Icaridin(a.k.a. Picaridin)A natural insect repellent
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 [Image: Chaoren Shen, created using Google Gemini] |
Well, chemically the molecule is related to piperidine, which is found in pepper plants, and whose extracts contain molecules with the piperidine ring. These extracts are also found in the black pepper which is commonly found as a spice on most dinner tables.
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| Black pepper in a grinder. | Piperine crystals extracted from black pepper (Piper nigrum) - recrystallized from acetone [Image: Impz, CC BY 3.0 via Wikimedia Commons] |
It was known that humans have used various kinds of peppers, including chilli plants containing capsaicin (see MOTM for April 2001) and black pepper, as pest and insect deterrents for centuries. So in the 1980s, with the aim of inventing a new insect repellent, scientists at the German company Bayer AG used molecular modelling to design a new molecule based on the piperine structure. They removed some sidegroups, and added new ones, but kept the important piperidine ring, and made a new molecule that they called KBR 3023.
How the names are related.
This molecule worked rather well as an insect repellent, and it was sold under the trade name Bayrepel and later as Saltidin, gaining popularity in the late 1990s.
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| Piperine | Piperidine | Icaridin (Picaridin) |
This molecule had the IUPAC name of hydroxyethyl isobutyl piperidine carboxylate - rather a mouthful! The World Health Organisation (WHO) and chemical companies needed a simple, non-proprietary name for it. So, following the rules governing the naming of new drugs, the name 'picaridin' was proposed to the WHO, but they approved 'icaridin' instead as the official generic name for the new molecule.
Not completely. Although it's known as icardin in Europe and most of the world, in some places, notably the USA, it is more commonly known as picardin. So the joke is still valid!
DEET (N,N-diethyl-meta-toluamide) (see MOTM for Jan 2011) was and still is the most widely used synthetic insect repellent in the world. Originally developed by the U.S. Army in 1946 for jungle warfare and approved for civilian use in 1957, it remains the gold standard for personal protection against biting arthropods like mosquitoes, ticks, chiggers, and fleas.
But there were concerns that DEET dissolves plastic, rubbers and synthetic coatings, is absorbed into the body with possible toxic effects, and may be toxic to aquatic species, compounded by the fact it has a long lifetime in rivers and lakes. So a more environmentally friendly alternative to DEET was highly sought after.
| Property | DEET | Icaridin |
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| Chemical Inertness | Acts as an organic solvent – dissolves plastic, rubbers and synthetic coatings | Completely chemically inert – safe on plastics and synthetic materials |
| Skin absorption | High transdermal absorption – ~10–20% enters the bloodstream | Significantly lower skin absorption (<6%) – non-irritating to skin and eyes |
| Sensory Experience | Greasy, oily feel with a distinct heavy chemical smell | Virtually odourless, lightweight and non-greasy on skin |
| Biodegradability | Slow aquatic breakdown with mild toxicity to cold-water species | Highly biodegradable with short environmental persistence and low eco-toxicity |
The DEET molecule also contains the bottom-half of the piperidine ring, just like the pepper extracts, so chemists kept this part of the molecule and completed the ring as this was the insect-repelling part, and introducing a hydroxyethyl group (-CH2CH2OH) at the 2-position. This made the molecule more soluble in water (and therefore less soluble in lipids and fats) while retaining exceptionally high vapour-phase repellent activity. This meant the new molecule (icaridin) would not penetrate through the skin as easily, but could be washed away and readily diluted in water, making it less toxic and easier to decompose.
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Icaridin is synthesized using a two-stage chemical route. First, 2-pyridineethanol undergoes low-pressure catalytic hydrogenation using a nickel catalyst to form 2-piperidineethanol. Sec-butyl chloroformate is then prepared from isobutanol and diphosgene), and then this reagent is reacted with 2-piperidineethanol to yield icaridin, which is then purified.
Synthesis of icaridin.
Well spotted! Icaridin indeed contains two stereocenters: one where the hydroxyethyl chain attaches to the ring, and one where the sec-butyl attaches to the oxygen of the carbamate, making 4 stereoisomers in total. The commercial insect repellent contains a mixture of all four stereoisomers.
Stereoisomers of icaridin.
Yes. Icaridin and DEET are currently the most effective insect repellents available. A systematic review of the 2 sprays in 2018 found no consistent difference in performance between picaridin and DEET in field studies. It concluded that they are equally preferred mosquito repellents at concentrations around 20%. 50% DEET did repel mosquitoes for longer, but this is not available in many countries nowadays. And icaridin comes with all the advantages mentioned in the table, above.
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| Anopheles gambiae mosquito [Image: James D. Gathany, PD-USGOV-HHS-CDC via Wikimedia Commons] |
Blood-fed Lutzomyia longipalpis sandfly [Image: Ray Wilson from Liverpool School of Tropical Medicine, CC BY 2.5 Generic via Wikimedia Commons] |
Research using Anopheles gambiae mosquitoes shows that icaridin binds to one of the proteins (AgamOBP1) in the mosquito's olfactory system ...
...Yes. This distracts the mosquito from smelling other scents, such as the ones that attact the mosquito to bite humans. With our scents masked, the mosquito (and other insects) cannot smell us, and so ignore us and hunt elsewhere for lunch!
Yes, icaridin can be added to Nylon and cotton fabrics to repel insects for a long time. For example, electrospinning of icaridin with nylon-66 can homogeneously distribute the insect repellent throughout the fibre matrix, enabling its controlled release over periods of several days.
Nylon-66 (PA66)
Lutzomyia longipalpis (a New-World sand fly) is the main vector of the protozoan Leishmania infantum, which causes the disease visceral leishmaniasis. Icaridin nanostructured solution applied onto cotton knitting fabric has proved to be an efficient repellent against L. longipalpis, repelling the flies even after washing.
Well, it seems to be as effective as DEET, without any of the side-effects or disadvantages. It's not a surprise that this combination of efficacy, safety, and cosmetic appeal led to the WHO designating icaridin as its "repellent of choice for malaria prevention" in 2001.
Back to Molecule of the Month page. [DOI:10.6084/m9.figshare.33277344]