Inhibition of myeloperoxidase: Evaluation of 2H-indazoles and 1H-indazolones
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Elsevier Ltd
Abstract
Myeloperoxidase (MPO) produces hypohalous acids as a key component of the innate immune response; however, release of these acids extracellularly results in inflammatory cell and tissue damage. The two-step, one-pot Davis-Beirut reaction was used to synthesize a library of 2H-indazoles and 1H-indazolones as putative inhibitors of MPO. A structure-activity relationship study was undertaken wherein compounds were evaluated utilizing taurine-chloramine and MPO-mediated H2O2 consumption assays. Docking studies as well as toxicophore and Lipinski analyses were performed. Fourteen compounds were found to be potent inhibitors with IC50 values <1 μM, suggesting these compounds could be considered as potential modulators of pro-oxidative tissue injury pertubated by the inflammatory MPO/H2O2/HOCl/HOBr system. © 2014 Elsevier Ltd. All rights reserved.
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Keywords
2h-indazole, Computational docking, Davis-beirut reaction, Myeloperoxidase, Structure-activity relationship, Binding sites, Catalytic domain, Chloramines, Humans, Indazoles, Molecular docking simulation, Peroxidase, Protein binding, Taurine, 1h indazolone derivative, 2 (4 ethynylphenyl) 3 methoxy indazole derivative, 2,3 dihydrooxazolo[3,2 b]indazole derivative, 2h indazole derivative, 3 alkoxy 2h indazole derivative, 4 aminobenzoic acid derivative, 4 aminobenzoic acid hydrazide, Hydrobromic acid, Hydrogen peroxide, Hypochlorous acid, Indazole derivative, Tosylchloramide sodium, Unclassified drug, [1,3]oxazino[3,2 b]indazole derivative, Chloramine derivative, Analytic method, Article, Carbon nuclear magnetic resonance, Chlorination, Controlled study, Drug determination, Drug structure, Enzyme inhibition, Enzyme inhibition assay, Hydrogen peroxide scavenging assay, Ic50, Lipinski analysis, Molecular docking, One pot synthesis, Oxidative stress, Proton nuclear magnetic resonance, Structure activity relation, Taurine chlorination assay, Toxicity testing, Toxicophore analysis, Antagonists and inhibitors, Binding site, Chemistry, Enzyme active site, Human, Metabolism