TY - JOUR
T1 - Insecticidal and Repellent Properties of Rapid-Acting Fluorine-Containing Compounds against Aedes aegypti Mosquitoes
AU - Zhu, Xiaolong
AU - Valbon, Wilson
AU - Qiu, Mengdi
AU - Hu, Chunhua T.
AU - Yang, Jingxiang
AU - Erriah, Bryan
AU - Jankowska, Milena
AU - Dong, Ke
AU - Ward, Michael D.
AU - Kahr, Bart
N1 - Funding Information:
This work was primarily supported by the New York University Materials Research Science and Engineering Center (MRSEC) program of the National Science Foundation under award number DMR-1420073. The NYU X-ray facility is supported partially by the NSF under Award Number CRIF/CHE-0840277. We thank Dr. Jeffery G. Scott (Cornell University) for providing the KDR:ROCK strain. We thank Dr. Amanda C. Túler for assistance with behavioral experiments. We thank Dr. Felipe Andreazza (Duke University) and Dr. Milena Jankowska (Duke University) for assistance with electrophysiological experiments.
Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society.
PY - 2023/7/14
Y1 - 2023/7/14
N2 - The development of safe and potent insecticides remains an integral part of a multifaceted strategy to effectively control human-disease-transmitting insect vectors. Incorporating fluorine can dramatically alter the physiochemical properties and bioavailability of insecticides. For example, 1,1,1-trichloro-2,2-bis(4-fluorophenyl)ethane (DFDT)─a difluoro congener of trichloro-2,2-bis(4-chlorophenyl)ethane (DDT)─was demonstrated previously to be 10-fold less toxic to mosquitoes than DDT in terms of LD50 values, but it exhibited a 4-fold faster knockdown. Described herein is the discovery of fluorine-containing 1-aryl-2,2,2-trichloro-ethan-1-ols (FTEs, for fluorophenyl-trichloromethyl-ethanols). FTEs, particularly per-fluorophenyl-trichloromethyl-ethanol (PFTE), exhibited rapid knockdown not only against Drosophila melanogaster but also against susceptible and resistant Aedes aegypti mosquitoes, major vectors of Dengue, Zika, yellow fever, and Chikungunya viruses. The R enantiomer of any chiral FTE, synthesized enantioselectively, exhibited faster knockdown than its corresponding S enantiomer. PFTE does not prolong the opening of mosquito sodium channels that are characteristic of the action of DDT and pyrethroid insecticides. In addition, pyrethroid/DDT-resistant Ae. aegypti strains having enhanced P450-mediated detoxification and/or carrying sodium channel mutations that confer knockdown resistance were not cross-resistant to PFTE. These results indicate a mechanism of PFTE insecticidal action distinct from that of pyrethroids or DDT. Furthermore, PFTE elicited spatial repellency at concentrations as low as 10 ppm in a hand-in-cage assay. PFTE and MFTE were found to possess low mammalian toxicity. These results suggest the substantial potential of FTEs as a new class of compounds for controlling insect vectors, including pyrethroid/DDT-resistant mosquitoes. Further investigations of FTE insecticidal and repellency mechanisms could provide important insights into how incorporation of fluorine influences the rapid lethality and mosquito sensing.
AB - The development of safe and potent insecticides remains an integral part of a multifaceted strategy to effectively control human-disease-transmitting insect vectors. Incorporating fluorine can dramatically alter the physiochemical properties and bioavailability of insecticides. For example, 1,1,1-trichloro-2,2-bis(4-fluorophenyl)ethane (DFDT)─a difluoro congener of trichloro-2,2-bis(4-chlorophenyl)ethane (DDT)─was demonstrated previously to be 10-fold less toxic to mosquitoes than DDT in terms of LD50 values, but it exhibited a 4-fold faster knockdown. Described herein is the discovery of fluorine-containing 1-aryl-2,2,2-trichloro-ethan-1-ols (FTEs, for fluorophenyl-trichloromethyl-ethanols). FTEs, particularly per-fluorophenyl-trichloromethyl-ethanol (PFTE), exhibited rapid knockdown not only against Drosophila melanogaster but also against susceptible and resistant Aedes aegypti mosquitoes, major vectors of Dengue, Zika, yellow fever, and Chikungunya viruses. The R enantiomer of any chiral FTE, synthesized enantioselectively, exhibited faster knockdown than its corresponding S enantiomer. PFTE does not prolong the opening of mosquito sodium channels that are characteristic of the action of DDT and pyrethroid insecticides. In addition, pyrethroid/DDT-resistant Ae. aegypti strains having enhanced P450-mediated detoxification and/or carrying sodium channel mutations that confer knockdown resistance were not cross-resistant to PFTE. These results indicate a mechanism of PFTE insecticidal action distinct from that of pyrethroids or DDT. Furthermore, PFTE elicited spatial repellency at concentrations as low as 10 ppm in a hand-in-cage assay. PFTE and MFTE were found to possess low mammalian toxicity. These results suggest the substantial potential of FTEs as a new class of compounds for controlling insect vectors, including pyrethroid/DDT-resistant mosquitoes. Further investigations of FTE insecticidal and repellency mechanisms could provide important insights into how incorporation of fluorine influences the rapid lethality and mosquito sensing.
KW - Aedes aegypti
KW - contact insecticide
KW - fluorine
KW - mosquito sensing
KW - rapid knockdown
KW - repellency
KW - stereoselectivity
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U2 - 10.1021/acsinfecdis.3c00161
DO - 10.1021/acsinfecdis.3c00161
M3 - Article
C2 - 37311068
AN - SCOPUS:85163458537
SN - 2373-8227
VL - 9
SP - 1396
EP - 1407
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
IS - 7
ER -