Medicinal Chemistry Optimization of a Diaminopurine Chemotype : Toward a Lead for Trypanosoma brucei Inhibitors
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, N2-(thiophen-3-yl)-N6-(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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:63 |
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| Enthalten in: |
Journal of medicinal chemistry - 63(2020), 17 vom: 10. Sept., Seite 9912-9927 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Singh, Baljinder [VerfasserIn] |
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| Links: |
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| Themen: |
Journal Article |
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| Anmerkungen: |
Date Completed 18.12.2020 Date Revised 11.09.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.0c01017 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM313609608 |
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| 245 | 1 | 0 | |a Medicinal Chemistry Optimization of a Diaminopurine Chemotype |b Toward a Lead for Trypanosoma brucei Inhibitors |
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| 500 | |a Date Revised 11.09.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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, N2-(thiophen-3-yl)-N6-(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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Purines |2 NLM | |
| 650 | 7 | |a Trypanocidal Agents |2 NLM | |
| 700 | 1 | |a Diaz-Gonzalez, Rosario |e verfasserin |4 aut | |
| 700 | 1 | |a Ceballos-Perez, Gloria |e verfasserin |4 aut | |
| 700 | 1 | |a Rojas-Barros, Domingo I |e verfasserin |4 aut | |
| 700 | 1 | |a Gunaganti, Naresh |e verfasserin |4 aut | |
| 700 | 1 | |a Gillingwater, Kirsten |e verfasserin |4 aut | |
| 700 | 1 | |a Martinez-Martinez, Maria Santos |e verfasserin |4 aut | |
| 700 | 1 | |a Manzano, Pilar |e verfasserin |4 aut | |
| 700 | 1 | |a Navarro, Miguel |e verfasserin |4 aut | |
| 700 | 1 | |a Pollastri, Michael P |e verfasserin |4 aut | |
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