Identification of 2-Aminoacyl-1,3,4-thiadiazoles as Prostaglandin E-2 and Leukotriene Biosynthesis Inhibitors

The application of a multi-step scientific workflow revealed an unprecedented class of PGE(2)/leukotriene biosynthesis inhibitors with in vivo activity. Specifically, starting from a combinatorial virtual library of similar to 4.2 x 10(5) 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, and 9) displayed marked anti-inflammatory properties in vitro by strongly inhibiting PGE(2) 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 PGE(2) biosynthesis in a lipopolysaccharide-stimulated J774A.1 macrophage cell line. The most promising compound 3 showed prominent in vivo anti-inflammatory activity in a mouse model, with efficacy comparable to that of dexamethasone, attenuating zymosan-induced leukocyte migration in mouse peritoneum with considerable modulation of the levels of typical pro-/anti-inflammatory cytokines.