Design, synthesis, bioactivity evaluation, and molecular modeling of pyridin-2-yl-pyrimidine: potential antimicrobial and anti-tuberculosis agents

The rise in antimicrobial resistance has underscored the urgent need for novel therapeutic agents. Pyrimidine derivatives, known for their broad-spectrum antimicrobial activity, have emerged as promising candidates. A new series of fused pyrimidine-5‑carbonitrile derivatives were synthesized and evaluated for their antibacterial, antifungal, and anti-tuberculosis (anti-TB) activities. Molecular docking studies were conducted to assess their binding affinity with the InhA enzyme, a key component in bacterial fatty acid synthesis, and compared their effectiveness to Ciprofloxacin. These compounds were synthesized using standard organic methods and characterized by NMR, mass spectrometry, and other spectroscopic techniques. Antibacterial and antifungal activities were evaluated using the agar well-diffusion and cup-plate agar diffusion methods, respectively. Anti-TB activity was assessed against the MTB H37Ra strain using the Resazurin assay. The Minimum Inhibitory Concentration (MIC) values ranged from 10.6 to 17.8 μg/mL, indicating potent antibacterial activity, particularly against both Gram-positive and Gram-negative bacteria for compounds 2a1, 2a3 and 2a20. Structural-activity relationship (SAR) studies revealed that lipophilic and electron-withdrawing groups enhanced antimicrobial potency. The promising results of compounds 2a1 and 2a20 highlight their potential as lead candidates in the development of new antimicrobial and anti-TB therapies.