Chemical Optimization of CBL0137 for Human African Trypanosomiasis Lead Drug Discovery

[Image: see text] 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...

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Detalles Bibliográficos
Autores principales: Singh, Baljinder, Sharma, Amrita, Gunaganti, Naresh, Rivers, Mitch, Gadekar, Pradip K., Greene, Brady, Chichioco, Michael, Sanz-Rodriguez, Carlos E., Fu, Courtney, LeBlanc, Catherine, Burchfield, Erin, Sharif, Nyle, Hoffman, Benjamin, Kumar, Gaurav, Purmal, Andrei, Mensa-Wilmot, Kojo, Pollastri, Michael P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9923759/
https://www.ncbi.nlm.nih.gov/pubmed/36695630
http://dx.doi.org/10.1021/acs.jmedchem.2c01767
Descripción
Sumario:[Image: see text] 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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