Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States.
Instituto de Parasitología y Biomedicina "López-Neyra" Consejo Superior de Investigaciones Científicas (CSIC), Granada 18100, Spain.
J Med Chem. 2024 Aug 22;67(16):13985-14006. doi: 10.1021/acs.jmedchem.4c00785. Epub 2024 Aug 13.
Human African trypanosomiasis is among the World Health Organization's designated neglected tropical diseases. Repurposing strategies are often employed in academic drug discovery programs due to financial limitations, and in this instance, we used human kinase inhibitor chemotypes to identify substituted 4-aminoazaindoles, exemplified by . Structure-activity and structure-property relationship analysis, informed by cheminformatics, identified as a potent inhibitor of growth. While appeared to be fast acting and cidal in the assays, it failed to cure a murine model of infection. Preliminary efforts to identify the potential mechanism of action of the series pointed to arginine kinase, though, as we demonstrate, this does not appear to be the sole target of our compounds. This comprehensive approach to drug discovery, encompassing cheminformatics, structure-potency and structure-property analysis, and pharmacophore identification, highlights our multipronged efforts to identify novel lead compounds for this deadly disease.
人体感染非洲锥虫病属于世界卫生组织指定的被忽视热带病之一。由于资金限制，重新利用策略通常被应用于学术药物发现计划中。在这种情况下，我们使用人类激酶抑制剂化学型来鉴定取代的 4-氨基氮杂吲哚，例如 。基于化学信息学的结构活性和结构性质关系分析，鉴定 为生长的有效抑制剂。虽然 在 测定中似乎作用迅速且具有杀菌作用，但它未能治愈感染的小鼠模型。为了确定该系列潜在作用机制的初步努力指向精氨酸激酶，但正如我们所证明的那样，这似乎不是我们化合物的唯一靶标。这种全面的药物发现方法，包括化学信息学、结构效力和结构性质分析以及药效团鉴定，突出了我们为这种致命疾病识别新型先导化合物的多管齐下的努力。
