Synthesis and Evaluation of Aminothiazole Derivatives as Hedgehog Pathway Inhibitors

Abstract

A series of aminothiazole derivatives bearing the benzimidazole moiety were synthesized and evaluated in Gli luciferase reporter assays. Lead optimization led to the discovery of potent hedgehog pathway antagonist 18 (2-[3-(1H-benzimidazol-2-yl)-4-chloroanilino]-N-[4-(trifluoromethyl)phenyl]-1,3-thiazole-4-carboxamide), with IC 50 values in nanomolar range. The molecular basis ascribed to hindering sonic hedgehog-driven Smoothened (Smo) localization within the primary cilium (PC). Moreover, compound 18 inhibited Gli1 mRNA expression in mutant Smo cell line and displayed moderate cytotoxicity against DAOY cancer cell.Figure 5. A) Cell viability of astrocytes and GES-1 cells treated with the indicated doses of compound 18 for 24 h. B) Cell viability of DAOY cells incubated with the indicated doses of vismodegib and compound 18 for 48 h. Error bars represent standard deviation of three parallel groups (n = 3).

Benzimidazole hybrids as anticancer drugs: An updated review on anticancer properties, structure–activity relationship, and mechanisms of action (2019–2021)

“…The benzimidazole-thiazole hybrids exhibited considerable antiproliferative activity, [49][50][51][52] and among them, hybrid 19 (Figure 4; IC 50 : 2.4-12.0 µM, MTT assay) was active against HT-29, DU145, A549, and MDA-MB-231 cancer cell lines and the activity was comparable to that of doxorubicin (IC 50 : 1.8 µM) against A549 cells. [52] The SAR indicated that the introduction of hydrazine into thiazole moiety was permitted and hybrid 20 (IC 50 : 6.3 µM, MTT assay) was not inferior to erlotinib (IC 50 : 4.2 µM) against MCF-7 cells.…”