Gasonoo Makafui, Guin Soumitra, Teixeira José E, Oboh Edmund, Gokanapalle Anusha, Miller Peter, Oliva Jonathan, Sverdrup Francis M, Huston Christopher D, Meyers Marvin J
Department of Chemistry, School of Science and Engineering, Saint Louis University, Saint Louis, Missouri 63103, United States.
Department of Medicine, University of Vermont Larner College of Medicine, Burlington, Vermont 05401, United States.
J Med Chem. 2025 Jan 9;68(1):832-849. doi: 10.1021/acs.jmedchem.4c02805. Epub 2024 Dec 23.
Cryptosporidiosis is a diarrheal disease caused by the parasite resulting in over 100,000 deaths annually. Here, we present a structure-activity relationship study of the benzoic acid position (R) of pyrazolo[3,4-]pyrimidine lead SLU-2815 (), an inhibitor of parasite phosphodiesterase PDE1, resulting in the discovery of benzoxaborole SLU-10906 () as a benzoic acid bioisostere. Benzoxaborole is 10-fold more potent than against the parasite in a cell-based infection model (EC = 0.19 μM) and non-cytotoxic. Furthermore, has a fast rate of parasite-killing and is orally efficacious in a 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 represents an important advance toward the optimization of the pyrazolo[3,4-]pyrimidine series and the identification of a drug to treat cryptosporidiosis.
隐孢子虫病是一种由寄生虫引起的腹泻疾病，每年导致超过10万例死亡。在此，我们展示了吡唑并[3,4 - ]嘧啶先导化合物SLU - 2815（一种寄生虫磷酸二酯酶PDE1的抑制剂）苯甲酸位置（R）的构效关系研究，从而发现苯并硼唑SLU - 10906（作为苯甲酸生物电子等排体）。在基于细胞的感染模型中，苯并硼唑对寄生虫的活性比[SLU - 2815]高10倍（EC₅₀ = 0.19 μM）且无细胞毒性。此外，[苯并硼唑]具有快速杀灭寄生虫的作用，并且在小鼠感染模型中口服有效（50 mg/kg，每日两次），尽管在药物治疗7天后观察到复发。与人类磷酸二酯酶相比，苯并硼唑基序保留了部分选择性特征，这是未来优化中需要改进的一个重要特征。苯并硼唑代表了吡唑并[3,4 - ]嘧啶系列优化以及鉴定治疗隐孢子虫病药物方面的一项重要进展。
