Coumarin‐Benzimidazole Hybrids as Multitarget Scaffolds for Antileishmanial Drug Discovery

Abstract

Leishmaniasis is a globally distributed zoonosis and a major challenge to public health, with increasing incidence and limited therapeutic options marked by toxicity and emerging resistance. Aiming to identify safer and more effective alternatives for disease control, this study evaluated the antileishmanial potential of coumarin‐benzimidazole hybrids through structure‐based virtual screening, targeting two essential enzymes of Leishmania spp., Cathepsin B (CatB), and N‐myristoyltransferase (NMT). Molecular docking simulations revealed higher binding affinities for all hybrids compared with the reference drug miltefosine (MTF), with CBZ2 and CBZ3 showing the strongest interactions with CatB and NMT, respectively. Molecular dynamics simulations (200 ns) confirmed the conformational stability of these complexes, supported by Root‐mean‐square deviation (RMSD)/Root‐mean‐square fluctuation (RMSF) analyses and persistent hydrogen bonds. MM/GBSA calculations further indicated favorable binding free energies. Additionally, CBZ2 and CBZ3 presented a favorable balance between permeability and lipophilicity, suggesting adequate passive membrane diffusion and a viable predicted pharmacokinetic profile. These findings highlight coumarin‐benzimidazole hybrids as promising candidates for future antileishmanial drug development research.