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

被引:18
作者
Kumar, Achutha Dileep [1 ]
Prabhudeva, Malledevarapura Gurumurthy [1 ]
Bharath, Srinivasan [2 ]
Kumara, Karthik [3 ]
Lokanath, Neratur Krishnappagowda [3 ]
Kumar, Kariyappa Ajay [1 ]
机构
[1] Univ Mysore, Yuvaraja Coll, Dept Chem, Mysuru 570005, India
[2] Marie Sklodowska Curie Act, Rua Quinta Grande, P-2780156 Oeiras, Portugal
[3] Univ Mysore, Dept Studies Phys, Mysuru 570006, India
关键词
Anti-inflammatory; Chalcone; Condensation; Pyrazole; Thiophene; BIOLOGICAL EVALUATION; CHALCONE DERIVATIVES; CRYSTAL-STRUCTURE; DOCKING; A(2); CYCLOOXYGENASES; LIPOXYGENASE; ANALOGS;
D O I
10.1016/j.bioorg.2018.06.023
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 sPLA(2) 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.
引用
收藏
页码:444 / 452
页数:9
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