Discovery of Selective Toxoplasma gondii Dihydrofolate Reductase Inhibitors for the Treatment of Toxoplasmosis

作者：Allen T. Hopper, A. Brockman, Andy Wise, Julie Gould, Jennifer Barks, Joshua B. Radke, L. David Sibley, Y. Zou, S. Thomas · 发表于：Journal of Medicinal Chemistry · 年份：2019 · DOI：10.1021/acs.jmedchem.8b01754 · 被引用次数：59 · 研究领域：Toxoplasma gondii Research Studies、Pneumocystis jirovecii pneumonia detection and treatment、Parasitic Infections and Diagnostics

High Resolution Image Download MS PowerPoint Slide A safer treatment for toxoplasmosis would be achieved by improving the selectivity and potency of dihydrofolate reductase (DHFR) inhibitors, such as pyrimethamine ( 1 ), for Toxoplasma gondii DHFR ( Tg DHFR) relative to human DHFR ( h DHFR). We previously reported on the identification of meta-biphenyl analog 2, designed by in silico modeling of key differences in the binding pocket between Tg DHFR and h DHFR. Compound 2 improves Tg DHFR selectivity 6.6-fold and potency 16-fold relative to 1 . Here, we report on the optimization and structure–activity relationships of this arylpiperazine series leading to the discovery of 5-(4-(3-(2-methoxypyrimidin-5-yl)phenyl)piperazin-1-yl)pyrimidine-2,4-diamine 3 . Compound 3 has a Tg DHFR IC 50 of 1.57 ± 0.11 nM and a h DHFR to Tg DHFR selectivity ratio of 196, making it 89-fold more potent and 16-fold more selective than 1 . Compound 3 was highly effective in control of acute infection by highly virulent strains of T. gondii in the murine model, and it possesses the best combination of selectivity, potency, and prerequisite drug-like properties to advance into IND-enabling, preclinical development.