PMID- 37311068 OWN - NLM STAT- MEDLINE DCOM- 20230717 LR - 20231121 IS - 2373-8227 (Electronic) IS - 2373-8227 (Linking) VI - 9 IP - 7 DP - 2023 Jul 14 TI - Insecticidal and Repellent Properties of Rapid-Acting Fluorine-Containing Compounds against Aedes aegypti Mosquitoes. PG - 1396-1407 LID - 10.1021/acsinfecdis.3c00161 [doi] 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) horizontal line a difluoro congener of trichloro-2,2-bis(4-chlorophenyl)ethane (DDT) horizontal line was demonstrated previously to be 10-fold less toxic to mosquitoes than DDT in terms of LD(50) 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. FAU - Zhu, Xiaolong AU - Zhu X AUID- ORCID: 0000-0003-1511-1566 AD - Department of Chemistry and Molecular Design Institute, New York University, 100 Washington Square East, New York, New York 10003 USA. FAU - Valbon, Wilson AU - Valbon W AD - Department of Biology, Duke University, 130 Science Drive, Durham, North Carolina 27708 USA. FAU - Qiu, Mengdi AU - Qiu M AD - Department of Chemistry and Molecular Design Institute, New York University, 100 Washington Square East, New York, New York 10003 USA. FAU - Hu, Chunhua T AU - Hu CT AUID- ORCID: 0000-0002-8172-2202 AD - Department of Chemistry and Molecular Design Institute, New York University, 100 Washington Square East, New York, New York 10003 USA. FAU - Yang, Jingxiang AU - Yang J AUID- ORCID: 0000-0002-0859-6668 AD - Department of Chemistry and Molecular Design Institute, New York University, 100 Washington Square East, New York, New York 10003 USA. FAU - Erriah, Bryan AU - Erriah B AUID- ORCID: 0000-0003-0608-8069 AD - Department of Chemistry and Molecular Design Institute, New York University, 100 Washington Square East, New York, New York 10003 USA. FAU - Jankowska, Milena AU - Jankowska M AD - Department of Biology, Duke University, 130 Science Drive, Durham, North Carolina 27708 USA. AD - Department of Animal Physiology and Neurobiology, Nicolaus Copernicus University, Lwowska 1 Street, Torun 87-100, Poland. FAU - Dong, Ke AU - Dong K AD - Department of Biology, Duke University, 130 Science Drive, Durham, North Carolina 27708 USA. FAU - Ward, Michael D AU - Ward MD AUID- ORCID: 0000-0002-2090-781X AD - Department of Chemistry and Molecular Design Institute, New York University, 100 Washington Square East, New York, New York 10003 USA. FAU - Kahr, Bart AU - Kahr B AUID- ORCID: 0000-0002-7005-4464 AD - Department of Chemistry and Molecular Design Institute, New York University, 100 Washington Square East, New York, New York 10003 USA. LA - eng PT - Journal Article PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20230613 PL - United States TA - ACS Infect Dis JT - ACS infectious diseases JID - 101654580 RN - 0 (Insecticides) RN - 284SYP0193 (Fluorine) RN - CIW5S16655 (DDT) RN - 0 (Fluorine Compounds) RN - 0 (Pyrethrins) SB - IM MH - Animals MH - Humans MH - *Insecticides/pharmacology MH - *Aedes MH - Fluorine/pharmacology MH - DDT/pharmacology MH - *Fluorine Compounds/pharmacology MH - Drosophila melanogaster MH - Insecticide Resistance/genetics MH - *Pyrethrins/pharmacology MH - *Zika Virus MH - *Zika Virus Infection MH - Mammals PMC - PMC10353007 OTO - NOTNLM OT - Aedes aegypti OT - contact insecticide OT - fluorine OT - mosquito sensing OT - rapid knockdown OT - repellency OT - stereoselectivity COIS- The authors declare the following competing financial interest(s): New York University has applied for a patent on the use of fluorine-containing 1-phenyl-2,2,2-trichloro-ethanols and propanols with X.Z., J.Y., M.D.W., and B.K. as inventors, to encourage development of pesticides. EDAT- 2023/06/13 19:15 MHDA- 2023/07/17 06:42 PMCR- 2023/07/18 CRDT- 2023/06/13 14:33 PHST- 2023/07/17 06:42 [medline] PHST- 2023/06/13 19:15 [pubmed] PHST- 2023/06/13 14:33 [entrez] PHST- 2023/07/18 00:00 [pmc-release] AID - 10.1021/acsinfecdis.3c00161 [doi] PST - ppublish SO - ACS Infect Dis. 2023 Jul 14;9(7):1396-1407. doi: 10.1021/acsinfecdis.3c00161. Epub 2023 Jun 13.