Towards multi-target antidiabetic agents: Discovery of biphenyl-benzimidazole conjugates as AMPK activators

[Display omitted] •New biphenyl derivatives of tricyclic benzimidazoles were synthesized.•2′-Cyanobiphenyl was identified as novel pharmacophore of AMPK-activating activity.•Lead compounds demonstrate submicromolar potency towards AMPK.•One of lead compounds target AMPK and AT1 receptor simultaneously.•One of derivatives is a potent inhibitor of advanced protein glycation end-products. Type 2 diabetes mellitus is a complex metabolic disorder requiring polypharmacology approaches for effective treatment. Combinatorial library of fifteen new tricyclic benzimidazole derivatives have been designed and synthesized to combine fragments commonly found in allosteric AMPK activators and AT1 receptor antagonists. It was found that 2′-cyanobiphenyl serves as the pharmacophore of AMPK-activating activity, which also increases with the expansion of the external hydrogenated cycle. Also, pronounced antiplatelet activity is characteristic of the studied compounds. One of derivatives was identified as a potent inhibitor of the formation of advanced protein glycation end-products with reactive dicarbonyl scavenging activity. Two submicromolar AMPK activators 2b and 3b prevents inflammatory activation of murine macrophages. Along with good water solubility and synthetic availability, these results render biphenyl derivatives of fused benzimidazoles as a valuable starting point for the development of AMPK activators with multi-target antidiabetic activity.