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Synthesis of novel 2-pyrazoline analogues with potent anti-inflammatory effect mediated by inhibition of phospholipase A2: Crystallographic,in silico docking and QSAR analysis
Authors:Devirammanahalli Mahadevaswamy Lokeshwari  Dileep Kumar Achutha  Bharath Srinivasan  Naveen Shivalingegowda  Lokanath Neratur Krishnappagowda  Ajay Kumar Kariyappa
Institution:1. Department of Chemistry, Yuvaraja College, University of Mysore, Mysuru, India;2. Center for the Study of Systems Biology, School of Biology, Georgia Institute of Technology, Atlanta, GA 30332, USA;3. Institution of Excellence, Vignan Bhavan, University of Mysore, Mysuru, India;4. Department of Studies in Physics, University of Mysore, Manasagangotri, Mysuru, India
Abstract:Oxidative-stress induces inflammatory diseases. Further, infections caused by drug-resistant microbial strains are on the rise. This necessitates the discovery of novel small-molecules for intervention therapy. A series of 3-(2,3-dichlorophenyl)-1-(aryl)prop-2-en-1-ones are synthesized as intermediates via Claisen-Schmidt reaction approach. Subsequently, these intermediates were transformed into 2-pyrazolines by their reaction with phenylhydrazine hydrochlorides in methanol and few drops of acetic acid under reflux conditions. Synthesized compounds were characterized by spectroscopic, crystallographic and elemental analyses studies and then, were evaluated for their in vitro antimicrobial and anti-inflammatory activities. Amongst the series, 3-(4-chlorophenyl)-5-(2,3-dichlorophenyl)-1-phenyl-4,5-dihydro-1H-pyrazole (5e), 5-(2,3-dichlorophenyl)-3-(4-fluorophenyl)-1-phenyl-4,5-dihydro-1H-pyrazole (5c) and 5-(2,3-dichlorophenyl)-3-(4-methoxyphenyl)-1-phenyl-4,5-dihydro-1H-pyrazole (5h) showed significant inhibition of phospholipase A2 with IC50 values of 10.2, 11.1 and 11.9 µM, respectively. Protein structure modelling and docking studies indicated that the compounds showed binding to a highly conserved calcium-binding pocket on the enzyme. Further, compounds (5e), 1-(3-chlorophenyl)-5-(2,3-dichlorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazole (5b), and 1-(3-chlorophenyl)-3-(4-chlorophenyl)-5-(2,3-dichlorophenyl)-4,5-dihydro-1H-pyrazole (5f) showed excellent antimicrobial activities against various bacterial and fungal strains. In conclusion, this study is a successful attempt at the synthesis and characterization of chalcone derivatives that can target phospholipase A2, an enzyme that is a prominent player in the physiological inflammatory cascade. Thus, these compounds show promise for development as next-generation nonsteroidal anti-inflammatory drugs.
Keywords:PLA2  phospholipase A2  COX-2  cyclooxeganse-2  LOX  Lipoxygenases  MIC  minimum inhibitory concentration  NSAIDs  Nonsteroidal anti-inflammatory drugs  Anti-inflammatory  Antimicrobial  MIC  Pyrazole  Chalcone  Phospholipase A2
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