| Autor: |
Singh B; Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States., Diaz-Gonzalez R; Instituto de Parasitología y Biomedicina 'López-Neyra' Consejo Superior de Investigaciones Científicas (CSIC), Granada 18016, Spain., Ceballos-Perez G; Instituto de Parasitología y Biomedicina 'López-Neyra' Consejo Superior de Investigaciones Científicas (CSIC), Granada 18016, Spain., Rojas-Barros DI; Instituto de Parasitología y Biomedicina 'López-Neyra' Consejo Superior de Investigaciones Científicas (CSIC), Granada 18016, Spain., Gunaganti N; Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States., Gillingwater K; Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051 Basel, Switzerland.; University of Basel, Petersplatz 1, 4001 Basel, Switzerland., Martinez-Martinez MS; Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline, Tres Cantos 28760, Spain., Manzano P; Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline, Tres Cantos 28760, Spain., Navarro M; Instituto de Parasitología y Biomedicina 'López-Neyra' Consejo Superior de Investigaciones Científicas (CSIC), Granada 18016, Spain., Pollastri MP; Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States. |
| Abstrakt: |
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 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 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)-9 H -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. |
