Theoretical Calculations and Experimental Verification of the Antibacterial Potential of Some Monocyclic β-Lactams Containing Two Synergetic Buried Antibacterial Pharmacophore Sites

Abstract

A new series of N-thiazole, 3-phenyl, 4-substituted phenyl azetidine-2-ones 4(a–h) have been synthesized in good yields starting from 2-aminothiazole 1. In the first step, then Schiff's bases 3(a–h) are prepared by the condensation of 2-aminothiazole 1 with different aryl aldehydes 2(a–h). Finally, monocyclic β-lactams, i.e. substituted azetidinones 4(a–h), were the products formed using three different methods by the dehydrative cyclocondensation of 3(a–h) with phenyl acetyl chloride in dioxane, phenyl acetic acid–thionyl chloride in dichloromethane and phenyl acetic acid–phosphorus oxychloride in dichloromethane in the presence of triethylamine. We found that latter method is the best as compared with the former two methods. The synthesized molecules 4(a–h) were screened for their antibacterial activity against four microorganisms: Staphylococcus aureus (Gram positive), Pseudomonas vulgaris (Gram positive), Pseudomonas aeruginosa (Gram negative), and Escherichia coli (Gram negative). Their antibacterial activities are reported, and on the basis of the screening data available, attempt is also made to elucidate the structure–activity relationship.

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Keywords:

• Antibacterial
• β-lactams
• Petra/Osiris/Molinspiration (POM) model
• SAR
• Schiff's bases
• virtual screening

Acknowledgments

This work is dedicated to Prof. Dr. Johann Gasteiger for his bioinformatic multiple services.

Financial support from University Grants Commission, New Delhi, is highly acknowledged. We are grateful to HEJ Research Institute of Chemistry, University of Karachi, for the help in undertaking NMR spectra and biological assay. Prof. T. Ben Hadda would like to thank ACTELION, the Biopharmaceutical Company of Switzerland, and in particular Dr. Johann Gasteiger for the on-line molecular properties calculations and precious and continuous help and discussion.