Identification of 2-aminoacyl-1,3,4-thiadiazoles as prostaglandin E2 and leukotriene biosynthesis inhibitors

The application of a multi-step scientific workflow revealed an unprecedented class of mPGES-1/leukotriene biosynthesis inhibitors with in vivo activity. Specifically, starting from a combinatorial virtual library of ~ 4.2 x 105 molecules, a small set of compounds was identified for the synthesis. Among these, four novel 2-aminoacyl-1,3,4-thiadiazole derivatives (3, 6, 7, 9) displayed marked anti-inflammatory properties in vitro by strongly inhibiting PGE2 biosynthesis, with IC50 values in the nanomolar range. The hit compounds also efficiently interfered with leukotriene biosynthesis in cell-based systems and modulated IL-6 and PGE2 biosynthesis in lipopolysaccharide-stimulated J774A.1 macrophages cell line. The most promising compound (3) showed prominent in vivo anti-inflammatory activity in a mouse model, with efficacy comparable to dexa-methasone, attenuating zymosan-induced leukocyte migration in mouse peritoneum with considerable modulation of the levels of typical pro/anti-inflammatory cytokines.