P-menthane-3,8-diol (PMD) is a natural insect repellent found in lemon eucalyptus. It is one of five chemicals recommended by the US Centers for Disease Control and Prevention as a mosquito repellent. Now, scientists have discovered that one type of PMD may be nearly as effective against certain types of mosquitoes as the industry-standard synthetic repellent, DEET, while being significantly less toxic to humans.
Mosquitoes are the deadliest animal on the planet, with mosquito-borne diseases killing over 1 million people each year. While DEET is frequently used to repel insects, it can irritate the skin and is neurotoxic. While natural alternatives such as cedar and lavender essential oils are less toxic, they frequently evaporate quickly, reducing their effectiveness. In comparison, PMD is more persistent.
PMD is found in nature as a mixture of four diastereomers—compounds with the same molecular formula and atom linkages but different 3D shapes.
Previous research suggested that these four diastereomers were equally active against the mosquito Anopheles gambiae, the primary malaria vector in Sub-Saharan Africa.
That puzzled organic chemist Marc Lemaire of Claude Bernard University Lyon 1 and his colleagues, because the smell of a molecule, and thus its effectiveness at repelling mosquitoes, is closely related to its shape.
To investigate PMD’s effect on mosquitoes, researchers in France teamed up with peers in Madagascar to verify how well each of the four diastereomers repelled Aedes albopictus, a species capable of transmitting diseases such as Zika, chikungunya, and dengue.
When tested in a laboratory setup with almost no air circulation, all diastereomers repelled mosquitoes to a similar degree. However, when the compounds were allowed to vaporize and disperse, as when applied to human skin, the results were significantly different.
Due to its lower evaporation rate, one diastereomer, (1R)-(+)-cis-PMD, was the clear winner for best repellent over time—the duration of its repellent effect is “very similar to DEET,” Lemaire says.
PMD is typically synthesized industrially from citronellal, which occurs naturally in citronella, rose, and geranium oils, as well as lemon eucalyptus. Lemaire and his colleagues discovered that by manipulating the temperature during synthesis, they could influence the predominant PMD diastereomer produced. Specifically, the more active cis forms of PMD are produced at lower reaction temperatures, Lemaire notes.
This finding may aid in the commercial production of the most effective PMD diastereomer.
Additionally, the researchers discovered that PMD was more effective at repelling mosquitoes when tested on three women versus three men. Female skin may release fewer mosquito attractants, such as carbon dioxide or lactic acid, allowing PMD to more effectively mask these compounds. However, “we really need to work on this point because it may be necessary to develop repellents tailored to specific skin types,” Lemaire says.
Apurba Bhattacharjee, a computational medicinal chemist at Georgetown University who has studied mosquito repellents and compounds against mosquito-borne diseases, notes that future research should examine how climate and temperature affect the effectiveness of these molecules.
“Remember, these products should mostly be useful in tropical countries with high levels of humidity,” Bhattacharjee told Chemical & Engineering, which was not involved in the study.
Lemaire and his colleagues now intend to “produce a blend of natural or almost natural chemicals with very high efficiency and long-duration effect—24 h could be optimal,” he explains.
Additionally, they are seeking molecules to incorporate into polymers to create protective materials such as nets and clothing.
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