Design, synthesis and biological evaluation of benzimidazole carbamide derivatives - potential autophagy inducers

Herein, we report a convenient synthetic approach and an in vitro evaluation of benzimidazole carbamide derivatives as potential autophagy activators. Two compounds exhibited autophagy-inducing activity at concentrations ≥100 μM. The most favorable activity-toxicity profile was observed for a benzimidazole derivative lacking a carbamide fragment. Mechanistic studies indicated that the compounds predominantly act via the AMPK pathway, while generally showing low selectivity toward individual components of this signaling cascade. Notably, the derivative bearing a pyridyl substituent in the carbamide moiety and a methylated benzimidazole core preferentially targeted AMPK within the signaling cascade. Overall, the synthesized benzimidazoles can be considered mild autophagy activators and relatively broad modulators of cellular signaling.