Structure-Activity Relationship Studies of the Aryl Acetamide Triazolopyridazines against Cryptosporidium Reveals Remarkable Role of Fluorine.
Structure-Activity Relationship Studies of the Aryl Acetamide Triazolopyridazines against Cryptosporidium Reveals Remarkable Role of Fluorine.
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芳基乙酰胺三唑并哒嗪抗隐孢子虫的构效关系研究揭示了氟的显着作用。
DOI：
10.1021/acs.jmedchem.3c00110
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发表时间：
2023
影响因子：
7.3
通讯作者：
Meyers,MarvinJ
中科院分区：
文献类型：
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作者：
Schubert,TannerJ;Oboh,Edmund;Peek,Hannah;Philo,Emily;Teixeira,JoséE;Stebbins,ErinE;Miller,Peter;Oliva,Jonathan;Sverdrup,FrancisM;Griggs,DavidW;Huston,ChristopherD;Meyers,MarvinJ
我们之前的工作将化合物 1 (SLU-2633) 确定为一种有效的先导化合物，用于鉴定由寄生虫隐孢子虫 (EC50= 0.17 μM) 引起的隐孢子虫病的新型治疗方法。虽然该化合物有效且口服有效，但该系列的作用机制和生物靶点目前尚不清楚。在这项研究中，我们合成了 70 种化合物，以开发芳基“尾部”基团周围的表型结构-活性关系。在此过程中，我们发现2-取代的化合物不活泼，证实吸电子基团优于给电子基团，并且氟在这些化合物的效力中发挥着显着的作用。这项工作产生的最有效的化合物是SLU-10482（52，EC50=0.07μM），发现其在隐孢子虫感染小鼠模型中口服有效，ED90<5mg/kg BID，优于SLU-2633。
Our previous work identified compound1(SLU-2633) as a potent lead compound toward the identification of a novel treatment for cryptosporidiosis, caused by the parasiteCryptosporidium(EC50= 0.17 μM). While this compound is potent and orally efficacious, the mechanism of action and biological target(s) of this series are currently unknown. In this study, we synthesized 70 compounds to develop phenotypic structure–activity relationships around the aryl “tail” group. In this process, we found that 2-substituted compounds are inactive, confirmed that electron withdrawing groups are preferred over electron donating groups, and that fluorine plays a remarkable role in the potency of these compounds. The most potent compound resulting from this work is SLU-10482 (52, EC50= 0.07 μΜ), which was found to be orally efficacious with an ED90< 5 mg/kg BID in aCryptosporidium-infection mouse model, superior to SLU-2633.