Design, Synthesis, and Structure–Activity Relationship (SAR) Studies of Novel Disubstituted Benzimidazole Derivatives as Potential Anti-HIV and Antimicrobial Agents

Human immunodeficiency virus (HIV), the causative agent of acquired immunodeficiency syndrome (AIDS), significantly weakens the immune system, increasing susceptibility to opportunistic infections such as tuberculosis, bacterial, and fungal diseases. In this study, a series of 17 novel benzimidazole-based derivatives were designed and synthesized via a reflux method using potassium carbonate as a catalyst. Structural confirmation of the synthesized molecules was achieved through advanced spectroscopic techniques, including proton and carbon nuclear magnetic resonance (¹H-NMR and ¹³C-NMR), mass spectrometry, and elemental analysis. The compounds were evaluated for their potential antiviral (anti-HIV), anti-mycobacterial, antibacterial, and antifungal activities. One of the synthesized benzimidazole derivatives demonstrated remarkable HIV inhibition, achieving approximately 88% relative inhibition. Another analog exhibited strong anti-mycobacterial activity against Mycobacterium smegmatis with a minimum inhibitory concentration (MIC) of 0.195 µg/mL, and also showed potent antibacterial effects against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa, with MIC values ranging from 3.125 µg/mL to 6.25 µg/mL. Additionally, a different benzimidazole derivative displayed significant antifungal activity, with MIC values of 6.25 µg/mL against Candida albicans and 3.125 µg/mL against Aspergillus niger. To gain insights into the molecular interactions and pharmacokinetic profiles, molecular docking studies and in silico ADME (Absorption, Distribution, Metabolism, and Excretion) predictions were conducted on the most active compounds. The results underscore the potential of benzimidazole-based scaffolds as promising multifunctional agents targeting HIV and co-infecting microbial pathogens.