Benzimidazole scaffolds are widely recognized as important structural motifs in medicinal chemistry; however, their potential to function as dual-acting agents against both oxidative stress and parasitic infections have not been extensively explored. In the present study, two novel benzimidazole derivatives a thiazine-conjugated analogue (Thz-BZIM) and an N-tosylated analogue (Ts-BZIM) were examined. Quantum chemical calculations suggest that these compounds possess notable radical-scavenging capability, primarily through favorable electron and proton transfer mechanisms. This behavior is further supported by thermochemical parameters and electronic structure descriptors that indicate good redox stability. Molecular docking studies reveal distinct target selectivity: Thz-BZIM preferentially binds to human 11β-hydroxysteroid dehydrogenase type 1 (HSD1, PDB ID: 2IRW), a regulator of metabolic inflammation; while Ts-BZIM shows favorable interactions with Leishmania major glycogen synthase kinase-3α (LmGSK-3α, PDB ID: 3E3P), which is essential for parasite survival. Furthermore, molecular dynamics simulations and pharmacophore modeling demonstrate the stability of the protein-ligand complexes and reveal consistent binding modes within the respective target proteins. ADMET evaluation also indicates that both derivatives possess favorable drug-like characteristics. Collectively, these results underscore the multifunctional potential of benzimidazole-based antioxidants, suggesting their ability to interact with different protein targets while preserving their antioxidant properties. Although further experimental validation is required, this in silico study provides valuable insights into protein-ligand interactions and establishes a rational foundation for the development of multifunctional therapeutics with potential relevance to metabolic disorders and parasitic infections.
Ahmed et al. (Wed,) studied this question.