Chemical Optimization of CBL0137 for Human African Trypanosomiasis Lead Drug Discovery
Department
Molecular and Cellular Biology
Document Type
Article
Publication Date
2-9-2023
Abstract
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.
Journal Title
Journal of Medicinal Chemistry
Journal ISSN
00222623
Volume
66
Issue
3
First Page
1972
Last Page
1989
Digital Object Identifier (DOI)
10.1021/acs.jmedchem.2c01767