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.
Subject(s)
Indazoles/chemistry , Peroxidase/antagonists & inhibitors , Binding Sites , Catalytic Domain , Chloramines/chemistry , Chloramines/metabolism , Humans , Indazoles/metabolism , Molecular Docking Simulation , Peroxidase/metabolism , Protein Binding , Structure-Activity Relationship , Taurine/chemistry , Taurine/metabolismABSTRACT
Methods for the construction of thiazolo-, thiazino-, and thiazepino-2H-indazoles from o-nitrobenzaldehydes or o-nitrobenzyl bromides and S-trityl-protected 1°-aminothioalkanes are reported. The process consists of formation of the requisite N-(2-nitrobenzyl)(tritylthio)alkylamine, subsequent deprotection of the trityl moiety with TFA, and immediate treatment with aq. KOH in methanol under Davis-Beirut reaction conditions to deliver the target thiazolo-, thiazino-, or thiazepino-2H-indazole in good overall yield. Subsequent S-oxidation gives the corresponding sulfone.
Subject(s)
Benzaldehydes/chemistry , Benzaldehydes/chemical synthesis , Benzyl Compounds/chemistry , Benzyl Compounds/chemical synthesis , Indazoles/chemistry , Indazoles/chemical synthesis , Thiazines/chemistry , Thiazines/chemical synthesis , Thiazoles/chemistry , Thiazoles/chemical synthesis , Molecular Structure , Oxidation-ReductionABSTRACT
We report the alkoxylation of methyl-substituted quinoxalino[2,3-c]cinnolines to give acetals and orthoesters in high yields. Routes to the precursors of this alkoxylation reaction as well as other quinoxalino[2,3-c]cinnoline and their 5-oxide derivatives are reported. Most of these quinoxalino[2,3-c]cinnolines were prepared by cyclization of the corresponding 2-amino-3-(2-nitrophenyl)quinoxaline, which, in turn, result from an unusual Beirut reaction from benzofurazan oxides plus 2-nitrobenzylcyanides. Mechanistic explanations for these intriguing reactions are presented.
