Design, synthesis and molecular modelling of phenoxyacetohydrazide derivatives as Staphylococcus aureus MurD inhibitors
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ORIGINAL PAPER
Design, synthesis and molecular modelling of phenoxyacetohydrazide derivatives as Staphylococcus aureus MurD inhibitors Srikanth Jupudi1 · Mohammed Afzal Azam1 · Ashish Wadhwani2 Received: 2 March 2020 / Accepted: 27 September 2020 © Institute of Chemistry, Slovak Academy of Sciences 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 I C50 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
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11696-020-01380-2) contains supplementary material, which is available to authorized users. Extended author information available on the last page of the article
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Chemical Papers
Keywords Phenoxyacetohydrazides · Minimum inhibitory concentration · MurD · Staphylococcus aureus · IC50 Abbreviations DAP 2,6-Diaminopimelic acid D-Glu D-glutamic acid MurC UDP-N-acetylmuramoyl-L-alanine ligase MRSA Methicillin-resistant Staphylococcus aureus MIC Minimum inhibitory concentration MBC Minimum bactericidal concentration MurD UDP-N-acetylmuramoyl-L-alanine:D-glutamate ligase MurE ligase UDP-N-acetylmuramoyl-L-alaninyl-D-glutamate-2,6-diaminopimelate (or L-lysine) ligase MurF ligase UDP-N-acetylmuramoyl-L-alanine-D-glutamyl-lysine-D-alanyl-D-alanine ligase MurNAc N-Acetyl muramic acid; UDP: uridine-5′-diphosphate UMA Uridine-5′-diphosphate-N-acetylmueamoyll-alanine RMSD Root mean square deviation UMAG UDP-N-acetylmuramoyl-L-alanine-D-glutamate
Introduction Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are major public health threat worldwide. MRSA is responsible for morbidity and mortality (Kong et al. 2016; Hamdy et al. 2017) with an alarming rise of resistance to most of the available antibiotics (Macmorran et al. 2017). This instigated new research effort to develop new class of antibacterial a
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