Synthesis and Biological Activity of Novel Succinate Dehydrogenase Inhibitor Derivatives as Potent Fungicide Candidates

In searching for novel fungicidal leads, the novel bioactive
succinate
dehydrogenase inhibitor (SDHI) derivatives were designed and synthesized
by the inversion of carbonyl and amide groups. Bioassay indicated
that compound 5i stood out with a broad spectrum of in
vitro activity against five fungi. Its EC50 value (0.73
μg/mL) was comparable to that of boscalid (EC50 of
0.51 μg/mL) and fluxapyroxad (EC50 of 0.19 μg/mL)
against Sclerotinia sclerotiorum. For Rhizoctonia cerealis, 5i and 5p with EC50 values of 4.61 and 6.48 μg/mL, respectively,
showed significantly higher activity than fluxapyroxad with the EC50 value of 16.99 μg/mL. In vivo fungicidal activity
of 5i exhibited an excellent inhibitory rate (100%) against Puccinia sorghi at 50 μg/mL, while the positive
control boscalid showed only a 70% inhibitory rate. Moreover, 5i showed promising fungicidal activity with a 60% inhibitory
rate against Rhizoctonia solani at
1 μg/mL, which was better than that of boscalid (30%). Compound 5i possessed better in vivo efficacy against P. sorghi and R. solani than boscalid. Molecular docking showed that even the carbonyl oxygen
atom of 5i was far from the pyrazole ring. It could also
form hydrogen bonds toward the hydroxyl hydrogen and amino hydrogen
of TYR58 and TRP173 on SDH, respectively, which consisted of the positive
control fluxapyroxad. Fluorescence quenching analysis and SDH enzymatic
inhibition studies also validated its mode of action. Our studies
showed that 5i was worthy of further investigation as
a promising fungicide candidate.