Abstract
Molecular field topology analysis, scaffold hopping, and molecular docking were used as complementary computational tools for the design of repellents for Aedes aegypti, the insect vector for yellow fever, chikungunya, and dengue fever. A large number of analogues were evaluated by virtual screening with Glide molecular docking software. This produced several dozen hits that were either synthesized or procured from commercial sources. Analysis of these compounds by a repellent bioassay resulted in a few highly active chemicals (in terms of minimum effective dosage) as viable candidates for further hit-to-lead and lead optimization effort.
Highlights
Natural sources, such as local herbs and gum, oil and plantbased smoke, have been used by mankind for millennia as mosquito repellents and are still utilized today by 50-90% of residents throughout the rural tropics [1]
Since the discovery of DEET, many experimental efforts have been devoted to finding a superior repellent and some of those consisted of evaluation of DEET analogues and other structurally similar carboxamides
2: Dataset The training set for QSAR analysis consisted of 43 carboxamides published previously by our group [13] together with 27 compounds for which the repellency was evaluated for this study
Summary
Natural sources, such as local herbs and gum, oil and plantbased smoke, have been used by mankind for millennia as mosquito repellents and are still utilized today by 50-90% of residents throughout the rural tropics [1]. The most effective widespectrum synthetic repellent to emerge from this program was N,N-diethyl-3-methylbenzamide (DEET) (see Figure 1) discovered in 1952. The naturally and synthetically available compound 2undecanone (2-U) was recently reported as a repellent against mosquitoes and ticks [6,7,8]. Since the discovery of DEET, many experimental efforts have been devoted to finding a superior repellent and some of those consisted of evaluation of DEET analogues and other structurally similar carboxamides. By a highly polar carboxyl group [9] Another 3D (threedimensional) QSAR model defined an optimal structural pattern that consists of two oxygen atoms (one of which belongs to an amide group) positioned a certain distance from each other and joined by a lipophilic moiety [10]. No valid information on putative molecular targets was available
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