RESUMEN
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.
Asunto(s)
Indazoles/química , Peroxidasa/antagonistas & inhibidores , Sitios de Unión , Dominio Catalítico , Cloraminas/química , Cloraminas/metabolismo , Humanos , Indazoles/metabolismo , Simulación del Acoplamiento Molecular , Peroxidasa/metabolismo , Unión Proteica , Relación Estructura-Actividad , Taurina/química , Taurina/metabolismoRESUMEN
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.
Asunto(s)
Benzaldehídos/química , Benzaldehídos/síntesis química , Compuestos de Bencilo/química , Compuestos de Bencilo/síntesis química , Indazoles/química , Indazoles/síntesis química , Tiazinas/química , Tiazinas/síntesis química , Tiazoles/química , Tiazoles/síntesis química , Estructura Molecular , Oxidación-ReducciónRESUMEN
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.