Skip to main content
NCBI home page
ACS AuthorChoice logoLink to ACS AuthorChoice
. 2023 Jun 13;9(7):1396–1407. doi: 10.1021/acsinfecdis.3c00161

Insecticidal and Repellent Properties of Rapid-Acting Fluorine-Containing Compounds against Aedes aegypti Mosquitoes

Xiaolong Zhu ⊥, Wilson Valbon ‡, Mengdi Qiu ⊥, Chunhua T Hu ⊥, Jingxiang Yang ⊥, Bryan Erriah ⊥, Milena Jankowska ‡,§, Ke Dong ‡,*, Michael D Ward ⊥,*, Bart Kahr ⊥,*
PMCID: PMC10353007  PMID: 37311068

Abstract

graphic file with name id3c00161_0008.jpg

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.

Keywords: contact insecticide, repellency, Aedes aegypti, fluorine, mosquito sensing, stereoselectivity, rapid knockdown

Introduction

Following trends in medicinal chemistry,1 many new fluorine-containing insecticides2 and other pesticides3−5 have been introduced in recent decades, facilitated by developments in fluoro-organic chemistry and motivated by the need to mitigate metabolic resistance. Representative fluorine-containing insecticides across diverse structural classes include metofluthrin, bifenthrin, fipronil, flupyradifuron, and bistrifluoron, as well as the pro-insecticide chlorfenapyr. The introduction of fluorine atoms and trifluoromethyl groups can significantly improve insecticide bioavailability by enhancing lipophilicity, cellular membrane permeability, metabolic stability (e.g., against cytochrome P450 enzymatic oxidations), and binding affinity with minimal steric perturbation.3,6−8

Malariologists9,10 have emphasized the continuing need for new, inexpensive, for indoor residual spraying and insecticide-treated bed nets. Neonicotinoids, which were approved by the WHO in 2018 as a new class of insecticides for combatting pyrethroid resistance, quickly faltered as resistance developed, presumably a result of their heavy use in agriculture.11 There is an urgent need for new chemical agents that can mitigate vector-borne diseases and overcome resistant organisms.

Previously, we reinvestigated a difluoro congener of DDT, DFDT (1,1,1-trichloro-2,2-(bis(4,4′- fluorophenyl)ethane),12 and its chiral monofluoro analog, MFDT13 (1,1,1-trichloro-2,2-(4-chlorophenyl)-(4-fluorophenyl)ethane).9 DFDT acted more rapidly than DDT against Drosophila and Anopheles quadrimaculatus, a vector of malaria, as well as Aedes aegypti, a vector of Zika, Yellow fever, Dengue, and Chikungunya viruses. Despite the fact that DFDT’s neurophysiological efficacy in vitro is 10-fold smaller than that of DDT, as well as the observation that DDT and DFDT are cross-resistant, amorphous DFDT is approximately 4 times faster than amorphous DDT in knocking down Aedes and Anopheles mosquitoes.14 This difference may be attributed to the fluorine-enhanced lipophilicity15 and thus bioavailability of DFDT molecules traversing cuticle and cellular membranes.6

Major insecticides used for public health are crystalline, with contact action like that of DDT.15 The speed of action (knockdown time) of contact insecticides depends on the release of molecules from the solid surface of the insecticide, followed by the penetration of molecules into the insect cuticle.16 We have demonstrated that the speed of action of organochlorine,17,18 organofluorine,9 pyrethroid,19 and neonicotinoid20 insecticides can be increased in metastable solid-state forms of a given compound. Metastable solid forms of the same chemical compound have higher free energies, thereby surrendering toxicant molecules from their surfaces more readily to insect tarsi upon contact. The differential lethality of polymorphs demonstrates that the rate of uptake from the solid surface is consequential. For instance, a commercial formulation of deltamethrin dispersed on chalk that had been heated briefly to 120 °C killed 100% of various resistant mosquito strains from Burkina Faso, without exception, whereas the commercial material as obtained was ineffective.21 This increased activity was attributed to the heat-induced transformation of commercial deltamethrin crystals to another crystalline form with a higher bioavailability.19 The more active form persists for 13 months and counting.21 Crystalline polymorphs with faster uptake can remove resistant organisms from a population where slower uptake polymorphs are indifferent. For this reason we have focused on inexpensive compounds that work quickly, especially as the WHO is moving toward new antimalarial compounds with previously unexplored mechanisms of action.22

Having synthesized MFDT and evaluated its enantioselectivity in insect knockdown, we tested the synthetic intermediate 1-phenyl-2,2,2-trichloro-ethanol. Herein, we describe the synthesis and evaluation of a group of related fluorine-containing 1-phenyl-2,2,2-trichloro-ethanol compounds, including per-fluorophenyl-trichloromethyl-ethanol (PFTE), with a particular focus on their liquid, amorphous, and crystalline phases and the role of fluorine. We also examine the insecticidal and repellent actions of PFTE against Ae. aegypti mosquitoes. Our findings indicate that fluorine-containing 1-phenyl-2,2,2-trichloro-ethanols are promising for combatting vector-borne human diseases.

Results and Discussion

Fluorinated DFDT Congeners and 1-Phenyl-2,2,2-trichloro-ethanols

Given that DFDT only has fluorine on its para positions, the introduction of additional aromatic fluorine atoms may further improve its knockdown speed. On the other hand, prior studies have demonstrated that the insecticidal potency of DDT decreased substantially when the trichloromethyl group was replaced with a trifluoromethyl group,23 or when the α-hydrogen was substituted by fluorine.24 Based on these results, we synthesized fluorinated DFDT congeners 2a–2e with aromatic fluorine substituents (Figures 1 and 2A, and Supporting Information).25,26 In addition, one synthetic intermediate, 1-(4-fluorophenyl)-2,2,2-trichloro-ethanol (1b; Figures 1 and 2A), was reported to have one- to two-fifths of DDT’s insecticidal activity against fruit flies (Drosophila melanogaster) in contact residual exposure bioassays.27 This active intermediate inspired the synthesis of compounds 1a (PFTE) and 1c with respective perfluoro- and trifluoromethyl-phenyl groups (Figures 1 and 2A, and Supporting Information).

Figure 1.

Figure 1

Open in a new tab

Synthetic routes of compounds with various chemical moieties.

Figure 2.

Figure 2

Open in a new tab

(A) Chemical structure of selected compounds. (B) Lethality of 1a (crystals), 1b (liquid), a-DFDT, DFDT Form I, 1c (crystals), and DDT Form I against D. melanogaster. The median knockdown time (KT50) for each curve is denoted by its intersection with the horizontal KT50 marker. Inset: Photograph of a typical female D. melanogaster. (C) Comparison of the KT50 values. 2a, 2b, and 2e were liquid, whereas 2c and 2d were amorphous. Error bars represent 95% confidence intervals (CI). Values with the same letter have overlapping 95% CIs, and differences are considered insignificant. Knockdown–time curves and logistic regression are available in the Supporting Information.

Figure 3 compares the median knockdown time (KT50) values for the compounds discussed throughout this paper. Because the knockdown speed of insecticides is highly dependent on their condensed phases,9,30−33 we prepared all compounds at room temperature to best reflect their efficacy in the field. Compounds 1a and 1c were always monomorphic from the evaporation of various solvents or from the melt (Figure 4A, Figures S1 and S2, and Table S1). 1b, 2a, 2b, and 2e were liquid at room temperature. Although 2c and 2d could grow into crystals at room temperature (Figures S1 and S2, and Table S1), their amorphous states, which were prepared by supercooling melts or fine mist spraying of solutions, persisted for at least 20 days at room temperature and were used for lethality measurements. Each crystalline form was ground into particles with sizes (50 μm) comparable to those of amorphous or liquid particles prepared by fine mist spraying. Female Drosophila melanogaster, an accepted proxy for evaluating insecticide potency against mosquitoes,28 were placed in Petri dishes and exposed to 2.0 mg (10.6 μg/cm2) of all compounds in Figure 2A in their amorphous, crystalline, or liquid forms. The experimental procedure was similar to that previously reported by our laboratory.9,32 The DDT crystalline polymorph designated Form I,30 the DFDT crystalline polymorph also designated Form I, amorphous DFDT (a-DFDT),9 and deltamethrin (DM, a leading pyrethroid29) likewise Form I32 were used for comparison (a-DFDT and DM were known for their rapid knockdown properties). Knockdown times were analyzed by measuring the motion of flies recorded with a video camera. The KT50 values, here the median knockdown times for a fly population, were calculated by performing logistic regression analysis of knockdown–time curves (Table S2).30 The KT50 values decreased in the order DDT-I (261 min) > 1c (168 min) > DFDT-I (152 min) > a-DFDT (54 min) > 1a (36 min) > DM-I (30 min) ≈ 1b (29 min) (Figure 2B,C). Liquid 1b was comparable to DM Form I in lethality, although the uptake of molecules from liquid would be expected to be more rapid than that from crystals.31 Notably, crystalline 1a and 1c both exhibited rapid knockdown, and the former was even faster in action than amorphous DFDT. In contrast, 2a–2e, whether in their amorphous or liquid forms, were all less active than a-DFDT (Figure 2C and Figure S3). These results suggested that the fluorination of 1-phenyl-2,2,2-trichloro-ethanol is a viable strategy for the discovery of rapid-acting agents.

Figure 3.

Figure 3

Open in a new tab

Structure–activity relationships. (A–D) Compounds with various chemical moieties. KT50 (min) for D. melanogaster are denoted in parentheses. Physical states are denoted by color: crystals, orange; liquid, blue. Values with the same letter have overlapping 95% confidence intervals, and differences are considered insignificant. Knockdown–time curves and logistic regression are available in the Supporting Information. (E) Chemical structure of compounds with good knockdown properties.

Figure 4.

Figure 4

Open in a new tab

(A) 1a crystallized into conglomerates with a chiral P21 space group. The enantiomers could not be separated from the conglomerates and were instead prepared by the asymmetric synthesis shown in Figure 2. Atom colors: hydrogen, white; carbon, gray; fluorine, magenta; chlorine, green. (B) Fluorinated compounds shown in Figure 3A, except 1a. 1f crystallized as a racemate with a P1 space group (shown as an example). Other crystal structures are available in the Supporting Information. The apparently skewed unit cell is a consequence of a perspective view along a general direction. (C) Similar to 1a, enantiomers of 1b prepared by the asymmetric synthesis shown in Figure 2.

Structure–Activity Relationships

Structure–activity relationship (SAR) studies were performed on 1a–1c to determine the key functionalities or moieties that may influence the insecticidal activity of 1-phenyl-2,2,2-trichloro-ethanol. Compounds 1d–1z, 4–6 with various chemical moieties were synthesized (Figure 1 and Supporting Information), and their individual knockdown times against female Drosophila were evaluated at 10.6 μg/cm2 (Figure 3, Figures S4 and S5, and Table S2). Female Drosophila in control groups typically began to become immobilized after 720 min; thus, compounds with KT50 values >720 min were considered inactive.

SAR studies revealed that aromatic substituents significantly affected lethality (Figure 3A). 1-Phenyl-2,2,2-trichloro-ethanols that contain aromatic substituents of F (1a, 1b, 1d–1i), OCF3 (1k), CF3 (1c, 1j, 1s), and a mixture of two fluorine functionalities (1q, 1r) exhibited rapid knockdown. In general, the ability of aromatic substituents to improve knockdown decreased in the order F > OCF3 > CF3. Aromatic fluorine substituents substantially influenced the physiochemical properties of compounds as well. Most compounds with ortho or para substituents were crystalline at room temperature, and their crystals were each prepared in their thermodynamically stable forms for lethality measurements (Figures S1 and S2, and Table S1). In contrast, meta substituents or the addition of the flexible OCF3 substituent decreased the melting points of some compounds to the extent that they were liquids at room temperature. Compounds 1a and 1b were respectively the fastest-acting crystalline and liquid compounds. Additionally, aromatic substituents with various steric and electronic effects were compared. Compounds that contain common electron-donating (1m, 1p) or -withdrawing (1n, 1o) groups were inactive. The switch from an OCF3 (1k) group to an SCF3 (1l) group, or from phenyl (1b, 1c) to other fluorinated aromatic systems (1t, 1y), led to a loss of activity. Moreover, the introduction of Cl (1z), Br (1v, 1x), CH3 (1u), or OPh (1w) substituent to fluoro- or trifluoromethylphenyl groups resulted in a significant lowering of activity.

Following the SAR studies for aromatic substituents, we investigated the effects of three moieties that were attached to the central carbon atom. Acetoxylation led to a loss of activity, corroborating the importance of free alcohol in conferring lethality (Figure 3B). In contrast, the switch from H (1a) to CH3 (5) substituent had little effect on knockdown speed (Figure 3C). A −CH3 substituent, however, prevented the crystallization of compound 5 at room temperature. The impact of halogenated methyl groups was also probed by changing the halogen (Figure 3D). CCl3 (1c) was superior to both CF3 (7) and CBr3 (6) substituents, presumably due to steric effects. In conclusion, the SAR studies showed that 1-aryl-2,2,2-trichloro-ethanols and -propanols containing one or more aromatic substituents of F, OCF3, or CF3 exhibited remarkable knockdown properties (Figure 3E).

Enantioselective Toxicities against Flies

The stereoisomers of a given insecticide may have different activities due to their unique interactions with the metabolic enzymes or the target site.40 For example, our previous studies demonstrated that the monofluoro congener of DDT—named MFDT—exhibited enantioselective lethality against Drosophila.9 Moreover, different insecticide stereoisomers may have different environmental impacts.32 Thus, single or enriched stereoisomer formulations of insecticides are preferable, because they can have both increased potency and reduced environmental impact.33 We explored the difference in the activity of enantiomers of 1a and 1b, because their degrees of fluorination are on opposite ends of the spectrum.

Interestingly, racemic 1a always crystallized as conglomerates34 (a mixture of homochiral enantiomer crystals) in the P21 space group from solution or from melts (Figure 4A). In contrast, other racemates displayed in Figure 3 all crystallized as racemates47 (equimolar amounts of enantiomers in the crystal lattices; Figure 4B and Figure S2). Since the crystals in conglomerates of 1a were tiny needles (<100 μm), the separation of enantiomer crystals based on crystal morphology (a Pasteur-like resolution) was not feasible. Instead, we prepared the enantiomers via asymmetric synthesis. Racemates were oxidized to yield ketones,35 which were reduced by catecholborane in the presence of chiral oxazaborolidine catalysts36 to yield 1a and 1b enantiomers, each having 99% and 95% enantiomeric excess (Figure 1, and Supporting Information). The absolute configuration of the 1a enantiomers was assigned using single-crystal X-ray analysis (Figure 4A, and Supporting Information).

Female Drosophila were exposed to racemates and enantiomers of both crystalline 1a and liquid 1b at various dosages. The R forms of 1a and 1b were always faster-acting than their respective S forms (Figure 5A–E and Table S2), suggesting enantioselectivity in insect uptake, metabolism, or neurotoxicity. (R)-1a was even faster-acting than DM Form I at very low dosages (Figure 5F and Figure S6). In contrast, both enantiomers of 1b were less effective (KT50 > 720 min) at 0.53 μg/cm2, requiring higher lethal doses than of 1a. Therefore, the rapid knockdown speeds of 1b and other figures shown for Figure 3 are presumably dominated by the kinetics of uptake of molecules.

Figure 5.

Figure 5

Open in a new tab

(A–E) Knockdown of 1a enantiomers (crystals) and 1b enantiomers (liquid) against D. melanogaster at various dosages. At 0.53 μg/cm2, both 1b enantiomers had KT50 values >720 min. The median knockdown time for each curve is denoted by its intersection with the horizontal KT50 marker. (F) KT50 values versus dosage. Error bars represent 95% confidence intervals (CI).

Toxicity of PFTE against Aedes aegypti Mosquitoes

To determine whether PFTE induces rapid knockdown of mosquitoes, we conducted a contact-based bioassay as described above for flies. Adult females of an insecticide-susceptible wild-type Ae. aegypti strain, Rockefeller, were all knocked down in less than 5 min upon contact exposure to PFTE at the concentration of 12.5 μg/cm2. Furthermore, we observed 77% mortality after Rockefeller mosquitoes were exposed to vapor emitted from PFTE of 12.5 μg/cm2 for 24 h (Figure S1).

Given that PFTE induced very rapid knockdown at 12.5 μg/cm2, we also conducted the contact bioassay using 1.25 μg/cm2 and recorded the percentage of knockdown over the course of 1 h (Figure 6). Next, we examined two pyrethroid/DDT-resistant strains, KDR:ROCK37 and Puerto Rico,38 which carry different sodium channel mutations that confer knockdown resistance (kdr) to DDT and pyrethroids.37,39 The Puerto Rico strain also possesses an enhanced P450-mediated metabolic detoxification mechanism of resistance.38 As shown in Figure 6, the KT50 values of PFTE against these pyrethroid/DDT-resistant mosquitoes were not significantly different from those against the susceptible mosquitoes, although KDR:ROCK mosquitoes were more sensitive to PFTE than Puerto Rico mosquitoes. These results show that, unlike in the case of DFDT,28 there is no cross-resistance between PFTE, DDT, and pyrethroids. Further, our functional examination of mosquito sodium channels expressed in Xenopus oocytes indicates that, unlike pyrethroids and DDT, PFTE does not alter the gating of mosquito sodium channels (Figure S2).

Figure 6.

Figure 6

Open in a new tab

Knockdown of Ae. aegypti mosquitoes by crystalline PFTE. At the dosage of 1.25 μg/cm2, PFTE had KT50 values of 15, 10, and 20 min for Rockefeller, KDR:ROCK and Puerto Rico mosquitoes, respectively. The median knockdown time for each curve is denoted by its intersection with the horizontal KT50 dotted line. Curves with the same letter do not differ according to Log-Rank test, and dots denote the value of each biological replicate (mosquito). Rockefeller vs KDR:ROCK: Log Rank: χ2 = 3.11, df = 1, P = 0.08; Rockefeller vs Puerto Rico: Log Rank: χ2 = 3.22, df = 1, P = 0.073. KDR:ROCK vs Puerto Rico: χ2 = 13.13, df = 1, P < 0.001.

These results indicate that PFTE may have unique target sites in the nervous system. An observation that may be related is that the miticide dicofol (2,2,2-trichloro-1,1-bis(4-chlorophenyl)ethanol), in which the α-carbon of DDT is hydroxylated, has a different mechanism of action than that of DDT itself.40 It is indifferent to houseflies with DDT-related kdr, and it elicits different symptoms of poisoning in susceptible flies, e.g., the absence of tremors. Subsequent research indicated that it may inhibit the octopamine-stimulated adenylate cyclase enzyme.41

Future studies using various nerve preparations are needed to elucidate the mechanism of PFTE action. Its perfluorination may not be subjected to detoxification by cytochrome P450 enzymes, but other metabolic detoxification pathways, such as glucuronidation, are still possible. The remarkably rapid knockdown by PFTE might be primarily attributed to the fact that fluorine significantly increases the lipophilicity, and thus bioavailability, of PFTE molecules, which are expected to rapidly traverse insect cuticle and cellular membranes.

Repellency of PFTE against Aedes aegypti Mosquitoes

The finding of PFTE vapor toxicity against Ae. aegypti prompted us to determine whether PFTE evokes spatial (noncontact) repellency using a hand-in-cage assay,42 as shown in Figure 7. PFTE was diluted in acetone and applied on a polyester netting (6.5 cm × 5.5 cm). After the acetone fully evaporated, the netting was fixed in a modified glove worn by a tester. Groups of female Rockefeller mosquitoes were exposed to PFTE vapor for 5 min at concentrations ranging from 10 to 10000 ppm. The repellency indexes at each concentration and control were determined by comparing the number of landings of mosquitoes in two trials: in a first trial with acetone-treated netting only and a second trial with PFTE-treated netting (see details in ref (42)). When the mosquitoes were exposed to PFTE-treated netting, significantly fewer landings were observed. The repellency by PFTE vapor was dose-dependent and observed at concentrations as low as 10 ppm of PFTE (Figure 7B). No mosquitoes were knocked down or exhibited locomotive modifications during the noncontact assay at all tested concentrations.

Figure 7.

Figure 7

Open in a new tab

PFTE elicits spatial repellency in Ae. aegypti mosquitoes. (A) Schematic drawing illustrating the hand-in-cage setup used to evaluate spatial repellency. (B) Dose-dependent PFTE repellency in Rockefeller (wild-type) mosquitoes. Student’s t-test, 10 ppm: t = −3.85, df = 13, P = 0.802; 100 ppm: t = −7.50, df = 18, P < 0.001; 1000 ppm: t = −10.49, df = 18, P < 0.001; 10000 ppm: t = −14.35, df = 13, P < 0.001. n values for control (0) = 10 cages, 10 ppm = 5 cages, 100 and 1000 ppm = 10 cages each, 10 000 ppm = 5 cages. (C) PFTE repellency in Rockefeller and KDR:ROCK mosquitoes. Student’s t-test, control: t = −0.41, df = 14, P = 0.685; 100 ppm: t = −0.34, df = 8, P = 0.738; 1000 ppm: t = −1.69, df = 18, P = 0.107. n values for control (0) for both Rockefeller and KDR:ROCK = 8 cages, 100 ppm for both strain = 5 cages each, 1000 ppm for both strains = 10 cages each. (D) PFTE repellency in Orlando (wild-type) and orco–/– mosquitoes. Student’s t-test, control: t = −0.02, df = 14, P = 0.982; 1000 ppm: t = 1.13, df = 18, P = 0.273. n values for control (0) for both Orlando and orco–/– = 8 cages, 1000 ppm for both Orlando and orco–/– = 10 cages. Data are presented as mean ± SEM. Dots over the bars represent individual replicate values. ns = not significant, **P < 0.01, ***P < 0.001.

We showed in a recent study that activation of voltage-gated sodium channels alone by transfluthrin, a volatile pyrethroid, was sufficient to elicit spatial repellency in Ae. aegypti and that kdr mutations in sodium channels reduced transfluthrin repellency.43 Here, we found that KDR:ROCK mosquitoes exhibited similar levels of repellency compared to wild-type Rockefeller mosquitoes when exposed to PFTE (Figure 7D). This result indicates that, unlike transfluthrin repellency, the kdr mutations did not affect repellency by PFTE, consistent with our toxicity results from contact assays (Figure 6). Taken together, our findings indicate that the mechanism of PFTE repellency is different from that of transfluthrin repellency and appears to be independent of sodium channel activation.

Given that spatial repellency can be elicited by compounds that activate odorant receptors in mosquitoes’ antennae,42,44 we examined whether PFTE repellency is mediated by activation of odorant receptor (Or) using an Ae. aegypti mutant strain in which the odorant receptor co-receptor gene (orco) was mutated.45 Orco is required for Or-mediated olfactory activities, and the null mutation of orco resulted in impaired Or-mediated olfactory pathways.45 We found that PFTE repellency was not reduced in orco–/– mosquitoes compared with wild-type (Orlando) mosquitoes. PFTE at 1000 ppm evoked around 70% repellency in both mosquito strains (Figure 7D). Our findings suggest that spatial repellency by PFTE is not mediated by activation of odorant receptors.

Compared with other compounds that were recently tested against Rockefeller mosquitoes in the hand-in-cage assay, the potency of PFTE in eliciting spatial repellency is comparable to those of plant-derived compounds, but lower than those of DEET and volatile pyrethroids.46−48 For instance, eucalyptol and camphor elicited 50–60% repellency at 100 ppm. Geranyl acetate elicited about 70–80% repellency at 100 ppm.46,48 PFTE is only slightly more potent than pyrethrin I and II which elicited 50–60% repellency at 1000 ppm.46 On the other hand, DEET, transfluthrin, and bioallethrin elicited ∼50% of mosquito repellency at 1–10 ppm.47,49

Rat Oral Toxicity

Compounds 1a and 1b were chosen for mammalian oral toxicity screening because their structures and lethality were similar to, and representative of, other compounds identified in Figure 3A. Mammalian toxicity screening was conducted as per the Organization for Economic Co-operation and Development (OECD)’s guideline on the fixed dose procedure using female adult rats.50 Compounds 1a and 1b both had oral median lethal dose (LD50) values in the range of 300–2000 mg/kg and could be allocated to Category 4, according to the Globally Harmonized System (GHS).51 This is well above the recommended minimum lethal dosage for public health insecticides (>50 mg/kg; above the range of GHS Category 2).52 The results indicated that compounds 1a and 1b were less toxic to mammals than conventional insecticides, including organochlorines, organophosphates, carbamates, and pyrethroids, and they were comparable to neonicotinoids in mammalian toxicity.40

Conclusions

Fluorine-containing 1-phenyl-2,2,2-trichloro-ethanol (FTEs) exhibit rapid knockdown properties, low mammalian toxicity, and no cross-resistance with DDT or pyrethroids. One enantiomer of any chiral FTE showed faster knockdown speed than its counterpart at various dosages, demonstrating chiral discrimination during the uptake of the molecule or when binding at target site. Furthermore, PFTE possesses both vapor toxicity and spatial repellent actions against Ae. aegypti mosquitoes. These results demonstrate the potential of FTEs for vector control, and they provide important insights regarding the unique role of fluorine in the design of active insecticidal and repellent compounds. Nevertheless, more toxicological, electrophysiological, ecological, and epidemiological studies must be performed to better understand the molecular mechanism of FTEs as insecticides and repellents and to fully anticipate unintended consequences, such as insecticide resistance.

Methods

Chemicals and Insects

All chemical reagents and solvents were purchased from Sigma-Aldrich or Fischer Chemical and used as supplied. 5 mL glass fine mist spray bottles, purchased from Infinity Jars, Inc., were used for spraying insecticide solutions. Fruit flies (Drosophila melanogaster) were raised in-house using standard protocols. We used five Ae. aegypti mosquito strains in this study: Rockefeller, KDR:ROCK, Puerto Rico, Orlando, and orco–/–. Rockefeller is an insecticide-susceptible wild-type strain. The KDR:ROCK strain was generated by crossing the pyrethroid-resistant strain Singapore53 with the Rockefeller strain, followed by four backcrosses to Rockefeller, and selected for the S989P+V1016G haplotype.37 The mechanism of resistance in the KDR:ROCK strain is solely due to the two kdr mutations (S989P and V1016G).37 Both Rockefeller and KDR:ROCK were kindly provided by J. G. Scott (Cornell University). Puerto Rico is a second pyrethroid-resistant strain (from BEI Resources at the National Institute of Allergy and Infectious Diseases (NIAID), NIH), which carries three kdr mutations, V410L, V1016G, and F1534C, and has an enhanced P450-mediated pyrethroid detoxification mechanism of resistance.38 Orlando (kindly provided by L. Vosshall, Rockefeller University) is another insecticide-susceptible wild-type strain, from which an Orco mutant, orco–/– (orco16 from BEI Resources, NIAID, NIH), was generated.45 In orco–/–, the orco gene was mutated resulting in impaired Or-mediated olfactory responses. Mosquitoes were maintained in an environmental growth chamber at Duke Phytotron in the Department of Biology, Duke University, at 27 °C, with 50–60% relative humidity and a 12:12 h light/dark photoperiod. Larvae were fed with beef liver powder (NOW Foods), and adults were fed with 10% aqueous sucrose. Adult females were blood-fed 5 days after emergence using defibrinated sheep blood (Colorado Serum Company).

Synthesis

Details of the chemical syntheses, 1H, 13C, and 19F NMR spectra, and chiral HPLC elution data of compounds 1a–1z, (R)-1a, (S)-1a, (R)-1b, (S)-1b, 2a–2e, 3a, 3b, and 4–6 can be found in the Supporting Information. 1H, 13C, and 19F NMR spectra were recorded on a Bruker AVIII 400 MHz spectrometer at 400, 100, and 377 MHz, respectively. Chemical shifts are reported in parts per million (ppm) relative to the residual deuterated chloroform peak (7.26 ppm for 1H NMR and 77.23 for proton-decoupled 13C NMR). 19F NMR chemical shifts are reported relative to the external standard α,α,α-trifluorotoluene, δ −63.72. Data are represented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (J) in Hertz (Hz), integration. HPLC traces were obtained using an Agilent 1260 Infinity instrument with CHIRALPAK OJ-H or OD-H columns.

Crystallization of Single Crystals

Single crystals of (R)-1a, (S)-1a, 1c, 1e, 1f, 1h, 1i, 2c, and 2d for X-ray analysis were prepared in 20 mL glass vials by slow evaporation from saturated acetone, ethanol, or dichloromethane solutions at room temperature. The X-ray intensity data were recorded on a Bruker D8 APEX-II CCD system using graphite-monochromated and 0.5 mm MonoCap-collimated Mo Kα radiation (λ = 0.71073 Å) with the ω scan method at 100 K. The selected crystallographic parameters are listed in Table S1. Crystallographic information files (CIFs), including the HKL and RES data, are deposited in the CCDC with numbers 2102296 ((R)-1a), 2102297 ((S)-1a), 2102298 (1c), 2102299 (1e), 2102300 (1f), 2102301 (1h), 2102302 (1i), 2102303 (2c), and 2102304 (2d).

Toxicological Assays

The lethality of solid-state forms of insecticide was determined by the residual exposure method. Each crystalline form was ground to a particle size similar to the size of the amorphous or liquid droplets prepared by fine mist spraying. For D. melanogaster flies, lethality measurements were performed in duplicate for each compound, each accompanied by two controls (no insecticide). Each microcrystalline form was added to a 10 cm diameter polystyrene Petri dish, which was subsequently shaken to disperse the microcrystals throughout the Petri dish. Amorphous or liquid forms were prepared by fine mist spraying a hexane stock solution, with various concentrations in 10 mL hexane, onto the top and bottom of 10 cm diameter polystyrene Petri dishes (two sprays = 0.280 mL) and allowing the hexane to evaporate at room temperature. Flies were sedated with carbon dioxide (for 30 s), and 25 females were transferred to each Petri dish. The top of the dish was then placed over the bottom, and the motion of the flies was recorded with a video camera (Sony HDR-CX455). The knockdown time was measured for each individual fly, with knockdown associated with an insect laying on the bottom surface of the Petri dish in a supine position without moving from its original position after 10 s.

For Ae. aegypti mosquitoes, lethality measurements were performed in similar conditions as described for flies. 1a microcrystalline form (ranging from 0.1 to 1.0 mg) was added to a 9 cm diameter polystyrene Petri dish, which was subsequently shaken to disperse the microcrystals throughout the Petri dish, providing concentrations that ranged from 1.25 to 12.5 μg/cm2. Twenty (4–9 days old) female mosquitoes were sedated with carbon dioxide (for 20 s) and transferred to the 9 cm diameter polystyrene Petri dish which was then covered with a lid to prevent their escape. Three Petri dishes containing 20 female mosquitoes each (replicates) were used, totaling 60 mosquitoes for each strain. The number of mosquitoes that were knocked down (i.e., an insect laying on the bottom surface of the Petri dish in a supine position without moving from its original position after 10 s) was recorded every 5 min (for 40 min). For the vapor toxicity assay we used 1.0 mg of 1a microcrystalline form, which was subsequently shaken to disperse the microcrystals throughout the Petri dish, providing concentrations of 12.5 μg/cm2. On top of the treated Petri dish a second modified Petri dish was placed. For that, a 9 cm diameter polystyrene Petri dish with a 7 cm diameter hole was used to create a window, and a polyester netting (Shason Textile Inc., part number WSB532-111, white; 8.0 cm of diameter) was fixed in the bottom of the modified Petri dish to prevent mosquitoes from making direct contact with the compound. This setup allowed the mosquitoes to be exposed to the vapor phase of compound 1a only (Figure 7B). Twenty (4–9 days old) female mosquitoes were sedated with carbon dioxide (for 20 s) and transferred to the modified Petri dish which was then covered with a lid to prevent their escape. Five replicates (i.e., modified Petri dishes containing 20 female mosquitoes each) were used. The mortality was evaluated after 24 h of exposure.

Electrophysiology Recordings

We evaluated whether compound 1a possesses pyrethroid and DDT-like activities on the mosquito wild-type sodium channel (AaNav1-1). AaNav1-1 channels were expressed in Xenopus oocytes and functionally characterized using a two-electrode voltage clamp as previously described.54,55 Briefly, the tail-current induced by compound 1a and deltamethrin (positive control) following a 100-pulse train of 5 ms depolarization from −120 mV to 0 mV with 10 ms was measured.56 We also tested the inhibitory effect of 1a on channel inactivation in the DDT protocol57 by measuring the remaining current at the end of a 500 ms depolarization to −10 mV from a holding potential of −120 mV. For this protocol cells were previously incubated for 3–4 h in 100 μM PFTE. Six oocytes (i.e., six replicates) expressing AaNav1-1 were tested for both control (i.e., DMSO) and compound 1a.

Repellency Assay

We assessed the spatial (i.e., noncontact) repellency elicited by compound 1a using a hand-in-cage assay.42 Briefly, a human hand wearing a modified nitrile glove (Ansell Protective Products, part number 37-155) was placed inside a 30 cm × 30 cm × 30 cm mosquito cage (BioQuip) with a digital camera (e-con Systems Inc., model e-CAM51A) mounted on its top. The camera was connected to a laptop computer to record mosquito landings.42 The nitrile rubber glove worn by a tester was cut on its back to create a window (6 cm × 5 cm). A rectangular (6.5 cm × 5.5 cm) magnetic frame was glued onto the cut window, which served as a base for stacking additional magnetic window frames. One piece of test-compound-treated polyester netting (Shason Textile Inc., part number WS-B532-111, Walmart no. 567948282, white; slightly larger than the dimension of the window, but smaller than the outer edge dimensions of the magnetic frames) was placed on this fixed magnetic frame, which was ∼3.0 mm above the glove and hand. To the compound-treated netting was applied 500 μL of either solvent (acetone) or test compound (PFTE) in a glass Petri dish, in an adjacent room. After acetone was fully evaporated (approximately 7 min), the netting was assembled into the window created in the glove. The hand makes no contact with the treated netting. The second piece of the netting was untreated and was placed ∼8.0 mm above the treated netting using a stack of four magnetic frames. The stacked magnetic frames were further secured with two binder clips. The stacking creates sufficient space between the treated netting and the untreated netting so that mosquitoes that land on the open window were not able to contact the treated netting or contact and pierce the skin of the hand in the glove. Eighteen hours before the assay, 4- to 9-day-old female mosquitoes (about 40, mated, non-blood-fed) were transferred into each cage. Groups of 40 female mosquitoes were exposed for 4 min to PFTE at different dilutions ranging from 10 to 10 000 ppm, which correspond to 0.14, 1.4, 14.0, and 140 μg/cm2. The cages were kept under controlled conditions inside an environmental growth chamber (27 °C, relative humidity of ∼55%, and 12 h photoperiod). A cotton ball soaked with distilled water was placed on the top of each cage. Any cage that gave a low landing number (i.e., <50% of the average landing compared with other cages) in the first run was not continued with the second run. Repellency index was calculated using the following equation: Percentage repellency = [1 – (cumulative number of landings on the window of treatment/cumulative number of landings on the window of solvent treatment)] × 100). For each concentration or mosquito strain we used at least five cages (i.e., 5 replicates).

Rat Oral Toxicity Test

The rat oral toxicity test was conducted at Envigo CRS GmbH, Germany, according to the OECD guideline for the fixed dose procedure,42 using female adults of the Wistar Ham strain. The test compounds were formulated at concentrations of 30 and 200 mg/mL in corn oil and administered at a constant dose volume of 10 mL/kg body weight. Clinical observations and inspections for morbidity/mortality were performed at least three times within the first 6 h after application, thereafter at least once daily for 14 days. If a rat displayed a high state of pain or distress, it was considered to be not surviving the treatment and was sacrificed immediately.

Statistical Analyses

Logistic regression of knockdown–time curves was preformed to obtain the median knockdown time (KT50) of the test flies and mosquitoes, the 95% confidence intervals (CI), slopes, and standard errors (SE) using Qcal software.41 To evaluate the mosquito knockdown time we used the survival analysis and estimated the median lethal time (i.e., KT50) applying Kaplan–Meier estimators (Log-rank method) available in SigmaPlot 12.0 (Systat 218 Software, San Jose, California, USA). For the repellency data unpaired Student’s t tests were used to compare two sets of data. All statistical analyses and figure plotting were done using SigmaPlot v.12.5 (Systat Software).

Acknowledgments

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.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsinfecdis.3c00161.

  • Vapor toxicity and repellency actions, electrophysiology, crystallographic indices, crystal structures, selected crystal data, knockdown–time curves of fluorinated DFDT analogs against Drosophila, knockdown–time curves of crystalline and liquid compounds against Drosophila, knockdown–time curves of deltamethrin Form I, logistic regression parameters, synthetic procedures, chromatographic elution data for stereoisomers, NMR data, and NMR spectra (PDF)

  • X-ray crystallographic data for (R)-1a (CIF)

  • X-ray crystallographic data for (S)-1a (CIF)

  • X-ray crystallographic data for 1c (CIF)

  • X-ray crystallographic data for 1e (CIF)

  • X-ray crystallographic data for 1f (CIF)

  • X-ray crystallographic data for 1h (CIF)

  • X-ray crystallographic data for 1i (CIF)

  • X-ray crystallographic data for 2c (CIF)

  • X-ray crystallographic data for 2d (CIF)

Author Contributions

† X.Z. and W.V. contributed equally.

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.

Supplementary Material

id3c00161_si_001.pdf (5.9MB, pdf)
id3c00161_si_002.cif (245.4KB, cif)
id3c00161_si_003.cif (241.4KB, cif)
id3c00161_si_004.cif (1.4MB, cif)
id3c00161_si_005.cif (705.6KB, cif)
id3c00161_si_006.cif (644.6KB, cif)
id3c00161_si_007.cif (954.1KB, cif)
id3c00161_si_008.cif (947.5KB, cif)
id3c00161_si_009.cif (620.5KB, cif)
id3c00161_si_010.cif (652KB, cif)

References

  1. Böhm H.-J.; Banner D.; Bendels S.; Kansy M.; Kuhn B.; Müller K.; Obst-Sander U.; Stahl M. Fluorine in medicinal chemistry. ChemBioChem 2004, 5, 637–643. 10.1002/cbic.200301023. [DOI] [PubMed] [Google Scholar]
  2. Mori T.; Ujihara K.; Matsumoto O.; Yanagi K.; Matsuo N. Synthetic studies of fluorine-containing compounds for household insecticides. J. Fluor. Chem. 2007, 128, 1174–1181. 10.1016/j.jfluchem.2007.07.016. [DOI] [Google Scholar]
  3. Jeschke P. The unique role of fluorine in the design of active ingredients for modern crop protection. ChemBioChem 2004, 5, 570–589. 10.1002/cbic.200300833. [DOI] [PubMed] [Google Scholar]
  4. Fujiwara T.; O’Hagan D. Successful fluorine-containing herbicide agrochemicals. J. Fluorine Chem. 2014, 167, 16–29. 10.1016/j.jfluchem.2014.06.014. [DOI] [Google Scholar]
  5. Ogawa Y.; Tokunaga E.; Kobayashi O.; Hirai K.; Shibata N. Current contributions of organofluorine compounds to the agrochemical industry. iScience 2020, 23, 101467. 10.1016/j.isci.2020.101467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Muller K.; Faeh C.; Diederich F. Fluorine in pharmaceuticals: looking beyond intuition. Science 2007, 317, 1881–1886. 10.1126/science.1131943. [DOI] [PubMed] [Google Scholar]
  7. Purser S.; Moore P. R.; Swallow S.; Gouverneur V. Fluorine in medicinal chemistry. Chem. Soc. Rev. 2008, 37, 320–330. 10.1039/B610213C. [DOI] [PubMed] [Google Scholar]
  8. Hagmann W. K. The many roles for fluorine in medicinal chemistry. J. Med. Chem. 2008, 51, 4359–4369. 10.1021/jm800219f. [DOI] [PubMed] [Google Scholar]
  9. Gravitz L. Vector control: the last bite. Nature 2012, 484, S26–S27. 10.1038/484S26a. [DOI] [PubMed] [Google Scholar]
  10. Sparks T. C. Insecticide discovery: An evaluation and analysis. Pestic. Biochem. Physiol. 2013, 107, 8–17. 10.1016/j.pestbp.2013.05.012. [DOI] [PubMed] [Google Scholar]
  11. Makoni M. Malaria fighters’ latest chemical weapon may not last long. Science 2020, 369, 1153. 10.1126/science.369.6508.1153. [DOI] [PubMed] [Google Scholar]
  12. Zhu X.; Hu C. T.; Yang J.; Joyce L. A.; Qiu M.; Ward M. D.; Kahr B. Manipulating solid forms of contact insecticides for infectious disease prevention. J. Am. Chem. Soc. 2019, 141, 16858–16864. 10.1021/jacs.9b08125. [DOI] [PubMed] [Google Scholar]
  13. Riemschneider R. Kurze mitteilungen über ein neues kontaktinsektizid der klasse der halogenkohlenwasserstoffe. Süddeutsche Apotheker-Zeitung 1947, 87, 62. [Google Scholar]
  14. Norris E. J.; Demares F.; Zhu X.; Bloomquist J. R. Mosquitocidal activity of p,p’-difluoro-diphenyl-trichloroethane (DFDT). Pestic. Biochem. Physiol. 2020, 170, 104686. 10.1016/j.pestbp.2020.104686. [DOI] [PubMed] [Google Scholar]
  15. World Health Organization . Prequalified lists: vector control product. WHO, 2020. https://www.who.int/pq-vector-control/prequalified-lists/en/ (accessed Feb 23, 2021).
  16. Scott J. G.; Georghiou G. P. Influence of temperature on knockdown, toxicity, and resistance to pyrethroids in the house fly Musca domestica. Pest. Biochem. Phys. 1984, 21, 53–62. 10.1016/0048-3575(84)90073-7. [DOI] [Google Scholar]
  17. Yang J.; Hu C. T.; Zhu X.; Zhu Q.; Ward M. D.; Kahr B. DDT polymorphism and the lethality of crystal forms. Angew. Chem., Int. Ed. 2017, 56, 10165–10169. 10.1002/anie.201703028. [DOI] [PubMed] [Google Scholar]
  18. Yang J.; Zhu X.; Hu C. T.; Qiu M.; Zhu Q.; Ward M. D.; Kahr B. Inverse correlation between lethality and thermodynamic stability of contact insecticide polymorphs. Cryst. Growth Des. 2019, 19, 1839–1844. 10.1021/acs.cgd.8b01800. [DOI] [Google Scholar]
  19. Yang J.; Erriah B.; Hu C. T.; Reiter E.; Zhu X.; López-Mejías V.; Carmona-Sepúlveda I. P.; Ward M. D.; Kahr B. A deltamethrin crystal polymorph for more effective malaria control. Proc. Natl. Acad. Sci. U. S. A. 2020, 117, 26633–26638. 10.1073/pnas.2013390117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Zhu X.; Hu C. T.; Erriah B.; Vogt-Maranto L.; Yang J.; Yang Y.; Qiu M.; Fellah N.; Tuckerman M. E.; Ward M. D.; Kahr B. Imidacloprid crystal polymorphs for improved control of disease vectors and pollinator protection. J. Am. Chem. Soc. 2021, 143, 17144–17152. 10.1021/jacs.1c07610. [DOI] [PubMed] [Google Scholar]
  21. Carson J.; Erriah B.; Herodotou S.; Shtukenberg A. G.; Smith L.; Ryazanskaya S.; Ward M. D.; Kahr B.; Lees R. S. Overcoming insecticide resistance in Anopheles mosquitoes by using faster-acting solid forms of deltamethrin. Malaria J. 2023, 22, 129. 10.1186/s12936-023-04554-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. World Health Organization World malaria report; WHO: Geneva, 2022. Licence: CC BY-NC-SA 3.0 IGO.
  23. Tahori A. Diaryl-trifluoromethylcarbinols as synergists for DDT against DDT-resistant houseflies. J. Econ. Entomol. 1955, 48, 638–642. 10.1093/jee/48.6.638. [DOI] [Google Scholar]
  24. Hennessy D. J.; Fratantoni J.; Hartigan J.; Moorefield H. H.; Weiden M. H. J. Toxicity of 2-(2-halo-4-chlorophenyl)-2-(4-chlorophenyl)-1,1,1-trichloroethanes to resistant houseflies. Nature 1961, 190, 341. 10.1038/190341a0. [DOI] [PubMed] [Google Scholar]
  25. Perryman M. S.; Harris M. E.; Foster J. L.; Joshi A.; Clarkson G. J.; Fox D. J. Trichloromethyl ketones: asymmetric transfer hydrogenation and subsequent Jocic-type reactions with amines. ChemComm 2013, 49, 10022–10024. 10.1039/c3cc46070c. [DOI] [PubMed] [Google Scholar]
  26. Cantillana T.; Sundstrom M.; Bergman A. Synthesis of 2-(4- chlorophenyl)-2-(4-chloro-3-thiophenol)-1,1-dichloroethene (3-SH-DDE) via Newman-Kwart rearrangement-a precursor for synthesis of radiolabeled and unlabeled alkylsulfonyl-DDEs. Chemosphere 2009, 76, 805–810. 10.1016/j.chemosphere.2009.04.042. [DOI] [PubMed] [Google Scholar]
  27. Browning H. C.; Fraser F. C.; Shapiro S. K.; Glickman I.; Dubrule M. The biological activity of DDT and related compounds. Can. J. Res. 1948, 26D, 282–300. 10.1139/cjr48d-021. [DOI] [PubMed] [Google Scholar]
  28. Schneider D. Using Drosophila as a model insect. Nat. Rev. Genet. 2000, 1, 218–226. 10.1038/35042080. [DOI] [PubMed] [Google Scholar]
  29. Casida J. E. Michael Elliott’s billion dollar crystals and other discoveries in insecticide chemistry. Pest Manage. Sci. 2010, 66, 1163–1170. 10.1002/ps.1982. [DOI] [PubMed] [Google Scholar]
  30. Lozano-Fuentes S.; Saavedra-Rodriguez K.; Black W. C.; Eisen L. QCal: A software application for the calculation of dose-response curves in insecticide resistance bioassays. J. Am. Mosq. Control Assoc. 2012, 28, 59–61. 10.2987/11-6192.1. [DOI] [PubMed] [Google Scholar]
  31. Kesisoglou F.; Wu Y. Understanding the effect of API properties on bioavailability. Through absorption modeling. AAPS J. 2008, 10, 516–525. 10.1208/s12248-008-9061-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Liu W.; Gan J.; Schlenk D.; Jury W. A. Enantioselectivity in environmental safety of current chiral insecticides. Proc. Natl. Acad. Sci. U. S. A. 2005, 102, 701–706. 10.1073/pnas.0408847102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Jeschke P. Progress of modern agricultural chemistry and future prospects. Pest Manage. Sci. 2016, 72, 433–455. 10.1002/ps.4190. [DOI] [PubMed] [Google Scholar]
  34. Jacques J.; Collet A.; Wilen S. H.. Enantiomers, Racemates, and Resolutions; Krieger Publishing Co.: Malabar, FL, 1994. [Google Scholar]
  35. Linderman R. J.; Graves D. M. An efficient procedure for the oxidation of fluorinated carbinols. Tetrahedron Lett. 1987, 28, 4259–4262. 10.1016/S0040-4039(00)96479-7. [DOI] [Google Scholar]
  36. Lebel H.; Piras H.; Bartholomeüs J. Rhodium-catalyzed stereoselective amination of thioethers with N-mesyloxycarbamates: DMAP and bis(DMAP)CH2Cl2 as key additives. Angew. Chem., Int. Ed. 2014, 53, 7300–7304. 10.1002/anie.201402961. [DOI] [PubMed] [Google Scholar]
  37. Smith L. B.; Kasai S.; Scott J. G. Voltage-sensitive sodium channel mutations S989P+ V1016G in Aedes aegypti confer variable resistance to pyrethroids, DDT and oxadiazines. Pest. Manag. Sci. 2018, 74, 737–745. 10.1002/ps.4771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Reid W. R.; Thornton A.; Pridgeon J. W.; Becnel J. J.; Tang F.; Estep A.; Clark G. G.; Allan S.; Liu N. Transcriptional analysis of four family 4 P450s in a Puerto Rico strain of Aedes aegypti (Diptera: Culicidae) compared with an Orlando strain and their possible functional roles in permethrin resistance. J. Med. Entomol. 2014, 51, 605–615. 10.1603/ME13228. [DOI] [PubMed] [Google Scholar]
  39. Pinch M.; Rodriguez S. D.; Mitra S.; Kandel Y.; Moore E.; Hansen I. A. Low levels of pyrethroid resistance in hybrid offspring of a highly resistant and a more susceptible mosquito strain. J. Insect Sci. 2020, 20, 1. 10.1093/jisesa/ieaa060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Sawicki R. M. Unusual response of DDT-resistant houseflies to carbinol analogues of DDT. Nature 1978, 275, 443–444. 10.1038/275443a0. [DOI] [PubMed] [Google Scholar]
  41. Soderlund D. M.; Adams P. M. Inhibition of octopamine-stimulated adenylate cyclase activity in two-spotted mites by dicofol and related diphenylcarbinol acaricides. Pest. Biochem. Phys. 1993, 46, 228–225. 10.1006/pest.1993.1054. [DOI] [Google Scholar]
  42. Liu F.; Wang Q.; Xu P.; Andreazza F.; Valbon W. R.; Bandason E.; Chen M.; Yan R.; Feng B.; Smith L. B.; Scott J. G.; Takamatsu G.; Ihara M.; Matsuda K.; Klimavicz J.; Coats J.; Oliveira E. E.; Du Y.; Dong K. A dual-target molecular mechanism of pyrethrum repellency against mosquitoes. Nat. Commun. 2021, 12, 2553. 10.1038/s41467-021-22847-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Andreazza F.; Valbon W. R.; Wang Q.; Liu F.; Xu P.; Bandason E.; Chen M.; Wu S.; Smith L. B.; Scott J. G.; Jiang Y.; Jiang D.; Zhang A.; Oliveira E. E.; Dong K. Sodium channel activation underlies transfluthrin repellency in Aedes Aegypti. PloS Negl. Trop. Dis. 2021, 15, e0009546 10.1371/journal.pntd.0009546. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Valbon W.; Andreazza F.; Oliveira E. E.; Liu F.; Feng B.; Hall M.; Klimavicz J.; Coats J. R.; Dong K. Bioallethrin activates specific olfactory sensory neurons and elicits spatial repellency in Aedes aegypti. Pest. Manag. Sci. 2022, 78, 438–445. 10.1002/ps.6682. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. DeGennaro M.; McBride C. S.; Seeholzer L.; Nakagawa T.; Dennis E. J.; Goldman C.; Jasinskiene N.; James A. A.; Vosshall L. B. orco mutant mosquitoes lose strong preference for humans and are not repelled by volatile DEET. Nature 2013, 498, 487–491. 10.1038/nature12206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Liu F.; Wang Q.; Xu P.; Andreazza F.; Valbon W. R.; Bandason E.; Chen M.; Yan R.; Feng B.; Smith L. B.; Scott J. G.; et al. A dual-target molecular mechanism of pyrethrum repellency against mosquitoes. Nat. Commun. 2021, 12, 2553. 10.1038/s41467-021-22847-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Andreazza F.; Valbon W. R.; Wang Q.; Liu F.; Xu P.; Bandason E.; Chen M.; Wu S.; Smith L. B.; Scott J. G.; Jiang Y.; et al. Sodium channel activation underlies transfluthrin repellency in Aedes Aegypti. PloS Negl. Trop. Dis. 2021, 15, e0009546 10.1371/journal.pntd.0009546. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Andreazza F.; Valbon W.; Dong K. Transfluthrin enhances odorant receptor-mediated spatial repellency in Aedes aegypti. Pestic. Biochem. Phys. 2023, 192, 105387. 10.1016/j.pestbp.2023.105387. [DOI] [PubMed] [Google Scholar]
  49. Valbon W.; Andreazza F.; Oliveira E. E.; Liu F.; Feng B.; Hall M.; Klimavicz J.; Coats J. R.; Dong K. Bioallethrin activates specific olfactory sensory neurons and elicits spatial repellency in Aedes aegypti. Pest. Manag. Sci. 2022, 78, 438–445. 10.1002/ps.6682. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Organisation for Economic Co-operation and Development . Guidance Document on Acute Oral Toxicity Testing; OECD Publishing: Paris, 2002. [Google Scholar]
  51. Organisation for Economic Co-operation and Development . Harmonised Integrated Classification System for Human Health and Environmental Hazards of Chemical Substances and Mixtures; OECD Publishing: Paris, 2002. [Google Scholar]
  52. Turner J. A.; Ruscoe C. N. E.; Perrior T. R. Discovery to development: insecticides for malaria vector control. Chimia 2016, 70, 684–693. 10.2533/chimia.2016.684. [DOI] [PubMed] [Google Scholar]
  53. Kasai S.; Komagata O.; Itokawa K.; Shono T.; Ng L. C.; Kobayashi M.; Tomita K. Mechanisms of pyrethroid resistance in the dengue mosquito vector, Aedes aegypti: target site insensitivity, penetration, and metabolism. PLoS Negl. Trop. Dis. 2014, 8, e2948 10.1371/journal.pntd.0002948. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Tan J.; Liu Z.; Tsai T.-D.; Valles S. M.; Goldin A. L.; Dong K. Novel sodium channel gene mutations in Blattella Germanica reduce the sensitivity of expressed channels to deltamethrin. Insect Biochem. Mol. Biol. 2002, 32, 445–454. 10.1016/S0965-1748(01)00122-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Tatebayashi H.; Narahashi T. Differential mechanism of action of the pyrethroid tetramethrin on tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels. J. Pharmacol. Exp. Ther. 1994, 270, 595–603. [PubMed] [Google Scholar]
  56. Du Y.; Nomura Y.; Satar G.; Hu Z.; Nauen R.; He S. Y.; Zhorov B. S.; Dong K. Molecular evidence for dual pyrethroid-receptor sites on a mosquito sodium channel. Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 11785–11790. 10.1073/pnas.1305118110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Du Y.; Nomura Y.; Zhorov B. S.; Dong K. Evidence for Dual Binding Sites for 1,1,1-Trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) in Insect Sodium Channels. J. Biol. Chem. 2016, 291, 4638–4648. 10.1074/jbc.M115.678672. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

id3c00161_si_001.pdf (5.9MB, pdf)
id3c00161_si_002.cif (245.4KB, cif)
id3c00161_si_003.cif (241.4KB, cif)
id3c00161_si_004.cif (1.4MB, cif)
id3c00161_si_005.cif (705.6KB, cif)
id3c00161_si_006.cif (644.6KB, cif)
id3c00161_si_007.cif (954.1KB, cif)
id3c00161_si_008.cif (947.5KB, cif)
id3c00161_si_009.cif (620.5KB, cif)
id3c00161_si_010.cif (652KB, cif)

Articles from ACS Infectious Diseases are provided here courtesy of American Chemical Society

RESOURCES