Medicinal Chemistry Optimization of a Diaminopurine Chemotype: Toward a Lead for Trypanosoma brucei Inhibitors
- 12 August 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 63 (17), 9912-9927
- https://doi.org/10.1021/acs.jmedchem.0c01017
Abstract
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 Trypanosoma brucei, previously we identified 797 potent kinasetargeting 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 the exploration of structure-activity and structure-property relationships around one of the high-throughput screening (HTS) hits, N-2-(thiophen-3-yl)-N-6-(2,2,2-trifluoroethyl)-9H-purine-2,6-diamine (1, NEU-1106). This work led to the identification of a potent lead compound (4aa, NEU-4854) with improved in vitro absorption, distribution, metabolism, and excretion (ADME) properties, which was progressed into proof-of-concept translation of in vitro antiparasitic activity to in vivo efficacy.Funding Information
- National Institute of Allergy and Infectious Diseases (R01AI104576, R01AI114685, R01AI124046, R01AI126311)
- Tres Cantos Open Lab Foundation
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