Convenient Synthesis, Antibacterial Activity, and In Silico Studies of Novel 6-Phenoxy-4,5-dihydro-1,2,6-oxazaphosphinine 6-Oxides

Abstract

Objective: The main objective of this work was to develop a convenient synthesis of a new class of oxazaphosphorines, namely 6-phenoxy-4,5-dihydro-1,2,6-oxazaphosphinine 6-oxides (IVa–IVe), for antibacterial screening. Methods: Oxazaphosphorines (IVa–IVe) were obtained through a three-step approach involving the microwave-assisted conjugative addition of diphenyl phosphite to α,β-unsaturated ketones, followed by oximation and intramolecular cyclization. The newly synthesized oxazaphosphorines were screened for their in vitro antibacterial activity against Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli, Salmonella typhimurium, and Pseudomonas aeruginosa) bacteria. The obtained results were also correlated with the in silico molecular docking studies in DNA gyrase enzyme active site. Results and Discussion: Oxazaphosphorines (IVa–IVe) were obtained in 47–60% yields. The biological assays showed that these compounds exhibited appreciable antibacterial activity. Compound (IVe) was found to be the most potent antibacterial agent with an inhibition zone diameter of 9.66 ± 0.89 mm, and MIC and MBC values of 10 and 25 mg/mL respectively, when tested against S. typhimurium. We also observed a fairly good agreement between these experimental in vitro antibacterial outcomes and the in silico molecular docking results in DNA gyrase enzyme active site. Conclusions: We have successfully developed a convenient synthesis of a new class of oxazaphosphorines, namely 6-phenoxy-4,5-dihydro-1,2,6-oxazaphosphinine 6-oxides (IVa–IVe). When screened for their in vitro antibacterial activity, compound (IVe) was found to be the most potent antibacterial agent. We tried to correlate these results with those obtained in the in silico molecular docking study. The obtained results suggest that the synthesized compound (IVe) is a potential DNA gyrase inhibitor and could be used as a lead compound for developing new potent antibacterial drugs.