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Design, synthesis and molecular modelling of phenoxyacetohydrazide derivatives as Staphylococcus aureus MurD inhibitors

Srikanth Jupudi, Mohammed Afzal Azam, and Ashish Wadhwani

Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Ooty, India

 

E-mail: afzal9azam@hotmail.com

Received: 2 March 2020  Accepted: 27 September 2020

Abstract:

In the present work we synthesized a new series of phenoxyacetohydrazide functional compounds 4a-k and characterized by spectral data. Synthesized compounds were screened in vitro for their antibacterial activity. Compounds 4a, 4j and 4k exhibited inhibitory activity against S. aureus NCIM 5022 with MIC value of 64 µg/ml These compounds also exhibited activity against methicillin resistant S. aureus ATCC 43300 with MIC of 128 µg/ml. Among all the tested compounds 4c and 4j showed highest activity, respectively against B. subtilis NCIM 2545 and K. pneumoniae NCIM 2706. Only one compound i.e. 4d showed activity against another Gram-negative bacteria P. aeruginosa NCIM 2036 with MIC value of 64 µg/ml. Among three tested compounds, 4k exhibited highest inhibitory activity against S. aureus MurD enzyme with IC50 value of 35.80 µM. Further binding interactions of 4a-k with the modelled S. aureus MurD catalytic pocket residues is investigated with the extra-precision molecular docking and binding free energy calculation by MM-GBSA approach. The van der Waals energy term was observed to be the driving force for binding. Further, 50 ns molecular dynamics simulations were performed to validate the stabilities of 4j- and 4k-modelled S. aureus MurD.

Graphic abstract

Keywords: Phenoxyacetohydrazides; Minimum inhibitory concentration; MurD; Staphylococcus aureus; IC50

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-020-01380-2

 

Chemical Papers 75 (3) 1221–1235 (2021)

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