Design and structure–activity relationship of 3-benzimidazol-2-yl-1H-indazoles as inhibitors of receptor tyrosine kinases

Benzimidazole: a medicinally important heterocyclic moiety

“…In a study of some novel fused heterocyclic compounds as eukaryotic topisomerase II inhibitors, it was observed that 5-methylcarboxylate-2-phenylthiomethylbenzimidazole, 12, was more active than the reference drug etoposide (McBride et al, 2006). DNA topoisomerase are ubiquitous enzymes that control and modify the topological states of DNA (Pinar et al, 2004).…”

Synthesis and characterization of 1'-benzyl-1,4'-dimethyl-2'propyl-1H,1'H-2,6'-dibenzimidazole derivatives and their antibacterial activity studies

“…Benzimidazole derivatives have been reported to have various bioactivities, including antiviral [3][4][5][6], antihypertensive [7], antimicrobial [8,9], antioxidant [10], anti-inflammatory [11] and anticancer [12][13][14][15][16][17][18][19][20] activities. There are several marketed benzimidazole based drugs, such as Astemizole (Janssen Pharmaceutica), Micardis (Boehringer Ingelheim), Omepraxole (Astra Zeneca) and Albendazole (GlaxoSmithKline) [3].In particular, benzimidazole derivatives have been explored as anticancer inhibitors of Topoisomerase I [12], PARP-1 [13,14], kinase Chk2 [15,16], Pgp and DNA synthesis [17], and tyrosine kinases [18][19][20].…”

“…There are several marketed benzimidazole based drugs, such as Astemizole (Janssen Pharmaceutica), Micardis (Boehringer Ingelheim), Omepraxole (Astra Zeneca) and Albendazole (GlaxoSmithKline) [3].In particular, benzimidazole derivatives have been explored as anticancer inhibitors of Topoisomerase I [12], PARP-1 [13,14], kinase Chk2 [15,16], Pgp and DNA synthesis [17], and tyrosine kinases [18][19][20]. Nonetheless, to the best of our knowledge, although several benzimidazole series have been developed as tyrosine kinase inhibitors, the 2-aryl benzimidazole series have not been explored as multi-target EGFR, VEGFR-2 and PDGFR inhibitors in published reports.…”

3-Benzimidazol-2-yl-1H-indazoles as potent c-ABL inhibitors

“…6-8 The 3-benzimidazol-2-yl-1H-indazole (3, hereafter referred to as indazole benzimidazole) series was designed, and the SAR explored. 9 During the course of that work, a subset of compounds was identified as potent c-ABL inhibitors. This SAR was developed and is presented here.…”

“…Compounds containing the piperidinylpiperidine amine inhibited other RTKs potently and exhibited good inhibition of cellular proliferation. 9 This moiety, then, was used in expanding the SAR around the subset of compounds shown to exhibit potent c-ABL activity. Compound 4 (Table 1), with no functionality on ring A, moderately inhibits c-ABL phosphorylation at 0.60 lM similar to the potency exhibited by Gleevec TM (1, 0.43 lM).…”