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  • 6-Arylpyrazine-2-carboxamides: A New Core for Trypanosoma brucei Inhibitors

    Author(s)
    Rahmani, Raphael
    Ban, Kung
    Jones, Amy J
    Ferrins, Lori
    Ganame, Danny
    Sykes, Melissa L
    Avery, Vicky M
    White, Karen L
    Ryan, Eileen
    Kaiser, Marcel
    Charman, Susan A
    Baell, Jonathan B
    Griffith University Author(s)
    Sykes, Melissa L.
    Avery, Vicky M.
    Year published
    2015
    Metadata
    Show full item record
    Abstract
    From a whole-organism high throughput screen of approximately 87000 compounds against Trypanosoma brucei brucei, we recently identified eight new unique compounds for the treatment of human African trypanosomiasis. In an effort to understand the structure–activity relationships around these compounds, we report for the first time our results on a new class of trypanocides, the pyrazine carboxamides. Attracted by the low molecular weight (270 g·mol–1) of our starting hit (9) and its potency (0.49 μM), the SAR around the core was explored, leading to compounds having an EC50 as low as 25 nM against T. b. brucei and being more ...
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    From a whole-organism high throughput screen of approximately 87000 compounds against Trypanosoma brucei brucei, we recently identified eight new unique compounds for the treatment of human African trypanosomiasis. In an effort to understand the structure–activity relationships around these compounds, we report for the first time our results on a new class of trypanocides, the pyrazine carboxamides. Attracted by the low molecular weight (270 g·mol–1) of our starting hit (9) and its potency (0.49 μM), the SAR around the core was explored, leading to compounds having an EC50 as low as 25 nM against T. b. brucei and being more than 1500 times less toxic against mammalian L6 and HEK293 cell lines. The most potent compounds in the series were exquisitely selective for T. brucei over a panel of other protozoan parasites, showing an excellent correlation with the human infective parasite Trypanosoma brucei rhodesiense, the most potent compound (65) having an EC50 of 24 nM. The compounds are highly drug-like and are able to penetrate the CNS, their only limitation currently being their rate of microsomal metabolism. To that effect, efforts to identify potential metabolites of selected compounds are also reported.
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    Journal Title
    Journal of Medicinal Chemistry
    Volume
    58
    Issue
    17
    DOI
    https://doi.org/10.1021/acs.jmedchem.5b00438
    Subject
    Medicinal and biomolecular chemistry
    Medicinal and biomolecular chemistry not elsewhere classified
    Organic chemistry
    Pharmacology and pharmaceutical sciences
    Publication URI
    http://hdl.handle.net/10072/101459
    Collection
    • Journal articles

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