Volgograd State Medical University, Pavshikh Bortsov Sq. 1, 400131 Volgograd, Russia.
Research Institute of Physical and Organic Chemistry, Southern Federal University, 194/2 Prosp. Stachki, 344090 Rostov-on-Don, Russia.
Bioorg Med Chem Lett. 2019 Sep 1;29(17):2443-2447. doi: 10.1016/j.bmcl.2019.07.035. Epub 2019 Jul 23.
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 AT 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.
2 型糖尿病是一种复杂的代谢紊乱疾病，需要采用多药物治疗方法进行有效治疗。设计并合成了十五个新的三环苯并咪唑衍生物组合文库，以结合变构 AMPK 激活剂和 AT 受体拮抗剂中常见的片段。研究发现，2'-氰基联苯是 AMPK 激活活性的药效团，其活性随着外部氢化环的扩展而增加。此外，研究化合物还具有明显的抗血小板活性。其中一种衍生物被鉴定为具有反应性二羰基清除活性的新型蛋白糖基化终产物形成抑制剂。两种亚毫摩尔 AMPK 激活剂 2b 和 3b 可防止小鼠巨噬细胞的炎症激活。这些结果表明，与良好的水溶性和合成可用性相结合，这些结果使得融合苯并咪唑的联苯衍生物成为具有多靶点抗糖尿病活性的 AMPK 激活剂的有价值起点。
