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
  • 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.
PMID: 36655121 DOI: 10.1021/acsmedchemlett.2c00343
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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