Synthesis of new dihydropyrimidine derivatives and investigation of their antimicrobial and DNA gyrase inhibitory activities

Abstract

Quinolone antibiotics are known for their antibacterial activity by inhibiting the enzyme DNA gyrase. Inspired by their mechanism, new compounds combining 1,4-dihydropyrimidine, a quinolone isostere, with pyridine/pyrimidine rings were synthesized. These derivatives showed antibacterial effects, likely through DNA gyrase inhibition, as supported by molecular docking and dynamics simulations. The synthesized compounds, 2-[(5-cyano-6-oxo-6-(pyridin-4-yl)-1,6-dihydropyrimidin-2-yl]-N-(benzothiazol-2-yl)-acetamide (5a-5g) and 2-[(5-cyano-6-oxo-6-(pyridin-4-yl)-1,6-dihydropyrimidin-2-yl)thio]-N-(thiazol-2-yl)acetamide (6a-6f), were evaluated for antibacterial activity. Compounds 5a, 6b, and 6c demonstrated significant bactericidal effects. Against Escherichia coli, compounds 6b and 6c exhibited minimum inhibitory concentration (MIC) values of 1.95 and 0.97 µg/mL, respectively, comparable to the standard drug. Compound 5a also showed strong activity against Escherichia faecalis. DNA gyrase inhibition studies confirmed that 5a, 6b, and 6c inhibit the enzyme, as no supercoiled DNA band was observed. These findings highlight the potential of these compounds as antibacterial agents. Future development could focus on optimizing these structures for enhanced activity, similar to quinolone antibiotics. © 2025 Deutsche Pharmazeutische Gesellschaft.