Chemical Optimization of CBL0137 for Human African Trypanosomiasis Lead Drug Discovery

Abstract

The carbazole CBL0137 (<b>1</b>) is a lead for drug development against human African trypanosomiasis (HAT), a disease caused by <i>Trypanosoma brucei</i>. To advance <b>1</b> as a candidate drug, we synthesized new analogs that were evaluated for the physicochemical properties, antitrypanosome potency, selectivity against human cells, metabolism in microsomes or hepatocytes, and efflux ratios. Structure-activity/property analyses of analogs revealed eight new compounds with higher or equivalent selectivity indices (<b>5j</b>, <b>5t</b>, <b>5v</b>, <b>5w</b>, <b>5y</b>, <b>8d</b>, <b>13i</b>, and <b>22e</b>). Based on the overall compound profiles, compounds <b>5v</b> and <b>5w</b> were selected for assessment in a mouse model of HAT; while <b>5v</b> demonstrated a lead-like profile for HAT drug development, <b>5w</b> showed a lack of efficacy. Lessons from these studies will inform further optimization of carbazoles for HAT and other indications.