Interrogating diarylquinoline toxicity with targeted organic synthesis

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 December 31st 2012. Alarmingly, this compound, has significant toxicities. Our hypothesis is that decreasing lipophilicity and basicity in this class of compounds while retaining target affinity will decrease toxicity but retain anti-TB activity. AIM 1. To synthesize novel heteroarylalkylamines distinct from bedaquiline and designed to be more polar, less basic, and metabolically more stable. AIM 2. To test all successfully synthesized target compounds for mechanism-based anti-tuberculosis activity, hERG-mediated cardiotoxicity, metabolic instability, and phospholipidosis.