Discovery of acrylonitrile-based small molecules active against Haemonchus contortus

作者：Gordon Christopher P; Hizartzidis Lacey; Tarleton Mark; Sakoff Jennette A; Gilbert Jayne; Campbell Bronwyn E; Gasser Robin B; McCluskey Adam^*

来源：Medchemcomm, 2014, 5(2): 159-164.

DOI：10.1039/c3md00255a

We report the discovery of a series of acrylonitrile-containing molecules and alpha-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 mu M whilst the alpha-amino amide methyl-2-[2-(2-benzoylphenylamino)-2-(4-methoxyphenyl) acetamido]acetate (12a) had an LD50 value of 10 mu M. 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 alpha-amino amide 12a displayed very low cytotoxicity, with a maximum of similar to 30% cell death at 25 mu M (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.

• 出版日期2014