brien, T.; Lew, W. 2-Aminobenzimidazoles as potent Aurora kinase inhibitors. Bioorg. Med. Chem. Lett., 2009, 19, 5158-5161.
(c) Cee, V.J.; Cheng, A.C.; Romero, K.; Bello, S.; Mohr, C.H.; Whittington, D.A.; Bak, A.; Bready, J.; Caenepeel, S.; Coxon, A.; Deak, J.L.; Fretland, J.; Gu, Y.; Hodousa, B.L.; Huang, X.; Kim, J.L.; Lin, J.; Long, A.M.; Nguyen, H.; Olivieri, P.H.R.; Patel, V.F.; Wang, L.; Zhou, Y.; Hughes, P. Geuns-Meyer, S. Pyridyl-pyrimidine benzimidazole derivatives as potent, selective, and orally bioavailable inhibitors of Tie-2 kinase. Bioorg. Med. Chem. Lett., 2009, 19(2), 424-427.
[http://dx.doi.org/10.1021/ja038025w] [PMID: 14677933]
[http://dx.doi.org/10.1021/jm701456r] [PMID: 18271517]
(b) Mpamhanga, C.P.; Spinks, D.; Tulloch, L.B.; Shanks, E.J.; Robinson, D.A.; Collie, I.T.; Fairlamb, A.H.; Wyatt, P.G.; Frearson, J.A.; Hunter, W.N.; Gilbert, I.H.; Brenk, R. One scaffold, three binding modes: Novel and selective pteridine reductase 1 inhibitors derived from fragment hits discovered by virtual screening. J. Med. Chem., 2009, 52(14), 4454-4465.
[http://dx.doi.org/10.1021/jm900414x] [PMID: 19527033]
(c) Bharti, N. Shailendra; Gonzalez Garza, M.T.; Cruz-Vega, D.E.; Castro-Garza, J.; Saleem, K.; Naqvi, F.; Maurya, M.R.; Azam, A. Synthesis, characterization and antiamoebic activity of benzimidazole derivatives and their vanadium and molybdenum complexes. Bioorg. Med. Chem. Lett., 2002, 12(6), 869-871.
[http://dx.doi.org/10.1016/S0960-894X(02)00034-3] [PMID: 11958982]
(d) Ravina, E.; Sanchez-Alonso, R.; Fueyo, J.; Baltar, M.P.; Bos, J.; Iglesias, R.; Sanmartin, M.L. Synthesis and potential anthelmintic activity of methyl-5-(4-salicyloyl-piperazin-1-yl)-benzimidazole-2-carbamates. Arzneimittelforschung, 1993, 43(6), 689-694.
[PMID: 8352825]
(e) Townsend, L.B.; Wise, D.S. The synthesis and chemistry of certain anthelmintic benzimidazoles. Parasitol. Today, 1990, 6, 107-112.
[http://dx.doi.org/10.1016/j.bmc.2007.06.017] [PMID: 17600722]
[http://dx.doi.org/10.1021/bi801136q] [PMID: 19049291]
[http://dx.doi.org/10.1124/jpet.108.143537] [PMID: 19001156]
[http://dx.doi.org/10.1039/c003732j] [PMID: 20523944]
(b) Spagnuolo, P.A.; Hu, J.; Hurren, R.; Wang, X.; Gronda, M.; Sukhai, M.A.; Di Meo, A.; Boss, J.; Ashali, I.; Beheshti Zavareh, R.; Fine, N.; Simpson, C.D.; Sharmeen, S.; Rottapel, R.; Schimmer, A.D. The antihelmintic flubendazole inhibits microtubule function through a mechanism distinct from Vinca alkaloids and displays preclinical activity in leukemia and myeloma. Blood, 2010, 115(23), 4824-4833.
[http://dx.doi.org/10.1182/blood-2009-09-243055] [PMID: 20348394]
(c) Laryea, D.; Gullbo, J.; Isaksson, A.; Larsson, R.; Nygren, P. Characterization of the cytotoxic properties of the benzimidazole fungicides, benomyl and carbendazim, in human tumour cell lines and primary cultures of patient tumour cells. Anticancer Drugs, 2010, 21, 33-42.
(d) Doudican, N.; Rodriguez, A.; Osman, I.; Orlow, S.J. Mebendazole induces apoptosis via Bcl-2 inactivation in chemoresistant melanoma cells. Mol. Cancer Res., 2008, 6(8), 1308-1315.
[http://dx.doi.org/10.1158/1541-7786.MCR-07-2159] [PMID: 18667591]
(e) Bai, R.Y.; Staedtke, V.; Aprhys, C.M.; Gallia, G.L.; Riggins, G.J. Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme. Neur Oncol., 2011, 13(9), 974-982.
[http://dx.doi.org/10.1093/neuonc/nor077] [PMID: 21764822]
[http://dx.doi.org/10.2298/APT0435231P]
(b) Kukalenko, S.S.; Udovenko, V.A.; Borysova, V.P.; Kulugina, N.L.; Burmakin, N.M.; Andreeva, E.L.U.S.S.R. SU 1,636,414. Odkrytiya Izobret, 11. 1999, 75.
[PMID: 11642009]
[http://dx.doi.org/10.1016/j.saa.2011.09.028] [PMID: 21981941]
(b) Jornet, D.; Bartovský, P.; Domingo, L.R.; Tormos, R.; Miranda, M.A. Experimental and theoretical studies on the mechanism of photochemical hydrogen transfer from 2-aminobenzimidazole to nπ* and ππ* aromatic ketones. J. Phys. Chem. B, 2010, 114(36), 11920-11926.
[http://dx.doi.org/10.1021/jp1053327] [PMID: 20735030]
(c) Ivanova, B.B. Solid state linear dichroic infrared spectral analysis of benzimidazoles and their N(1)-protonated salts. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2005, 62(1-3), 58-65.
[http://dx.doi.org/10.1016/j.saa.2004.12.011] [PMID: 16257693]
[http://dx.doi.org/10.1016/j.bmc.2012.09.013] [PMID: 23031649]
[http://dx.doi.org/10.1016/j.tetlet.2015.03.099]
[http://dx.doi.org/10.3390/molecules190913878] [PMID: 25255762]
[http://dx.doi.org/10.1021/cr60151a002] [PMID: 24541208]
[http://dx.doi.org/10.1007/BF00473548]
[http://dx.doi.org/10.1016/j.bmc.2007.06.017] [PMID: 17600722]
[http://dx.doi.org/10.1016/j.tetlet.2008.01.100]
[http://dx.doi.org/10.1021/jm00157a010] [PMID: 2879912]
[http://dx.doi.org/10.1021/jm960442e] [PMID: 9046349]
[http://dx.doi.org/10.1016/S0040-4039(97)01273-2]
[http://dx.doi.org/10.1016/S0040-4039(98)00517-6]
[http://dx.doi.org/10.1016/S0040-4039(99)00290-7]
[http://dx.doi.org/10.1016/S0040-4039(99)01350-7]
[http://dx.doi.org/10.1021/jo0266339] [PMID: 12662063]
[http://dx.doi.org/10.1016/j.bmc.2005.04.060] [PMID: 15896964]
[http://dx.doi.org/10.1021/jm049854a] [PMID: 15566294]
[http://dx.doi.org/10.1016/j.bmc.2012.05.038] [PMID: 22698781]
[http://dx.doi.org/10.1021/acs.jmedchem.5b00114] [PMID: 25906200]
[http://dx.doi.org/10.1016/j.bmc.2005.09.063] [PMID: 16263297]
[http://dx.doi.org/10.1021/jm060065y] [PMID: 16759115]
[http://dx.doi.org/10.1016/j.bmcl.2004.11.021] [PMID: 15664844]
[http://dx.doi.org/10.1021/jm800809f] [PMID: 18998663]
[http://dx.doi.org/10.1016/j.bmc.2013.05.001] [PMID: 23719283]
[http://dx.doi.org/10.1016/j.ejmech.2014.07.038] [PMID: 25036797]
[http://dx.doi.org/10.1016/j.bmcl.2012.09.025] [PMID: 23025998]
[http://dx.doi.org/10.1021/jo900743y] [PMID: 19719252]
[http://dx.doi.org/10.1021/jo402742k] [PMID: 24490887]
[http://dx.doi.org/10.1002/adsc.201000022]
[http://dx.doi.org/10.1021/jo200014v] [PMID: 21413745]
[http://dx.doi.org/10.1002/adsc.201000469]
[http://dx.doi.org/10.1021/acs.joc.5b00614] [PMID: 26056863]
[http://dx.doi.org/10.1021/ol900298e] [PMID: 19254040]
(b) Monguchi, D.; Yamamura, A.; Fujiwara, T.; Somete, T.; Mori, A. Oxidative dimerization of azoles via copper(II)/silver(I)-catalyzed CH homocoupling. Tetrahedron Lett., 2010, 51, 850-852.
[http://dx.doi.org/10.1016/j.tetlet.2009.12.016]
(c) Mitsuda, Sh.; Fujiwara, T.; Kimigafukuro, K.; Monguchi, D.; Mori, A. Copper-catalyzed oxidative C‒H, N‒H coupling of azoles and thiophenes. Tetrahedron, 2012, 68, 3585-3590.
[http://dx.doi.org/10.1016/j.tet.2012.03.001]
(d) Wang, Q.; Schreiber, S.L. Copper-mediated amidation of heterocyclic and aromatic C-H bonds. Org. Lett., 2009, 11(22), 5178-5180.
[http://dx.doi.org/10.1021/ol902079g] [PMID: 19860425]
(e) Armstrong, A.; Collins, J.C. Direct azole amination: C-H functionalization as a new approach to biologically important heterocycles. Angew. Chem. Int. Ed. Engl., 2010, 49(13), 2282-2285.
[http://dx.doi.org/10.1002/anie.200906750] [PMID: 20186895]
[http://dx.doi.org/10.1039/c3ra41496e]
[http://dx.doi.org/10.1016/j.tetlet.2012.09.064]
[http://dx.doi.org/10.1002/anie.201311029] [PMID: 24668522]
[http://dx.doi.org/10.1021/jacs.7b07661] [PMID: 28753007]
[http://dx.doi.org/10.1021/jo900912h] [PMID: 19527012]
[http://dx.doi.org/10.1021/ol027061h] [PMID: 12529123]
[http://dx.doi.org/10.1007/s00044-013-0888-6]
[http://dx.doi.org/10.1021/jo901813g] [PMID: 19908912]
[http://dx.doi.org/10.1021/ol502815p] [PMID: 25474397]
[http://dx.doi.org/10.1021/ol403672p] [PMID: 24479902]
[http://dx.doi.org/10.1039/C6NJ00478D]
[http://dx.doi.org/10.1248/cpb.41.301] [PMID: 8500198]
(b) Beaulieu, C.; Wang, Z.; Denis, D.; Greig, G.; Lamontagne, S.; O’Neill, G.; Slipetz, D.; Wang, J. Benzimidazoles as new potent and selective DP antagonists for the treatment of allergic rhinitis. Bioorg. Med. Chem. Lett., 2004, 14, 3195-3199.
(c) Kling, A.; Backfisch, G.; Delzer, J.; Geneste, H.; Graef, C.; Holzenkamp, U.; Hornberger, W.; Lange, U.E.W.; Lauterbach, A.; Mack, H.; Seitz, W.; Subkowski, T. Synthesis and SAR of N-substituted dibenzazepinone derivatives as novel potent and selective RV3 antagonists. Bioorg. Med. Chem. Lett., 2002, 12, 441-446.
(d) Scheffer, U.; Strick, A.; Ludwig, V.; Peter, S.; Kalden, E.; Göbel, M.W. Metal-free catalysts for the hydrolysis of RNA derived from guanidines, 2-aminopyridines, and 2-aminobenzimidazoles. J. Am. Chem. Soc., 2005, 127, 2211-2217.
[http://dx.doi.org/10.1021/jm020113o] [PMID: 12139450]
[http://dx.doi.org/10.1016/j.bmcl.2006.07.058] [PMID: 16889961]
[http://dx.doi.org/10.1021/cc0200080] [PMID: 12099854]
[http://dx.doi.org/10.1016/j.tet.2004.08.031]
[http://dx.doi.org/10.1016/j.tetlet.2004.07.042]
[http://dx.doi.org/10.1016/j.tetlet.2006.03.112]
[http://dx.doi.org/10.1016/j.bmc.2006.02.028] [PMID: 16513356]
[http://dx.doi.org/10.1021/cc060106b] [PMID: 17096580]
[http://dx.doi.org/10.1002/ejoc.200800901]
[http://dx.doi.org/10.1021/cc100124q] [PMID: 20718465]
[http://dx.doi.org/10.1055/s-0029-1219395]
[http://dx.doi.org/10.1016/j.tetlet.2011.05.146]
[http://dx.doi.org/10.1016/j.tetlet.2016.10.060]
[http://dx.doi.org/10.1055/s-0032-1316849]
[http://dx.doi.org/10.1016/j.tet.2018.03.049]
[http://dx.doi.org/10.1002/slct.201802754]
[http://dx.doi.org/10.1016/j.tetlet.2007.12.022]
[http://dx.doi.org/10.1016/j.bmcl.2012.07.046] [PMID: 22877629]
[http://dx.doi.org/10.1021/jm500715u] [PMID: 25007124]
[http://dx.doi.org/10.1016/S0040-4039(02)01754-9]
[http://dx.doi.org/10.1016/j.bmcl.2014.05.009] [PMID: 24856063]
[http://dx.doi.org/10.1021/jo500360k] [PMID: 24641629]
[http://dx.doi.org/10.1016/j.tetlet.2014.03.040]
[http://dx.doi.org/10.1016/j.tetlet.2015.09.076] [PMID: 26516292]
[http://dx.doi.org/10.1016/j.bmcl.2014.07.035] [PMID: 25091926]
[http://dx.doi.org/10.2174/1570178615666180914114010]