Design, Synthesis, and Antibacterial Evaluation of Pyrazole Pyrimidine Hybrids: Integrative In Vitro and In Silico Studies

Abstract

Several novel pyrimidine–pyrazole hybrids were synthesized and evaluated for their antimicrobial potential against diverse bacterial pathogens, focusing on targeting penicillin-binding protein 3 (PBP3), a key enzyme in bacterial cell wall synthesis. Among the tested derivatives, seven derivatives exhibited significant antibacterial activity against E. faecium at 50–200 µg/mL with the cyclopentane-substituted compound (6d) showing the highest activity (50 µg/mL). Notably, the 3-fluoro,5-trifluoromethyl compound (6a) demonstrated broad-spectrum activity (200 µg/mL) against S. aureus, E. faecium, A. baumannii, and K. pneumoniae. Docking studies revealed strong binding affinity with HMG-CoA synthase, an essential enzyme in bacterial metabolism. In silico pharmacokinetic predictions indicated favourable safety profiles and drug-likeness. These results suggest pyrimidine–pyrazole hybrids as promising antibacterial agents targeting PBP3, warranting further investigation through enzymatic inhibition assays and in vivo studies.