1. Academic Validation
  2. Identification of 2-Aminoacyl-1,3,4-thiadiazoles as Prostaglandin E2 and Leukotriene Biosynthesis Inhibitors

Identification of 2-Aminoacyl-1,3,4-thiadiazoles as Prostaglandin E2 and Leukotriene Biosynthesis Inhibitors

  • ACS Med Chem Lett. 2022 Dec 9;14(1):26-34. doi: 10.1021/acsmedchemlett.2c00343.
Marianna Potenza 1 2 Assunta Giordano 1 3 Maria G Chini 4 Anella Saviano 5 Christian Kretzer 6 Federica Raucci 5 Marina Russo 5 Gianluigi Lauro 1 Stefania Terracciano 1 Ines Bruno 1 Maria Iorizzi 4 Robert K Hofstetter 6 Simona Pace 6 Francesco Maione 5 Oliver Werz 6 Giuseppe Bifulco 1
Affiliations

Affiliations

  • 1 Department of Pharmacy, University of Salerno, via Giovanni Paolo II, 132, 84084, Fisciano, Italy.
  • 2 The FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy.
  • 3 Institute of Biomolecular Chemistry (ICB), Consiglio Nazionale delle Ricerche (CNR), Via Campi Flegrei 34, Pozzuoli, 80078 Napoli, Italy.
  • 4 Department of Biosciences and Territory, University of Molise, Contrada Fonte Lappone, Pesche, 86090 Isernia, Italy.
  • 5 ImmunoPharmaLab, Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.
  • 6 Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, 07743 Jena, Germany.
Abstract

The application of a multi-step scientific workflow revealed an unprecedented class of PGE2/leukotriene biosynthesis inhibitors with in vivo activity. Specifically, starting from a combinatorial virtual library of ∼4.2 × 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, and 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 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.

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