Design and Amberlyst-15 mediated synthesis of novel thienyl-pyrazole carboxamides that potently inhibit Phospholipase A2 by binding to an allosteric site on the enzyme

Dileep Kumar, A. and Prabhudeva, M. G. and Bharath, Srinivasan and Karthik Kumara and Lokanath, N. K. and Ajay Kumar, K. (2018) Design and Amberlyst-15 mediated synthesis of novel thienyl-pyrazole carboxamides that potently inhibit Phospholipase A2 by binding to an allosteric site on the enzyme. Bioorganic Chemistry, 80. 444 - 452. ISSN 1090-2120

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Official URL: https://doi.org/10.1016/j.bioorg.2018.06.023

Abstract

Inflammation-mediated disorders are on the rise and hence, there is an urgent need for the design and synthesis of new anti-inflammatory drugs with higher affinity and specificity for their potential targets. The current study presents an effective and new protocol for the synthesis of thienyl-pyrazoles through 3 + 2 annulations using a recyclable heterogeneous catalyst Amberlyst-15. Chalcones 3(a-g) prepared from 3-methylthiophene-2-carbaldehyde and acetophenones by Claisen-Schmidt approach reacted with semicarbazide hydrochloride 4 in the presence of Amberlyst-15 in acetonitrile at room temperature producing thienyl-pyrazole carboxamides 5(a-h) in good yields. Alternatively, the compounds 5(a-h) were prepared by conventional method using acetic acid (30) medium. Structures of synthesized new pyrazoles were confirmed by spectral and crystallographic studies. All the new compounds were evaluated for their in vitro inhibition of Phospholipase A2 from Vipera russelli and preliminary studies revealed that, amongst the designed series, compounds 5b, 5c and 5h showed promising inhibition. Further, the compounds exhibited linear mixed-type inhibition behavior for the sPLA2 enzyme indicating that they bind to an allosteric site distinct from either the calcium or substrate binding site on the enzyme. These kinetic conclusions were further validated by macromolecular rigid-body docking whereby compounds 5c and 5h showed binding to distinct pockets on the protein. These findings present a promising series of lead molecules that can serve as prototypes for the treatment of inflammatory related disorders.

Item Type: Article
Uncontrolled Keywords: Anti-inflammatory, Chalcone, Condensation, Pyrazole, Thiophene
Subjects: C Chemical Science > Chemistry
Divisions: Yuvaraj college > Chemistry
Depositing User: manjula User
Date Deposited: 06 Jul 2019 07:42
Last Modified: 06 Jul 2019 07:42
URI: http://eprints.uni-mysore.ac.in/id/eprint/4827

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