Spiroindolines Identify the Vesicular Acetylcholine Transporter as a Novel Target for Insecticide Action

Abstract

The efficacy of all major insecticide classes continues to be eroded by the development of resistance mediated, in part, by selection of alleles encoding insecticide insensitive target proteins. The discovery of new insecticide classes acting at novel protein binding sites is therefore important for the continued protection of the food supply from insect predators, and of human and animal health from insect borne disease. Here we describe a novel class of insecticides (Spiroindolines) encompassing molecules that combine excellent activity against major agricultural pest species with low mammalian toxicity. We confidently assign the vesicular acetylcholine transporter as the molecular target of Spiroindolines through the combination of molecular genetics in model organisms with a pharmacological approach in insect tissues. The vesicular acetylcholine transporter can now be added to the list of validated insecticide targets in the acetylcholine signalling pathway and we anticipate that this will lead to the discovery of novel molecules useful in sustaining agriculture. In addition to their potential as insecticides and nematocides, Spiroindolines represent the only other class of chemical ligands for the vesicular acetylcholine transporter since those based on the discovery of vesamicol over 40 years ago, and as such, have potential to provide more selective tools for PET imaging in the diagnosis of neurodegenerative disease. They also provide novel biochemical tools for studies of the function of this protein family.

Molecular diversity of spirooxindoles. Synthesis and biological activity

“…For example, Ibutamoren (MK-677, L-163,191) is a potent, orally active growth hormone secretagogue that mimics the stimulating action of the endogenous hormone ghrelin [158,159]. Some spiro[indoline-3,4 -piperidines] have been identified as vesicular acetylcholine transporters (Fig.…”

Regiospecific Isomerization of 2‐Benzoxazinon‐2‐yl Benzoic Acid Toward Some Nitrogen Nucleophiles as Environmental Insecticide

“…New analogues, which may provide some useful information for future design of new insecticides to dramatically reduce reaction time, increase product yields and enhance product purities by reducing unwanted side reactions . By analyzing the data, we found that all the designed analogues have better insecticidal performance than fipronil and SYN351 . Most of our designed analogues exhibited excellent insecticide activities against Nilaparvata lugen and A .…”

2, 3-Dimethylmaleic anhydride (3, 4-Dimethyl-2, 5-furandione): A plant derived insecticidal molecule from Colocasia esculenta var. esculenta (L.) Schott

“…Even though these chemicals have brought with them undesired environmental and health problems, they are being used extensively 28 29 30 31 . Similarly, the recently introduced Diamides, found effective on various pests, acts on the ryanodine receptor of nervous system 32 33 34 . Since the pests continue to evolve resistance to the various compounds which are currently in use, an effective new alternative compound is in urgent need 7 35 36 .…”