title: Inhibition of myeloperoxidase: evaluation of 2H-indazoles and 1H-indazolones.
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 <1μM, suggesting these compounds could be considered as potential modulators of pro-oxidative tissue injury pertubated by the inflammatory MPO/H2O2/HOCl/HOBr system.
authors.affiliation: Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616, United States.
authors.forename: Aaron
authors.initials: A
authors.lastname: Roth
authors.affiliation: Department of Internal Medicine, Division of Pulmonary/Critical Care Medicine, 4150 V Street, Suite 3100, Sacramento, CA 95817, United States.
authors.forename: Sean
authors.initials: S
authors.lastname: Ott
authors.affiliation: Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616, United States.
authors.forename: Kelli M
authors.initials: KM
authors.lastname: Farber
authors.affiliation: Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616, United States.
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Palazzo
authors.affiliation: Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616, United States.
authors.forename: Wayne E
authors.initials: WE
authors.lastname: Conrad
authors.affiliation: Department of Chemistry, American University of Beirut, Beirut, Lebanon.
authors.forename: Makhluf J
authors.initials: MJ
authors.lastname: Haddadin
authors.affiliation: Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616, United States.
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Tantillo
authors.affiliation: Department of Internal Medicine, Division of Pulmonary/Critical Care Medicine, 4150 V Street, Suite 3100, Sacramento, CA 95817, United States.
authors.forename: Carroll E
authors.initials: CE
authors.lastname: Cross
authors.affiliation: Department of Internal Medicine, Division of Pulmonary/Critical Care Medicine, 4150 V Street, Suite 3100, Sacramento, CA 95817, United States.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Eiserich
authors.affiliation: Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616, United States. Electronic address: mjkurth@ucdavis.edu.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Kurth
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D002700:Chloramines / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007191:Indazoles / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D009195:Peroxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013654:Taurine / Q000737:chemistry / Q000378:metabolism
chemical_list: D002700:Chloramines; D007191:Indazoles; D013654:Taurine; D009195:Peroxidase; C030816:chloramine
keywords: 2H-Indazole; Computational docking; Davis–Beirut reaction; Myeloperoxidase; Structure–activity relationship