Structure-activity relationship analysis of novel farnesyl transferase inhibitors / 药学学报

Farnesyltransferase (FTase) was selected as a target for virtual screening of inhibitors using the Glide v4.0 program in the Schrödinger software package. We discovered 13 novel structures as farnesyltransferase inhibitors (FTIs) with moderate potency. By analyzing the binding modes of representative compounds 8 (IC50 = 2.29 μmol·L-1) and 18 (IC50 = 0.41 μmol·L-1) with farnesyltransferase, it was found that compounds 8 and 18 didn't coordinate with Zn2+, indicating that the coordination between FTIs with Zn2+ is not essential for the bioactivity of the inhibitors. The structure-activity relationship was summarized by analyzing the predicted binding modes of representative compounds. It was found that the scaffolds of the discovered FTIs had room for structural optimization, which lay foundation for obtaining highly active and selective FTIs.

Synthesis, stability and activity of the prodrugs of dihydroorotate dehydrogenase inhibitors / 药学学报

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.

Design, synthesis and structure-activity relationship studies of human dihydroorotate dehydrogenase inhibitors / 药学学报

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.