Woodring Jennifer L, Bachovchin Kelly A, Brady Kimberly G, Gallerstein Mitchell F, Erath Jessey, Tanghe Scott, Leed Susan E, Rodriguez Ana, Mensa-Wilmot Kojo, Sciotti Richard J, Pollastri Michael P
Northeastern University Department of Chemistry & Chemical Biology, 360 Huntington Avenue, Boston, MA 02115, USA.
New York University School of Medicine, Department of Microbiology, Division of Parasitology, 341 E. 25th St., New York, NY 10016, USA.
Eur J Med Chem. 2017 Dec 1;141:446-459. doi: 10.1016/j.ejmech.2017.10.007. Epub 2017 Oct 6.
Human African trypanosomiasis (HAT) is a deadly disease in need of new chemotherapeutics that can cross into the central nervous system. We previously reported the discovery of 2 (NEU-617), a small molecule with activity against T. brucei bloodstream proliferation. Further optimization of 2 to improve the physicochemical properties (LogP, LLE, [1], and MPO score) [2] have led us to twelve sub-micromolar compounds, most importantly the headgroup variants 9i and 9j, and the linker variant 18. Although these 3 compounds had reduced potency compared to 2, they all had improved LogP, LLE and MPO scores. Cross-screening these analogs against other protozoan parasites uncovered 9o with potent activity towards T. brucei, T. cruzi and L. major, while four others compounds (17, 18, 21, 26) showed activity towards P. falciparum D6. This reinforces the effectiveness of lead repurposing for the discovery of new protozoan disease therapeutics.
人类非洲锥虫病（HAT）是一种致命疾病，急需能够进入中枢神经系统的新型化疗药物。我们之前报道了2（NEU - 617）的发现，这是一种对布氏锥虫血流增殖具有活性的小分子。对2进行进一步优化以改善其物理化学性质（LogP、LLE、[1]和MPO评分）[2]，使我们得到了12种亚微摩尔级的化合物，最重要的是头部基团变体9i和9j以及连接体变体18。尽管这3种化合物与2相比效力有所降低，但它们的LogP、LLE和MPO评分均有所提高。对这些类似物针对其他原生动物寄生虫进行交叉筛选，发现9o对布氏锥虫、克氏锥虫和硕大利什曼原虫具有强效活性，而其他四种化合物（17、18、21、26）对恶性疟原虫D6显示出活性。这强化了通过重新利用先导化合物来发现新型原生动物疾病治疗药物的有效性。
