Thomas Michael G, De Rycker Manu, Cotillo Torrejon Ignacio, Thomas John, Riley Jennifer, Spinks Daniel, Read Kevin D, Miles Tim J, Gilbert Ian H, Wyatt Paul G
Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
Kinetoplastid DPU, Global Health R&D, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Spain.
Bioorg Med Chem Lett. 2018 Oct 1;28(18):3025-3030. doi: 10.1016/j.bmcl.2018.08.005. Epub 2018 Aug 3.
Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, affects 8-10 million people across the Latin American population and is responsible for around 12,500 deaths per annum. The current frontline treatments, benznidazole and nifurtimox, are associated with side effects and lack efficacy in the chronic stage of the disease, leading to an urgent need for new treatments. A high throughput screening campaign against the physiologically relevant intracellular form of the parasite identified a series of 2,4-diamino-6-methylpyrimidines. Demonstrating the series did not work through the anti-target TcCYP51, and was generally cytocidal, confirmed its suitability for further development. This study reports the optimisation of selectivity and metabolic stability of the series and identification of a suitable lead for further optimisation.
恰加斯病由原生动物寄生虫克氏锥虫引起，影响拉丁美洲约800万至1000万人，每年导致约12500人死亡。目前的一线治疗药物苯硝唑和硝呋替莫有副作用，且在疾病的慢性阶段缺乏疗效，因此迫切需要新的治疗方法。一项针对该寄生虫生理相关细胞内形式的高通量筛选活动鉴定出了一系列2,4-二氨基-6-甲基嘧啶。证明该系列药物不是通过抗靶点TcCYP51起作用，且一般具有杀细胞作用，证实了其适合进一步开发。本研究报告了该系列药物的选择性和代谢稳定性的优化以及确定了一个适合进一步优化的先导化合物。
