Integrated Computational Design, Green Synthesis, and Characterization of 3,4-Dihydropyrimidine Derivatives Targeting Enoyl-Acyl Carrier Protein Reductase for Tuberculosis Treatment

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a contagious infectious disease that mainly affects the lungs but can also involve other organs. Despite being preventable and curable, TB remains a major global health challenge. According to the WHO Global Tuberculosis Report 2025, approximately 10.7 million people developed TB and 1.23 million died from the disease in 2024. The increasing burden of drug-resistant TB (DR-TB) highlights the urgent need for new and effective anti-tubercular drugs. Enoyl-acyl carrier protein reductase (InhA), a key enzyme in the fatty acid synthase II (FAS-II) pathway, plays an essential role in the biosynthesis of mycolic acids required for the mycobacterial cell wall, making it an attractive drug target. Pyrimidine derivatives, particularly 3,4-dihydropyrimidines (DHPMs), possess diverse biological activities and exhibit promising anti-tubercular properties by inhibiting InhA.Computational molecular docking using GEMDOCK was employed to evaluate the binding affinity of synthesized DHPM derivatives toward the InhA enzyme, facilitating efficient drug discovery. The compounds were synthesized through a green, microwave-assisted Biginelli reaction, providing an environmentally friendly and cost-effective approach.FTIR spectroscopy confirmed the presence of characteristic functional groups, indicating successful synthesis of the target compounds and supporting their potential as promising anti-tubercular drug candidates.