Molecular similarity analysis between insect juvenile hormone andN, N-diethyl-m-toluamide (DEET) analogs may aid design of novel insect repellents

Abstract

Molecular similarity analysis of stereoelectronic properties between natural insect juvenile hormone (JH), ­a synthetic insect juvenile hormone mimic (JH‐mimic, undecen‐2‐yl carbamate), and N,N‐diethyl‐m‐toluamide (DEET) and its analogs reveals similarities that may aid the design of more efficacious insect repellents and give a better insight into the mechanism of repellent action. The study involves quantum chemical calculations using the AM1 semi‐empirical computational method enabling a conformational search for the lowest and most abundant energy conformers of JH, JH‐mimic, and 15 DEET compounds, followed by complete geometry optimization of the conformers. Similarity analyses of stereoelectronic properties such as structural parameters, atomic charges, dipole moments, molecular electrostatic potentials, and highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies were performed on JH, JH‐mimic and the DEET compounds. The similarity of stereoelectronic attributes of the amide/ester moiety, the negative electrostatic potential regions beyond the van der Waals surface, and the large distribution of hydrophobic regions in the compounds appear to be the three important factors leading to a similar interaction with the JH receptor. The similarity of electrostatic profiles beyond the van der Waals surface is likely to play a crucial role in molecular recognition interaction with the JH receptor from a distance. This also suggests electrostatic bioisosterism of the amide group of the DEET compounds and JH‐mimic and, thus, a model for molecular recognition at the JH receptor. The insect repellent property of the DEET analogs may thus be attributed to a conflict of complementarity for the JH receptor binding sites. Copyright © 2000 John Wiley & Sons, Ltd.

Mosquito repellents: a review of chemical structure diversity and olfaction

“…This is largely because of the many questions still surrounding the mode of action of DEET. There are multiple hypotheses including specific olfactory receptors in the antennae that influence chemosensory response to lactic acid and 1‐octen‐3‐ol27 and the potential binding to a juvenile hormone receptor 28. Even with well‐designed mechanistic experiments like these, validation of the mechanism is needed at the mosquito level.…”

Semi‐Empirical Predictions on the Structure and Properties of ent‐Kaurenoic Acid and Derivatives

“…Calculated LUMO density maps of the molecules indicated that the carbonyl group at the bridgehead position and the carboxylic acid moiety (blue region) are indeed the groups most susceptible to nucleophilic attack for kaurane diterpenoids and ent-kaurenoic acid, respectively. The calculated HOMO and LUMO energies revealed, as testified by the relatively smaller magnitude of the E LUMO, that the molecules exhibit more electrophilic and electron accepting properties than their corresponding counterparts 19 . It is also noteworthy to point out that ent-kaurenoic acid possessed the greatest value of η or index of intrinsic reactivity which indicates that ent-kaurenoic acid is the least reactive among the compounds.…”

“…Since electrostatic interactions play a crucial role in ligand -protein binding mechanism, this suggests that the electrostatic differences between ent-kaurenoic acid and the kaurane diterpenoids is also responsible for the observed selective affinity they exhibit to their respective targets. This is due to the fact that the ligand orients itself towards the binding site in such a way that the polarized centers of the ligand are aligned with their corresponding counterparts in order to facilitate optimum contact with the binding site 19 .…”

“…Figure 5. LUMO density map (from L-R: L, 1,2,3,4,5,6,7)The calculated HOMO and LUMO energies revealed, as testified by the relatively smaller magnitude of the E LUMO, that the molecules exhibit more electrophilic and electron accepting properties than their corresponding counterparts19 . It is also noteworthy to point out that ent-kaurenoic acid possessed the greatest value of η or index of intrinsic reactivity which indicates that ent-kaurenoic acid is the least reactive among the compounds.…”

Synthesis, Characterization, Biological Evaluation and Docking Study of Heterocyclic-Based Synthetic Sulfonamides as Potential Pesticide Against G. mellonella

“…Chemical synthesis has been the simplest and direct approach toward the development of new class of juvenile hormone analogs with juvenile hormone activity. Large number of juvenile hormone analogs (JHAs) have been synthesized in the literature and found to have potent JH activity against lepidopteran insects [5][6][7][8][9][10][11][12]. JH, hydrophobic hormone, is released from corpora allata and after passing through the plasma membrane binds to the receptor protein present in the cytoplasm or nucleus.…”