Small Molecule Inhibitors of Metabolic Enzymes Repurposed as a New Class of Anthelmintics

The enormous prevalence of infections
caused by parasitic nematodes
worldwide, coupled to the rapid emergence of their resistance to commonly
used anthelmintic drugs, presents an urgent need for the discovery
of new drugs. Herein, we have identified several classes of small
molecules with broad spectrum activity against these pathogens. Previously,
we reported the identification of carnitine palmitoyltransferases
(CPTs) as a representative class of enzymes as potential targets for
metabolic chokepoint intervention that was elucidated from a combination
of chemogenomic screening and experimental testing in nematodes. Expanding
on these previous findings, we have discovered that several chemical
classes of known small molecule inhibitors of mammalian CPTs have
potent activity as anthelmintics. Cross-clade efficacy against a broad
spectrum of adult parasitic nematodes was demonstrated for multiple
compounds from different series. Several analogs of these initial
hit compounds were designed and synthesized. The compounds we report
represent a good starting point for further lead identification and
optimization for development of new anthelmintic drugs with broad
spectrum activity and a novel mechanism of action.