Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States.
Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, Georgia 30144, United States.
J Med Chem. 2023 Feb 9;66(3):1972-1989. doi: 10.1021/acs.jmedchem.2c01767. Epub 2023 Jan 25.
The carbazole CBL0137 () is a lead for drug development against human African trypanosomiasis (HAT), a disease caused by . To advance as a candidate drug, we synthesized new analogs that were evaluated for the physicochemical properties, antitrypanosome potency, selectivity against human cells, metabolism in microsomes or hepatocytes, and efflux ratios. Structure-activity/property analyses of analogs revealed eight new compounds with higher or equivalent selectivity indices (, , , , , , , and ). Based on the overall compound profiles, compounds and were selected for assessment in a mouse model of HAT; while demonstrated a lead-like profile for HAT drug development, showed a lack of efficacy. Lessons from these studies will inform further optimization of carbazoles for HAT and other indications.
咔唑 CBL0137() 是一种针对人类非洲锥虫病 (HAT) 的药物开发的先导化合物，HAT 是由引起的疾病。为了推进作为候选药物，我们合成了新的类似物，并对其理化性质、抗锥虫活性、对人细胞的选择性、微粒体或肝细胞中的代谢以及外排率进行了评估。类似物的结构-活性/性质分析揭示了八种具有更高或等效选择性指数的新化合物(、、、、、、和)。基于整体化合物特征，选择化合物和进行 HAT 小鼠模型评估；而显示出 HAT 药物开发的类似物特征，而显示出缺乏疗效。这些研究的经验教训将为 HAT 和其他适应症的咔唑类化合物的进一步优化提供信息。
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