Optimization of pyrazolopyridine derivatives for the treatment of human African trypanosomiasis
Year: 2026
Type: preprint
Abstract: Despite recent advances in the development of therapeutics for human African trypanosomiasis, new treatments are needed to populate the drug pipeline in case of failure and resistance. A previously reported high throughput screen of human kinase inhibitors identified the pyrazolopyridine scaffold as an inhibitor of Trypanosoma brucei ( T.b .), which was subsequently optimized for antiparasitic activity. We report the structure-activity relationships (SAR) of the series, focused on improving antitrypanosomal activity and ADME properties, while using structure-based drug design (SBDD) to introduce parasite selectivity. Through these efforts, we identified analogs up to 11-fold more potent than the initial hits, and with up to 40-fold improvement in aqueous solubility. Selectivity for T. brucei over human kinases remains an area for improvement.
Source: ChemRxiv
Authors: Vinou Val, Ben Sokol, Tyler Walker, Jiwon Aiden You, Jia A. Mei, Alma Jukic, Rosario Diaz-González, Cristina Bosch-Navarrete, Carlos Cordón-Obras, Guiomar Pérez-Moreno, Blanca Martínez-Arribas, Charles J. Eyermann, Michael P. Pollastri, Dolores González-Pacanowska, Amy B. Dounay, Lori Ferrins
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7169815080