Design, synthesis, and antimicrobial evaluation of novel quinazoline piperazine phosphorodiamidate hybrids as potent DNA gyrase inhibitors

Abstract

Abstract Antimicrobial resistance poses a critical challenge to global public health, exacerbating morbidity and mortality associated with bacterial infections. This study addresses the urgent need for novel antibacterial agents by exploring the design and synthesis of quinazoline-piperazine phosphorodiamidate hybrids (6a-g) as potential DNA gyrase inhibitors. Antibacterial activity was evaluated using the agar well diffusion method, revealing significant inhibition zones for compounds 6f, 6 g, 6a, and 6c compared to the standard drug Amoxyclav. Minimum inhibitory concentration (MIC) measurements further supported the potent antibacterial effects of these compounds. Additionally, compounds 6f, 6 g, and 6a exhibited notable antifungal activity superior to Fluconazole. Molecular docking simulations against DNA gyrase demonstrated strong binding affinities of compounds 6f and 6a with dock scores surpassing that of a standard antibiotic, ciprofloxacin. Detailed analysis of binding interactions highlighted key residues involved in stabilizing the ligand-protein complexes, providing insights into their mechanism of action. Furthermore, in silico ADMET prediction studies revealed that the targeted analogs satisfied the drug like characteristics of CNS acting drugs against antimicrobial diseases.