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A new efficient domino approach for the synthesis of coumarin-pyrazolines as antimicrobial agents targeting bacterial D-alanine-D-alanine ligase

Abstract

Inhibition of D-alanine-D-alanine ligase (Ddl) prevents bacterial growth, which makes this enzyme an attractive and viable target in the urgent search of novel effective antimicrobial drugs. In this work, a series of novel coumarin linked pyrazoline inhibitors of D-alanine-D-alanine ligase were synthesized and evaluated as inhibitors of Escherichia coli DdlB ligase in order to target resistant strain of bacteria by using environmentally benign β-cyclodextrin as a supramolecular catalyst via one-pot four component synthesis in water as a green reaction media. All the newly synthesized compounds have been characterized by elemental analysis and various spectroscopic methods. The new procedure has noteworthy advantages including easy work-up, short reaction times, high yields of products and column free synthesis. The synthesized compounds were evaluated in vitro for their antimicrobial activity. Among the synthesized compounds, namely 3-(5-(4-hydroxy-3-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)-2H-chromen-2-one (5f) was found to be the most potent D-Alanine-D-Alanine ligase enzyme inhibitor with IC50 value 106 M and the compound 3-(5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-2H-chromen-2-one (5g) was found to be the second most potent inhibitor of the DdlB enzyme with IC50 value 111 M against the standard D-Cycloserine. In addition, SAR study provides the evidence that -OH, -CH3 and –OCH3 group at 4- and 3-position of the coumarins linked to pyrazolines scaffold is increasing the enzymatic inhibition, followed by the molecular docking study of most active compounds 5a, 5g, and 5j against DdlB enzyme of E. coli exhibited good binding properties.

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Supplementary files

Publication details

The article was received on 09 Feb 2019, accepted on 06 May 2019 and first published on 06 May 2019


Article type: Paper
DOI: 10.1039/C9NJ00703B
New J. Chem., 2019, Accepted Manuscript

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    A new efficient domino approach for the synthesis of coumarin-pyrazolines as antimicrobial agents targeting bacterial D-alanine-D-alanine ligase

    A. V. CHATE, A. A. Redlawar, G. M. Bondle, A. Sarkate, S. V. Tiwari and D. Lokwani, New J. Chem., 2019, Accepted Manuscript , DOI: 10.1039/C9NJ00703B

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