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Issue 2, 2014
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Discovery of acrylonitrile-based small molecules active against Haemonchus contortus

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Abstract

We report the discovery of a series of acrylonitrile-containing molecules and α-amino amides which cause 99–100% lethality in H. contortus. Of the 22 acrylonitrile analogues investigated, the most active were 2-cyano-3-[1-(3-dimethylaminopropyl)-2-methyl-1H-indol-3-yl]-N-hexylacrylamide (13a), 2-cyano-3-[1(2-dimethylaminoethyl)-2-methyl-1H-indol-3-yl]-N-hexylacrylamide (13b), 2-cyano-3-{4-[3-(dimethylamino)propoxy]phenyl}-N-octylacrylamide (21), and 2-cyano-3-{1-[3-(dimethylamino)propyl]-1H-pyrrol-2-yl}-N-octylacrylamide (22) with each displaying LD50 values <15 μM whilst the α-amino amide methyl-2-[2-(2-benzoylphenylamino)-2-(4-methoxyphenyl)acetamido]acetate (12a) had an LD50 value of 10 μM. A cytotoxicity screen of the acrylonitrile analogues (13a, 13b, 21 and 22) against nine cancer cell lines indicated modest to high cytotoxicity. In contrast, the α-amino amide 12a displayed very low cytotoxicity, with a maximum of ∼30% cell death at 25 μM (A2780, an ovarian carcinoma derived cell line) and with a mean of 11% cell death across all cell lines evaluated. Thus, 12a is considered a promising lead candidate for the development of a new anthelmintic.

Graphical abstract: Discovery of acrylonitrile-based small molecules active against Haemonchus contortus

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Publication details

The article was received on 09 Sep 2013, accepted on 02 Dec 2013 and first published on 11 Dec 2013


Article type: Concise Article
DOI: 10.1039/C3MD00255A
Citation: Med. Chem. Commun., 2014,5, 159-164
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    Discovery of acrylonitrile-based small molecules active against Haemonchus contortus

    C. P. Gordon, L. Hizartzidis, M. Tarleton, J. A. Sakoff, J. Gilbert, B. E. Campbell, R. B. Gasser and A. McCluskey, Med. Chem. Commun., 2014, 5, 159
    DOI: 10.1039/C3MD00255A

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