Inspired by pharmacophore, the development of new phenylbenzimidazole derivatives: synthesis, characterization and anti-inflammatory activity

Inflammation is a complex biological response governed by intricate interactions among soluble mediators and p38 MAP kinases are one of such mediators. Our previous reported pharmacophore based virtual screening has identified benzimidazole bearing new hits and hence we embarked on the design of novel 2-phenylbenzimidazole amides through molecular hybridization. The designed molecules were synthesized, and characterized by spectroscopic methods. Compounds were subjected for rigorous evaluation for their anti-inflammatory potential in in vivo carrageenan induced paw edema model. Notably, compounds 7c, 7d, and 7k demonstrated potent anti-inflammatory activity and exhibited remarkable inhibitions of 95.65, 96.89 and 97.61%. Additionally, compounds 7i and 7k displayed commendable neuroprotective effect and exhibited notable inhibition of key pro-inflammatory cytokines, including TNF-α and IL-6 levels. Molecular docking studies on p38 kinase carried to explore the putative mechanism of action underlying the observed anti-inflammatory effects. Compounds 7c, 7a, and 7j were found to occupy the active pocket of the kinase by establishing crucial interactions with Met 109, as evidenced by favorable docking energies of -7.4, -9.0 and -7.7 kcal/mol respectively. Molecular dynamics simulations validated the enduring stability of ligands within the binding groove of p38 kinase across a comprehensive 230 ns time scale, providing valuable insights into the molecular underpinnings of their therapeutic efficacy.