Synthesis, Anthelmintic Activity, and Mechanism of Action of 5‑Aryl‑1H‑indoles

TL;DR

This paper explores new 5-phenyl-1H-indole compounds that show anthelmintic activity against various nematode species with low mammalian toxicity.

Contribution

The study introduces novel 5-phenyl-1H-indole derivatives with anthelmintic properties and proposes a mechanism of action involving mitochondrial complex II inhibition.

Findings

Compounds with 4-chloro, 4-fluoro, and 4-trifluoromethoxy groups effectively inhibit nematode larval motility.

These compounds show reduced potency against plant-parasitic nematodes compared to animal parasites.

Molecular modeling and experiments suggest mitochondrial complex II inhibition as the mechanism of action.

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.

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