Synthesis, Antimicrobial Evaluation, Molecular Docking, and In Silico ADME Analysis of Benzimidazole‐Based 4‐Phenylbut‐3‐en‐2‐imine Schiff Bases

ABSTRACT

A series of novel benzimidazole‐based 4‐phenylbut‐3‐en‐2‐imine Schiff base derivatives ( KP‐1 to KP‐6 ) were designed, synthesized, and evaluated for antimicrobial activity. The target compounds were prepared through a simple multistep synthetic route involving cyclization of O ‐phenylenediamine to afford a benzimidazole intermediate ( 3 ), followed by Claisen–Schmidt condensation and Schiff base formation under mild conditions. The antibacterial activities of the synthesized derivatives were evaluated against selected Gram‐negative and Gram‐positive bacterial strains, using ciprofloxacin as the reference drug. The compounds demonstrated moderate to good antibacterial activity, with MIC values ranging from 20 to 36 µg/mL. Among the derivatives, KP‐1 exhibited the most promising antibacterial activity against both Gram‐negative and Gram‐positive bacteria. Antifungal activity was assessed against Fusarium oxysporum, Fusarium solani , and Penicillium citrinum ( P. citrinum ) with fluconazole as the standard. KP‐4 displayed the best antifungal activity, particularly against P. citrinum . Structure–activity relationship analysis indicated that hydroxyl and methoxy substituents significantly influenced antimicrobial activity. Molecular docking against PDB ID 1RX2 supported the experimental findings, with KP‐1 showing the highest binding affinity (G‐score −8.378; binding energy −73.410 kcal/mol). In silico ADME analysis indicated compliance with Lipinski's rule of five and favorable drug‐like properties.