Optimization of physicochemical properties for 4-anilinoquinazoline inhibitors of trypanosome proliferation
| Autor: | Kimberly G. Brady, Richard J. Sciotti, Mitchell F. Gallerstein, Jessey Erath, Jennifer L. Woodring, Kelly A. Bachovchin, Ana Rodriguez, Susan E. Leed, Kojo Mensa-Wilmot, Scott Tanghe, Michael P. Pollastri |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Trypanosoma Trypanosoma brucei brucei Pharmacology Trypanosoma brucei 01 natural sciences Article Structure-Activity Relationship 03 medical and health sciences parasitic diseases Drug Discovery Humans Potency Leishmania major Trypanosoma cruzi Cell Proliferation Aniline Compounds Dose-Response Relationship Drug Molecular Structure biology 010405 organic chemistry Chemistry Organic Chemistry Plasmodium falciparum General Medicine biology.organism_classification Trypanocidal Agents Small molecule Virology 0104 chemical sciences 3. Good health Trypanosomiasis African 030104 developmental biology Quinazolines Linker |
| Zdroj: | European Journal of Medicinal Chemistry. 141:446-459 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2017.10.007 |
| Popis: | Human African trypanosomiasis (HAT) is a deadly disease in need of new chemotherapeutics that can cross into the central nervous system. We previously reported the discovery of 2 (NEU-617), a small molecule with activity against T. brucei bloodstream proliferation. Further optimization of 2 to improve the physicochemical properties (LogP, LLE, [1], and MPO score) [2] have led us to twelve sub-micromolar compounds, most importantly the headgroup variants 9i and 9j, and the linker variant 18. Although these 3 compounds had reduced potency compared to 2, they all had improved LogP, LLE and MPO scores. Cross-screening these analogs against other protozoan parasites uncovered 9o with potent activity towards T. brucei, T. cruzi and L. major, while four others compounds (17, 18, 21, 26) showed activity towards P. falciparum D6. This reinforces the effectiveness of lead repurposing for the discovery of new protozoan disease therapeutics. |
| Databáze: | OpenAIRE |
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