Medicinal chemistry optimization of a diaminopurine chemotype: Towards a lead for Trypanosoma brucei inhibitors

• Published in: Journal of medicinal chemistry Vol. 63; no. 17; pp. 9912 - 9927
• Main Authors: Singh, Baljinder, Diaz-Gonzalez, Rosario, Ceballos-Perez, Gloria, Rojas-Barros, Domingo I., Gunaganti, Naresh, Gillingwater, Kirsten, Martinez-Martinez, Maria Santos, Manzano, Pilar, Navarro, Miguel, Pollastri, Michael P.
• Format: Journal Article
• Language: English
• Published: 13.08.2020
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c01017

Human African trypanosomiasis (HAT), or sleeping sickness, is caused by the protozoan parasite Trypanosoma brucei and transmitted through the bite of infected tsetse flies. The disease is considered fatal if left untreated. To identify new chemotypes against T. brucei , previously we identified 797 potent kinase-targeting inhibitors grouped into 59 clusters plus 53 singleton compounds with at least 100-fold selectivity over HepG2 cells. From this set of hits, a cluster of diaminopurine-derived compounds was identified. Herein we report our medicinal chemistry investigation involving exploration of structure-activity and structure-property relationships around one of the HTS hits, N 2 -(thiophen-3-yl)-N 6 -(2,2,2-trifluoroethyl)-9H-purine-2,6-diamine ( 1 , NEU-1106). This work lead to the identification of a potent lead compound ( 4aa , NEU-4854) with improved ADME properties, which was progressed into proof-of-concept translation of in vitro antiparasitic activity to in vivo efficacy.