Chemical Optimization of CBL0137 for Human African Trypanosomiasis Lead Drug Discovery

The carbazole CBL0137 (1) is a lead for
drug development
against human African trypanosomiasis (HAT), a disease caused by Trypanosoma brucei. To advance 1 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 (5j, 5t, 5v, 5w, 5y, 8d, 13i, and 22e). Based on the overall compound profiles, compounds 5v and 5w were selected for assessment in a mouse
model of HAT; while 5v demonstrated a lead-like profile
for HAT drug development, 5w showed a lack of efficacy.
Lessons from these studies will inform further optimization of carbazoles
for HAT and other indications.