Investigation into potential Dirofilaria immitis drug targets through rational anthelmintic synthesis and design

Abstract

Dirofilaria immitis is a mosquito-transmitted parasitic nematode that can cause debilitating disease in dogs. D. immitis is present in Canada and over the years has increased in prevalence due to several factors including climate change. Anthelmintic resistance is becoming increasingly problematic and as such, the aim of this thesis was to synthesize several novel compounds and examine their activity on the anthelmintic receptor targets of interest, ACC-2 which is an acetylcholine-gated chloride channel unique to nematodes and the UNC-49 GABA receptor. In total, 22 compounds, 12 of which are novel, were synthesized, including imidazole-4-acetic acid like compounds, levamisole derivatives, and a levamisole dimer. Compounds 8-15 were tested on the Hco-ACC-2 receptor using electrophysiological techniques and all demonstrated various degrees of receptor activation. Compound 13, which had the highest response, was further evaluated using computer-based ligand docking on a homology model of the Hco-ACC-2 receptor