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

• Published in: ACS medicinal chemistry letters 2023-01, Vol.14 (1), p.26-34
• Main Authors: Potenza, Marianna, Giordano, Assunta, Chini, Maria G, Saviano, Anella, Kretzer, Christian, Raucci, Federica, Russo, Marina, Lauro, Gianluigi, Terracciano, Stefania, Bruno, Ines, Iorizzi, Maria, Hofstetter, Robert K, Pace, Simona, Maione, Francesco, Werz, Oliver, Bifulco, Giuseppe
• Format: Article
• Language: English
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.2c00343

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.