Structural Exploration of Novel Pyrethroid Esters and Amides for Repellent and Insecticidal Activity against Mosquitoes

The emergence of pyrethroid-resistant mosquitoes is a worldwide problem that necessitates further research into the development of new repellents and insecticides. This study explored the modification of existing pyrethroid acids to identify structural motifs that might not be affected by kdr active site mutations that elicit pyrethroid resistance. Because synthetic pyrethroids almost always contain activity-dependent chiral centers, we chose to focus our efforts on exploring alkoxy moieties of esters obtained with 1R-trans-permethrinic and related acids, which we showed in previous studies to have repellent and/or repellent synergistic properties. To this end, compounds were synthesized and screened for spatially acting repellency and insecticidal activity against the susceptible, Orlando, and pyrethroid-resistant, Puerto Rico, strains of Aedes aegypti mosquito. Screening utilized a high-throughput benchtop glass tube assay, and the compounds screened included a mixture of branched, unbranched, aliphatic, halogenated, cyclic, non-cyclic, and heteroatom-containing esters. Structure–activity relationships indicate that n-propyl, n-butyl, n-pentyl, cyclobutyl, and cyclopentyl substituents exhibited the most promising repellent activity with minimal kdr cross resistance. Preliminary testing showed that these small alcohol esters can be synergistic with phenyl amides and pyrethroid acids. Further derivatization of pyrethroid acids offer an interesting route to future active compounds, and while mosquitoes were the focus of this work, pyrethroid acids and esters have potential for use in reducing pest populations and damage in cropping systems as well

Enantioselective Deprotonative Ring Contraction of <i>N</i>1‑Methyl‑<i>N</i>4‑Boc-benzo[<i>e</i>][1,4]diazepine-2,5-diones

N1-Methyl-N4-Boc-benzo­[e]­[1,4]­diazepine-2,5-diones were prepared in good yield and high stereochemical purity from five amino acids. Upon deprotonation, these compounds undergo ring contraction to the corresponding quinolone-2,4-diones with high enantioselectivity, providing efficient entry to a potentially useful drug scaffold. Mechanistic commentary and comparisons to related reactions are provided

Enantioselective Deprotonative Ring Contraction of <i>N</i>1‑Methyl‑<i>N</i>4‑Boc-benzo[<i>e</i>][1,4]diazepine-2,5-diones

<i>N</i>1-Methyl-<i>N</i>4-Boc-benzo­[<i>e</i>]­[1,4]­diazepine-2,5-diones were prepared in good yield and high stereochemical purity from five amino acids. Upon deprotonation, these compounds undergo ring contraction to the corresponding quinolone-2,4-diones with high enantioselectivity, providing efficient entry to a potentially useful drug scaffold. Mechanistic commentary and comparisons to related reactions are provided

Resistance-Breaking Insecticidal Activity of New Spatial Insecticides against Aedes aegypti

The use of N-aryl amide derivatives as spatially acting insecticides remains relatively unexplored. To expand this knowledge, we synthesized eighty-nine N-aryl amide analogues and screened them for mortality against an insecticide-susceptible strain of Aedes aegypti mosquitoes, Orlando (OR), using a vapor exposure glass tube assay. Of the screened compounds, twenty-two produced >92% mortality at 24 h and warranted further investigation to determine LC50 values. Fifteen of these analogues had LC50 values within 2 orders of magnitude of transfluthrin, and of significant interest, N-(2,6-dichloro-4-(trifluoromethyl)­phenyl)-2,2,3,3,3-pentafluoropropanamide (compound 70) was nearly as potent as transfluthrin and exhibited greater toxicity than metofluthrin when screened against OR A. aegypti. Compounds exhibiting potent toxicity against OR A. aegypti or whose structure–activity relationship potentially offered beneficial insights into structure optimization were screened against the insecticide-resistant, Puerto Rico (PR), strain of A. Aegypti, and it was discovered that not only did these N-arylamides typically show little resistance, some such as N-(2,6-dichloropyridin-4-yl)-2,2,3,3,4,4,4-heptafluorobutanamide (compound 36) and 2,2,3,3,4,4,4-heptafluoro-N-(3,4,5-trifluorophenyl)­butanamide (compound 40) were actually more potent against the PR mosquitoes. Due to this promising insecticidal activity, five compounds were administered orally to mice to determine acute oral rodent toxicity. All five compounds were found to have mouse oral toxicity LD50 values well above the minimum safe level as set by the Innovative Vector Control Consortium (50 mg/kg). In addition to the promising biological activity documented here, we report the structure–activity relationship analysis used to guide the derivatization approach taken and to further inform future efforts in the development of N-arylamides as potential resistance-breaking, spatially acting insecticides

Image_1_Induction Coil Heating Improves the Efficiency of Insect Olfactory Studies.TIFF

Electroantennography (EAG) is a commonly used method to study the olfactory responses of insects, but many behaviorally relevant odorant responses are difficult to evaluate because only a small amount of chemical sample is available in the vapor phase. We have assembled a coupled induction heating-electroantennogram (IH-EAG) system to improve the release efficiency of tested compounds. This system allows precise temperature control from room temperature to 600°C of the carbon steel wire without changing significantly the air delivery temperature to the antennae. After heating to 135°C (wire temperature read by a calibrated thermocouple), EAG response to 0.1 mg of DEET increased from 0.11 to 0.33 mV, which is not significantly different from the EAG response to 1 mg at room temperature (ca. 25°C). Likewise, response to 1-octen-3-ol was detected at 0.1 mg after heating to 135°C and was equivalent to 1 mg at room temperature. For the low volatility compound VUAA-1, an experimental insect repellent, the EAG response increased 60-fold, from 0.16 to 9.52 mV after heating to 500°C without degradation of the sample, as determined by NMR. Overall, this system can easily reduce the amount of chemical used in an EAG assay up to 10-fold and provided the compound is not thermally labile, allows for rapid testing of slow acting, less volatile compounds for eliciting an olfactory response from insects or other animals.</p

Pyrethroid-Derived Acids and Alcohols: Bioactivity and Synergistic Effects on Mosquito Repellency and Toxicity

Pyrethroids are one of the most commonly used classes of insecticides, and their acid and alcohol components are esterase degradation products, usually considered to be biologically inactive. In this study, it was found that several pyrethroid acids had a spatial repellent activity that was greater than DEET, often more active than the parent pyrethroids, and showed little cross resistance in a pyrethroid-resistant Puerto Rico strain of Aedes aegypti mosquitoes. Further investigation revealed that the acids can synergize not only contact repellent standards but also other pyrethroid components as well as the parent pyrethroids themselves. Synergism by the pyrethroid acids is expressed as both increased spatial repellency and vapor toxicity as well as human bite protection. Electrophysiological studies confirmed that pyrethroid acids (100 μM) had no effect on neuronal discharge in larval Drosophila melanogaster CNS and were detected by electroantennography, and there was little resistance to olfactory sensing of these acids in antennae from Puerto Rico strain mosquitoes carrying kdr mutations. Thus, the data suggest that the pyrethroid acids have a different mode of action than the parent pyrethroids, unrelated to the voltage-sensitive sodium channel. The results highlight the potential of pyrethroid acids to be useful in future repellent formulations