Interrogating diarylquinoline toxicity with targeted organic synthesis

贝达奎林是FDA于2012年12月31日批准的过去40年来唯一具有新作用机制的治疗结核病的新一线药物。令人担忧的是，这种化合物具有显著的毒性。在这个项目中检验的假设是，降低这类化合物的亲脂性和碱性，同时保持靶标亲和力，将降低毒性，但保持抗结核活性。该项目的目标是：合成不同于贝达奎林的新型杂芳烷基胺，设计为更极性、更少碱性和代谢更稳定；并测试所有成功合成的目标化合物的基于机制的抗结核活性、HERG介导的心脏毒性、代谢不稳定性和磷脂代谢。

Bedaquiline is the only new first-line treatment with a new mechanism of action to treat TB in the last 40 years, approved by the FDA on 31 December 2012. Alarmingly, this compound, has significant toxicities. The hypothesis tested in this project is that decreasing lipophilicity and basicity in this class of compounds while retaining target affinity will decrease toxicity but retain anti-TB activity. The project aims to: synthesise novel heteroarylalkylamines distinct from bedaquiline and designed to be more polar, less basic, and metabolically more stable; and, test all successfully synthesised target compounds for mechanism-based anti-tuberculosis activity, hERG-mediated cardiotoxicity, metabolic instability, and phospholipidosis.