See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/45152665

Mosquito repellents: A review of chemical structure diversity and olfaction

Article  in  Pest Management Science · September 2010

DOI: 10.1002/ps.1974 · Source: PubMed

CITATIONS READS

83 16,717

3 authors, including:

Lyric Bartholomay Joel R Coats

University of Wisconsin–Madison Iowa State University
164 PUBLICATIONS   5,023 CITATIONS    334 PUBLICATIONS   10,337 CITATIONS   

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Assessing the risk of insecticide exposures to monarch butterflies View project

Development of novel green chemistry for pest management View project

All content following this page was uploaded by Joel R Coats on 11 July 2018.

The user has requested enhancement of the downloaded file.

Review
Received: 9 December 2009 Revised: 12 February 2010 Accepted: 15 February 2010 Published online in Wiley Interscience:

(www.interscience.wiley.com) DOI 10.1002/ps.1974

Mosquito repellents: a review of chemical

structure diversity and olfaction
Gretchen Paluch, Lyric Bartholomay and Joel Coats∗

Abstract
Research on mosquito chemical repellents continues to advance, along with knowledge of mosquito olfaction and behavior,
mosquito–host interactions and chemical structure. New tools and technologies have revealed information about insect
olfactory mechanisms and processing, providing a more complex approach for the interpretation of how chemical repellents
influence host-seeking and feeding behavior. Even with these advances, there is still a large amount of information contained
in the early works on insect repellents. Many of the standard test methods and chemicals that are still used for evaluating active
repellents were developed in the 1940s. These studies contain valuable references to the activity of different structural classes
of chemicals, and serve as a guide to optimization of select compounds for insect repellency effects.

c 2010 Society of Chemical Industry

Keywords: insect repellent; DEET; chemical structure; olfaction

1 INTRODUCTION tional Institutes of Health.15,16 Other substantial contributions to

Even with a long history of research investigating how chem-
icals can influence mosquitoes, there are many challenges for
the advancement of insect repellent science. With the large ac-
cumulation of information, it has become increasingly difficult
to interpret the significance of repellents tested under differ-
ent laboratory conditions, or to explain how compounds with a
wide variety of structures can influence insect behavior under
field conditions. Much of current knowledge of repellents was
acquired in the United States during the 1940s with research
on the development of synthetic chemicals to repel arthro-
pods, which resulted in products containing dimethyl phthalate
(DMP), indalone (butyl 3,3-dihydro-2,2-dimethyl-4-oxo-2H-pyran-
6-carboxylate) and ethyl hexanediol, known as Rutgers 612
(2-ethyl-1,3-hexanediol) (Figs 1 and 2). It was also around this
time that DEET (N,N-diethyltoluamide) (Fig. 1), the gold standard
of repellents, was first tested by the USDA Orlando, FL, laboratory
and further developed for use in topical applications in the 1950s.
Since that time there have been significant efforts in academia,
government and the private sector to identify new insect repel-
lents. They were largely driven by reports of DEET toxicity,1 – 4
minimal efficacy against some arthropod vectors (e.g. Anophe-
les spp. of mosquitoes),5 high incidence of arthropod-borne
diseases,6,7 decreasing consumer acceptance8 – 10 and the po-
tential for insects to develop resistance to certain chemicals.11
Recent partnerships between the United States Department of
Agriculture, Agricultural Research Service (USDA-ARS) and the
Department of Defense’s Deployed War-Fighter Protection Pro-
gram (DWFP) in 2004 have funded research in the areas of novel
insecticide chemistries and formulations, including repellents, ap-
plication technology and personal protective measures.12 The
Centers for Disease Control and Prevention (CDC) have actively
supported ongoing research efforts and provide continual rec-
ommendations based on efficacy data for use of current insect
repellents.13,14 Government support for more basic research has
also come from the National Science Foundation and the Na-
repellents research include private funding from the Bill & Melinda
Gates Foundation, through their Grand Challenges Grant Program.
These sources represent new and relatively large funding contri-
butions to research on insect olfaction and behavior.17 As a result,
significant advances in basic research have occurred within the last
10 years. There is increased knowledge of several components in
the insect olfactory and neural pathways, and more tools are avail-
able for future studies, including genomic and proteomic data.
There are efforts towards improved standardization of behavioral
repellency bioassays18,19 and development of new synthetic and
botanical chemistries with repellent activity.20 – 23
In recent years, universities have played an important role in
the advancement of insect science by providing verification of
new product efficacy for registration, as well as exploring novel
repellent chemistries. One example is the development of the
BioUD active compound 2-undecanone, which was identified as a
mosquito repellent by Farrar and Kennedy24 at North Carolina State
University and then licensed to HOMS, LLC, a North Carolina-based
biotech company. The active compound was identified from a wild
tomato, Lycopersicon hirsutum Dunal f. glabratum CH Müll, and is
thought to play a role in natural plant defense mechanisms against
insect herbivores.25 Zhu et al.26 at Louisiana State University have
been working with the insecticidal and repellent properties of
vetiver grass, Vetiveria zizanioides Lynn Nash, essential oil. One
of the primary components, nootkatone (4,4a-dimethyl-6-prop-1-
en-2-yl-3,4,5,6,7,8-hexahydronaphthalen-2-one), a sesquiterpene,
was also investigated by Dietrich et al.21 at Oregon State University
as one of the repellent components of Alaska yellow cedar oil,
Chamaecyparis nootkatensis (D. Don) Spach.
∗ Correspondence to: Joel Coats, 112 Insectary Building, Department of Entomol-
ogy, Iowa State University, Ames, IA 50011, USA. E-mail: jcoats@iastate.edu
Department of Entomology, Iowa State University, Ames, IA, USA

Pest Manag Sci (2010) www.soci.org

c 2010 Society of Chemical Industry
 www.soci.org G Paluch, L Bartholomay, J Coats

Figure 1. Structures of common insect repellents. (A) Amides and Imides, (B) piperidines.

Many of the new repellent technologies that offer alternatives
to the older synthetic chemistries have to undergo a long devel-
opmental process, which includes thorough laboratory and field
studies. Careful consideration of these data becomes essential, as
companies need to address questions about registration and mar-
ketability prior to final formulation and product development. With
the current status of the regulatory requirements for topical re-
pellents being reviewed by the Environmental Protection Agency
(EPA), and proposed alterations of some biopesticide/pesticide
guidelines (cases where the final product is not applied topi-
cally, but may be registered for use in a lawn, home or garden),
there is substantial risk for any company introducing a new
repellent product in the market. Both companies investing in
new repellent technologies and regulatory bodies are met with
several significant challenges, which include the evaluation of
new repellent chemistries, improvement of standardized effi-
cacy testing guidelines for registration and comparison against
other classes of repellents, development of new application tech-

www.interscience.wiley.com/journal/ps

c 2010 Society of Chemical Industry Pest Manag Sci (2010)
Structural diversity of mosquito repellents www.soci.org

Figure 2. Structures of common insect repellents. (A) Phthalates, (B) Miscellaneous.

nologies and improved personal protection, understanding of
mosquito species-specific differences dictating behaviors involved
in haematophagy and, ultimately, complete elucidation of the
mechanism of repellency.
There are basic laboratory studies needed to improve under-
standing of the mechanisms by which even the most successful
repellents affect host-seeking behaviors. 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 mechanis-
tic experiments like these, validation of the mechanism is needed
at the mosquito level. A recent study of DEET’s mode of action
proposed that mosquitoes are able to detect the DEET molecule,
and supported this with findings of a DEET-sensitive olfactory
neuron in the antenna by Syed and Leal.29 However, these authors
noted that there were changes in the chemical emanations from
human skin following topical applications of DEET. This might also
significantly influence insect attraction to a host.
Studies of mosquito behavior are absolutely essential to
identify the relevance of different modes of action of chemical
repellents. There is often limited attention paid to the importance
of connecting data from the organismal to the suborganismal

Pest Manag Sci (2010)

c 2010 Society of Chemical Industry www.interscience.wiley.com/journal/ps
 www.soci.org G Paluch, L Bartholomay, J Coats

studies of mosquito–host interactions. The term ‘phagomone’ was

Table 1. Chemical class percentage distribution of 59 materials tested
introduced recently and approaches the functionality of repellents by the USDA Orlando, FL, Laboratory50 that were effective in repelling
with a broader perspective, i.e. ‘a chemical that affects feeding the yellow fever mosquito, Aedes aegypti. Table adapted from Travis
behavior, negatively or positively, by any mode of action’.30 The et al.52
advantage of this approach reiterates the fact that an insect bite is
Time effective
not an independent event, but rather encompasses a larger set of
behaviors and events over time and space (e.g. host-seeking and Chemical class 3–5 h 5 h or more
feeding behavior).
Hydrocarbons 0 0
Acids and anhydrides 1.9 6.8
2 STRUCTURAL DIVERSITY OF CHEMICAL RE- Aldehydes 1.7 1.7
PELLENTS Esters, lactones 30.4 16.9
2.1 Early research and identification of repellents Ethers, acetals 17.8 10.2
Ketones 1.7 0
Plants and their extracts have been used for millennia to protect
Alcohols (including phenols) 14.2 16.9
against or repel arthropods. Some of the earliest recorded uses of
Nitrogen compounds
repellents are noted in the writings of Herodotus (484 BCE –ca 425
a. Amides, imides 18.5 35.6
BCE) detailing the use of a plant oil by an Egyptian fisherman to repel
b. Amines 4.9 1.7
mosquitoes.31,32 Evidence of the bioactivity of plant extracts is
c. Nitriles 2.6 1.7
apparent in their continued use today. The neem tree (Azadirachta
d. Nitro compounds 1.3 3.4
indica A. Juss) is an excellent example, as it has a long history
e. Any other (azo, azoxy, 1.3 1.7
of use in a number of agricultural applications. As a repellent, hydrazo, nitroso,
leaves from the neem tree were also used to repel mosquitoes in thiocyanates, oximes, etc.)
Africa, South America and Sri Lanka.33 – 35 The active properties Halides 1.7 3.4
(including antifeedant activity, growth regulation, repellency, a. Sulfur compounds 0.6 0
fecundity suppression and toxicity) of this tree are still utilized b. Phosphorus compounds 0.3 0
today in numerous commercial formulations. It is also interesting to
note that oil of citronella was one of the earliest recommendations
made by JB Smith in 190836 for repellent protection against
insects. This oil is still used today in a variety of applications War II. Dimethyl phthalate and dibutyl phthalate (Fig. 2) were
and has historically served as a standard for comparison of new among the earliest synthetic repellents synthesized and were
repellents.37 Other early essential oils and household remedies identified as fly repellents in 1929 by Moore (US Patent 1,727,305).
included those from cassia oil,38 pennyroyal, cedar, lavender, Later synthetics included indalone, which was patented by Kilgore
eucalyptus, peppermint, castor oil, menthol, nutmeg, crushed in 1937 (US Patent 2,070,603), and Rutgers 612, developed by
pepper, lemon juice and leeks.39 An initial compilation of these Granett at Rutgers University. With the outbreak of war, there
mixtures and their application as repellents and insecticides was was an immediate need for repellents to protect US soldiers
summarized by Howard40 and Howard and Bishopp.41 against arthropod-borne diseases overseas. This threat eventually
Prior to the start of World War II, there were limited data available translated into a total of 821 184 cases of malaria and 302 deaths
on candidate repellents, or methods for evaluating repellents both reported among US troops overseas.48 Traditional repellents such
in the laboratory and field. Some reports even questioned the as oil of citronella and various formulations of pyrethrum were
validity of earlier work owing to issues of chemical or essential oil tested but found to be inadequate.42 Much work and progress
purity and variability in testing procedures.39,42 Tests conducted by in the identification and evaluation of efficacious compounds
Bacot and Talbot,38 Bunker and Hirschfelder,39 Rudolfs,43 Moore44 and mixtures were reported by Granett and Haynes at Rutgers
and Granett45 represent some of the first documented work University,49 the Naval Medical Research Institute, Bethesda,
on evaluating chemicals and mixtures for insect repellency. At MD, and largely the Orlando, FL, USDA Laboratory, Bureau of
the time there were limited reports on activity of individual Entomology and Plant Quarantine, FL, from 1942 to 1947,50 which
compounds, as many recommended repellents were mixtures was supported by the USDA Office of Scientific Research and
or plant extracts. Bunker and Hirschfelder39 were among the Development and the US Army.51 The large-scale screening effort
first to approach these questions from a chemical perspective by evaluated approximately 6000 chemicals37,50 – 52 against several
testing a series of simple hydrocarbons, aldehydes, ketones, ethers, dipteran species (the yellow-fever mosquito, Aedes aegypti L., a
esters, alcohols and phenols. From this study they concluded malaria mosquito, Anopheles quadrimaculatus Say, and the stable
that alcohols, esters, ketones and aldehydes were more effective fly, Stomoxys calcitrans L.) and found only a small percentage
than the hydrocarbons and phenol ethers tested. Moore44 made to equal that of existing standards. A report summarized
another early attempt to decipher relationships between chemical the most active chemicals tested (59 in total) in the USDA
structure and repellency. Many of the compounds evaluated Orlando, FL, laboratory. Compounds that provided more than
by Moore were terpenes and phenols. The study concluded five hours of protection against Ae. aegypti yielded a percentage
that esters improved on corresponding alcohol moieties and distribution of 35.6% nitrogen compounds (amides and imides),
that unsaturated alcohols were better repellents compared with 16.9% alcohols, 16.9% esters and lactones and 10% ethers
saturated alcohols. Much of the early work summarizing the and acetals27 (Table 1). Another interpretation was published in
structural basis of repellent compounds was later summarized in 1953 by Roadhouse,46 who sectioned compounds into chemical
reviews by Roadhouse46 and Garson and Winnike.47 groups and then calculated a class average (Table 2). Using this
Dimethyl phthalate, indalone and ethyl hexanediol were the approach, Roadhouse46 identified monoalcohols, hydroxyl acid
primary synthetic repellents available prior to the start of World esters, glycols, aldehydes and ketones, and a select number of

www.interscience.wiley.com/journal/ps

c 2010 Society of Chemical Industry Pest Manag Sci (2010)
Structural diversity of mosquito repellents www.soci.org

ethyl-1,3-propanediol) and NMRI-448 (70% 2-phenylcyclohexanol

Table 2. Relative repellency of chemical classes calculated by
Roadhouse46 from screening trials conducted by Morton et al.50 Table and 30% 2-cyclohexylcyclohexanol). Other commonly used
adapted from Roadhouse46 components of insect repellent mixtures included MGK R11
[2,3 : 4,5-bis(2-butylene)-tetrahydro-2-furaldehyde], MGK 264 (N-
Relative repellencies of typical
molecular groups in compounds tested by octyl-bicycloheptene-dicarboximide) and MGK 326 (dipropyl
Morton et al. (groups 1a and 2b ) pyridine-2,5-dicarboxylate) (Figs 1 and 2), with the prefix of each
representing the initials of the manufacturer, McLaughlin Gorm-
Class
Chemical class Number tested average ley King Co. These were reported as effective general repellents,
as they maintained repellent activity against multiple species of
Group 1 insects tested. In addition to variability in repellency response
Hydroxyethers 134 2.5 across species, selection of candidate repellents was guided by
Glycols 112 2.3 toxicity issues, which were investigated by the US Food and Drug
Amides, imides, 270 2.2 Administration.
amide-esters
Major contributions from this era also include the development
Hydroxyesters 221 2.2
Monoalcohols 196 1.9
and standardization of measures of repellency such as ‘time until
Aldehydes, ketones and 254 1.8 the first bite’,57 which is still used as a repellency index in testing
hydroxy-ketones today. As a result of the extensive screening process, there was a
Ether esters and epoxy esters 200 1.7 large amount of data generated on individual compounds, both
Nitriles 137 1.6 natural and synthetic. Mixtures containing some of the most active
Esters and keto-esters 1600 1.5 compounds were developed for use.
Ethers 349 1.3 Perhaps one of the most significant advances from this time
Hydrocarbons 100 1.3 period was the work conducted by McCabe et al.,53 which
Group 2 examined structural improvements of N,N-dialkylamides based on
Nitrogen heterocyclic 70 2.1 the performance of propyl N,N-diethylsuccinamate, o-chloro-N,N-
compounds diethylbenzamide and o-ethoxy-N,N-diethylbenzamide. Testing of
Acid anhydrides 50 2.1 different diethylamides prepared from a variety of aromatic acids
Acetals 70 2.0 (e.g. succinic, toluic and cyclohexane-carboxylic) showed that the
Amines 52 2.0 ring-substituted diethyl benzamides resulted in higher repellency.
Organosulfur compounds 69 1.4 Different substituents on the ring were synthesized and tested
Natural oils 67 1.3 (alkoxy, bromo and chloro), but it was the alkyl substitutions that
a Group 1, more than 100 tested. performed the best. The first N,N-diethylbenzamide was patented
b Group 2, 50–100 tested. as an insect repellent by Gertler in 1946 (US Patent 2,408,389),
Example calculation of class average by Roadhouse:46 of 196 substances while the first report of mosquito repellency to ortho-, meta- and
in the monoalcohol group tested by Morton et al., 30 had been rated
at ‘4’, 14 at ‘3’, 52 at ‘2’, and 100 at ‘1’; the value of this chemical group para-N,N-diethyltoluamide isomers was made by McCabe et al.53
was therefore Soon after, validation of DEET’s repellent activity was observed in
laboratory and field trials with multiple insects.54 – 56 Around this
(30 × 4) + (14 × 3) + (52 × 2) + (100 × 1) time, additional studies were published on the optimization of the
= 1.87
196 amide structure for repellency, including Gouck et al.,58 Gertler
et al.,59 Alexander and Beroza60 and Johnson et al.61
Since the time DEET entered the market in the 1950s, it has
provided good residual protection against a broad spectrum of
insects, including mosquitoes, black flies, chiggers, ticks, bedbugs
miscellaneous compounds to evaluate. This study also reiterated
and fleas.62 The general public registered DEET for public use in
the importance of the oxygen with respect to most of the
1957 and completed a re-registration eligibility decision in 199863
compounds tested, first noted by Bunker and Hirshfelder.39 Work
for use in households and in topical applications to human body
by McCabe et al.53 and Gilbert et al.54 – 56 on N,N-diethylamides and,
and clothing, cats, dogs and horses. Complications with DEET
more specifically, N-N-diethyltoluamide, was also largely guided
toxicity were reported in some circumstances among children
by the data generated by the USDA Orlando, FL, laboratory. It is
interesting to note that this group also approached their study and elderly people.64 – 66 Significant amounts of this chemical can
from a structural perspective and recognized N,N-dialkylamide and be absorbed through the skin,67 and there is some evidence
diol groups as the two ‘promising leads as a source of mosquito of neurotoxicity resulting from high-level exposure of DEET in
repellents’.53 combination with permethrin and pyridostigmin bromide (all of
In 1947, following this large screening effort, initial recommen- which were commonly used by soldiers during the Persian Gulf
dations by the USDA Bureau of Entomology and Plant Quarantine War).68 In addition, DEET can also dissolve plastics, and it has been
still included the early synthetics: dimethyl phthalate, indalone, described by some as having an unfavorable odor and as feeling
Rutgers 612, dimethyl carbate, as well as mixtures (e.g. Rutgers greasy. Even with these concerns, estimates report that DEET is
6-2-2 containing 60% dimethyl phthalate, 20% indalone and 20% used by approximately 30% of the US population.69 According
Rutgers 612), for protection against biting arthropods.51 Other mix- to a recent survey by HealthStyles, 40.3% of respondents had
tures developed during this period included M-2020 (40% dimethyl repellents containing DEET in the household.70 For over 50 years,
phthalate, 30% Rutgers 612 and 30% dimethyl carbate), M-1960 DEET has maintained the status of a general-use insect repellent
(30% benzyl benzoate, 30% n-butylacetanilide and 30% 2-butyl-2- with minimal toxicity and safety issues.

Pest Manag Sci (2010)

c 2010 Society of Chemical Industry www.interscience.wiley.com/journal/ps
 www.soci.org
2.2 Recent developments in insect repellent chemistries
Since the 1950s, DEET has dominated the market for topical insect
repellents, and as a result there have been few improvements on
alternative repellent chemistries. This is apparent in the literature,
as there is only a limited amount of data available for select groups.
Significant efforts towards advancing many of these ‘alternative’
chemistry groups are discussed, including synthesis of new deriva-
tives and modeling structure–activity according to similarities in
chemical structure for amides, piperidines, diols and phthalates.
2.2.1 Amides
The amides represent the most commercially successful class of
modern insect repellents. The early work by Gertler on the insect
repellency of N,N-diethylbenzamides (US Patent 2,408,389) in
1949, and then by McCabe et al.53 with ortho-, meta- and para- N,N-
diethyltoluamide isomers, initiated the development of today’s
most widely used active repellent. Some of the early work with
derivatives included ring-substitutions with hydroxyl, alkoxy, and
dihalogen, which were less effective. It was the alkyl-substituted
diethylbenzamides that were more active repellents.53,54,59 A trend
was also seen with the number of carbons between the ring and
amide group, which showed that one carbon was optimal and
that an increase in the number of carbons decreased repellent
activity.58 Further exploration of this class of compounds was
conducted on acid amides.71 Other promising amides that were
made included DEPA (N,N-diethyl phenylacetamide),53 MGK 264,
MGK 326 and ethyl N-acetyl-N-butyl-3-aminopropionate (IR 3535
or MERCK 3535), formulated by Merck in 1975.72
In addition to these early studies on chemical structure, there
have been more recent efforts to identify specific physical-
chemical and electronic descriptors that can predict mosquito
repellency of the diethylbenzamides.73 – 75 One of the first attempts
at a quantitative structure–activity relationship approach was
made by Suryanarayana et al.74 and yielded a model containing log
lipophilicity (P), log vapor pressure (VP) and log molecular length
(ML). Although the predictive value of this model was not high
(R2 = 0.304), it provided a quantitative approach to measuring
the importance of selected physical-chemical properties that were
reported in the repellents literature, including vapor pressure.76
More recent investigations, including those by Ma et al.,73 suggest
that the van der Waals surface, dipole moments, electrostatic
potential and charge of the amide nitrogen, as well as the
electrostatic potential of the amide oxygen, are essential for activity
within this class of repellents. Interpretation of the electrostatic
potential and dipole moment descriptors was that the intrinsic
electrophilicity of the amide is important, and that there is an
optimal range for lipophilicity or hydrophobicity (3.25–3.82 D).77
Further, a more negative charge on the nitrogen atom yields a
lower level of protection time.
2.2.2 Piperidines
These cyclic amines have been studied by Agricultural Research
Service laboratories in Gainesville, FL, and Beltsville, MS, since the
1970s.62 One of the more recent piperidine repellents developed
is SS220, which was derived from an earlier repellent, AI3-37 220,
comprising a racemic mixture of four isomers of 1-cyclohexen-
3-yl 2-methylpiperidin-1-yl ether (Fig. 1).67,78,79 Interestingly, the
1S, 2S stereoisomer (SS220) is the most effective isomer against
mosquitoes.79 Some of the early synthesis work on derivatives
of cyclic amines includes a study by Alexander and Beroza60
on repellency of aliphatic amides of cyclic amines (C4, C5 and
www.interscience.wiley.com/journal/ps

c 2010 Society of Chemical Industry
G Paluch, L Bartholomay, J Coats
C6). It was McGovern et al. who first synthesized and tested AI3-
37 220 and AI3-35 765 (3-cyclohexen-1-yl 1-piperidinyl ether),80
in addition to a series of N-acyl and N-alkylsulfonyl derivatives
of heterocyclic amines, and N,N-dialkylalkanesulfonamides.80 – 82
Other significant advances from the work conducted through
the USDA laboratories include a recent publication on the
development of an artificial neural network model to predict
the repellent activity of series of N-acylpiperidines.83
Another major piperidine repellent was developed by Bayer
in the 1990s, called Picaridin, or KBR 3023 [sec-butyl 2-(2-
hydroxyethyl)piperidine-1-carboxylate] (Fig. 1).84 Using a molec-
ular overlay approach, Natarajan et al.85 compared topological
descriptors to develop a stereochemical structure–activity rela-
tionship. In this model, Picaridin, SS220 and DEET shared similar
structural motifs that might be useful for developing new repel-
lents. Further, a three-dimensional quantitative structure–activity
relationship (QSAR) was developed to improve on this initial
model.86 Given that these models will serve as accurate predic-
tors of insect repellency, there is good potential for continued
optimization of the piperdine structure.
2.2.3 Diols
In McCabe et al,53 two structural groups were identified from
the screening program conducted by the USDA Orlando, FL,
laboratory; ‘certain diols and the N,N-dialkylamides, especially
diethylamides, furnish very promising leads as a source of
mosquito repellents’. Even with the focus of this paper on amides,
the importance of diols as repellents was mentioned. In an earlier
review, Christophers42 cited diols (and other high alcohols with
a high boiling point) as one of the three types of compound
that ‘especially exhibit repellency’. This was likely due to the
success of early repellents such as ethyl hexanediol and 2-butyl-2-
ethyl-1,3-propanediol (Fig. 2). In particular, ethylhexanediol was a
very effective repellent against mosquitoes developed by Granett
and Haynes49 as part of a screening initiated in 1935. Some
amino analogs of ethylhexanediol were synthesized and evaluated
against Ae. aegypti, but did not offer large improvements to
the parent compound.87 Beroza et al.88 evaluated comparative
repellency of the ethylhexanediol diastereosiomers and did not
show any differences between the threo and erythro isomers.
Another commercially successful diol is p-menthane-3,8-diol
(Fig. 2), which is a primary component of Quwenling or oil of
lemon eucalyptus, Corymbia citriodora (Hook) Hill & Johnson.
Development of this compound was delayed until work in the
1990s revisited this oil,89 – 93 which is used widely in China as
a mosquito repellent. In the United States, products containing
oil of lemon eucalyptus are recommended by the CDC as a
long-lasting plant-based repellent. However, lemon eucalyptus
oil products are not approved for use on children under 3 years
old.94 Since then, there has been some interest in optimizing the
structural activity of p-menthane-3,8-diol. Barasa et al.95 examined
the comparative activity of four stereoisomers and found that all
were active repellents. Both the historical significance and the
efficacy of select structures within this group suggest that there is
good potential for the development of new potent repellents.
2.2.4 Phthalates
The initial work on phthalate-repellent chemistries was with
dimethyl phthalate in 1929 by Moore (US Patent 1,727,305).
Activity within this class was first described with regard to dibutyl
and dimethyl esters of phthalic acid, but was later expanded with
Pest Manag Sci (2010)
Structural diversity of mosquito repellents
dioctyl phthalate and dimethyl carbate or dimalone (dimethyl
bicyclo[2.2.1]hept-2-ene-5,6-dicarboxylate) (Fig. 2).96 In a later
paper, Moore44 also evaluated the repellency of compounds and
concluded that esters, primarily cyclic esters, were superior to
alcohols and hydrocarbons. Other than these early studies, there
is minimal data available on optimization of phthalate structure
for use as repellents.
2.2.5 Miscellaneous Repellents
As a result of the large-scale screening efforts, many compounds
have been evaluated for insect repellent activity. Much of
the work on optimizing repellent structure has focused on
amides, piperdines and, to a lesser extent, diols. However, there
are a variety of other structural groups that have not been
thoroughly investigated. Some that have a limited literature
base include benzofurans (e.g. MGK 11), mandelic acid esters,97,98
hydroxyethers, glycols, hydroxyesters, hydroxyketones, phenols
and monoalcohols.47,99
2.2.6 Botanicals
A large amount of literature exists on the repellent activity
of botanicals and has been summarized thoroughly in some
reviews.9,100,101 These compounds have been shown to protect
against pest arthropods including mites, lice and mosquitoes.
A few studies have shown that certain species of birds will
incorporate botanical chemical defenses into their nests, including
citrus peels and marigold flowers.102,103 Additionally, there is
evidence that these compounds benefit the host plant, aiding in
pollination and seed production. One recent study showed that a
nicotine repellent in the floral composition reduced the levels of
florivory and nectar robbing.104 Repellents have also been shown
to reduce the amount of nectar removed by hawk moth pollinators,
and to increase the number of visits to flowers, all of which would
serve as an advantage for the flowering plant.105
There exist several diverse classes of plant-based chemistries
that consistently show some insect repellent or deterrent activity,
including alkaloids, phenols, terpenes, quinones, nitriles, furans
and lactones.95 Of these groups, terpenes make up a large
portion of repellent-active plant essential oil composition. The
essential oils of citronella, Cymbopogon nardus (L.) Rendle, and
lemon eucalyptus are examples of commercially successful
terpenes. The historical significance of these oils and their major
components (citronella – citronellal, citronellol, and geraniol;
lemon eucalyptus – p-menthane-3,8-diol) (Fig. 2) was discussed
earlier. Evidence of optimization and formulation of these plant
essential oils can be seen in the current scientific and patent
literature, including synergistic effects identified by EcoSMART
Technologies (US Patent 7,238,726). The structural activity of other
terpenes still remains an area for development of new repellents,
in particular the sesquiterpenes.106,107
In order more fully to utilize these natural chemistries, more
studies are needed to explore what features of the molecule are
important for insect repellency. A study by Wang et al.108 is one
attempt to develop a predictive model for mosquito repellent
activity of pinene-related terpenes. With more studies, it may
be possible to synthesize new compounds that improve on the
activity of the parent compound, potentially increasing repellent
potency, broadening the spectrum of activity, as well as increasing
residual effects.
Pest Manag Sci (2010)

c 2010 Society of Chemical Industry
www.soci.org
3 IMPORTANCE OF MOSQUITO–HOST INTER-
ACTIONS
One of the constant challenges facing research on repellents
is how exogenous chemicals can influence insect behavior.
These studies require attention to the larger set of behaviors
and events over time and space that are associated with host-
seeking and feeding. Thus, mosquito–host interactions are the
basis for connecting suborganismal studies to organismal studies
of chemical repellents.
3.1 Mosquito host-seeking behavior
There are considerable risks associated with haematophagy
because detection by the host can in many cases be fatal to the
arthropod. A successful mosquito is able to locate and approach a
potential host, evaluate the quality of the food source and begin
feeding without alerting the host to its presence. Careful execution
of this process is needed for mosquito growth and reproduction,
and is controlled on different levels. Life history characteristics
of the female mosquito are important for consideration, as
these details often pertain to host-seeking ability.109 One major
distinction is that of autogeny versus anautogeny, where some
female mosquitoes emerge from the pupal state with enough
protein for egg development while others require a blood meal
to provide the nutritional requirements for egg maturation. In
the yellow fever mosquito, Ae. aegypti, which is an example of
an anautogenous female, there is a time period required for
maturation and the increased sensitivity of the receptors needed
for host location.110
The literature on mosquito host-seeking behavior broadly
outlines the following sequence of events111 – 113 in the progress
to a host:
[Appetitive search] → Activation → Orientation
→ [Attraction] → [Host acceptance]
A mosquito’s appetitive search state varies accordingly with
endogenous circadian rhythms and hunger state, which are
dependent on the length of food deprivation.109 It is viewed as an
undirected or sometimes random search that terminates when a
host stimulus is detected. This single event is termed activation.
There is sufficient evidence that supports the role of one particular
host cue, carbon dioxide, in both the activation and orientation
response. It is very possible that other host cues in addition to
carbon dioxide are also important in the activation response.
Differences are likely due to interspecific variation, particularly
across anthropophilic and zoophilic mosquito species.
Following exposure to carbon dioxide, individual mosquitoes
will take off and begin a sustained flight that is governed by a
programmed flight behavior known as optomotor anemotaxis.111
Patterns of mosquito upwind flight closely mimic those of other
insects that follow a pulsed chemical gradient towards a source,
referred to as orientation. Once at close range, mosquitoes are
thought to depend on visual, motion, heat and olfactory cues from
their potential host for attraction.
There is surprisingly minimal behavioral data available on
patterns associated with this event and those that direct host
acceptance for mosquitoes. A variety of host surface volatiles
and chemicals have been tested and identified as attractants,
but the underlying behavioral mechanisms that guide this
short-range approach are poorly understood. It is during this
short-range approach that the mosquito would encounter the
www.interscience.wiley.com/journal/ps
 www.soci.org
greatest diversity of host cues, including a complex volatile blend
comprising semi- and highly volatile compounds. In order to
appreciate the multitude of chemicals emitted by the host, it is
necessary to consider: (1) primary odors, which do not change
regardless of changes in an individual’s diet; (2) secondary odors,
which are related to an individual’s diet and interaction in the
environment; (3) tertiary odors, which arise from outside sources
(e.g. lotions, hair products, make-up, etc.).114 Researchers have
identified a variety of compounds prevalent in skin emanations,
armpit odor and even released while breathing that include short-
chain (C4–C12) acids, aldehydes, alcohols, esters and ketones. It
has been noted in multiple publications that there is a significant
variation in these components within individuals of the same
species.114,115
Once the mosquito lands on the host, it must locate an optimal
place to feed. An individual may make multiple probes before
finally committing to a feeding location and accepting a host
as suitable. This is an important decision, as the mosquito must
choose an optimal location for blood-feeding and avoid detection
by the host.
4 IMPORTANCE OF MOSQUITO OLFACTION
Within the last 10 years there has been a large effort to dissect the
underlying mechanisms of insect olfaction, which is summarized
in several recent review articles.116 – 118 Building on these studies,
researchers are starting to utilize more mechanistic approaches to
understand the mode of action of repellents.
4.1 Insect olfaction
Insect olfaction begins with a molecule, usually hydrophobic,
entering the sensilla on either the antennae and/or maxillary
palpi. These chemosensilla have been characterized into three
morphological types: basiconic, trichoid and coeloconic. Olfactory
binding proteins (OBP) are secreted by accessory cells and then
transport these molecules through the aqueous environment
surrounding the olfactory receptor neurons. Current research
suggests that the pheromone binding protein (PBP)–ligand
binding mechanism might be pH dependent.119 However, it is still
unclear whether these OBP are required for binding to the olfactory
receptor (OR) or if their function is primarily in transport. Studies
with silk moths have demonstrated that different concentrations
and combinations of PBP can affect neuron sensitivity.120 It is
possible that OBP play an important role in the binding of
the ligand to the OR.121 One hypothesis is that OBP interact
with sensory neuron membrane proteins (SNMP) and enhance
delivery of the odorant/pheromone.122 These two transmembrane
domain membrane proteins were first identified in insect olfactory
neurons (ON), and their role in the olfactory pathway is still under
investigation.123 More recently, it was shown that an SNMP was
required for sensitivity to a pheromone, 11-cis-vaccenyl acetate, in
Drosophila.124 The role and specificity of these OBP is still debated,
as there are studies in Drosophila that show that many different OR
genes can maintain their specific response spectra after interaction
with a single set of OBP.125,126 Other studies report highly specific
responses from OBP.127
Olfactory receptors are more specifically G-protein-coupled re-
ceptors with seven transmembrane domains that, on binding to
their ligand, cause a conformational change and activate enzymes
including adenyl cyclase and phospholipase. Downstream mes-
sengers are cyclic AMP (cAMP) and inositol-3-phosphate (IP3) +
www.interscience.wiley.com/journal/ps

c 2010 Society of Chemical Industry
G Paluch, L Bartholomay, J Coats
diacyl glycerol (DAG); cAMP and IP3 are both capable of opening
Na+ or Ca++ channels for ion influx, after which depolarization of
the neuron occurs.
Olfactory neurons converge on the antennal lobe, and sensory
processing is believed to be combinatorial (one molecule can
stimulate multiple classes of ON, and individual ON can respond
to more than one chemical). Information conveyed by ON can
include chemical identity, concentration and chemical dynamics
(fluctuations in concentration). Olfactory neurons contained in the
basiconic sensillum of Drosophila have been extensively studied
and can serve as an example of odor neuron-processing.128 – 130
The ON in the antennal basiconic sensillum have been studied and
fall into 24 functional classes, designated by their responses to
different chemicals.131,132 Some classes are more narrowly tuned
than others, as is seen with some pheromone ON in moths.
Currently there appears to be a numerical relationship between
OR genes, the different functional classes of ON and the olfactory
glomeruli, as is shown in a study by Couto et al.133 Much
information on the connection between OR and ON has come
from studies with Drosophila
halo mutants and Xenopus laevis
oocytes.129,134 These studies demonstrate that the removal of
the OR genes results in loss of the ON capacity to respond to
a range of chemical stimuli, but does not eliminate ON firing
activity.129 Additionally, OR genes have been shown to relay the
same response spectra when expressed in mutant neurons, even
ON normally expressed in morphologically distinct sensilla. This
change in the response spectra includes differences in ligand
specificity, firing rate, response dynamics and signaling mode.
Many uncertainties still exist, as there are still OR with unique
response spectra that do not match known ON. It is also known
that multiple OR can be expressed in a single ON, which leads to
more questions about OR gene expression and olfactory coding.130
Studies of sequence similarities between OR genes show that
these are highly divergent within and across species. This excludes
the Or83b coreceptor, which appears to be a highly conserved
gene, expressed in the majority of olfactory neurons, and is
necessary for proper neuron function. It is currently hypothesized
that this OR plays a role in localizing other proteins and might also
assist in odorant binding and signal transduction.135
Once the ON has fired, signaling is believed to cease owing to
signal cascades commonly associated with G-protein receptors.
These include protein kinases and arrestins, which uncouple
the receptor and cease the signaling cascade. Some arrestin
functions include interference with G-protein binding (termination
of the ligand signal), interaction with dynamin and other
proteins to trigger endocytotic internalization of the receptor and
sometimes stimulation of the mitogen-activated protein (MAP)
kinase pathway.
4.2 Recent developments concerning insect repellent mode
of action
After more than 50 years of use, the mode of action of DEET is
still debated in the scientific literature. Some of the most recent
hypotheses involve interactions within the olfactory pathway.
Research in the 1970s suggested that DEET affects mosquito
sensitivity to lactic acid, as studied in the ON in the antennae of
Ae. aegypti,136 which was later supported by behavioral data.137
More recent work with OR in Drosophila showed that DEET
blocks sensitivity to certain food odors by inhibiting the OR +
OR83b (coreceptor) complex in select neurons located in the
antennae.27 A component of this study also showed An. gambiae
Pest Manag Sci (2010)
Structural diversity of mosquito repellents
electrophysiological data with inhibition of the ON response to 1-
octen-3-ol, a component of human breath, following applications
of DEET. This relates to the previous finding in Drosophila because
the mosquito response is mediated by gustatory receptors, GPOR8
+ GPOR7 (coreceptor), which share similarity with Drosophila
ortholog OR83b. The most recent finding of a DEET-sensitive
olfactory neuron in the antennae and maxillary palps of Culex
quinquefasciatus Say suggests that mosquitoes are able to respond
directly to the DEET molecule and that the repellency effect is not
due to inhibition of a coreceptor/odorant complex.29
5 CONCLUSIONS
Within the last 10 years there has been some progress in
developing alternative insect repellents, including other chemicals
that fall into the amide, piperdine, diol and terpene classifications.
The newer repellent compounds recommended by the US CDC
that fall into these groups include IR3535, picaradin and p-
menthane-3,8-diol. It is encouraging to follow the advancement
of some of these repellent chemistries, particularly in the
understudied chemical classes such as piperdines and terpenes.
There are also still large efforts towards standardization of efficacy
testing for registration and comparison with other candidate
repellents, as well as new application technologies. However,
one of the most intriguing questions remains the mode of
action by which repellents work. Schreck138 stated that, following
the development of DEET, there was interest in understanding
repellent mode of action and the functionality of repellents. Today,
numerous advances in technology are available, as well as funding
support for research on arthropod repellents, largely driven by the
need for effective control of arthropod disease vectors.
REFERENCES
1 Sudakin DL and Trevathan WR, DEET: a review and update of safety
and risk in the general population. Clin Toxicol 41:831–839 (2003).
2 Fradin MS, Mosquitoes and mosquito repellents: a clinician’s guide.
Ann Internat Med 128:931–940 (1998).
3 Robbins PJ and Cherniack MG, Review of the biodistribution and
toxicity of the insect repellent N,N-diethyl-m-toluamide (DEET). J
Toxicol Environ Health 18:503–525.
4 Corbel V, Stankiewicz M, Pennetier C, Fournier D, Stojan J, Girard E,
et al, Evidence for inhibition of cholinesterases in insect and
mammalian nervous systems by the insect repellent deet. BMC
Biol 7:47 (2009).
5 Rutledge LC, Moussa MA, Lowe CA and Sofield RK, Comparative
sensitivity of mosquito species and strains to the repellent
diethyltoluamide. J Med Entomol 14:536–541 (1978).
6 West Nile Virus, Statistics, Surveillance, and Control. [On-
line]. Centers for Disease Control and Prevention. Avail-
able: http://www.cdc.gov/ncidod/dvbid/westnile/surv&control.
htm#maps [2 February 2010].
7 Lyme Disease Statistics. [Online]. Centers for Dis-
ease Control and Prevention. Available: http://www.
cdc.gov/ncidod/dvbid/Lyme/ld statistics.htm [2 February
2010].
8 Coats JR, Risks from natural versus synthetic insecticides. Annu Rev
Entomol 39:489–515 (1994).
9 Isman MB, Botanical insecticides, deterrents, and repellents in
modern agriculture and an increasingly regulated world. Annu
Rev Entomol 51:45–66 (2006).
10 Adler J, The new greening of America. Newsweek 17:42–52 (2006).
11 Reeder NL, Ganz PJ, Carlson JR and Saunders CW, Isolation of
deet-insensitive mutant of Drosophila melanogaster (Diptera:
Drosophilidae). J Econ Entomol 94:1584–1588 (2001).
12 Cope SE, Strickman DA and White GB, The deployed warfighter
protection research program: finding new methods to vanquish
old foes. US Army Med Dep J (April–June): 9–20 (2008).
Pest Manag Sci (2010)

c 2010 Society of Chemical Industry
www.soci.org
13 Updated Information Regarding Insect Repellents. Centers
for Disease Control and Prevention. [Online]. Available:
http://www.cdc.gov/ncidod/dvbid/westnile/repellentupdates.
htm [10 February 2010].
14 Dolan MC, Jordan RA, Schultze TL, Schulze CJ, Manning MC,
Ruffolo R, et al, Ability of two natural products, nootkatone
and carvacrol, to suppress Ixodes scapularis and Amblyomma
americanum (Acari: Ixodidae) in a lyme disease endemic area of
New Jersey. J Econ Entomol 102:2316–2324 (2009).
15 Sato K, Pellegrino M, Nakagawa T, Nakagawa T, Vosshall LB and
Touhara K, Insect olfactory receptors are heteromeric ligand-gated
ion channels. Nature 452:1002–1006 (2008).
16 Fishilevich E, Domingos AI, Asahina K, Naef F, Vosshall LB and
Louis M, Chemotaxis behavior mediated by single larval olfactory
neurons in Drosophila. Curr Biol 15:2086–2096 (2005).
17 Bonn D, Gates injects global health research with $437 million. Lancet
Infect Dis 5:473 (2005).
18 Klun JA and Debboun M, A new module for quantitative evaluation
of repellent efficacy using human subjects. J Med Entomol
37:177–181 (2000).
19 Klun JA, Kramer M and Debboun M, A new in vitro bioassay system
for discovery of novel human-use mosquito repellents. J Am Mosq
Control Assoc 21:64–70 (2005).
20 Katritzky AR, Wang Z, Slavov S, Tsikolia M, Dobchev D, Akhme-
dov NG, et al, Synthesis and bioassay of improved mosquito
repellents predicted from chemical structure. Proc Natl Acad Sci
105:7359–7364 (2008).
21 Dietrich G, Dolan MC, Peralta-Cruz J, Schmidt J, Piesman J, Eisen RJ,
et al, Repellent activity of fractioned compounds from
Chamaecyparis nootkatensis essential oil against nymphal Ixodes
scapularis (Acari: Ixodidae). J Med Entomol 43:957–961 (2006).
22 Cantrell CL, Klun JA, Bryson CT, Kobaisy M and Duke SO, Isolation and
identification of mosquito bite deterrent terpenoids from leaves of
America (Callicarpa americana) and Japanese (Callicarpa japonica)
beautyberry. J Agric Food Chem 53:5948–5953 (2005).
23 Krajick K, Keeping the bugs at bay. Science 313:36–38 (2006).
24 Farrar RR and Kennedy GG, 2-Undecanone, a constituent of the
glandular trichomes of Lycopersicon hirsutum f. glabratum: effects
on Heliothis zea and Manduca sexta growth and survival. Entomol
Exp Appl 43:17–23 (1987).
25 Kennedy GG, Tomato, pests, parasitoids, and predators: tritrophic
interactions involving the genus Lycopersicon. Annu Rev Entomol
48:51–72 (2003).
26 Zhu BC, Henderson RG, Chen F, Fei H and Laine RA, Evaluation of
vetiver oil and seven insect-active essential oils against the
Formosan subterranean termite. JChemEcol 27:1617–1625 (2001).
27 Ditzen M, Pellegrino M and Vosshall LB, Insect odorant receptors
are molecular targets of the insect repellent DEET. Science
319:1838–1842 (2008).
28 Bhattacharjee AK, Gupta RK, Ma D and Karle JM, Molecular similarity
analysis between insect juvenile hormone and N,N-diethyl-m-
toluamide (DEET) analogs may aid design of novel insect
repellents. J Mol Recognit 13:213–220 (2000).
29 Syed Z and Leal WS, Mosquitoes smell and avoid the insect repellent
DEET. Proc Natl Acad Sci 105:13598–13603 (2008).
30 White GB, Terminology of insect repellents, in Insect Repellents:
Principles, Methods, and Uses, ed. by Debboun M, Frances SP and
Strickman D. CRC Press, London, UK, pp. 31–46 (2007).
31 Herodotus, The Histories. Penguin, London, UK, reprint (1996).
32 Charlwood D, Did Herodotus describe the first airborne use of
mosquito repellents? Trends Parasitol 19:555–556 (2003).
33 Palsson K and Jaenson TG, Plant products used as mosquito
repellents in Guinea Bissau West Africa. Acta Trop 72:39 (1999).
34 Sears R, An ethnobotanical survey of insect repellents in Brazil, in
Tropical Resources Institute Working Pages. Yale School of Forestry
and Environmental Studies, Tropical Resources Institute, New
Haven, CT (1996).
35 Konradsen F, van der Hoek W, Amerasinghe P, Amerasinghe F and
Fonseka K, Household responses to malaria and their costs: a study
from rural Sri Lanka. Trans R Soc Trop Med Hyg 91:127–130 (1997).
36 Smith JB, Report of the Entomological Dept. N J Agric Coll Exp Sta
542:(1901).
37 Dethier VG, Repellents. Annu Rev Entomol 1:181–202 (1956).
38 Bacot A and Talbot G, The comparative effectiveness of certain
culicifuges under laboratory conditions. Parasitol 11:221–236
(1919).
www.interscience.wiley.com/journal/ps
 www.soci.org
39 Bunker CWO and Hirschfelder AD, Mosquito repellents. Amer J Trop
Med Hyg 5:359–383 (1925).
40 Howard LO, Remedies and preventatives against mosquitoes. Fmrs
Bull W W Dep Agric No. (1570):(1917).
41 Howard LO and Bishopp FC, Remedies and preventatives against
mosquitoes. Fmrs Bull US Dep Agric No. (1570):(1928).
42 Christophers SR, Mosquito repellents. Being a report of the work
of the mosquito repellent inquiry, Cambridge 1943–1945. J Hyg
45:176–231 (1947).
43 Rudolfs W, Effects of chemicals upon the behaviour of mosquitoes.
Bull N J Agric Exp Sta No. (496):(1930).
44 Moore W, Esters as repellents. J N Y Entomol Soc 42:185–192 (1934).
45 Granett P, Studies of mosquito repellents. II. Relative performance
of certain chemicals and commercially available mixtures as
mosquito repellents. J Econ Entomol 33:566–572 (1940).
46 Roadhouse LAO, Laboratory studies on insect repellency. Can J Zool
31:535–546 (1953).
47 Garson LR and Winnike ME, Relationships between insect repellency
and chemical and physical parameters – a review. J Med Entomol
5:339–352 (1968).
48 Mowrey FH, Statistics of malaria, in Internal Medicine in World
War II. Volume II. Infectious Diseases, ed. by Heaton LD, Coates
JB and Havens WP. [Online]. Medical Department, United
States Army, Washington, DC, pp. 449–463 (1963). Available:
http://history.amedd.army.mil/booksdocs/wwii/infectiousdisvolii
/frameindex.html [14 October 2008].
49 Granett P and Haynes HL, Insect-repellent properties of 2-
ethylhexane-1,3-diol. J Econ Entomol 38:671–675 (1945).
50 Morton FA, Travis BV and Linduska JP, Results of screening tests with
materials evaluated as insecticides, miticides, and repellents at the
Orlando Laboratory, April 1942 to April 1947. US Dept Agric Bur
Entomol Plant Quaran E-733:(1947).
51 Travis BV, Mosquito repellents. Am Perf 50:141–142 (1947).
52 Travis BV, Morton FA, Jones HA and Robinson JH, The more effective
mosquito repellents tested at the Orland, Fla., Laboratory,
1942–47. J Econ Entomol 42:686–694 (1949).
53 McCabe ET, Barthel WF, Gertler SI and Hall SA, Insect repellents. III.
N,N-diethylamides. J Org Chem 19:493–498 (1954).
54 Gilbert IH, Gouck HK and Smith CN, New mosquito repellents. J Econ
Entomol 48:741–743 (1955).
55 Gilbert IH, Gouck HK and Smith CN, New insect repellent. Soap Chem
Specialties 33:115–117, 129–133 (1957).
56 Gilbert HI, Gouck HK and Smith CN, New insect repellent. Part II.
Clothing treatments. Soap Chem Specialties 33:95–99, 109 (1957).
57 Granett P, Comparison of mosquito repellency tests under laboratory
and field conditions. Proc 25th Ann Meet N J Mosq Exterm Ass,
pp. 51–57 (1938).
58 Gouck HK, Hall A, Smith CN and Gilbert IH, Repellency of homologous
series of cyclohexane aliphatic acids and amides. J Econ Entomol
50:175–177 (1957).
59 Gertler SI, Gouck HK, and Gilbert IH, N-Alkyl toluamides in cloth as
repellents for mosquitoes, ticks, and chiggers. J Econ Entomol
55:451–452 (1962).
60 Alexander BH and Beroza M, Aliphatic amides of cyclic amines and
tolyl maleimides as mosquito repellents. J Econ Entomol 56:58–60
(1963).
61 Johnson HL, Skinner WA, Maibach HI and Pearson TR, Repellent
activity and physical properties of ring-substituted N,N-
diethylbenzamides. J Med Chem 60:173–176 (1967).
62 Moore SJ and Debboun M, History of insect repellents, in Insect
Repellents: Principles, Methods, and Uses, ed. by Debboun M,
Frances SP and Strickman D. CRC Press, London, UK, pp. 3–30
(2007).
63 Reregistration Eligibility Decision (RED) DEET. EPA738-R-98-
010. [Online]. Environmental Protection Agency. Available:
http://www.epa.gov/oppsrrd1/REDs/0002red.pdf [20 October
2008].
64 Clem JR, Havemann DF and Raebel MA, Insect repellent (N,N-
diethyl-m-toluamide) – cardiovascular toxicity in an adult. Ann
Pharmacother 27:289–293 (1993).
65 Goodyer L and Behrens RH, Short report: The safety and toxicity of
insect repellents. Am J Trop Med Hyg 59:323–324 (1998).
66 Veltri JC, Osimitz TG, Bradford DC and Page BC, Retrospective
analysis of calls to poison control centers resulting from exposure
to the insect repellent N,N-diethyl-m-toluamide (DEET) from
1985–1989. J Toxicol Clin Toxicol 32:1–16 (1994).
www.interscience.wiley.com/journal/ps

c 2010 Society of Chemical Industry
G Paluch, L Bartholomay, J Coats
67 Qiu H, Jun HW and McCall JW, Pharmacokinetics, formulation, and
safety of insect repellent N,N-diethyl-3-methylbenzamide (DEET):
a review. J Am Mosq Control Assoc 14:12–27 (1998).
68 Cherstniakvoa SA, Garcia GE, Strong J, Bi D, Weitz J, Roy MJ, et al,
Rapid determination of N,N-diethyl-m-toluamide and permethrin
in human plasma by gas chromatography–mass spectrometry
and pyridostigmine bromide by high-performance liquid
chromatography. J Anal Toxicol 30:21–26 (2006).
69 ToxFAQs forDEET. [Online]. Agency for Toxic Substances and Disease
Registry. Available: http://www.atsdr.cdc.gov/tfacts185.html [5
November 2008].
70 Zielinski-Gutierrez E, Hayden M and West-Kowalski J, Is Anyone
Using Repellent? . . . How Hard Can it Be? [Online]. Avail-
able: www.cdc.gov/ncidod/dvbid/westnile/conf/ppt/Zielinski
WS2 04.ppt [20 October 2008].
71 Piper DE, Hall RH and Wright GF, Chemistry of insect repellency.
Chem Can 3:97–98 (1951).
72 Klier M and Kuhlow F, Neue Insektenabwehrmittel – am Stickstoff
disubstituierte beta-Alaninderivate. J Soc Cosmet Chem 27:141
(1976).
73 Ma D, Bhattacharjee AK, Gupta RK and Karle JM, Predicting mosquito
repellent potency of N,N-diethyl-m-toluamide (DEET) analogs from
molecular electronic properties. Am J Trop Med Hyg 60:1–6 (1999).
74 Suryanarayana MVS, Pandey KS, Prakash A, Raghuveeran CD,
Dangi RS, Swamy RV, et al, Structure–activity relationship studies
with mosquito repellent amides. J Pharm Sci 80:1055–1057 (1991).
75 Katritzky AR, Dobchev DA, Tulp I, Karelson M and Carlson DA, QSAR
study of mosquito repellents using Codessa Pro. Bioorg Med Chem
Lett 16:2306–2311 (2006).
76 Johnson HL and Skinner WA, Topical mosquito repellents. II.
Repellent potency and duration in ring-substituted N,N-dialkyl-
and aminoalkylbenzamides. J Med Chem 11:1265–1268 (1968).
77 Gupta RK and Bhattacharjee AK, Discovery and design of new
arthropod/insect repellents by computer-aided molecular
modeling, in Insect Repellents: Principles, Methods, and Uses, ed.
by Debboun M, Frances SP and Strickman D. CRC Press, London,
UK, pp. 195–228 (2007).
78 Klun JA, Ma D and Gupta R, Optically active arthropod repellents for
use against disease vectors. J Med Entomol 37:182–187 (2000).
79 Klun JA, Schmidt WF and Debboun M, Stereochemical effects in an
insect repellent. J Med Entomol 38:809–812 (2001).
80 McGovern TP, Schreck CE and Jackson J, Mosquito repellents:
alicyclic amides as repellents for Aedes aegypti and Anopheles
quadrimaculatus. Mosq News 38:346–349 (1978).
81 McGovern TP, Gouck HK, Burden GS, Srmiento R, Beroza M and
Schmidt CH, N,N-substituted n-alkanesulfonamides as repellents
for the yellow fever mosquito and German cockroach. J Econ
Enomol 67:71–71 (1974).
82 McGovern TP, Schreck CE, Jackson J and Beroza M, n-Acylamides
and n-alkylsulfonamides from heterocyclic amines as repellents
for yellow fever mosquitoes. Mosq News 35:204–210 (1975).
83 Katritzky AR, Wang Z, Slavov S, Tsikolia M, Dobchev D, Akhme-
dov NG, et al, Synthesis and bioassay of improved mosquito
repellents predicted from chemical structure. Proc Natl Acad Sci
105:7359–7364 (2008).
84 Boeckh J, Breer H, Geier M, Hoever FP, Früger BW, Nentwig G, et al,
Acylate 1,3-aminopropanols as repellents against bloodsucking
arthropods. Pestic Sci 48:359–373 (1996).
85 Natarajan R, Basak SC, Balaban AT, Klun JA and Schmidt WF,
Chirality index, molecular overlay, and biological activity
of diastereoisomeric mosquito repellents. Pest Manag Sci
61:1193–1201 (2005).
86 Basak SC, Natarajan R, Nowak W, Miszta P and Klun JA, Three
dimensional structure–activity relationships (3D-QSAR) for insect
repellency of diastereoisomeric compounds: a hierarchical
molecular overlay approach. SAR QSAR Environ Res 18:237–250
(2007).
87 Quintana RP, Mui PT, Lassio A and Boulware MA, Synthesis of insect-
repellent amino analogs of 2-ethyl-1,3-hexanediol (Rutgers 612). J
Med Chem 15:1073–1074 (1972).
88 Beroza M, Acree F, Turner RB and Braun BH, Separation and insect
repellent activity of diastereoisomers of 2-ethyl-1,3-hexanediol
against Aedes aegypti. J Econ Entomol 59:376–378 (1966).
89 Curtis CF, Lines JD, Baolin L and Renz A, Natural and synthetic
repellents, in Appropriate Technology for Vector Control, ed. by
Curtis CF. CRC Press, Boca Raton, FL, pp. 76–92 (1990).
Pest Manag Sci (2010)
Structural diversity of mosquito repellents
90 Curtis CF., Lines JD, Lu B and Renz A, Natural and synthetic repellents,
in Control of Disease Vectors in the Community, ed. by Curtis CF.
Wolfe, London, UK, pp. 75–92 (1991).
91 Schreck CE and Leonhardt BA, Efficacy assessment of quwenling: a
mosquito repellent from China. JAmMosqControlAssoc 7:433–435
(1991).
92 Trigg JK, Evaluation of Eucalyptus-based repellent against Anopheles
spp. in Tanzania. J Am Mosq Control Assoc 12:243 (1996).
93 Trigg JK and Hill N, Laboratory evaluation of Euclyptus-based
repellent against four biting arthropods. Phytother Res 10:43–46
(1996).
94 Insect Repellent Use and Safety. [Online]. Centers
for Disease Control and Prevention. Available:
http://www.cdc.gov/ncidod/dvbid/westnile/qa/insect
repellent.htm [10 February 2009].
95 Barasa SS, Ndiege IO, Lwande W and Hassanali A, Repellent activities
of stereoisomers of p-menthane-3,8-diols against Anopheles
gambiae (Diptera: Culicidae). J Med Entomol 39:736–741 (2002).
96 Goldenson J and Sass S, Determination of the insect repellent,
dimalone. Anal Chem 20:1118–1120 (1948).
97 Barthel WF, Leon J and Hall SA, Insect repellents. I. Esters of mandelic
and substituted mandelic acids. J Org Chem 19:485–489 (1954).
98 Leon J, Barthel WF and Hall SA, Insect repellents. II. Esters of 1-
hydroxycyclohexane carboxylic acid. J Org Chem 19:490–492
(1954).
99 Jachowski LA and Pijoan M, Two new effective insect repellents,
NMRI-201 and NMRI-448. Science 104:266–269 (1946).
100 Peterson C and Coats J, Insect repellents – past, present and future.
Pestic Outlook 12:154–158 (2001).
101 Sukumar K, Perich MJ and Boobar LR, Botanical derivatives in
mosquito control: a review. J Am Mosq Control Assoc 7:210–237
(1991).
102 Clark L and Mason JR, Effect of biologically active plants used as nest
material and the derived benefit to starling nestlings. Oecologia
77:174–180 (1988).
103 Clayton DH and Moore J, Common grackle anting with lime fruit and
its effects on ectoparasites. Auk 110:951–952 (1993).
104 Kessler D, Gase K and Baldwin IT, Field experiments with transformed
plants reveal the sense of floral scents. Science 321:1200–1202
(2008).
105 Euler M and Baldwin IT, The chemistry of defense and apparency in
the corollas of Nicotiana attenuate. Oecologia 107:102–112 (1996).
106 Paluch G, Grodnitzky J, Bartholomay L and Coats J, Quantitative
structure–activity relationship of botanical sesquiterpenes: spatial
and contact repellency to the yellow fever mosquito, Aedes aegypti.
J Agric Food Chem 57:7618–7625 (2009).
107 Paluch G, Zhu J, Bartholomay L and Coats J, Amyris and Siam-wood
essential oils: insect activity of sesquiterpenes, in Household,
Structural and Residential Pest Management, ed. by Peterson C.
American Chemical Society, Washington, DC, pp. 5–18 (2009).
108 Wang Z, Song J, Chen J, Song Z, Shang S, Jiang Z, et al, QSAR study
of mosquito repellents from terpenoid with a six-member-ring.
Bioorg Med Chem Lett 18:2854–2859 (2008).
109 Roitberg BD and Friend WG, A general theory for host seeking
decisions in mosquitoes. Bull Math Biol 54:401–412 (1992).
110 Davis EE, Regulation of sensitivity in the peripheral chemoreceptor
systems for host-seeking behaviour by haemolymph-borne factor
in Aedes aegypti. J Insect Physiol 30:179–183 (1984).
111 Gillies MT, The role of carbon dioxide in host-finding by mosquitoes
(Diptera: Culicidae): a review. Bull Entomol Res 70:525–532 (1980).
112 Sutcliffe JF, Distance orientation of biting flies to their hosts. Insect
Sci Applic 8:611–616 (1987).
113 Klowden MJ, Vector behavior, in The Biology of Disease Vectors, ed. by
Beaty BJ and Marquardt WC. University Press of Colorado, Boulder,
CO, pp. 34–50 (1996).
114 Curran AM, Rabin SI, Prada PA and Furton KG, Comparison of the
volatile organic compounds present in human odor using SPME-
GC/MS. J Chem Ecol 31:1607–1619 (2005).
115 Bernier UR, Kline DL and Posey KH, Human emanations and related
natural compounds that inhibit mosquito host-finding abilities, in
Pest Manag Sci (2010)

c 2010 Society of Chemical Industry
View publication stats
www.soci.org
Insect Repellents: Principles, Methods, and Uses, ed. by Debboun M,
Frances SP and Strickman D. CRC Press, London, UK, pp. 31–46
(2007).
116 Jacquin-Joly E and Merlin C, Insect olfactory receptors: contributions
of molecular biology to chemical ecology. J Chem Ecol
30:2359–2397 (2004).
117 Rutzler M and Zwiebel LJ, Molecular biology of insect olfaction: recent
progress and conceptual models. J Comp Physiol A 191:777–790
(2005).
118 Hallem EA, Dahanukar A and Carlson JR, Insect odor and taste
receptors. Annu Rev Entomol 51:113–135 (2006).
119 Wogulis M, Morgan T, Ishida Y, Leal WS and Wilson DK, The crystal
structure of an odorant binding protein from Anopheles gambiae:
evidence for a common ligand release mechanism. Biochem
Biophys Res Comm 339:157–164 (2006).
120 Pophof B, Pheromone-binding proteins contribute to the activation
of olfactory receptor neurons in the silkmoths Antheraea
polyphemus and Bombyx mori. Chem Senses 29:117–125 (2004).
121 Große-Wilde E, Svatoš A and Krieger J, A pheromone-binding protein
mediates the bombykol-induced activation of a pheromone
receptor in vitro. Chem Senses 31:547–555 (2006).
122 Rogers ME, Sun M, Lerner MR and Vogt RG, Snmp-1, a novel
membrane protein of olfactory neurons of the silk moth Antheraea
polyphemus with homology to the CD36 family of membrane
proteins. J Biol Chem 272:14792–14799 (1997).
123 Nichols Z and Vogt RG, The SNMP/CD36 gene family in Diptera,
Hymenoptera and Coleoptera: Drosophila melanogaster, D.
pseudoobscura, Anopheles gambiae, Aedes aegypti, Apis
mellifera, and Tribolium castaneum. Insect Biochem Mol Biol
38:398–415 (2008).
124 Jin X, Ha TS and Smith DP, SNMP is a signaling component required
for pheromone sensitivity in Drosophila. Proc Natl Acad Sci
105:10996–11001 (2008).
125 Laissue PP, Reiter C, Hiesinger PR, Halter S, Fischbach KF and
Stocker RF, Three-dimensional reconstruction of the antennal lobe
of Drosophila melanogaster. J Comp Neurol 405:543–552 (1999).
126 Kreher SA, Kwon JY and Carlson JR, The molecular basis of odor
coding in the Drosophila larva. Neuron 46:445–456 (2005).
127 Xu P, Atkinson R, Jones DNM and Smith DP, Drosophila OBP LUSH
is required for activity of pheromone-sensitive neurons. Neuron
45:193–200 (2005).
128 Fishilevich E and Vosshall LB, Genetic and functional subdivision of
the Drosophila antennal lobe. Curr Biol 15:1548–1553 (2005).
129 Hallem EA, Ho MG and Carlson JR, The molecular basis of odor coding
in the Drosophila antenna. Cell 117:965–979 (2004).
130 de Bruyne M and Warr CG, Molecular and cellular organization of
insect chemosensory neurons. BioEssays 28:23–34 (2005).
131 de Bruyne M, Clyne PJ and Carlson JR, Odor coding in a model
olfactory organ: the Drosophila maxillary palp. J Neurosci
19:4520–4532 (1999).
132 Elmore T, Ignell R, Carlson JR and Smith DP, Targeted mutation of a
Drosophila odor receptor defines requirements in a novel class of
sensillum. J Neurosci 23:9906–9912 (2003).
133 Couto A, Alenius M and Dickson BJ, Molecular, anatomical, and
functional organization of the Drosophila olfactory system. Curr
Biol 15:1535–1547 (2005).
134 Nakagawa T, Sakurai T, Nishioka T and Touhara K, Insect sex-
pheromone signals mediated by specific combinations of olfactory
receptors. Science 307:1638–1640 (2005).
135 Larsson MC, Domingos AI, Jones WD, Chiappe ME, Amrein H and
Vosshall LB, Or83b encodes a broadly expressed odorant receptor
essential for Drosophila olfaction. Neuron 43:703–714 (2004).
136 Davis EE and Sokolove PG, Lactic acid-sensitive receptors on the
antennae of the mosquito, Aedes aegypti. J Comp Physiol
105:43–54 (1976).
137 Dogan EB, Ayres JW and Rossignol PA, Behavioural mode of action
of DEET: inhibition of lactic acid attraction. Med Vet Entomol
13:97–100 (1999).
138 Shreck CE, Techniques for the evaluation of insect repellents: a critical
review. Annu Rev Entomol 22:101–119 (1977).
www.interscience.wiley.com/journal/ps