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 IC50 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.
Keywords: Gli1, hedgehog signaling; Smo; aminothiazole; benzimidazole; cytotoxicity; synthesis.
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