期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 141, 期 -, 页码 446-459出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.10.007
关键词
Neglected tropical disease; Human African trypanosomiasis; Target class repurposing; Trypanosoma brucei; Leishmania major; Trypanosoma cruzi; Plasmodium falciparum
资金
- National Institutes of Health [R56AI099476]
- National Science Foundation [IGERTeNS-FeDGE 0965843]
- Northeastern University
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 90 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. (C) 2017 Elsevier Masson SAS. All rights reserved.
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