Synthesis and molecular docking of novel pyrazole, pyrimidine, and pyridine derivatives as potent antimicrobial, antibiofilm, and anticancer agents

Abstract

Abstract The development of novel antimicrobial and anticancer agents remains a priority due to rising drug resistance and high systemic toxicity of current treatments. A series of novel pyrazole ( 2–6 ), pyrimidine ( 7–10 ), and pyridine/oxazinone ( 11–14 ) derivatives were synthesized from a chalcone scaffold ( 1 ). They were evaluated for antimicrobial, antibiofilm ( Pseudomonas aeruginosa ), and cytotoxic (HepG2 cells) activities. Molecular docking and qRT-PCR were performed to study their mechanism. Pyrazoles 3–5 and oxazinone 13 showed potent antibacterial activity against S. aureus (MIC = 2–3.12 µg/mL). Compounds 4 and 13 effectively eradicated P. aeruginosa biofilms, achieving a ≥ 5 log 10 reduction within 4 h at 0.8 × MIC, driven by disruption of the bacterial respiratory chain. For anticancer activity, compounds 10 and 13 selectively reduced HepG2 cell viability to 35–40% via oxidative stress-mediated apoptosis. Mechanistically, compound 4 reduced gyrB expression in E. coli by approximately 4.6-fold, while molecular docking supported its interaction with the ATP-binding pocket of DNA gyrase. Overall, the functionalized heterocycles, particularly compounds 4 and 13 , represent promising dual-acting candidates with potent antibacterial, antibiofilm, and selective anticancer activities.