Design, synthesis and structure-activity relationship studies of human dihydroorotate dehydrogenase inhibitors
10.16438/j.0513-4870.2016-1120
- VernacularTitle:二氢乳清酸脱氢酶抑制剂的设计、合成和构效关系研究
- Author:
Ying-hui GONG
1
;
Li LIU
1
;
Tian-tian QI
1
;
Hong-lin LI
1
;
Li-li ZHU
1
;
Zhen-jiang ZHAO
1
Author Information
1. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
- Publication Type:ORIGINAL ARTICLES
- Keywords:
human dihydroorotate dehydrogenase inhibitor;
triazole derivative;
autoimmune disease;
complex co-crystal structure;
structure-activity relationship
- From:
Acta Pharmaceutica Sinica
2017;52(2):264-270
- CountryChina
- Language:Chinese
-
Abstract:
In this study, 1-(3-(4-chlorophenyl)-5-methylthio-1H-1,2,4-triazol-1-yl)-butan-1-one discovered previously in our lab was selected as a inhibitor of human dihydroorotate dehydrogenase (HsDHODH) for structural optimization. The co-crystal of HsDHODH with the hit was obtained and analyzed for guiding the subsequent structural optimization. As a result, a series of novel triazole derivatives were designed and synthesized as potent HsDHODH inhibitors. Among them, compound (3-(4-chlorophenyl)-5-ethylthio-1H-1,2,4-triazol-1-yl)-furan-2-yl-methanone displayed high potency in the inhibition of HsDHODH with an IC50 value of 1.50 μmol·L-1. Meanwhile, the structure-activity relationships were analyzed based on the biological data and the co-crystal structure. These results provide a valuable reference for optimization of 1H-1,2,4-triazole derivatives as HsDHODH inhibitors in the future.
