Molecularly Modified Benzimidazole Derivatives: Rational Design and Antimicrobial Potentials for Next-Generation Therapeutics

Abstract

This review presents the rational design, structure-activity relationships, and antimicrobial potential of molecularly modified benzimidazole derivatives as next-generation therapeutics. Addressing the urgent challenge of antimicrobial resistance, the paper details how strategic substitutions at key positions (N1, C2, C5, C6) and the introduction of functional groups (urea, thio-urea, heteroaromatic) enhance biological activity against a broad spectrum of bacteria and fungi. The analysis combines computational, SAR, and docking studies to explain the multi-target mechanisms enzyme inhibition, DNA intercalation, membrane disruption, and redox interactions driving the superior potency, selectivity, and pharmacokinetics of these analogs. The review also discusses hurdles in synthesis, toxicity, and clinical translation, emphasizing the future promise of hybrid molecules, metal complexes, and nanocarrier systems. Overall, benzimidazoles emerge as highly adaptable scaffolds for developing effective therapies to combat microbial resistance and improve clinical outcomes.