Structure-based screening for the discovery of 1,2,4-oxadiazoles as promising hits for the development of new anti-inflammatory agents interfering with eicosanoid biosynthesis pathways

被引:20
作者
Potenza, Marianna [1 ,2 ]
Sciarretta, Martina [3 ]
Chini, Maria Giovanna [4 ]
Saviano, Anella [3 ]
Maione, Francesco [3 ]
D'Auria, Maria Valeria [3 ]
De Marino, Simona [3 ]
Giordano, Assunta [1 ,5 ]
Hofstetter, Robert Klaus [2 ]
Festa, Carmen [3 ]
Werz, Oliver [2 ]
Bifulco, Giuseppe [1 ]
机构
[1] Univ Salerno, Dept Pharm, Via Giovanni Paolo II,132, I-84084 Fisciano, Italy
[2] Friedrich Schiller Univ Jena, Inst Pharm, Dept Pharmaceut Med Chem, Philosophenweg 14, D-07743 Jena, Germany
[3] Univ Naples Federico II, Dept Pharm, Via Domenico Montesano 49, I-80131 Naples, Italy
[4] Univ Molise, Dept Biosci & Terr, I-86090 Pesche, Isernia, Italy
[5] Consiglio Nazl Ric CNR, Inst Biomol Chem ICB, Via Campi Flegrei 34, I-80078 Naples, Italy
关键词
Combinatorial chemistry; Oxadiazoles; Eicosanoid biosynthesis pathways; Polypharmacology; Anti-inflammatory activity; PROSTAGLANDIN E-2 SYNTHASE; IN-VIVO; INHIBITORS; MPGES-1; POTENT; DESIGN; INFLAMMATION; SCAFFOLD; TARGET; 1,3,4-OXADIAZOLES;
D O I
10.1016/j.ejmech.2021.113693
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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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页数:13
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