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

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 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.

Synthesis, Bioactivity Evaluation,3D‐QSAR, and Molecular Docking of Novel Pyrazole‐4‐carbohydrazides as Potential Fungicides Targeting Succinate Dehydrogenase

“…Compounds 7d and 7l (Figures 6A—6D) showed three visible strong hydrogen bonds with the side chain amino acid residues of Tyr58 and Trp173, which play a crucial role in maintaining fungicidal activity. [ 38‐39 ] In addition, the residues ARG43, HIS216, ILE40 and PRO169 are also critical in a continuous belt of hydrophobic interactions encircling pyrazole and benzene ring of compounds 7l and 7d . Obviously, compound 7r (Figures 6E and 6F) also showed strong interactions with SDH protein in the same active pocket and formed two hydrogen bonds with amino acid residues of Tyr58 and Trp173, which maintain its certain fungicidal activity.…”

Design, synthesis and antifungal/anti‐oomycete activity of pyrazolyl oxime ethers as novel potential succinate dehydrogenase inhibitors

“…An SDH assay kit (Solarbio, BC0950) was used to determine the SDH enzymatic activity according to the reported procedure 33,41 . R. solani was cultivated in sterilized potato dextrose broth (PDB) for 48 h and then treated with different concentrations of the selected compounds and the SDHI fungicide boscalid.…”

“…1(b)). 29–34 Whether compounds without an amide bond in the bridge could be developed as SDHI fungicides has rarely been reported. Here we propose a new perspective to develop novel SDHI compounds by replacing the amide bond with an oxime ether group in the bridge.…”

Design, Synthesis, and Evaluation of Fungicidal Activity of Novel Pyrazole‐Containing Strobilurin Derivatives†

“…SDHIs fungicides containing difluoromethyl substituted pyrazole substructure such as fluxapyroxad and benzovindiflupyr show a broad spectrum of excellent fungicidal activity. [ 22‐25 ] To solve the resistance and improve potency of strobilurin fungicides, here, we designed and synthesized a series of novel strobilurin derivatives containing a difluoromethyl pyrazole moiety with an active substructure splicing method (Figure 1). [ 26 ] All title compounds were characterized by 1 H NMR, 13 C NMR and HRMS.…”