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

The application of a multi-step scientific workflow revealed an unprecedented class of PGE/leukotriene biosynthesis inhibitors with activity. Specifically, starting from a combinatorial virtual library of ∼4.2 × 10 molecules, a small set of compounds was identified for the synthesis. Among these, four novel 2-aminoacyl-1,3,4-thiadiazole derivatives (, , , and ) displayed marked anti-inflammatory properties by strongly inhibiting PGE biosynthesis, with IC values in the nanomolar range. The hit compounds also efficiently interfered with leukotriene biosynthesis in cell-based systems and modulated IL-6 and PGE biosynthesis in a lipopolysaccharide-stimulated J774A.1 macrophage cell line. The most promising compound showed prominent 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.