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.