Skip to main content

Advertisement

Log in

Development of drugs based on imidazole and benzimidazole bioactive heterocycles: recent advances and future directions

  • Review Article
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

Imidazole and benzimidazole rings are the most important nitrogen-containing heterocycles, which are widely explored and utilized by the pharmaceutical industry for drug discovery. Due to their special structural features and electron-rich environment, imidazole- and benzimidazole-containing drugs bind to a variety of therapeutic targets, thereby exhibiting a broad spectrum of bioactivities. Numerous imidazole- and benzimidazole-based drugs have been extensively used in the clinic to treat various types of diseases with high therapeutic potential. Due to their enormous medicinal value, the research and development of imidazole- and benzimidazole-containing drugs is an increasingly active and attractive topic of medicinal chemistry. This review enlightens the landscape of the discovery and development of imidazole- and benzimidazole-based drugs with an emphasis on structure activity relationship features (SAR), medicinal chemistry, and their mechanism of action. Furthermore, the present review also provides the recent advances in the development of imidazole- and benzimidazole-based drugs along with new perspectives. We hope that this paper will open up new opportunities for researchers to design future generation novel and potent imidazole- and benzimidazole-containing drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14
Fig. 15
Fig. 16
Fig. 17
Fig. 18
Fig. 19
Fig. 20
Fig. 21
Fig. 22

Similar content being viewed by others

References

  • Actor P, Anderson EL, DiCuollo CJ, Ferlanto RJ, Hoover JRE, Pagano JF, Ravin LR, Scheidy SF, Stedman RJ, Theodorides VJ (1967) New broad spectrum anthelmintic, methyl 5(6)-butyl-2-benzimidazolecarbamate. Nature 215:321–322

    Article  PubMed  CAS  Google Scholar 

  • Alomar A, Videla S, Delgadillo J, Gich I, Izquierdo I, Forn J (1995) Flutrimazole 1 % dermal cream in the treatment of dermatomycoses: a multicenter, double-blind, randomized, comparative clinical trial with bifonazole 1 % cream. Efficacy of flutrimazole 1 % dermal cream in dermatomycoses. Catalan flutrimazole study group. Dermatology 190:295–300

    Article  PubMed  CAS  Google Scholar 

  • Arrang JM, Garbarg M, Lancelot JC, Lecomte JM, Pollard H, Robba M, Schunack W, Schwartz JC (1988) Highly potent and selective ligands for a new class H3 of histamine receptor. Invest Radiol 23:S130–S132

    Article  PubMed  CAS  Google Scholar 

  • Aulakh GK, Sodhi RK, Singh M (2007) An update on non-peptide angiotensin receptor antagonists and related RAAS modulators. Life Sci 81:615–639

    Article  PubMed  CAS  Google Scholar 

  • Barker HA, Smyth RD, Weissbach H, Toohey JI, Ladd JN, Volcani BE (1960) Isolation and properties of crystalline cobamide coenzymes containing benzimidazole or 5,6 dimethylbenzimidazole. J Biol Chem 235:480–488

    PubMed  CAS  Google Scholar 

  • Barnes NM, Hales TG, Lummis SCR, Peters JA (2009) The 5-HT3 receptor-the relationship between structure and function. Neuropharmacology 56:273–284

    Article  PubMed  CAS  Google Scholar 

  • Beck DE, Agama K, Marchand C, Chergui A, Pommier Y, Cushman M (2014) Synthesis and biological evaluation of new carbohydrate-substituted indenoisoquinoline topoisomerase I inhibitors and improved syntheses of the experimental anticancer agents Indotecan (LMP400) and Indimitecan (LMP776). J Med Chem 57:1495–1512

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Belch JJ, Cormie J, Newman P, McLaren M, Barbenel J, Capell H, Leiberman P, Forbes CD, Prentice CR (1983) Dazoxiben, a thromboxane synthetase inhibitor, in the treatment of Raynaud’s syndrome: a double-blind trial. Br J Clin Pharmacol 15:113S–116S

    Article  PubMed  PubMed Central  Google Scholar 

  • Bennett JE (1981) Miconazole in cryptococcosis and systemic candidiasis: a word of caution. Ann Intern Med 94:708–709

    Article  PubMed  CAS  Google Scholar 

  • Bhatnagar A, Sharma PK, Kumar N (2011) A review on “Imidazoles”: their chemistry and pharmacological potentials. Int J PharmTech Res 3:268–282

    CAS  Google Scholar 

  • Bhatt HG, Agrawal YK, Raval HG, Manna K, Desai PR (2010) Histamine H4 receptor: a novel therapeutic target for immune and allergic responses. Mini Rev Med Chem 10:1293–1308

    Article  PubMed  CAS  Google Scholar 

  • Bielory L, Lien KW, Bigelsen S (2005) Efficacy and tolerability of newer antihistamines in the treatment of allergic conjunctivitis. Drugs 65:215–228

    Article  PubMed  CAS  Google Scholar 

  • Biron KK, Harvey RJ, Chamberlain SC, Good SS, Smith AA III, Davis MG, Talarico CL, Miller WH, Ferris R, Dornsife RE, Stanat SC, Drach JC, Townsend LB, Koszalka GW (2002) Potent and selective inhibition of human cytomegalovirus replication by 1263W94: a benzimidazole L-riboside with a unique mode of action. Antimicrob Agents Chemother 46:2365–2372

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Black JW, Duncan WAM, Durant CJ, Ganellin CR, Parsons EM (1972) Definition and antagonism of histamine H2-receptors. Nature 236:385–390

    Article  PubMed  CAS  Google Scholar 

  • Blum AL, Shah G, St Pierre T, Helander HF, Sung CP, Wiebelhaus VD, Sachs G (1971) Properties of soluble ATPase of gastric mucosa. Biochim Biophys Acta 249:101–111

    Article  PubMed  CAS  Google Scholar 

  • Brimblecombe RW, Duncan WA, Durant GJ, Emmett JC, Ganellin CR, Leslie GB, Parsons ME (1978) Characterization and development of cimetidine as a histamine H2-receptor antagonist. Gastroenterology 74:339–347

    PubMed  CAS  Google Scholar 

  • Brown HD, Matzuk AR, Ilves IR, Peterson LH, Harris SA, Sarett LH, Egerton JR, Yakstis JJ, Campbell WC, Cuckler AC (1961) Antiparasitic drugs. IV. 2-(4'-Thiazolyl)-benzimidazole, a new anthelmintic. J Am Chem Soc 83:1764–1765

    Article  CAS  Google Scholar 

  • Burgess MA, Bodey GP (1972) Clotrimazole (Bay b 5097): in vitro and clinical pharmacological studies. Antimicrob Agents Chemother 2:423–426

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Burnier M (2001) Angiotensin II type 1 receptor blockers. Circulation 103:904–912

    Article  PubMed  CAS  Google Scholar 

  • Burnier M, Brunner HR (2000) Angiotensin II receptor antagonists. Lancet 355:637–645

    Article  PubMed  CAS  Google Scholar 

  • Butler A, Hill JM, Ireland SJ, Jordan CC, Tyers MB (1988) Pharmacological properties of GR38032F, a novel antagonist at 5-HT3 receptors. Br J Pharmacol 94:397–412

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Carini DJ, Duncia JV, Aldrich PE, Chiu AT, Johnson AL, Pierce ME, Price WA, Santella JB III, Wells GJ, Wexler RR, Wong PC, Yoo S, Timmermans PBMWM (1991) Nonpeptide angiotensin II receptor antagonists: the discovery of a series of N-(biphenylylmethyl)imidazoles as potent, orally active antihypertensives. J Med Chem 34:2525–2547

    Article  PubMed  CAS  Google Scholar 

  • Chang H, Saccomani G, Rabon E, Schackmann R, Sachs G (1977) Proton transport by gastric membrane vesicles. Biochim Biophys Acta 464:313–327

    Article  PubMed  CAS  Google Scholar 

  • Chey WD, Cash BD (2005) Cilansetron: a new serotonergic agent for the irritable bowel syndrome with diarrhea. Expert Opin Investig Drugs 14:185–193

    Article  PubMed  CAS  Google Scholar 

  • Chodosh LA, Fire A, Samuels M, Sharp PA (1989) 5,6-Dichloro-1-beta-D- ribofuranosylbenzimidazole inhibits transcription elongation by RNA polymerase II in vitro. J Biol Chem 264:2250–2257

    PubMed  CAS  Google Scholar 

  • Clapp RH, Luckman SM (2012) Proxyfan acts as a neutral antagonist of histamine H3 receptors in the feeding-related hypothalamic ventromedial nucleus. Br J Pharmacol 167:1099–1110

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Clarke RW, Harris J (2002) RX 821002 as a tool for physiological investigation of alpha(2)- adrenoceptors. CNS Drug Rev 8:177–192

    Article  PubMed  CAS  Google Scholar 

  • Cooper DS (1984) Antithyroid drugs. N Engl J Med 311:1353–1362

    Article  PubMed  CAS  Google Scholar 

  • Corcostegui R, Labeaga L, Innerarity A, Berisa A, Orjales A (2005) Preclinical pharmacology of bilastine, a new selective histamine H1 receptor antagonist: receptor selectivity and in vitro antihistaminic activity. Drugs RD 6:371–384

    Article  CAS  Google Scholar 

  • Coruzzi G, Adami M, Guaita E, De Esch IJ, Leurs R (2007) Anti-inflammatory and antinociceptive effects of the selective histamine H4-receptor antagonists JNJ7777120 and VUF6002 in a rat model of carrageenan-induced acute inflammation. Eur J Pharmacol 563:240–244

    Article  PubMed  CAS  Google Scholar 

  • Cosar C, Julou L (1959) The activity of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole (R.P. 8823) against experimental Trichomonas vaginalis infections. Ann Inst Pasteur 96:238–241

    CAS  Google Scholar 

  • DeRemer DL, Katsanevas K, Ustun C (2011) Critical appraisal of nilotinib in frontline treatment of chronic myeloid leukemia. Cancer Manag Res 3:65–78

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • DeSimone RW, Currie KS, Mitchell SA, Darrow JW, Pippin DA (2004) Privileged structures: applications in drug discovery. Comb Chem High T Scr 7:473–494

    CAS  Google Scholar 

  • Diacon AH, Dawson R, Groote-Bidlingmaier F, Symons G, Venter A, Donald PR, Niekerk C, Everitt D, Hutchings J, Burger DA, Schall R, Mendel CM (2015) Bactericidal activity of pyrazinamide and clofazimine alone and in combinations with pretomanid and bedaquiline. Am J Respir Crit Care Med 191:943–953

    Article  PubMed  CAS  Google Scholar 

  • DoCampo R (1990) Sensitivity of parasites to free radical damage by antiparasitic drugs. Chem Biol Interact 73:1–27

    Article  PubMed  CAS  Google Scholar 

  • Elizabeth B, Lurie P, Wolfe SM (2000) Alosetron for irritable bowel syndrome. Lancet 356:2009

    Article  Google Scholar 

  • Emerson CR, Marzella N (2010) Dexlansoprazole: a proton pump inhibitor with a dual delayed- release system. Clin Ther 32:1578–1596

    Article  PubMed  CAS  Google Scholar 

  • Fainstein V, Bodey GP (1980) Cardiorespiratory toxicity due to miconazole. Ann Intern Med 93:432–433

    Article  PubMed  CAS  Google Scholar 

  • Fei F, Zhou Z (2013) New substituted benzimidazole derivatives: a patent review (2010–2012). Expert Opin Ther Pat 23:1157–1179

    Article  PubMed  CAS  Google Scholar 

  • Fellenius E, Berglindh T, Sachs G, Olbe L, Elander B, Sjostrand S, Wallmark B (1981) Substituted benzimidazoles inhibit gastric acid secretion by blocking (H++K+) ATPase. Nature 290:159–161

    Article  PubMed  CAS  Google Scholar 

  • Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136:E359–E386

    Article  PubMed  CAS  Google Scholar 

  • Fernandez-Torres B, Inza I, Guarro J (2003) In vitro activities of the new antifungal drug eberconazole and three other topical agents against 200 strains of dermatophytes. J Clin Microbiol 41:5209–5211

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fisher MH (1986) Chemistry of antinematodal agents. In: Campbell WC, Rew RS (eds) Chemotherapy of parasitic diseases. Plenum Press, New York, pp 239–266

    Chapter  Google Scholar 

  • Freston JW (1982) Cimetidine. I. developments, pharmacology, and efficacy. Ann Intern Med 97:573–580

    Article  PubMed  CAS  Google Scholar 

  • Fromtling RA (1986) Butoconazole: a new antifungal agent. Rev Recent Work. Drugs Today 22:261–263

    CAS  Google Scholar 

  • Fromtling RA (1988) Overview of medically important antifungal azole derivatives. Clin Microbiol Rev 1:187–217

    PubMed  PubMed Central  CAS  Google Scholar 

  • Gaba M, Singh D, Singh S, Sharma V, Gaba P (2010) Synthesis and pharmacological evaluation of novel 5-substituted-1-(phenylsulphonyl)-2-methylbenzimidazole derivatives as anti- inflammatory and analgesic Agents. Eur J Med Chem 45:2245–2249

    Article  PubMed  CAS  Google Scholar 

  • Gaba M, Singh S, Mohan C (2014) Benzimidazole: an emerging scaffold for analgesic and anti- inflammatory agents. Eur J Med Chem 76:494–505

    Article  PubMed  CAS  Google Scholar 

  • Gaba M, Gaba P, Uppal D, Dhingra N, Bahia MS, Silakari O, Mohan C (2015) Benzimidazole derivatives: search for GI-friendly anti-inflammatory analgesic agents. Acta Pharm Sin B 5:337–342

    Article  PubMed  PubMed Central  Google Scholar 

  • Gaddum JH, Picarelli ZP (1957) Two kinds of tryptamine receptor. Br J Pharmacol Chemother 12:323–328

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gerra G, Zaimovic A, Giusti F, Gennaro CD, Zambelli U, Gardini S, Delsignore R (2001) Lofexidine versus clonidine in rapid opiate detoxification. J Subst Abuse Treat 21:11–17

    Article  PubMed  CAS  Google Scholar 

  • Gewurz BE, Jacobs M, Proper JA, Dahl TA, Fujiwara T, Dezube BJ (2004) Capravirine, a nonnucleoside reverse-transcriptase inhibitor in patients infected with HIV-1: a phase 1 study. J Infect Dis 190:1957–1961

    Article  PubMed  Google Scholar 

  • Geyer R, Buschauer A (2011) Synthesis and histamine H3 and H4 receptor activity of conformationally restricted cyanoguanidines related to UR-PI376. Arch Pharm 344:775–785

    Article  CAS  Google Scholar 

  • Giese JL, Stanley TH (1983) Etomidate: a new intravenous anesthetic induction agent. Pharmacotherapy 3:251–258

    Article  PubMed  CAS  Google Scholar 

  • Godefroi EF, Heeres J, Van Cutsem J, Janssen PA (1969) The preparation and antimycotic properties of derivatives of 1-phenethylimidazole. J Med Chem 12:784–791

    Article  PubMed  CAS  Google Scholar 

  • Gordon SG, Miller MW, Saunders AB (2006) Pimobendan in heart failure therapy-a silver bullet. J Am Anim Hosp Assoc 42:90–93

    Article  PubMed  Google Scholar 

  • Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, Khan AP, Quist MJ, Jing XJ, Lonigro RJ, Brenner JC, Asangani IA, Ateeq B, Chun SY, Siddiqui J, Sam L, Anstett M, Mehra R, Prensner JR, Palanisamy N, Ryslik GA, Vandin F, Raphael BJ, Lakshmi PK, Rhodes DR, Pienta KJ, Chinnaiyan AM, Tomlins SA (2012) The mutational landscape of lethal castration-resistant prostate cancer. Nature 487:239–243

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Griffith RK (2003) Adrenergics and adrenergic-blocking agents. In: Abraham DJ (ed) Burger’s medicinal chemistry and drug discovery. Wiley, Hoboken, pp 1–37

    Google Scholar 

  • Hartmann M, Zimmer CH (1972) Investigation of cross-link formation in DNA by the alkylating cytostatica IMET 3106, 3393 and 3943. Biochim Biophys Acta 287:386–389

    Article  PubMed  CAS  Google Scholar 

  • Hauel NH, Nar H, Priepke H, Ries U, Stassen JM, Wienen W (2002) Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem 45:1757–1766

    Article  PubMed  CAS  Google Scholar 

  • Hawwa AF, Millership JS, Collier PS, Vandenbroeck K, McCarthy A, Dempsey S, Cairns C, Collins J, Rodgers C, McElnay JC (2008) Pharmacogenomic studies of the anticancer and immunosuppressive thiopurines mercaptopurine and azathioprine. Br J Clin Pharmacol 66:517–528

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Heel RC, Brogden RN, Parke GE, Speight TM, Avery GS (1980) Miconazole: a preliminary review of its therapeutic efficacy in systemic fungal infections. Drugs 19:7–30

    Article  PubMed  CAS  Google Scholar 

  • Heeres J, Backx LJ, Mostmans JH, Van Cutsem J (1979) Antimycotic imidazoles. Part 4. Synthesis and antifungal activity of ketoconazole, a new potent orally active broad- spectrum antifungal agent. J Med Chem 22:1003–1005

    Article  PubMed  CAS  Google Scholar 

  • Heinz BA, Vance LM (1995) The antiviral compound enviroxime targets the 3A coding region of rhinovirus and poliovirus. J Virol 69:74189–74197

    Google Scholar 

  • Herling AW, Weidmann K (1994) Progress in medicinal chemistry. In: Ellis GP, Luscombe DK (ed) Gastric H+/K+ATPase inhibitors. Elsevier Science BV, pp 233–264

  • Hernandez Molina JM, Llosa J, Martinez Brocal A, Ventosa A (1992) In vitro activity of cloconazole, sulconazole, butoconazole, isoconazole, fenticonazole, and five other antifungal agents against clinical isolates of Candida albicans and Candida spp. Mycopathalogia 118:15–21

    Article  CAS  Google Scholar 

  • Hoff DR (1982) In: Bindra JS, Lednicer D (eds) Chronicles of drug discovery. Wiley, New York, pp 239–256

    Google Scholar 

  • Hoff DR, Fisher MH, Bochis RJ, Lusi RJ, Waksmunski A, Egerton RJ, Yastis JJ, Cuckler AC, Campbell WC (1970) A new broad spectrum anthelmintic: 2-(4-thiazolyl)-iso- propoxycarbonyl aminobenzimidazole. Experientia 26:550–552

    Article  PubMed  CAS  Google Scholar 

  • Hough LB (2001) Genomics meets histamine receptors: new subtypes, new receptors. Mol Pharmacol 59:415–419

    PubMed  CAS  Google Scholar 

  • http://www.healthline.com/health/parasitic-infections#Overview1

  • http://www.lef.org/protocols/infections/fungal_infections_candida_01.htm

  • http://www.dddmag.com/news/2012/08/ferrer-files-arasertaconazole-ind

  • Igel P, Dove S, Buschauer A (2010) Histamine H4 receptor agonists. Bioorg Med Chem Lett 20:7191–7199

    Article  PubMed  CAS  Google Scholar 

  • Ingle RG, Magar DD (2011) Heterocyclic chemistry of benzimidazoles and potential activities of derivatives. Int J Drug Res Tech 1:26–32

    Google Scholar 

  • Insel PA (1996) Adrenergic receptors-evolving concepts and clinical implications. N Engl J Med 334:580–585

    Article  PubMed  CAS  Google Scholar 

  • Ishikawa H (1999) Mizoribine and mycophenolate mofetil. Curr Med Chem 6:575–597

    PubMed  CAS  Google Scholar 

  • Jansen FP, Wu TS, Voss HP, Steinbusch HW, Vollinga RC, Rademaker B, Bast A, Timmerman H (1994) Characterization of the binding of the first selective radiolabelled histamine H3-receptor antagonist, 125I-iodophenpropit, to rat brain. Br J Pharmcol 113:355–362

    Article  CAS  Google Scholar 

  • Jansen FP, Mochizuki T, Maeyama K, Leurs R, Timmerman H (2000) Characterization of histamine H3 receptors in mouse brain using the H3 antagonist 125Iiodophenpropit. Naunyn-Schmiedeberg Arch Pharmacol 362:60–67

    Article  CAS  Google Scholar 

  • Janssen PA, Niemegeers CJ, Schellekens KH, Marsboom RH, Herin VV, Amery WK, Admiraal PV, Bosker JT, Crul JF, Pearce C, Zegveld C (1971) Bezitramide (R 4845), a new potent and orally long-acting analgesic compound. Arzneim Forsch 21:862–867

    CAS  Google Scholar 

  • Jarrad AM, Karoli T, Blaskovich MAT, Lyras D, Coope MA (2015) Clostridium difficile drug pipeline: challenges in discovery and development of new agents. J Med Chem 58:5164–5185

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jerchel D, Fischer H, Fracht M (1952) Zur Darstellung der benzimidazole. Liebigs Ann Chem 575:162–173

    Article  CAS  Google Scholar 

  • Jevons S, Gymer GE, Brammer KW, Cox DA, Leeming MRG (1979) Antifungal activity of tioconazole (UK-20, 349), a new imidazole derivative. Antimicrob Agents Chemother 15:597–602

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Johns TG, Piper DC, James GW (1979) The pharmacological profile of a potential hypnotic compound RU 31158. Arch Int Pharmacodyn Ther 240:53–65

    PubMed  CAS  Google Scholar 

  • Jones CD, Andrews DM, Barker AJ, Blades K, Daunt P, East S, Geh C, Graham MA, Johnson KM, Loddick SA, McFarland HM, McGregor A, Moss L, Rudge DA, Simpson PB, Swain ML, Tam KY, Tucker JA, Walker M (2008) The discovery of AZD5597, a potent imidazole pyrimidine amide CDK inhibitor suitable for intravenous dosing. Bioorg Med Chem Lett 18:6369–6373

    Article  PubMed  CAS  Google Scholar 

  • Josephy PD, Palcic B, Skarsgard LD (1981) In vitro metabolism of misonidazole. Br J Cancer 43:443–450

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kapetanovic IM, Kupferberg HJ (1984) Nafimidone, an imidazole anticonvulsant, and its metabolite as potent inhibitors of microsomal metabolism of phenytoin and carbamazepine. Drug Metab Dispos 12:560–564

    PubMed  CAS  Google Scholar 

  • Kapoor VK, Chadha R, Venisetty PK, Prasanth S (2003) Medicinal significance of nitroimidazoles: some recent advances. J Sci Ind Res 62:659–665

    CAS  Google Scholar 

  • Kath R, Blumenstengel K, Fricke HJ, Hoffken K (2001) Bendamustine monotherapy in advanced and refractory chronic lymphocytic leukemia. J Cancer Res Clin Oncol 127:48–54

    Article  PubMed  CAS  Google Scholar 

  • Kemp KM, Henderlight L, Neville M (2008) Pre-cedex: is it the future of cooperative sedation? Crit Care Insider 38:50–55

    Google Scholar 

  • Khabnadideh S, Rezaei Z, Khalafi NA, Motazedian MH, Eskandari M (2007) Synthesis of metronidazole derivatives as antigiardiasis agents. DARU J Pharm Sci 15:17–20

    CAS  Google Scholar 

  • Kitbunnadaj R, Zuiderveld OP, Christophe B, Hulscher S, Menge WM, Gelens E, Snip E, Bakker RA, Celanire S, Gillard M, Talaga P, Timmerman H, Leurs R (2004) Identification of 4-(1H-imidazol-4(5)-ylmethyl)pyridine (immethridine) as a novel, potent, and highly selective histamine H(3) receptor agonist. J Med Chem 47:2414–2417

    Article  PubMed  CAS  Google Scholar 

  • Kohara Y, Kubo K, Imamiya E, Wada T, Inada Y, Naka T (1996) Synthesis and angiotensin II receptor antagonistic activities of benzimidazole derivatives bearing acidic heterocycles as novel tetrazole bioisosteres. J Med Chem 39:5228–5235

    Article  PubMed  CAS  Google Scholar 

  • Kromer W (1995) Similarities and differences in the properties of substituted benzimidazoles: a comparison between pantoprazole and related compounds. Digestion 56:443–454

    Article  PubMed  CAS  Google Scholar 

  • Kupietzky A, Houpt MI (1993) Midazolam: a review of its use for conscious sedation of children. Pediatr Dent 15:237–241

    PubMed  CAS  Google Scholar 

  • Leurs R, Bakker RA, Timmerman H, de Esch IJ (2005) The histamine H3 receptor: from gene cloning to H3 receptor drugs. Nat Rev Drug Discov 4:107–120

    Article  PubMed  CAS  Google Scholar 

  • Li EC, Davis LE (2003) Zoledronic acid: a new parenteral bisphosphonate. Clin Ther 25:2669–2708

    Article  PubMed  CAS  Google Scholar 

  • Lindberg P, Carlsson E (2006) Analogue-based drug discovery. In: Fischer J, Ganellin CR (eds) Esomeprazole in the framework of proton-pump inhibitor development. Wiley-VCH Verlag, Weinheim, pp 81–113

    Google Scholar 

  • Lutwick L, Rytel MW, Yanez JP, Galgiani JN, Stevens DA (1979) Deep infections from Petriellidium boydii treated with miconazole. J Am Med Assoc 241:271–272

    Article  Google Scholar 

  • Martin RJ (1997) Modes of action of anthelmintic drugs. Vet J 154:11–34

    Article  PubMed  CAS  Google Scholar 

  • McCracken RO, Lipkowitz KB (1990) Structure-activity relationships of benzothiazole and benzimidazole anthelmintics: a molecular modeling approach to in vivo drug efficacy. J Parasitol 76:853–864

    Article  PubMed  CAS  Google Scholar 

  • McFarland JW (1972) The chemotherapy of intestinal nematodes. Prog Drug Res 16:157–193

    PubMed  CAS  Google Scholar 

  • Miura S, Okabe A, Matsuo Y, Karnik SS, Saku K (2013) Unique binding behavior of the recently approved angiotensin II receptor blocker azilsartan compared with that of condensation. Hypertens Res 36:134–139

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Morris STW, Reid JL (1997) Moxonidine: a review. J Hum Hypertens 11:629–635

    Article  PubMed  CAS  Google Scholar 

  • Motawaj M, Arrang JM (2011) Ciproxifan, a histamine H3-receptor antagonist / inverse agonist, modulates methamphetamine-induced sensitization in mice. Eur J Neurosci 33:1197–1204

    Article  PubMed  Google Scholar 

  • Munson K, Garcia R, Sachs G (2005) Inhibitor and ion binding sites on the gastric H, K- ATPase. Biochemistry 44:5267–5284

    Article  PubMed  CAS  Google Scholar 

  • Naik P, Murumkar P, Giridhar R, Yadav MR (2010) Angiotensin II receptor type 1 (AT1) selective nonpeptidic antagonists-a perspective. Bioorg Med Chem 18:8418–8456

    Article  PubMed  CAS  Google Scholar 

  • Nakamura S (1955) Structure of azomycin, a new antibiotic. Pharm Bull 3:379–383

    Article  PubMed  CAS  Google Scholar 

  • Nakata-Fukuda M, Hirata T, Keto Y, Yamano M, Yokoyama T, Uchiyama Y (2014) Inhibitory effect of the selective serotonin 5-HT3 receptor antagonist ramosetron on duodenal acidification-induced gastric hypersensitivity in rats. Eur J Pharmacol 15:88–92

    Article  CAS  Google Scholar 

  • Narasimhan B, Sharma D, Kumar P (2011) Biological importance of imidazole nucleus in the new millennium. Med Chem Res 20:1119–1140

    Article  CAS  Google Scholar 

  • Nimura K, Niwano Y, Ishiduka S, Fukumoto R (2001) Comparison of in vitro antifungal activities of topical antimycotics launched in 1990s in Japan. Int J Antimicrob Agents 18:173–178

    Article  PubMed  CAS  Google Scholar 

  • Njar VC, Brodie AM (2015) Discovery and development of Galeterone (TOK-001 or VN/124-1) for the treatment of all stages of prostate cancer. J Med Chem 58:2077–2087

    Article  PubMed  CAS  Google Scholar 

  • Ogata M, Matsumoto H, Hamada Y, Takehara M, Tawara K (1983) 1-[1-[2-[(3-chlorobenzyl) oxy] phenyl] vinyl]-1H-imidazole hydrochloride, a new potent antifungal agent. J Med Chem 26:768–770

    Article  PubMed  CAS  Google Scholar 

  • Olbe L, Carlsson E, Lindberg P (2003) A proton-pump inhibitor expedition: the case histories of omeprazole and esomeprazole. Nat Rev Drug Discov 2:132–139

    Article  PubMed  CAS  Google Scholar 

  • Ortiz JA (1992) Sertaconazole (FI-7045). A new antifungal agent. Arzneim Forsch 42:689–690

    CAS  Google Scholar 

  • Ozkay Y, Tunali Y, Karaca H, Isikdag I (2010) Antimicrobial activity and a SAR study of some novel benzimidazole derivatives bearing hydrazone moiety. Eur J Med Chem 45:3293–3298

    Article  PubMed  CAS  Google Scholar 

  • Palacin C, Tarrago C, Agut J, Guglietta A (2001) In vitro activity of sertaconazole, ketoconazole, fenticonazole, clotrimazole and itraconazole against pathogenic vaginal yeast infections. Methods Find Exp Clin Pharmacol 23:61–64

    Article  PubMed  CAS  Google Scholar 

  • Parsons ME, Ganellin CR (2006) Histamine and its receptors. Br J Pharmacol 147:S127–S135

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pectasides D, Yianniotis H, Alevizakos N, Bafaloukos D, Barbounis V, Varthalitis J, Dimitriadis M, Athanassiou A (1989) Treatment of metastatic malignant melanoma with dacarbazine, vindesine and cisplatin. Br J Cancer 60:627–629

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Penning TD, Zhu GD, Gandhi VB, Gong J, Liu X, Shi Y, Klinghofer V, Johnson EF, Donawho CK, Frost DJ, Bontcheva-Diaz V, Bouska JJ, Osterling DJ, Olson AM, Marsh KC, Luo Y, Giranda VL (2009) Discovery of the Poly(ADP-ribose) polymerase (PARP) inhibitor 2-[(R)- 2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (ABT-888) for the treatment of cancer. J Med Chem 52:514–523

    Article  PubMed  CAS  Google Scholar 

  • Pertovaara A, Haapalinna A, Sirvio J, Virtanen R (2005) Pharmacological properties, central nervous system effects, and potential therapeutic applications of atipamezole, a selective alpha2-adrenoceptor antagonist. CNS Drug Rev 11:273–288

    Article  PubMed  CAS  Google Scholar 

  • Plempel M, Regel E, Buchel KH (1983) Antimycotic efficacy of bifonazole in vitro and in vivo. Arzneimittelforschung 33:517–524

    PubMed  CAS  Google Scholar 

  • Polak A (1982) Oxiconazole, a new imidazole derivative. Evaluation of antifungal activity in vitro and in vivo. Arzneimittelforschung 32:17–24

    PubMed  CAS  Google Scholar 

  • Prakash A, Lamb HM (1998) Mizolastine: a review of its use in allergic rhinitis and chronic idiopathic urticaria. BioDrugs 10:41–63

    Article  PubMed  CAS  Google Scholar 

  • Raats JI, Falkson G, Falkson HC (1992) A study of fadrozole, a new aromatase inhibitor, in postmenopausal women with advanced metastatic breast cancer. J Clin Oncol 10:111–116

    PubMed  CAS  Google Scholar 

  • Rabasseda X (2002) Ramosetron, a 5-HT3 receptor antagonist for the control of nausea and vomiting. Drugs Today 38:75–89

    Article  PubMed  CAS  Google Scholar 

  • Radziszewski B (1882) Ueber die Constitution des Lophins und verwandter Verbindungen. Chem Ber 15:1493–1496

    Article  Google Scholar 

  • Ren J, Nichols C, Bird LE, Fujiwara T, Sugimoto H, Stuart DI, Stammers DK (2000) Binding of the second generation nonnucleoside inhibitor S-1153 to HIV-1 reverse transcriptase involves extensive main chain hydrogen bonding. J Biol Chem 275:14316–14320

    Article  PubMed  CAS  Google Scholar 

  • Rezaei Z, Khabnadideh S, Zomorodian K, Pakshir K, Kashi G, Sanagoei N, Gholami S (2011) Design, synthesis and antifungal activity of some new imidazole and triazole derivatives. Arch Pharm Chem Life Sci 344:658–665

    Article  CAS  Google Scholar 

  • Sachs G, Wallmark B (1989) The gastric H+, K+-ATPase: the site of action of omeprazole. Scand J Gatroenterol 66:3–11

    Article  Google Scholar 

  • Sachs G, Collier RH, Schoemaker RL, Hirschowitz BI (1968) The energy source of gastric acid secretion. Biochim Biophys Acta 162:210–219

    Article  PubMed  CAS  Google Scholar 

  • Sachs G, Shin JM, Vagin O, Lambrecht N, Yakubov I, Munson K (2007) The gastric H, K ATPase as a drug target. J Clin Gastroenterol 41:S226–S242

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sander K, Kottke T, Stark H (2008) Histamine H3 receptor antagonists go to clinics. Biol Pharm Bull 31:2163–2181

    Article  PubMed  CAS  Google Scholar 

  • Savic I, Widen L, Stone-Elander S (1991) Feasibility of reversing benzodiazepine tolerance with flumazenil. Lancet 337:133–137

    Article  PubMed  CAS  Google Scholar 

  • Savola JM, Hill M, Engstrom M, Merivuori H, Wurster S, McGuire SG, Fox SH, Crossman AR, Brotchie JM (2003) Fipamezole (JP-1730) is a potent alpha2 adrenergic receptor antagonist that reduces levodopa-induced dyskinesia in the MPTP-lesioned primate model of parkinson’s disease. Mov Disord 18:872–883

    Article  PubMed  Google Scholar 

  • Sawyer PR, Brogden RN, Pinder RM, Speight TM, Avery (1975) Clotrimazole: a review of its antifungal activity and therapeutic efficacy. Drugs 9:424–447

    Article  PubMed  CAS  Google Scholar 

  • Scarpignato C, Hunt RH (2008) Proton pump inhibitors: the beginning of the end or the end of the beginning? Curr Opin Pharmacol 8:677–684

    Article  PubMed  CAS  Google Scholar 

  • Scheinfeld N (2003) Cimetidine: a review of the recent developments and reports in cutaneous medicine. Dermatol Online J 9:4

    PubMed  Google Scholar 

  • Schimke K, Davis TM (2007) Drug evaluation: rivoglitazone, a new oral therapy for the treatment of type 2 diabetes. Curr Opin Investig Drugs 8:338–344

    PubMed  CAS  Google Scholar 

  • Senn-Bilfinger J, Sturm E (2006) Analogue-based drug discovery. In: Fischer J, Ganellin CR (eds) The development of a new proton-pump inhibitor: The case history of pantoprazole. Wiley-VCH Verlag, Weinheim, pp 115–136

    Google Scholar 

  • Shadomy S (1971) In vitro antifungal activity of clotrimazole (Bay b 5097). Infect Immun 4:143–148

    PubMed  PubMed Central  CAS  Google Scholar 

  • Sharma S (1990) Vector-borne diseases. Prog Drug Res 35:365–485

    PubMed  CAS  Google Scholar 

  • Sheehan DJ, Hitchcock CA, Sibley CM (1999) Current and emerging azole antifungal agents. Clin Microbiol Rev 12:40–79

    PubMed  PubMed Central  CAS  Google Scholar 

  • Shin JM, Sachs G (2009) Long lasting inhibitors of the gastric H, K-ATPase. Expert Rev Clin Pharmacol 2:461–468

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Shin JM, Munson K, Vagin O, Sachs G (2008) The gastric H+-K-ATPase: structure, function, and inhibition. Pflug Arch Eur J Phy 457:609–622

    Article  CAS  Google Scholar 

  • Shinn DLS (1962) Metronidazole in acute ulcerative gingivitis. Lancet 279:1191

    Article  Google Scholar 

  • Singh M, Jadhav HR (2013) Histamine H3 receptor function and ligands: recent developments. Mini Rev Med Chem 13:47–57

    Article  PubMed  CAS  Google Scholar 

  • Spasov AA, Yozhitsa IN, Bugaeva LI, Anisimova VA (1999) Benzimidazole derivatives: spectrum of pharmacological activity and toxicological properties. Pharm Chem J 33:232–243

    Article  CAS  Google Scholar 

  • Stahle H (2000) A historical perspective: development of clonidine. Baillieres Clin Anaesthesiol 14:237–246

    CAS  Google Scholar 

  • Stark H (2003) Recent advances in histamine H3/H4 receptor ligands. Expert Opin Ther Pat 13:851–865

    Article  CAS  Google Scholar 

  • Stringer A, Wright MA (1976) The toxicity of benomyl and some related 2-substituted benzimidazoles to the earthworm Lumbricus terrestris. Pest Sci 7:459–464

    Article  CAS  Google Scholar 

  • Sun L, Li D, Dong X, Yu H, Dong JT, Zhang C, Lu X, Zhou J (2008) Small-molecule inhibition of Aurora kinases triggers spindle checkpoint-independent apoptosis in cancer cells. Biochem Pharmacol 75:1027–1034

    Article  PubMed  CAS  Google Scholar 

  • Tageja N, Nagi J (2010) Bendamustine: something old, something new. Cancer Chemother Pharmacol 66:413–423

    Article  PubMed  CAS  Google Scholar 

  • Tajana A, Sibilia C, Cappelletti R, Cova A, Nardi D (1981) Physico-chemical, structural and analytical studies on fenticonazole, a new drug with antimycotic properties. Arzneim Forsch 31:2127–2133

    CAS  Google Scholar 

  • Tarral A, Blesson S, Mordt OV, Torreele E, Sassella D, Bray MA, Hovsepian L, Evene E, Gualano V, Felices M, Strub-Wourgaft N (2014) Determination of an optimal dosing regimen for fexinidazole, a novel oral drug for the treatment of human African trypanosomiasis: first-in-human studies. Clin Pharmacokinet 53:565–580

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Tettenborn D (1974) Toxicity of clotrimazole. Postgrad Med J 50:17–20

    PubMed  CAS  Google Scholar 

  • Thiele K, Zirngibl L, Pfenniger MH, Egli M, Dobler M (1987) Antimycotic imidazolyl-alkenes Synthesis and X-ray crystal structure of omoconazole. Helv Chim Acta 70:441–444

    Article  CAS  Google Scholar 

  • Thomas X, Elhamri M (2007) Tipifarnib in the treatment of acute myeloid leukemia. Biologics 1:415–424

    PubMed  PubMed Central  CAS  Google Scholar 

  • Tiligada E, Zampeli E, Sander K, Stark H (2009) Histamine H3 and H4 receptors as novel drug targets. Expert Opin Invest Drugs 18:1519–1531

    Article  CAS  Google Scholar 

  • Townsendand LB, Wise DS (1990) The synthesis and chemistry of certain anthelmintic benzimidazoles. Parasitol Today 6:107–112

    Article  Google Scholar 

  • Uchida K, Nishiyama Y, Yamaguchi H (2004) In vitro antifungal activity of luliconazole (NND-502), a novel imidazole antifungal agent. J Infect Chemother 10:216–219

    Article  PubMed  CAS  Google Scholar 

  • Unger T, Scholkens BA (ed), Angiotensin Vol. II, Maillard M, Burnier M, Clinical pharmacology of angiotensin II receptor antagonists, Springer:Berlin. (2004) pp 454–476

  • Upton AM, Cho S, Yang TJ, Kim Y, Wang Y, Lu Y, Wang B, Xu J, Mdluli K, Ma Z, Franzblau SG (2015) In vitro and in vivo activities of the nitroimidazole TBA-354 against Mycobacterium tuberculosis. Antimicrob Agents Chemother 59:136–144

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Vahlquist A, Blockhuys S, Steijlen P, Van Rossem K, Didona B, Blanco D, Traupe H (2014) Oral liarozole in the treatment of patients with moderate/severe lamellar ichthyosis: results of a randomized, double-blind, multinational, placebo-controlled phase II/III trial. Br J Dermatol 170:173–181

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Vanden Bossche H (1974) Biochemical effects of miconazole on fungi. Biochem Pharmacol 23:887–899

    Article  CAS  Google Scholar 

  • Varia MA, Calkins-Adams DP, Rinker LH, Kennedy AS, Novotny DB Jr, Fowler WC, Raleigh JA (1998) Pimonidazole: a novel hypoxia marker for complementary study of tumor hypoxia and cell proliferation in cervical carcinoma. Gynecol Oncol 71:270–277

    Article  PubMed  CAS  Google Scholar 

  • Weide R (2008) Bendamustine HCL for the treatment of relapsed indolent non-Hodgkin’s lymphoma. Ther Clin Risk Manag 4:727–732

    PubMed  PubMed Central  CAS  Google Scholar 

  • Wexler RR, Greenlee WJ, Irvin JD, Goldberg MR, Prendergast K, Smith RD, Timmermans PB (1996) Nonpeptide angiotensin II receptor antagonists: the next generation in antihypertensive therapy. J Med Chem 39:625–656

    Article  PubMed  CAS  Google Scholar 

  • Woolley DW (1944) Some biological effects produced by benzimidazole and their reversal by purines. J Biol Chem 152:225–232

    CAS  Google Scholar 

  • Wright JB (1951) The chemistry of the benzimidazoles. Chem Rev 48:397–541

    Article  PubMed  CAS  Google Scholar 

  • Xavier AS, Lakshmanan M (2014) Delamanid: a new armor in combating drug-resistant tuberculosis. J Pharmacol Pharmacother 5:222–224

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yadav G, Ganguly S (2015) Structure activity relationship (SAR) study of benzimidazole scaffold for different biological activities: a mini-review. Eur J Med Chem 97:419–443

    Article  PubMed  CAS  Google Scholar 

  • Yanagiasawa H, Amemiya Y, Kanazaki T, Shimoji Y, Fujimoto K, Kitahara Y, Sada T, Mizuno M, Ikeda M, Miyamoto S, Furukawa Y, Koike H (1996) Nonpeptide angiotensin II receptor antagonists: synthesis, biological activities, and structure-activity relationships of imidazole-5-carboxylic acids bearing alkyl, alkenyl, and hydroxyalkyl substituents at the 4-position and their related compounds. J Med Chem 39:323–338

    Article  Google Scholar 

  • Yanagisawa H, Koike H, Miura S (2012) Case studies in modern drug discovery and development. In: Huang X, Aslanian RG (eds) Olmesartan medoxomil: an angiotensin II receptor blocker. Wiley, USA, pp 46–64

    Google Scholar 

  • Yang Y, Jin C, Li H, He Y, Liu Z, Bai L, Dou K (2012) Improved radiosensitizing effect of the combination of etanidazole and paclitaxel for hepatocellular carcinoma in vivo. Exp Ther Med 3:299–303

    PubMed  PubMed Central  CAS  Google Scholar 

  • Yoshida H, Kasuga O, Yamaguchi T (1984) Studies on antifungal activities of sulconazole. Chemotherapy 32:477–484

    CAS  Google Scholar 

  • Yu F, Bonaventure P, Thurmond RL (2010) Histamine in inflammation. In: Thurmond RL (ed) The future antihistamines: histamine H3 and H4 receptor ligands. Landes Bioscience. Springer, Berlin, pp 125–140

    Google Scholar 

  • Zajac P, Holbrook A, Super ME, Vogt M (2013) An overview: current clinical guidelines for the evaluation, diagnosis, treatment, and management of dyspepsia. Osteopath Fam Physician 5:79–85

    Article  Google Scholar 

  • Zhou Z, Vorperian VR, Gong Q, Zhang S, January CT (1999) Block of HERG potassium channels by the antihistamine astemizole and its metabolites desmethyl astemizole and nor astemizole. J Cardiovasc Electrophysiol 10:836–843

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The author(s) would like to acknowledge Punjab Technical University, Kapurthala, Punjab, India, and ASBASJSM College of Pharmacy, Bela, for providing an institutional research platform and necessary facilities. The authors would like to thank Mr. Sarbjot Singh, Senior Research Scientist at Panacea Biotec Ltd., for proof reading the manuscript and his constant support.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Monika Gaba.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gaba, M., Mohan, C. Development of drugs based on imidazole and benzimidazole bioactive heterocycles: recent advances and future directions. Med Chem Res 25, 173–210 (2016). https://doi.org/10.1007/s00044-015-1495-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-015-1495-5

Keywords

Navigation