Discovery of succinate dehydrogenase fungicide via computational substitution optimization

Succinate dehydrogenase (SDH) has been identified as an important target fungicide discovery and the SDH inhibitor (SDHI) displayed a broad-spectrum activity against various fungal species. The report from Phillips McDougall showed that the global market of SDHI fungicides would reach up to US $3.4 billion by 2026. Therefore, the discovery of novel SDHI is a very hot area in pesticide discovery.
Previously, we designed and developed a fungicidal candidate flubeneteram bearing diphenyl-ether fragment. Herein, scaffold hopping (SH) method was used to further explore its chemical space. A computational substitution optimization protocol, forced on bioisosteric replacement, was designed to produce virtual molecules to perform virtual screening. Then, some virtual molecules were selected and synthesized according to Vina score. The greenhouse and field trials results showed that compound 17c exhibited very high and broad-spectrum fungicidal activity, displaying great potential of industry development. This presentation highlights the additional chemical space of the diphenyl-ether fragment and compound 17c would be another fungicide candidate for SDH.

The design protocol of compound 17c. (WPM: wheat powdery mildew. SCR: south corn rust. SBR: soybean rust. CPM: cucumber powdery mildew. RSB: rice sheath blight.)