Design, synthesis, and fungicidal evaluation of novel oxysterol binding protein inhibitors for combatting resistance associated with oxathiapiprolin

• Published in: Pesticide biochemistry and physiology 2020-10, Vol.169, p.104673-104673, Article 104673
• Main Authors: Li, Jian-Long, Zhou, Li-Ming, Gao, Meng-Qi, Huang, Zhong-Qiao, Liu, Xi-Li, Zhu, Xiao-Lei, Yang, Guang-Fu
• Format: Article
• Language: English
• Subjects: Molecular design; Oxathiapiprolin; Oxysterol binding protein; Resistance
• ISSN: 0048-3575; 1095-9939
• DOI: 10.1016/j.pestbp.2020.104673

Oxathiapiprolin, the first successful oxysterol binding protein (OSBP) inhibitor for oomycete control, is regarded as an important milestone in the history of fungicide discovery. However, its interaction with OSBP remain unclear. Moreover, some plant pathogenic oomycetes have developed medium to high resistance to oxathiapiprolin. In this paper, the three-dimensional (3D) structure of OSBP from Phytophthora capsici (pcOSBP) was built, and its interaction with oxathiapiprolin was systematically investigated by integrating molecular docking, molecular dynamics simulations, and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations. The computational results showed that oxathiapiprolin bound to pcOSBP forms H-bonds with Leu73, Lys74, Ser69, and water molecules. Then, based on its interaction with pcOSBP, oxathiapiprolin was structurally modified to discover new analogs with high fungicidal activity and a low risk of resistance. Fortunately, compound 1e was successfully designed and synthesized as the most potent candidate, and it showed a much lower resistance risk (RF