Novel Carboxamides as Potential Mosquito Repellents

Abstract

A model was developed using 167 carboxamide derivatives, from the United States Department of Agriculture archival database, that were tested as arthropod repellents over the past 60 yr. An artificial neural network employing CODESSA PRO descriptors was used to construct a quantitative structure-activity relationship model for prediction of novel mosquito repellents. By correlating the structure of these carboxamides with complete protection time, a measure of repellency based on duration, 34 carboxamides were predicted as candidate mosquito repellents. There were four additional compounds selected on the basis of their structural similarity to those predicted. The compounds were synthesized either by reaction of 1-acylbenzotriazoles with secondary amines or by reaction of acid chlorides with secondary amines in the presence of sodium hydride. The biological efficacy was assessed by duration of repellency on cloth at two dosages (25 and 2.5 micromol/cm2) and by the minimum effective dosage to prevent Aedes aegypti (L.) (Diptera: Culicidae) bites. One compound, (E)-N-cyclohexyl-N-ethyl-2-hexenamide, was superior to N,N-diethyl-3-methylbenzamide (deet) at both the high dosage (22 d versus 7 d for deet) and low dosage (5 d versus 2.5 d for deet). Only one of the carboxamides, hexahydro-1-(l-oxohexyl)-1H-azepine, had a minimum effective dosage that was equivalent or slightly better than that of deet (0.033 micromol/cm2 versus 0.047 micromol/cm2).

Anopheles gambiae odorant binding protein crystal complex with the synthetic repellent DEET: implications for structure-based design of novel mosquito repellents

“…These derivatives have been characterized as physiologically relevant lead compounds with repellent properties [24,26,27]. To evaluate the accuracy of our methodology, DEET and 1-NPN were used as bench-mark molecules.…”

“…The test dataset included ten piperidine derivatives (Table 3; a/a 1-10) proposed by Katritzky et al [27] with structural features essential for repellency of Aedes aegypti; and two carboxamides (Table 3; a/a 11, 12) with improved duration of repellency and minimum effective dosage (MED), also suggested by Katritzky et al [26]. Additionally, we have investigated 12 carboxamides proposed by Gaudin et al [24].…”

“…To date, a number of QSAR studies of carboxamides [24][25][26] and piperidines [27] have been employed for the development of more efficient and environmentally friendly repellents and insecticides. However, in the absence of structural data on repellents in complex with a macromolecular target, a rational structure-based design approach by necessity has yet to be realized.…”

Defensive Spiroketals from Asceles glaber (Phasmatodea): Absolute Configuration and Effects on Ants and Mosquitoes

“…Repellency was assessed using a cage test(Barnard et al 2007) and treatments were tested using the “cloth patch” assay method described in depth previously (Katritzky et al 2010). The treatments consisted of 2( R )-(+)-spiroketal and 2( S )-(−)-spiroketal dissolved in acetone; N, N-diethyl-3-methylbenzamide (DEET) (Sigma-Aldrich, Milwaukee, WI) was also included as the standard.…”

Discovery and structure activity relationships of 2-pyrazolines derived from chalcones from a pest management perspective

“…Each test was conducted by having a volunteer affix the treated cloth onto a plastic sleeve to cover a 32-cm 2 window previously cut into the sleeve. Each of the volunteers wore this sleeve/cloth assembly above a nylon stocking covering their arm, with their hands protected by a glove (Katritzky et al, 2010). The arm with the sleeve/-cloth assembly was inserted into a cage in which approximately 500 female Ae.…”