Synthesis, Anthelmintic Activity, and Mechanism of Action of 5-Aryl-1H-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-1H-indole derivatives bearing various substituents on the phenyl ring and assessed their efficacy against nematodes. Using Caenorhabditis elegans, 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 Hemonchus contortus while exhibiting limited cytotoxicity in mammalian cell cultures. These compounds showed similar effects against the plant-parasitic nematodes Heterodera schachtii and Ditylenchus destructor, 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 C. elegans complex II mutants.