2D and 3D structure–activity modelling of mosquito repellents: a review^$

Abstract

Repellents disrupt the behaviour of blood-seeking mosquitoes protecting humans against their bites which can transmit serious diseases. Since the mid-1950s, N,N-diethyl-m-toluamide (DEET) is considered as the standard mosquito repellent worldwide. However, DEET presents numerous shortcomings. Faced with the heightening risk of mosquito expansion caused by global climate changes and increasing international exchanges, there is an urgent need for a better repellent than DEET and the very few other commercialised repelling molecules such as picaridin and IR3535. In silico approaches have been used to find new repellents and to provide better insights into their mechanism of action. In this context, the goal of our study was to retrieve from the literature all the papers dealing with qualitative and quantitative structure-activity relationships on mosquito repellents. A critical analysis of the SAR and QSAR models was made focusing on the quality of the biological data, the significance of the molecular descriptors and the validity of the statistical tools used for deriving the models. The predictive power and domain of application of these models were also discussed. The hypotheses to compute homology and pharmacophore models, their interest to find new repellents and to provide insights into the mechanisms of repellency in mosquitoes were analysed. The interest to consider the mosquito olfactory system as the target to compute new repellents was discussed. The potential environmental impact of these chemicals as well as new ways of research were addressed.

Topological QSAR Modelling of Carboxamides Repellent Activity to Aedes Aegypti

“…The studied carboxamides (of general formula R 1 ‐CO‐NR 2 R 3 ) correspond only to a very scarce number of the possble combinations of the R 1 and NR 2 R 3 radicals investigated. One interest of the full model proposed above (equation 1) is to provide at a screening level the estimation of the activity of new alternatives to DEET, which has been associated to multiple undesired effects to human and the environment . For example, with in mind the similar activity of radicals N(C 2 H 5 ) (C 4 H 11 ) and cyclo (NC 6 H 12 ), listed in Table , we have estimated, with MLR, the potential activity of 4 new compounds with structure R 1 ‐CO−Cyclo(NC 6 H 12 ) where R 1 is respectively CH(C 2 H 5 ) 2 , iBu, 2 Me−C 6 H 4 and C 3 H 6 C≡CH.…”

“…Another important way for protection of humans is afforded by repellents, blocking the recognition of human odours and so avoiding (or limiting) bites . N,N‐diethyl‐ m ‐toluamide (DEET) is the most marketed and efficient active ingredient for insect repellent in the world since the 50’ .…”

“…suggests pro‐angiogenic properties in humans and highlights the need to implement human risk assessment, to secure safe use of DEET‐based products. The need for new effective repellents alternative to DEET and devoid of detrimental side effects is urgent . In the search for new active molecules, SAR and QSAR – (quantitative) structure‐activity relationships – are privileged tools.…”

“…In the search for new active molecules, SAR and QSAR – (quantitative) structure‐activity relationships – are privileged tools. SAR and QSAR have been used largely and increasingly for activity prediction in pharmacological and toxicological processes . They also may give – in favourable cases – some clues for a better understanding of the mechanisms of action of active molecules, although correlation does not automatically imply causality .…”

“…However, according to a recent, extensive and well documented review, despite of the huge number of chemicals tested, highlighting the importance of the presence of given atoms or atomic groups, a rather limited number of quantitative relationships were up to now proposed to find valid alternatives to DEET . The data set of 40 carboxamides presented in the pioneering work of Suryanarayana et al .…”