Chemical Optimization of CBL0137 for Human African Trypanosomiasis Lead Drug Discovery

Authors

Baljinder Singh, Northeastern University
Amrita Sharma, Kennesaw State University
Naresh Gunaganti, Northeastern University
Mitch Rivers, Northeastern University
Pradip K. Gadekar, Northeastern University
Brady Greene, Northeastern University
Michael Chichioco, Northeastern University
Carlos E. Sanz-Rodriguez, University of Georgia
Courtney Fu, Northeastern University
Catherine LeBlanc, Northeastern University
Erin Burchfield, Northeastern University
Nyle Sharif, Northeastern University
Benjamin Hoffman, University of Georgia
Gaurav Kumar, Kennesaw State University
Andrei Purmal, Incuron LLC
Kojo Mensa-Wilmot, Kennesaw State University
Michael P. Pollastri, Northeastern University

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