Discovery of acrylonitrile-based small molecules active against Haemonchus contortus

Abstract

We report the discovery of a series of acrylonitrile-containing molecules and a-amino amides which cause 99-100% lethality in H. contortus. Of the 22 acrylonitrile analogues investigated, the most active were 22) with each displaying LD 50 values <15 mM whilst the a-amino amide methyl-2-[2-(2benzoylphenylamino)-2-(4-methoxyphenyl)acetamido]acetate (12a) had an LD 50 value of 10 mM. 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 a-amino amide 12a displayed very low cytotoxicity, with a maximum of $30% cell death at 25 mM (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.

Low cost whole-organism screening of compounds for anthelmintic activity

“…Unpublished work has also shown that the structurally similar pyrazol derivative compound GW461487A which contains a pyrazolo-ring and therefore is structurally similar to that of DB0323, also possesses activity against L1s in a conventional LDA for H. contortus (cf. Gordon et al, 2014); DB03023 might also have activity against xL3 or L4 H. contortus and thus warrants testing in ourthis newly developed assay. Interestingly, ourthe biphenyl amide analog (GW800172X) did not have any activity on H. contortus L1s in LDA.…”

A perspective on genomic-guided anthelmintic discovery and repurposing using Haemonchus contortus

“…We have employed such an approach for proof-of-principle studies, and identified effective targets for nematocides (e.g., Campbell et al, 2011;Gordon et al, 2014). We have also suggested the use of a complementary approach to infer enzymatic chokepoints intrinsic to the metabolome of a parasite (Jex et al, 2011;Young et al, 2012).…”

Monepantel: the most studied new anthelmintic drug of recent years

“…On the other hand, resistance development also increases the ongoing interest to identify and develop further classes of anthelmintic agents. Gordon et al (2014) have turned an attention to a series of pyrrolacrylonitriles, which potentially represent privileged anthelmintic molecular scaffolds. In addition, they have investigated the acrylonitrile scaffold to determine the crucial features required for anthelmintic activity and establish an expanded pharmacophore that is lethal to H. contortus .…”