Potent and selective indole-based inhibitors targeting disease-transmitting mosquitoes

Area of Science:

• Medicinal Chemistry
• Entomology
• Biochemistry

Background:

• Insecticide resistance and off-target effects necessitate novel vector control agents.
• Acetylcholinesterase 1 (AChE1) is a key target for insecticides in disease-transmitting mosquitoes.
• Indole derivatives are explored as potential active ingredients for new insecticides.

Purpose of the Study:

• To design, synthesize, and evaluate indole-based compounds as selective AChE1 inhibitors.
• To investigate the structure-activity relationship for potency and selectivity against mosquito AChE1.
• To assess the insecticidal efficacy of promising compounds against disease vectors.

Main Methods:

• Synthesis of 26 indole-based compounds.
• Biochemical evaluation of inhibition against Anopheles gambiae AChE1, Aedes aegypti AChE1, and human AChE.
• Structure-activity relationship analysis, X-ray crystallography, and molecular dynamics simulations.
• In vivo topical application testing on Anopheles gambiae and Aedes aegypti.

Main Results:

• Indole-based compounds demonstrated potent inhibition of mosquito AChE1.
• Compounds exhibited selectivity for mosquito AChE1 over human AChE.
• N-Methylation and bulkier benzyl moieties enhanced potency and selectivity, respectively.
• Four compounds showed strong insecticidal effects against Anopheles gambiae and Aedes aegypti.

Conclusions:

• Indole-based compounds are effective inhibitors of mosquito AChE1.
• This class of compounds represents a promising alternative for developing new insecticides.
• Selective AChE1 inhibitors offer a viable strategy for vector control, mitigating resistance and toxicity issues.