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

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Abstract
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 was outstood with broad-spectrum of in vitro activity against five fungi, its EC50 value (0.73 μg/mL) was comparable to 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 the EC50 of 4.61 μg/mL and 6.48 μg/mL respectively, showed significant higher activity than fluxapyroxad with the EC50 of 16.99 μg/mL. In vivo fungicidal activity of 5i exhibited excellent inhibitory rate (100%) against Puccinia sorghi at 50 μg/mL, while the positive control boscalid showed only 70% of inhibitory rate. Moreover, 5i showed promising fungicidal activity with 60% inhibitory rate against Rhizoctonia solani at 1 μg/mL, which was better than boscalid (30%). Compound 5i possessed better in vivo efficacy against P. sorghi and R. solani than boscalid. Molecular docking showed, even the carbonyl oxygen atom of 5i was far from pyrazole ring, it could also form hydrogen bonds towards the hydroxyl hydrogen, amino hydrogen of TYR58 and TRP173 on SDH, respectively, which consisted with 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 for further investigation as a promising fungicide candidate.
Funding Information
  • Natural Science Foundation of Tianjin Municipality (18JCZDJC33500)
  • Nankai University (63191743)
  • Ministry of Science and Technology of the People's Republic of China (2014DFR41030)
  • Russian Foundation for Basic Research (18-316-20018)
  • National Natural Science Foundation of China (31571991, 31872007)
  • Tianjin Development Program for Innovation and Entrepreneurship

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