期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 -, 期 -, 页码 -出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.2c00343
关键词
Combinatorial virtual screening; 2-Aminoacyl-1,3,4-thiadiazole; mPGES-1; Leukotriene biosynthesis pathway; Anti-inflammatory activity
资金
- AIRC [21397]
- MUR [2017A95NCJ/201795NCJ, 2017A95NCJ/201795NCJ_002]
- University of Naples Federico II PhD scholarship fellowship in Pharmaceutical Sciences
- Dompe farmaceutici S.p.A scholarship fellowship
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [SFB 1278/1, 316213987]
A multi-step scientific workflow led to the discovery of a novel class of PGE(2)/leukotriene biosynthesis inhibitors with in vivo activity. Four new compounds showed strong anti-inflammatory properties in vitro and demonstrated prominent anti-inflammatory activity in a mouse model.
The application of a multi-step scientific workflow revealed an unprecedented class of PGE(2)/leukotriene biosynthesis inhibitors with in vivo activity. Specifically, starting from a combinatorial virtual library of similar to 4.2 x 10(5) 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 PGE(2) 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 PGE(2) 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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