Synthesis, Anthelmintic Activity, and Mechanism of Action of 5-Aryl-1<i>H</i>-indoles.

Abstract

Parasitic nematodes are a significant concern in human and veterinary medicine as well as agriculture. In this study, we prepared twenty-seven 5-phenyl-1<i>H</i>-indole derivatives bearing various substituents on the phenyl ring and assessed their efficacy against nematodes. Using <i>Caenorhabditis elegans</i>, we selected the most potent compounds and evaluated their toxicity on selected animal and plant-parasitic nematode species. Compounds featuring 4-chloro, 4-fluoro, and 4-trifluoromethoxy groups on the phenyl ring inhibited the motility of exsheathed L3 larvae of <i>Hemonchus contortus</i> while exhibiting limited cytotoxicity in mammalian cell cultures. These compounds showed similar effects against the plant-parasitic nematodes <i>Heterodera schachtii</i> and <i>Ditylenchus destructor</i>, albeit with reduced potency. We propose that the compounds might act as inhibitors of mitochondrial complex II as inferred from molecular modeling, decreased mitochondrial membrane potential, and reduced activity in <i>C. elegans</i> complex II mutants.