Monocyclic β-lactam and unexpected oxazinone formation: synthesis, crystal structure, docking studies and antibacterial evaluation

Abstract

Novel monocyclic β-lactam derivatives bearing aryl, phenyl and heterocyclic rings were synthesized as possible antibacterial agents. Cyclization of imines (3h, 3t) with phenylacetic acid in the presence of phosphoryl chloride and triethyl amine did not afford the expected β-lactams. Instead, highly substituted 1,3-oxazin-4-ones (4h, 4t) were isolated as the only product and confirmed by single crystal X-ray analysis of 4t. The results of antibacterial activity showed that compound 4l exhibited considerable antibacterial activity with MIC and MBC values of 62.5 µg/mL against Klebsiella pneumoniae. Cytotoxicity assay on Chinese Hamster Ovary (CHO) cell line revealed non-cytotoxic behavior of compounds 4d, 4h, 4k and 4l up to 200 μg/mL conc. Molecular docking was performed for compound 4l with penicillin binding protein-5 to identify the nature of interactions. The results of both in silico and in vitro evaluation provide the basis for compound 4l to be carried as a potential lead molecule in the drug discovery pipeline against bacterial infections.

• 1,3-Oxazin-4-one
• antibacterial
• cytotoxicity
• docking
• β-lactam

Acknowledgements

The authors are thankful to Prof. S. Chandershekhran, Department of Organic Chemistry, IISc Bangalore for providing DEPT spectrum.

Declaration of interest

Authors have no conflict of interest. Mohammad Abid gratefully acknowledges the Young Scientist Award from Science & Engineering Research Board (Grant No. SR/FT/LS-03/2011), Govt. of India, New Delhi, India. U.Y. acknowledges UGC for “Raman Research Fellowship Award”. B.A. and M.I. would like to acknowledge UGC for non-NET fellowship.

Supplementary materials online only

CCDC1022181–1022182 contains the supplementary crystallographic data for 4t and 4e reported in this article. This data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/. Supplementary data includes X-ray crystallographic analysis of 4e and 4t.