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

Our previous work identified compound 1 (SLU-2633) as a potent lead compound toward the identification of a novel treatment for cryptosporidiosis, caused by the parasite Cryptosporidium (EC50 = 0.17 μM). While this compound is potent and orally efficacious, the mechanism of action and biological tar...

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Bibliographic Details
Published in:Journal of medicinal chemistry Vol. 66; no. 12; pp. 7834 - 7848
Main Authors: Schubert, Tanner J., Oboh, Edmund, Peek, Hannah, Philo, Emily, Teixeira, José E., Stebbins, Erin E., Miller, Peter, Oliva, Jonathan, Sverdrup, Francis M., Griggs, David W., Huston, Christopher D., Meyers, Marvin J.
Format: Journal Article
Language:English
Published: United States American Chemical Society 22-06-2023
Subjects:
Animals
Cryptosporidiosis - drug therapy
Cryptosporidium
Fluorine
Mice
Structure-Activity Relationship
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Summary:Our previous work identified compound 1 (SLU-2633) as a potent lead compound toward the identification of a novel treatment for cryptosporidiosis, caused by the parasite Cryptosporidium (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 a Cryptosporidium-infection mouse model, superior to SLU-2633.
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Author Contributions. MM, TS and EO designed compounds. TS, EO, HP, and EP synthesized compounds. DG, JO and FS conducted the pharmacokinetic experiments. ES, JT, PM and CDH tested compounds for anticryptosporidial activity. MM, TS, DG, JO, FS and CH designed and directed the experiments. TS, MM and CH wrote the manuscript. All authors have approved of the final version of the manuscript.
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.3c00110