Discovery of an Orally Efficacious Pyrazolo[3,4-d]pyrimidine Benzoxaborole as a Potent Inhibitor of Cryptosporidium

IF 6.8 1区 医学 Q1 CHEMISTRY, MEDICINAL Journal of Medicinal Chemistry Pub Date : 2024-12-23 DOI:10.1021/acs.jmedchem.4c02805
Makafui Gasonoo, Soumitra Guin, José E. Teixeira, Edmund Oboh, Anusha Gokanapalle, Peter Miller, Jonathan Oliva, Francis M. Sverdrup, Christopher D. Huston, Marvin J. Meyers
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Abstract

Cryptosporidiosis is a diarrheal disease caused by the parasite Cryptosporidium resulting in over 100,000 deaths annually. Here, we present a structure–activity relationship study of the benzoic acid position (R6) of pyrazolo[3,4-d]pyrimidine lead SLU-2815 (1), an inhibitor of parasite phosphodiesterase CpPDE1, resulting in the discovery of benzoxaborole SLU-10906 (63) as a benzoic acid bioisostere. Benzoxaborole 63 is 10-fold more potent than 1 against the parasite in a cell-based infection model (EC50 = 0.19 μM) and non-cytotoxic. Furthermore, 63 has a fast rate of parasite-killing and is orally efficacious in a Cryptosporidium mouse infection model (50 mg/kg BID), although relapse was observed 7 days post-drug treatment. The partial selectivity profile versus human phosphodiesterases is preserved with the benzoxaborole motif and represents an important feature to improve in future optimization. Benzoxaborole 63 represents an important advance toward the optimization of the pyrazolo[3,4-d]pyrimidine series and the identification of a drug to treat cryptosporidiosis.

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来源期刊
Journal of Medicinal Chemistry
Journal of Medicinal Chemistry 医学-医药化学
CiteScore
4.00
自引率
11.00%
发文量
804
审稿时长
1.9 months
期刊介绍: The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.
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