Structure–Activity Relationship Studies of Tolfenpyrad Reveal Subnanomolar Inhibitors of Haemonchus contortus Development

Recently, we have discovered that the registered pesticide, tolfenpyrad, unexpectedly and potently inhibits the development of the L4 larval stage of the parasitic nematode Haemonchus contortus with an IC50 value of 0.03 μM while displaying good selectivity, with an IC50 of 37.9 μM for cytotoxicity. As a promising molecular template for medicinal chemistry optimization, we undertook anthelmintic structure–activity relationships for this chemical. Modifications of the left-hand side (LHS), right-hand side (RHS), and middle section of the scaffold were explored to produce a set of 57 analogues. Analogues 25, 29, and 33 were shown to be the most potent compounds of the series, with IC50 values at a subnanomolar level of potency against the chemotherapeutically relevant fourth larval (L4) stage of H. contortus. Selected compounds from the series also showed promising activity against a panel of other different parasitic nematodes, such as hookworms and whipworms.

近期研究发现，已登记农药唑虫酰胺（tolfenpyrad）可意外且强效地抑制寄生线虫捻转血矛线虫（Haemonchus contortus）的第四期幼虫（L4）发育，其半最大效应浓度（IC50）为0.03 μM，且具有良好的选择性，细胞毒性的IC50值为37.9 μM。作为一种极具潜力的药物化学优化分子模板，本研究针对该化合物开展了抗蠕虫活性的构效关系研究。通过对该母核（scaffold）的左侧（LHS）、右侧（RHS）及中间区域进行结构修饰，我们合成了共计57个类似物。化合物25、29与33为本系列中活性最强的分子，针对具有临床治疗相关性的捻转血矛线虫第四期幼虫（L4）的IC50值达到亚纳摩尔级别。本系列中部分筛选出的化合物对包括钩虫、鞭虫在内的多种其他寄生线虫也表现出良好的抗虫活性。