Design, synthesis, antifungal activity, and molecular docking of novel trifluoromethyl pyrimidine derivatives containing 1,3,4-oxadiazole and thioether moieties as potential succinate dehydrogenase inhibitors

Succinate dehydrogenase (SDH), a pivotal enzyme linking the respiratory electron transport chain and tricarboxylic acid (TCA) cycle, has been identified as an ideal target for developing effective fungicides. In this study, 20 novel trifluoromethyl pyrimidine derivatives containing 1,3,4-oxadiazole and thioether moieties were prepared and characterized their structures by H-1 NMR, C-13 NMR, and HRMS. Bioassay results showed that some of the target compounds revealed moderate to good in vitro antifungal activities toward Rhizoctonia solani (R. solani), Botryosphaeria dothidea (B. dothidea), Phomopsis sp., Botrytis cinerea (B. cinerea), Fusarium oxysporum (F. oxysporum), Sclerotinia sclerotiorum (S. sclerotiorum), Phytophthora infestans (P. infestans), and Magnaporthe oryzae (M. oryzae). In particular, compounds 6g and 6i had better in vitro antifungal activity against B. cinerea, with the EC50 values of 19.43 and 28.22 & mu;g/mL, respectively, than that of Pyrimethanil (57.30 & mu;g/mL). As well, compound 6r exhibited good in vitro antifungal activity against F. oxysporum, with the EC50 value of 3.61 & mu;g/mL, which were lower than that of Boscalid (0.40 & mu;g/mL). In addition, the molecular docking simulation revealed that compound 6r interacted with GLN-150, ASP-153, LYS-151, GLY-154, and GLY-228 of SDH through hydrogen bond, which could explain the probable mechanism of action between the target compounds and SDH. This is the first report on the antifungal activity of novel trifluoromethyl pyrimidine derivatives containing 1,3,4-oxadiazole and thioether moieties as potential SDH inhibitors.

Automated summary

In this study, 20 novel trifluoromethyl pyrimidine derivatives containing 1,3,4-oxadiazole and thioether moieties were synthesized and characterized. Some of the target compounds showed moderate to good in vitro antifungal activities against various fungi. Compound 6g and 6i exhibited better antifungal activity against B. cinerea than Pyrimethanil, with EC50 values of 19.43 and 28.22 μg/mL, respectively. Compound 6r showed good antifungal activity against F. oxysporum, with an EC50 value of 3.61 μg/mL, lower than that of Boscalid. Molecular docking simulation indicated that compound 6r interacted with specific residues of SDH through hydrogen bonds.