Fredo Naciuk Fabrício, do Nascimento Faria Jéssica, Gonçalves Eufrásio Amanda, Torres Cordeiro Artur, Bruder Marjorie
Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials, Campinas-SP 13083-100, Brazil.
ACS Med Chem Lett. 2020 Apr 27;11(6):1250-1256. doi: 10.1021/acsmedchemlett.0c00106. eCollection 2020 Jun 11.
Chagas disease is a parasitic infection affecting millions of people across Latin America, imposing a dramatic socioeconomic burden. Despite the availability of drugs, nifurtimox and benznidazole, lack of efficacy and incidence of side-effects prompt the identification of novel, efficient, and affordable drug candidates. To address this issue, one strategy could be probing the susceptibility of parasites toward NADP-dependent enzyme inhibitors. Recently, steroids of the androstane group have been described as highly potent but nonselective inhibitors of parasitic glucose-6-phosphate dehydrogenase (G6PDH). In order to promote selectivity, we have synthesized and evaluated 26 steroid derivatives of epiandrosterone in enzymatic assays, whereby 17 compounds were shown to display moderate to high selectivity for over the human G6PDH. In addition, three compounds were effective in killing intracellular forms infecting rat cardiomyocytes. Altogether, this study provides new SAR data around G6PDH and further supports this target for treating Chagas disease.
恰加斯病是一种寄生虫感染病，影响着拉丁美洲数百万人口，带来了巨大的社会经济负担。尽管有硝呋替莫和苯硝唑等药物，但疗效欠佳以及副作用的发生率促使人们寻找新型、高效且价格合理的候选药物。为解决这一问题，一种策略可能是探究寄生虫对依赖烟酰胺腺嘌呤二核苷酸磷酸（NADP）的酶抑制剂的敏感性。最近，雄甾烷类甾体已被描述为对寄生虫葡萄糖-6-磷酸脱氢酶（G6PDH）具有高效但非选择性的抑制剂。为了提高选择性，我们合成并在酶促试验中评估了26种表雄酮的甾体衍生物，其中17种化合物对寄生虫G6PDH显示出中度至高选择性，优于人类G6PDH。此外，三种化合物对感染大鼠心肌细胞的细胞内寄生虫形式具有杀灭作用。总之，本研究提供了围绕G6PDH的新的构效关系（SAR）数据，并进一步支持将该靶点用于治疗恰加斯病。
