RESUMO
Nematode parasites of humans and livestock pose a significant burden to human health, economic development, and food security. Anthelmintic drug resistance is widespread among parasites of livestock and many nematode parasites of humans lack effective treatments. Here, we present a nitrophenyl-piperazine scaffold that induces motor defects rapidly in the model nematode Caenorhabditis elegans. We call this scaffold Nemacol and show that it inhibits the vesicular acetylcholine transporter (VAChT), a target recognized by commercial animal and crop health groups as a viable anthelmintic target. We demonstrate that it is possible to create Nemacol analogs that maintain potent in vivo activity whilst lowering their affinity to the mammalian VAChT 10-fold. We also show that Nemacol enhances the ability of the anthelmintic Ivermectin to paralyze C. elegans and the ruminant nematode parasite Haemonchus contortus. Hence, Nemacol represents a promising new anthelmintic scaffold that acts through a validated anthelmintic target.
Assuntos
Anti-Helmínticos , Nematoides , Animais , Humanos , Caenorhabditis elegans , Proteínas Vesiculares de Transporte de Acetilcolina , Anti-Helmínticos/farmacologia , Ivermectina/farmacologia , Resistência a Medicamentos , MamíferosRESUMO
A highly effective and operationally simple method for the regioselective deuteration of anilines is presented. A variety of electron-rich and electron-deficient anilines are efficiently deuterated at the ortho and/or para position with respect to the nitrogen in the presence of 1 equiv of conc HCl in D 2O. Under the present conditions, aromatic methoxy groups do not facilitate deuteration, enabling a chemo- and regioselective deuteration of p-anisidine.