Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 224, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2021.113693
Keywords
Combinatorial chemistry; Oxadiazoles; Eicosanoid biosynthesis pathways; Polypharmacology; Anti-inflammatory activity
Categories
Funding
- AIRC [21397]
- Ministero dell'Universita e della Ricerca (MIUR) under PRIN 2017 Stolen molecules - Stealing natural products from the depot and reselling them as new drug candidates [2017A95NCJ]
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [316213987, SFB 1278 PolyTarget]
- Dompe farmaceutici S.p.A fellowship
- MIUR PhD fellowship for PhD program in Pharmaceutical Science (University of Naples Federico II)
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This study identified three 1,2,4-oxadiazole compounds as potential multi-target inhibitors in the treatment of inflammatory disorders, with compound 5 showing promising results in in vivo experiments. The results suggest the potential for developing novel anti-inflammatory agents with a favorable pharmacological profile by expanding chemical diversity around the 1,2,4-oxadiazole central core.
The multiple inhibition of biological targets involved in pro-inflammatory eicosanoid biosynthesis represents an innovative strategy for treating inflammatory disorders in light of higher efficacy and safety. Herein, following a multidisciplinary protocol involving virtual combinatorial screening, chemical synthesis, and in vitro and in vivo validation of the biological activities, we report the identification of 1,2,4-oxadiazole-based eicosanoid biosynthesis multi-target inhibitors. The multidisciplinary scientific approach led to the identification of three 1,2,4-oxadiazole hits (compounds 1, 2 and 5), all endowed with IC50 values in the low micromolar range, acting as 5-lipoxygenase-activating protein (FLAP) antagonists (compounds 1 and 2), and as a multi-target inhibitor (compound 5) of arachidonic acid cascade enzymes, namely cyclooxygenase-1 (COX-1), 5-lipoxygenase (5-LO) and microsomal prostaglandin E-2 synthase-1 (mFGES-1). Moreover, our in vivo results demonstrate that compound 5 is able to attenuate leukocyte migration in a model of zymosan-induced peritonitis and to modulate the production of IL-1 beta and TNF-alpha. These results are of interest for further expanding the chemical diversity around the 1,2,4-oxadiazole central core, enabling the identification of novel anti-inflammatory agents characterized by a favorable pharmacological profile and considering that moderate interference with multiple targets might have advantages in re-adjusting homeostasis. (C) 2021 Elsevier Masson SAS. All rights reserved.
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