2. Academic Validation
  3. Chemical Optimization of CBL0137 for Human African Trypanosomiasis Lead Drug Discovery

Chemical Optimization of CBL0137 for Human African Trypanosomiasis Lead Drug Discovery

  • J Med Chem. 2023 Feb 9;66(3):1972-1989. doi: 10.1021/acs.jmedchem.2c01767.
Baljinder Singh 1,  Amrita Sharma 2,  Naresh Gunaganti 1,  Mitch Rivers 1,  Pradip K Gadekar 1,  Brady Greene 1,  Michael Chichioco 1,  Carlos E Sanz-Rodriguez 3,  Courtney Fu 1,  Catherine LeBlanc 1,  Erin Burchfield 1,  Nyle Sharif 1,  Benjamin Hoffman 3,  Gaurav Kumar 2,  Andrei Purmal 4,  Kojo Mensa-Wilmot 2 3,  Michael P Pollastri 1
Affiliations

Affiliations

  • 1 Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States.
  • 2 Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, Georgia 30144, United States.
  • 3 Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia 30602, United States.
  • 4 Incuron Inc., Buffalo, New York 14203, United States.
PMID: 36695630 DOI: 10.1021/acs.jmedchem.2c01767
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.

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