Bioactivities and modes of action of VUAA1

Abstract BACKGROUND The compound 2‐((4‐ethyl‐5‐(pyridin‐3‐yl)‐4H‐1,2,4‐triazol‐3‐yl)thio)‐N‐(4‐ethylphenyl) acetamide (VUAA1) is reported to be an odorant receptor co‐receptor (Orco) agonist in insects with potential use as an insect repellent. For this study, the biological activity of VUAA1 was investigated in several bioassays with Aedes aegypti, including adult contact, spatial repellency, and larval repellency assays, as well as topical, injection, and feeding toxicity assays. Neurophysiological action was further explored by analysis of fruit fly central nervous system firing, cockroach axon recordings, patch clamp analysis of Kv2 potassium channel, and acetylcholinesterase inhibition studies. Finally, the metabolic impact on the toxicity of VUAA1 was explored by applying it in combination with established metabolic synergists. RESULTS In repellency and bite protection screens, VUAA1 showed little activity against adult mosquitoes, apparently due to its low volatility, since its effectiveness was increased by heating or mixing with transfluthrin acid and citronella oil. It did produce measurable repellency of mosquito larvae that was more potent than N,N‐diethyl‐m‐toluamide (DEET). Overall, VUAA1 showed low acute toxicity to both insects and mice, and it was weakly synergized by triphenyl phosphate. There was no observed cross‐resistance in a pyrethroid‐resistant strain of Anopheles gambiae. VUAA1 showed a two‐phase effect on the central nervous system, with neuroexcitation at 1 μmol L‐1 and an inhibitory effect at 100 μmol L‐1 that may relate to block of Kv2 potassium channels. CONCLUSIONS VUAA1 presented low toxicity, similar to other insect repellents. Its limited solubility, low volatility, and resulting poor adult repellency without additional adjuvants may restrict the utility of VUAA1 in typical public health applications. © 2020 Society of Chemical Industry