Department of Chemistry, Portland State University, Portland, Oregon 97201, United States.
Department of Veterans Affairs Medical Center, Portland, Oregon 97239, United States.
J Med Chem. 2020 Jun 11;63(11):6179-6202. doi: 10.1021/acs.jmedchem.0c00539. Epub 2020 May 26.
The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. With increasing drug resistance and the absence of a clinically available vaccine, there is an urgent need for novel, affordable, and safe drugs for prevention and treatment of malaria. Previously, we described a novel antimalarial acridone chemotype that is potent against both blood-stage and liver-stage malaria parasites. Here, we describe an optimization process that has produced a second-generation acridone series with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. These findings highlight the therapeutic potential of dual-stage targeting acridones as novel drug candidates for further preclinical development.
尽管为消灭疟疾做出了广泛的努力，但疟疾的全球影响仍然惊人。随着耐药性的增加和缺乏临床可用的疫苗，人们迫切需要新型、经济实惠且安全的药物来预防和治疗疟疾。此前，我们描述了一种新型抗疟吖啶酮化学型，对血期和肝期疟原虫均有很强的作用。在这里，我们描述了一个优化过程，产生了第二代吖啶酮系列，在疗效、代谢稳定性、药代动力学和安全性方面都有显著改善。这些发现突出了双阶段靶向吖啶酮作为新型候选药物在进一步临床前开发中的治疗潜力。
