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

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. Peptidic pyrazinones: Anti‐inflammatory scaffolds were prepared by a rapid two‐step protocol involving a Ugi four‐component reaction followed by a tandem process. All analogues demonstrate anti‐inflammatory activity in the tetradecanoylphorbol acetate (TPA) topical model, especially those with Me and CF3 groups. The most active candidate was also found to significantly deplete myeloperoxidase (MPO) activity to decrease edema induced by TPA administration.