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

• Published in: Journal of medicinal chemistry Vol. 62; no. 3; pp. 1562 - 1576
• Main Authors: Hopper, Allen T, Brockman, Adam, Wise, Andy, Gould, Julie, Barks, Jennifer, Radke, Joshua B, Sibley, L. David, Zou, Yongmao, Thomas, Stephen
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.02.2019; Amer Chemical Soc
• Subjects: Animals; Antiparasitic Agents - chemical synthesis; Antiparasitic Agents - chemistry; Antiparasitic Agents - therapeutic use; Chemistry, Medicinal; Dogs; Female; Folic Acid Antagonists - chemical synthesis; Folic Acid Antagonists - chemistry; Folic Acid Antagonists - therapeutic use; Humans; Life Sciences & Biomedicine; Madin Darby Canine Kidney Cells; MCF-7 Cells; Mice; Molecular Structure; Pharmacology & Pharmacy; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - therapeutic use; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - therapeutic use; Science & Technology; Structure-Activity Relationship; Tetrahydrofolate Dehydrogenase - metabolism; Toxoplasma - enzymology; Toxoplasmosis - drug therapy; PNEUMOCYSTIS-CARINII; IN-VITRO; POTENT; IMMUNOCOMPROMISED PATIENTS; HIV; PYRIMETHAMINE; GENOTYPE; RESISTANCE; TOXICITY; RETINOCHOROIDITIS
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.8b01754

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 (TgDHFR) relative to human DHFR (hDHFR). We previously reported on the identification of meta-biphenyl analog 2, designed by in silico modeling of key differences in the binding pocket between TgDHFR and hDHFR. Compound 2 improves TgDHFR 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 TgDHFR IC50 of 1.57 ± 0.11 nM and a hDHFR to TgDHFR 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.