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    Substituted 2-Phenylimidazopyridines: A New Class of Drug Leads for Human African Trypanosomiasis
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    † § Departments of †Chemistry, ‡Medicine, and §Biochemistry, University of Washington, Seattle, Washington 98195, United States
    ∥ Genomics Institute of the Novartis Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
    ⊥ Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002 Basel, Switzerland
    # University of Basel, 4003 Basel, Switzerland
    *F.S.B.: phone, 206-616-9214; e-mail, [email protected]
    *M.H.G.: phone, 206-543-7142; e-mail, [email protected]
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2014, 57, 3, 828–835
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    https://doi.org/10.1021/jm401178t
    Published December 19, 2013
    Copyright © 2013 American Chemical Society
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    Abstract

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    A phenotypic screen of a compound library for antiparasitic activity on Trypanosoma brucei, the causative agent of human African trypanosomiasis, led to the identification of substituted 2-(3-aminophenyl)oxazolopyridines as a starting point for hit-to-lead medicinal chemistry. A total of 110 analogues were prepared, which led to the identification of 64, a substituted 2-(3-aminophenyl)imidazopyridine. This compound showed antiparasitic activity in vitro with an EC50 of 2 nM and displayed reasonable druglike properties when tested in a number of in vitro assays. The compound was orally bioavailable and displayed good plasma and brain exposure in mice. Compound 64 cured mice infected with Trypanosoma brucei when dosed orally down to 2.5 mg/kg. Given its potent antiparasitic properties and its ease of synthesis, compound 64 represents a new lead for the development of drugs to treat human African trypanosomiasis.

    Copyright © 2013 American Chemical Society

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    Synthesis of compounds and pharmacokinetics data. This material is available free of charge via the Internet at http://pubs.acs.org.

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2014, 57, 3, 828–835
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    https://doi.org/10.1021/jm401178t
    Published December 19, 2013
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