biostudies-literatureSingh BNational Institute of Allergy and Infectious DiseasesNIAID NIH HHS1972-1989https://www.ebi.ac.uk/biostudies/studies/S-EPMC9923759biostudies-literatureUnknown66(3)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 HAJournal of medicinal chemistryChemical Optimization of CBL0137 for Human African Trypanosomiasis Lead Drug Discovery.PMC9923759R01AI126311R01AI124046R01 AI124046R01 AI126311Purmal AGadekar PKMensa-Wilmot KPollastri MPSingh BSanz-Rodriguez CEHoffman BLeBlanc CSharma AGunaganti NGreene BFu CKumar GSharif NBurchfield ERivers MChichioco MfalseChemical 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 HA2023-01-01T00:00:00Z2023 Feb2026-07-14T20:11:08.806Z2025-04-06T02:55:35.385ZS-EPMC99237593669563010.1021/acs.jmedchem.2c01767