A Two-Step Multicomponent Synthetic Approach and Anti-inflammatory Evaluation of N-Substituted 2-Oxopyrazines.

Abstract

Inflammation is widely reported as a main factor for the development of chronic diseases such as cancer, diabetes, and even metabolic syndrome. Thus, the search for novel anti-inflammatory compounds is required. Herein we describe the synthesis of a collection of peptidic pyrazinones by a convenient approach involving a multicomponent isocyanide-based reaction followed by a tandem deprotection/oxidative cyclization step. This series of compounds were tested for their potential anti-inflammatory capacity in an in vivo murine model, and four compounds were identified to inhibit tetradecanoylphorbol acetate (TPA)-induced edema by more than 75 %. The two most active compounds, N-benzyl-2-(4-hydroxy-3,5-dimethoxyphenyl)-2-[2-oxopyrazin-1(2H)-yl]acetamide (10 o) and N-cyclohexyl-2-[2-oxopyrazin-1(2H)-yl]-2-[4-(trifluoromethyl)phenyl]acetamide (10 x), with methyl and trifluoromethyl groups, were also able to decrease myeloperoxidase activity and leukocyte infiltration. Moreover, 10 x decreased the thickness of TPA-treated mouse ears, as observed in histological analysis of the tissues.