Synthesis, stability and activity of the prodrugs of dihydroorotate dehydrogenase inhibitors
10.16438/j.0513-4870.2017-0992
- VernacularTitle:二氢乳清酸脱氢酶抑制剂前药的合成和稳定性及活性评价
- Author:
Ji-wei SHAN
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:
dihydroorotate dehydrogenase inhibitor;
prodrug design;
drug stability;
inhibitory activity evaluation
- From:
Acta Pharmaceutica Sinica
2018;53(3):410-415
- CountryChina
- Language:Chinese
-
Abstract:
This study was conducted to improve structural instability of a highly active DHODH inhibitor A found in our group. Twelve prodrugs were synthesized by modifying the carboxyl group. The enzyme activity test of 12 prodrugs A1−A12 demonstrated that A1−A5 displayed weak inhibitory activity, and A6−A12 displayed no activity, which met the action mechanism of designed prodrug. The structural stability of A1−A12 in methanol and pH 2.0, 9.0 buffers were tested, and the results showed that A12 could avoid intramolecular ring-formation in CH3OH, A1−A8 were easily hydrolyzed under acidic conditions, and A9−A12 were inclined to hydrolyze under alkaline conditions. The cell proliferation inhibitory activity of 12 prodrugs were evaluated, in which compound A12 displayed excellent activity (IC50=0.63 μmol·L−1) similar to brequinar. These results laid a good foundation for conducting further vivo studies.
