Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, 2520, South Africa.
Center for Discovery and Innovation in Parasitic Diseases, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
ChemMedChem. 2024 May 2;19(9):e202300667. doi: 10.1002/cmdc.202300667. Epub 2024 Feb 23.
Nagana and Human African Trypanosomiasis (HAT), caused by (sub)species of Trypanosoma, are diseases that impede human and animal health, and economic growth in Africa. The few drugs available have drawbacks including suboptimal efficacy, adverse effects, drug resistance, and difficult routes of administration. New drugs are needed. A series of 20 novel quinolone compounds with affordable synthetic routes was made and evaluated in vitro against Trypanosoma brucei and HEK293 cells. Of the 20 compounds, 12 had sub-micromolar potencies against the parasite (EC values=0.051-0.57 μM), and most were non-toxic to HEK293 cells (CC values>5 μM). Two of the most potent compounds presented sub-micromolar activities against other trypanosome (sub)species (T. cruzi and T. b. rhodesiense). Although aqueous solubility is poor, both compounds possess good logD values (2-3), and either robust or poor microsomal stability profiles. These varying attributes will be addressed in future reports.
那加那病和人类非洲锥虫病（HAT）由锥虫（亚种）引起，这些疾病会阻碍非洲的人类和动物健康以及经济增长。现有的少数几种药物存在一些缺点，包括疗效不佳、副作用、耐药性和给药途径困难。需要开发新的药物。本研究合成了一系列 20 种具有经济实用合成路线的新型喹诺酮化合物，并在体外对非洲锥虫和 HEK293 细胞进行了评估。在 20 种化合物中，有 12 种对寄生虫具有亚微摩尔的效力（EC 值=0.051-0.57 μM），且大多数对 HEK293 细胞没有毒性（CC 值>5 μM）。两种最有效的化合物对其他锥虫（亚种）（克氏锥虫和 T. b. rhodesiense）也具有亚微摩尔的活性。尽管水溶性较差，但这两种化合物均具有良好的 logD 值（2-3），且具有良好或较差的微粒体稳定性。这些不同的特性将在未来的报告中进行讨论。
