Department of Pesticide Science, College of Plant Protection, Nanjing Agricultural University, Weigang 1, Xuanwu District, Nanjing 210095, People's Republic of China.
Department of Pesticide Science, College of Plant Protection, Nanjing Agricultural University, Weigang 1, Xuanwu District, Nanjing 210095, People's Republic of China; Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Guiyang 550025, People's Republic of China; Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, People's Republic of China.
Eur J Med Chem. 2017 Aug 18;136:114-121. doi: 10.1016/j.ejmech.2017.04.073. Epub 2017 May 2.
The bioactivity-guided mixed synthesis was conceived, in which the designed mix-reactions were run in parallel for simultaneous construction of different kinds of analogs. The valuable ones were protruded by biological screening. This tactic will facilitate more rapid incorporation of bioactive candidates into pesticide chemists' repertoire, exemplified by the optimization of less explored homodrimanes as antifungal ingredients. The discovery of D9 as a potent fungicidal agent can be completed in <2 weeks by one student, with EC of 3.33 mg/L and 2.45 mg/L against S. sclerotiorum and B. cinerea, respectively. To confirm the practicability, time-efficiency, and reliability, specific homodrimanes (82 derivatives) were synthesized and elucidated separately and determined for EC values. The SAR correlated well with the intentionally mixed synthesis and the potential was further confirmed by the in vivo bioassay. This methodology will foster more efficient exploration of biologically relevant chemical space of natural products in pesticide discovery, and can also be tailored readily for the lead optimization in medicinal chemistry.
本研究提出了一种基于生物活性导向的混合合成策略，其中设计的混合反应可以并行进行，同时构建不同类型的类似物。通过生物筛选突出有价值的类似物。这种策略将促进更多具有生物活性的候选物更快地纳入农药化学家的研究范围，以探索较少的同源二聚体作为抗真菌成分的优化为例。通过一名学生在不到 2 周的时间内可以完成 D9 作为一种有效的杀菌剂的优化，其对 S. sclerotiorum 和 B. cinerea 的 EC 值分别为 3.33 mg/L 和 2.45 mg/L。为了确认其实用性、时间效率和可靠性，分别合成并阐明了特定的同源二聚体（82 个衍生物），并测定了它们的 EC 值。SAR 与有意混合合成密切相关，体内生物测定进一步证实了其潜力。这种方法将促进更有效地探索农药发现中天然产物具有生物学相关性的化学空间，并且也可以方便地用于药物化学中的先导优化。
