Design, Synthesis, and Insecticidal Activity of Isoxazoline Derivatives Incorporating an Acylhydrazine Moiety.

The long-term use of agricultural insecticides has led to the development of resistant strains. In this context, the isoxazoline structure has become an active area of pesticide research owing to its wide insecticidal spectrum, nontoxicity to mammals, and lack of cross-resistance with known insecticides. In the present study, based on the discovery of compound G22 in our previous work, a series of novel isoxazoline compounds containing acylhydrazine were designed and synthesized using a scaffold hopping strategy. The insecticidal activities of the target compounds were assessed, and compound L17 (LC50 = 0.489 mg/L) showed insecticidal activity against Spodoptera frugiperda superior to those of the commercial insecticides indoxacarb (LC50 = 3.14 mg/L) and fluralaner (LC50 = 0.659 mg/L). Theoretical calculations indicated that the introduction of acylhydrazine plays an important role in the biological activity of the target compounds. Furthermore, the enzyme-linked immunosorbent assay and molecular docking results indicated that L17 may act on the GABA receptor of the target insect. These results indicated that L17 is a potential candidate compound for controlling S. frugiperda populations in agriculture.

Fecal elimination of fluralaner in different carnivore species after oral administration.

Fluralaner is a recent external parasiticide, first of a new class of drugs (isoxazoline parasiticides). It is widely used in companion animals both for its wide spectrum (fleas, ticks and other mites) but also for its ease of use (oral tablets given once for 1 to three months). It is known to be eliminated primarily via the feces (>90%) as the unchanged compound. In zoo carnivores, controlling external parasites is also important and there are no specific products with a marketing authorization to control them. The first objective of this study was to evaluate the pharmacokinetic profile of fluralaner in zoo carnivores. The second objective was to demonstrate that fluralaner can be eliminated over a prolonged period of time, thereby raising questions about its potential impact on non-target species such as arthropods. After adjusting the oral dose using allometric equations, animals were dosed and fecal samples were collected on a regular basis for up to three months to determine the fecal elimination curve of fluralaner as a surrogate of plasma kinetics (for ethical and safety reasons, plasma samples were not considered). All samples were analyzed with a validated LC-MSMS technique. Our results show that, despite limitations and a limited number of animals included, most carnivores eliminate fluralaner in their feces for several weeks to months (in Lions, fluralaner was still detectable after 89 days). To our knowledge, this is the first study demonstrating such a long elimination period in animals. Further studies would be required to investigate the risk associated with the presence of active residues in other carnivore feces for the environment, especially in dogs and cats, considering the large use of this class of compounds.

Design, synthesis, and evaluation of novel isoxazoline derivatives containing 2-phenyloxazoline moieties as potential insecticides.

Isoxazoline insecticides have shown broad-spectrum insecticidal activity against a variety of insect pests. However, the high toxicity of isoxazoline compounds towards honeybees restricts their application in crop protection. To mitigate this issue, a series of isoxazoline derivatives containing 2-phenyloxazoline were designed and synthesized. Bioassays revealed that several compounds exhibited promising insecticidal activities against Plutella xylostella, with G28 showing particularly excellent insecticidal activity, reflected by an LC50 value of 0.675 mg/L, which is comparable to that of fluxametamide (LC50 = 0.593 mg/L). Furthermore, G28 also exhibited effective insecticidal activity against Solenopsis invicta. Importantly, bee toxicity experiments indicated that G28 had significantly lower acute oral toxicity (LD50 = 2.866 µg/adult) compared to fluxametamide (LD50 = 1.083 µg/adult) and fluralaner (LD50 = 0.022 µg/adult), positioning it as a promising candidate with reduced toxicity to bees. Theoretical simulation further elucidated the reasons for the selective differences in the ability of isoxazoline to achieve higher insecticidal activity while maintaining lower bee toxicity. This research suggests that isoxazoline compounds containing 2-phenyloxazoline group hold potential as new insecticide candidates and offers insights into the development of novel isoxazoline insecticides with both high efficacy and environmental safety.

Efficacy and innocuity of lotilaner in the treatment of otodectic mange in ferrets.

Otodectes cynotis is a contagious ear mite generally responsible of a parasitic otitis. This prospective study evaluates the efficacy, safety and impact on quality of life (QoL) of oral lotilaner for the treatment of Otodectes infestation in ferrets. Ferrets of weight greater than 500 g, with Otodectes mites confirmed on ear swabs examination and that did not receive an acaricidal treatment in the previous two weeks were included. Oral lotilaner (Credelio 12 mg, ELANCO FRANCE, Sèvres, France) was administered at inclusion day (D0) and 28 days later (D28). Parasitic counts and clinical examination were performed at D0, D28 and D56. A QoL and owner satisfaction questionnaire was given at D0 and D56. Statistical analysis was performed with Shapiro-Wilk test for normality and Wilcoxon test for mean comparison (significance: p<0.05). Eleven ferrets were included, two were asymptomatic. Mean weight was 1.2 kg (0.68-2.66). Mean lotilaner dose was 12.3 mg/kg (9-17.6). Mean eggs, adults or nymphs, larvae, and fragments counts were 30.4 (3-104), 11.2 (1-61), 5.4 (0-36), 3.5 (1-7) respectively at D0; 0, 0, 0.1 (0-1), 0.5 (0-3) respectively at D28; 0, 0, 0, 0.14 (0-1) respectively at D56. Differences were statistically significant from baseline in all cases (p<0.05). Pruritus was absent in all cases at D56. No adverse effects were reported. All owners were "completely satisfied" with the treatment. Mean impact of the disease on QoL was 4.5/18 (SD=4.15) at D0 and 0 at D56 (significant difference, p<0.05). Oral lotilaner appears as a safe, efficient, easy to use and satisfactory treatment of Otodectes cynotis infestation in ferrets.

Successful yeast microencapsulation of fluralaner and its potential as a larvicide for vector control.

Fly control for any species is most effectively implemented in the immature stages when insects can be eliminated before emerging as adults capable of transmitting pathogens or becoming nuisance pests. Yet a limited number of insecticide classes are available for treating larval development sites for dipteran pest species. The most recently introduced class of insecticides in the United States (US) is the isoxazolines, including fluralaner. In the US, fluralaner is currently exclusively labeled for use against ectoparasites in companion animals. However, research has shown that it has a wider effective target range beyond ectoparasites and could be developed as an insecticide for vector control. Here we tested a novel, proprietary, yeast microencapsulated (YME) formulation of fluralaner against the larvae of three pest species: Musca domestica L. (Diptera: Muscidae), Aedes albopictus Skuse (Diptera: Culicidae), and Culicoides sonorensis Wirth and Jones (Diptera: Ceratopogonidae). These species all naturally consume microorganisms as larvae, including yeasts. Fluralaner was successfully microencapsulated in Saccharomyces cerevisiae yeast. YME fluralaner was reconstituted in water at concentrations of 0.00001-0.1 mg/mL (Aedes and Culicoides) or 1-50 mg/mL (Musca) for use in dose-response assays. For each species, the LC50 at 24 h was estimated using probit analyses. YME fluralaner was highly effective against all species tested (Ae. albopictus LC50 = 0.000077 mg/mL; C. sonorensis LC50 = 0.00067 mg/mL; M. domestica LC50 = 2.58 mg/mL). Additionally, laboratory assays were conducted to determine product reapplication rates using LC50 rates. Reapplication rates to maintain <50 % emergence were five weeks (Ae. albopictus) and greater than eight weeks (C. sonorensis). The results presented here indicate YME fluralaner is a promising candidate for controlling larval insects that naturally feed on detritus, thereby bypassing cuticular penetration barriers and safely delivering the active ingredient to the target species.

The weather determined how 'hot' the tick paralysis season was in eastern Australia: 2018-2024.

The eastern paralysis tick, Ixodes holocyclus, is a tick of much veterinary importance in Australia. Each year, thousands of dogs and cats present to veterinary clinics and hospitals with signs of tick paralysis. In a previous paper, we constructed two models to explain prevalence and temporal distributions of tick paralysis cases presenting to emergency veterinary hospitals in South East Queensland (2009-2020) and the Northern Beaches of Sydney (1999-2017). The first model accounted for the intensity of the clinical burden of tick paralysis based on the prevalence of cases of tick paralysis in the tick paralysis season whereas the second model accounted for the start of the tick paralysis season. In the present paper, we test our models further, with much additional data from 2021 to 2023 (South East Queensland) and from 2018 to 2023 (Northern Beaches of Sydney). During the defined tick paralysis season in these locations, 10.3 % (3207 of 31,217) of veterinary-consultations were for tick paralysis. On average, predictions for the prevalence of cases of tick paralysis were 1.3 % (0.013) away from the actual prevalence whereas predictions for the start of the tick paralysis season were 1.7 weeks away from the actual start of the season. The prediction of the prevalence of tick paralysis cases was most accurate for Brisbane and least accurate for the Northern Beaches of Sydney whereas, curiously, the prediction for the start of the tick paralysis season was most accurate for the Northern Beaches of Sydney and least accurate for Brisbane. We re-fitted the models with the new data. We predict that about 10 % (Sunshine Coast), 5 % (Brisbane), 7 % (Gold Coast) and 12 % (Northern Beaches of Sydney) of veterinary-consultations in the tick paralysis season of 2024 will be cases of tick paralysis, resulting in a tick paralysis clinical burden intensity of similar magnitude to previous years. Such predictions allow for timely public education campaigns around the importance of prevention and appropriate resource planning for veterinary clinics.

Synthesis and In Silico Analysis of New Polyheterocyclic Molecules Derived from [1,4]-Benzoxazin-3-one and Their Inhibitory Effect against Pancreatic α-Amylase and Intestinal α-Glucosidase.

This study focuses on synthesizing a new series of isoxazolinyl-1,2,3-triazolyl-[1,4]-benzoxazin-3-one derivatives 5a-5o. The synthesis method involves a double 1,3-dipolar cycloaddition reaction following a "click chemistry" approach, starting from the respective [1,4]-benzoxazin-3-ones. Additionally, the study aims to evaluate the antidiabetic potential of these newly synthesized compounds through in silico methods. This synthesis approach allows for the combination of three heterocyclic components: [1,4]-benzoxazin-3-one, 1,2,3-triazole, and isoxazoline, known for their diverse biological activities. The synthesis procedure involved a two-step process. Firstly, a 1,3-dipolar cycloaddition reaction was performed involving the propargylic moiety linked to the [1,4]-benzoxazin-3-one and the allylic azide. Secondly, a second cycloaddition reaction was conducted using the product from the first step, containing the allylic part and an oxime. The synthesized compounds were thoroughly characterized using spectroscopic methods, including 1H NMR, 13C NMR, DEPT-135, and IR. This molecular docking method revealed a promising antidiabetic potential of the synthesized compounds, particularly against two key diabetes-related enzymes: pancreatic α-amylase, with the two synthetic molecules 5a and 5o showing the highest affinity values of 9.2 and 9.1 kcal/mol, respectively, and intestinal α-glucosidase, with the two synthetic molecules 5n and 5e showing the highest affinity values of -9.9 and -9.6 kcal/mol, respectively. Indeed, the synthesized compounds have shown significant potential as antidiabetic agents, as indicated by molecular docking studies against the enzymes α-amylase and α-glucosidase. Additionally, ADME analyses have revealed that all the synthetic compounds examined in our study demonstrate high intestinal absorption, meet Lipinski's criteria, and fall within the required range for oral bioavailability, indicating their potential suitability for oral drug development.

Recent Research Progress in Oxime Insecticides and Perspectives for the Future.

In recent decades, the unique structural attributes and purported insecticidal properties of oximes have garnered increasing attention. A variety of insecticides, encompassing fluxametamide, fluhexafon, and lepimectin, have been synthesized, all of which incorporate oximes. This review endeavors to encapsulate the insecticidal efficacy, structure-activity correlations, and operative mechanisms of oxime-containing compounds. Furthermore, it delves into the conceptual frameworks underpinning the design of innovative oxime-based insecticides, thereby shedding light on prospective advancements in this field.

Novel aza-bicyclic 2-isoxazoline acylhydrazone hybrids and their synergistic potential with fluconazole against a drug-resistant Candida albicans strain.

As the prevalence of drug-resistant Candida isolates continues to rise, the imperative for identifying novel compounds to enhance the arsenal of antifungal drugs becomes increasingly critical. Consequently, exploring new treatment strategies, including synthesizing molecular hybrids and applying combination therapy, is essential. For this reason, this study evaluated the efficacy of ten molecular hybrids of aza-bicyclic 2-isoxazoline-acylhydrazone belonging to two series 90 and 91 as possible anti-Candida agents. In addition, we also investigated the interaction between the hybrids and fluconazole, a commonly used antifungal drug. We evaluated the antifungal effect of aza-bicyclic 2-isoxazoline-acylhydrazone hybrid compounds against six Candida spp. strains that target planktonic cells. However, none of these new molecules were inhibitory active at the tested concentrations (2 to 1,024 µg/mL). Moreover, we analyzed the interaction between the ten new hybrid molecules and fluconazole using the checkerboard assay, employing two different methodologies for reading the plate. For this, one isolate fluconazole-resistant was selected. We observed that only one combination, 6-(4-tert-butylbenzoil)-4,5,6,6a-tetrahydro-3a-H-pirrole[3,2-d]isoxazole-3-carboxylic(furan-2-metilidene)-hydrazide (91e) and fluconazole, exhibited a synergistic interaction (FICI range 0.0781 to 0.4739). The combination successfully inhibited the growth of C. albicans CA2 fluconazole-resistant, and no interaction was observed in an isolate susceptible to fluconazole. Additionally, these results emphasize the continued need for research into new compounds and the importance of using combined approaches to increase their activity.

Control of Rhipicephalus microplus on taurine cattle with fluralaner in a subtropical region.

BACKGROUND: In Rio Grande do Sul, Brazil, a region with a subtropical climate, Rhipicephalus microplus is present in taurine cattle raised for beef and milk. In addition, ticks resistant to multiple acaricides are present in this region. Recently, fluralaner (isoxazoline) was launched on the market. Thus, there is a need to evaluate the effects of fluralaner for the control of R. microplus on taurine cattle. In addition, occurrence of myiasis by Cochliomyia hominivorax larvae after tick parasitism and weight gain of cattle during the experimental period were evaluated. METHODS: Thirty naturally infested cattle were divided into two experimental groups: T01, treated with fluralaner (2.5 mg/kg) pour-on; T02, control. T01 received fluralaner on Days 0 (early summer in January), 42 and 84 (early autumn), whereas T02, a control group, received palliative treatment with a spray formulation when the group mean was ≥ 30 ticks. Counts of R. microplus females and calculation of the efficacy of fluralaner were performed on Days 3, 7, 14, 28, 35, 42, 56, 70, 84, 98, 112 and 126. The occurrence of myiasis was assessed throughout the study period. In addition, the weight, weight gain and daily weight gain of the animals were evaluated. RESULTS: In the 12 evaluations performed, the parasitic load of T01 was near zero. Fluralaner showed 99.5% efficacy on the 3rd day after the first treatment and 100% efficacy from Day 7 to Day 126. Cochliomyia hominivorax larvae (n = 6; p = 0.0251) were found only in the control group (T02). At the end of the study, the animals subjected to treatments with fluralaner gained 32.8 kg more than the animals in the control group. CONCLUSIONS: Application of fluralaner in summer and autumn, with 42-day intervals between treatments, was effective to control R. microplus on taurine cattle, which also gained more weight than control cattle. Additionally, no cases of myasis were documented in animals treated with fluralaner.

Enzootic stability of tick fever in Holstein calves grazing in a tropical region, subjected to strategic cattle tick control with fluralaner.

BACKGROUND: In 2022, fluralaner was launched on the market for use in the control of the cattle tick Rhipicephalus microplus after showing 100% efficacy in registration trials against the causative agents of cattle tick fever (TFAs). The aim of the present study was to determine whether a strategic control regimen against R. microplus using fluralaner (FLU) in Holstein calves grazing in a tropical region would alter the enzootic stability status of cattle tick fever, triggering outbreaks in these animals up to 22 months age. METHODS: In this study, a group of calves treated with FLU was compared with a control group treated with the regimen currently being used on the farm, which consisted of the fipronil + fluazuron formulation (FIFLUA). In the first experiment, the efficacy of the FIFLUA pour-on formulation was evaluated in a field study. In the second experiment, which lasted 550 days, two experimental groups (n = 30/group) of Holstein calves naturally infested with R. microplus were analyzed. Calves aged 4 to 10 months received either a specific treatment regimen with FLU (experimental group) or FIFLUA (control group). During this period, tick counts, animal weight measurement, feces collection (to determine eggs and oocysts per gram of feces), tick fever monitoring, blood smears (to ascertain enzootic stability of the herd), PCR testing for TFAs and serology (indirect enzyme-linked immunosorbent assay [iELISA]) were performed. All calves were evaluated for signs of tick fever between ages 11 and 22 months. RESULTS: FIFLUA showed an acaricidal efficacy of > 90% from post-treatment days 14 to 35. Regarding treatments against the TFAs, the average number of treatments was similar between groups, but animals treated with FLU had a smaller reduction in packed cell volume on some of the evaluation dates of the second and third treatment against TFAs. In calves aged 10 months in the FLU group, B. bovis was not detected by PCR (0/15 samples), 40% of the samples had antibody titers and 33% (10/30) of the samples had positive blood smears. Regarding B. bigemina, > 86% of the samples in both groups tested positive for B. bigemina DNA and antibodies; there was no difference in the antibody titers between the groups. There were no clinical cases of cattle tick fever in calves aged 11 to 22 months. CONCLUSIONS: In comparison with the control treatment, the strategic control regimen against R. microplus with FLU that was implemented in the present study did not negatively affect the enzootic stability status of A. marginale and B. bigemina in the herd up to 22 months of age. The enzootic stability status of B. bovis was not reached by either group. These results likely represent a characteristic of the local tick population, so further studies should be performed.

tert-Butyl Nitrite-Induced Radical Nitrile Oxidation Cycloaddition: Synthesis of Isoxazole/Isoxazoline-Fused Benzo 6/7/8-membered Oxacyclic Ketones.

A practical metal-free and additive-free approach for the synthesis of 6/7/8-membered oxacyclic ketone-fused isoxazoles/isoxazolines tetracyclic or tricyclic structures is reported through Csp3-H bond radical nitrile oxidation and the intramolecular cycloaddition of alkenyl/alkynyl-substituted aryl methyl ketones. This convenient approach enables the simultaneous formation of isoxazole/isoxazoline and 6/7/8-membered oxacyclic ketones to form polycyclic architectures by using tert-butyl nitrite (TBN) as a non-metallic radical initiator and N-O fragment donor.

Use of sarolaner in the treatment of tungiasis in naturally infested dogs.

Tungiasis is an endemic dermatological parasitic zoonosis in Latin America, caused by the sand flea Tunga spp. (Siphonaptera, Tungidae), which promotes intense discomfort, swelling, erythema, itching, pain, secondary bacterial infection, cellulitis and necrosis. Sarolaner has been used to control different ectoparasites, but there is no record of its use for the treatment of tungiasis in dogs. The objective of this study was to evaluate the effectiveness of sarolaner for the treatment dogs naturally infested by Tunga spp. kept in the same infested environment. Three of four animals were medicated with sarolaner orally with a single dose of 2 mg/kg, as recommended by the manufacturer, and one animal remained without medication. After 24 hours, the fleas from all four dogs were mechanically removed. The animals were reevaluated on days +15 and +30 to assess possible reinfestation. The medicated animals remained free of fleas, while the untreated animal had fleas on the days previously defined for reevaluation. We can thus conclude that the use of sarolaner is an effective choice for tungiasis treatment.

Tungíase é uma zoonose parasitária dermatológica endêmica na América Latina, causada pela pulga da areia Tunga spp. (Siphonaptera, Tungidae), que promove intenso desconforto, edema, eritema, prurido, dor, infecção bacteriana secundária, celulite e necrose. Sarolaner tem sido utilizado no controle de diversos ectoparasitas, mas não existem registros de seu uso no tratamento de tungíase em cães. O objetivo deste estudo foi avaliar a eficácia do sarolaner no tratamento de cães naturalmente infestados por Tunga spp. mantidos no mesmo ambiente infestado. Três dos quatro animais foram medicados com sarolaner por via oral em dose única de 2 mg/kg, conforme recomendação do fabricante, e um animal permaneceu sem medicação. Após 24 horas, as pulgas dos quatro cães foram removidas mecanicamente. Os animais foram reavaliados nos dias +15 e +30 para avaliar uma possível reinfestação. Os animais medicados permaneceram livres de pulgas, enquanto o animal não tratado apresentou pulgas nos dias previamente definidos para reavaliação. Podemos assim concluir que o uso do sarolaner é uma escolha eficaz para o tratamento da tungíase.

Construction and Single-Crystal Structures of N-Isoxazolin-5-ylcarbonylindole Derivatives, and Their Pesticidal Activities and Toxicology Study.

To explore natural product-based pesticide candidates, a series of indole derivatives containing the isoxazoline skeleton at the N-1 position were synthesized by 1,3-dipolar [2 + 3] cycloaddition reaction. Their structures were characterized by melting points (mp), infrared (IR) spectra, proton nuclear magnetic resonance spectra (1H NMR), carbon-13 nuclear magnetic resonance spectra (13C NMR), and high resolution mass spectrometry (HRMS). The single-crystal structures of five compounds were presented. Against Tetranychus cinnabarinus Boisduval, compound 3b showed greater than 3.8-fold acaricidal activity of indole and good control effects under glasshouse conditions. Against Aphis citricola Van der Goot, compounds 3b and 3q exhibited 48.3- and 36.8-fold aphicidal activity of indole and 6-methylindole, respectively. Particularly, compound 3b showed good bioactivities against T. cinnabarinus and A. citricola. Against Eriosoma lanigerum Hausmann, compound 3h and 3i showed 2.1 and 1.9 times higher aphicidal activity compared to indole. Furthermore, the construction of the epidermal cuticle layer of 3b-treated carmine spider mites was distinctly damaged, which ultimately led to their death.

Putative pemphigus-like reaction to oral fluralaner in a dog.

A 9-month-old mixed-breed dog developed generalised pustular dermatitis, accompanied by lethargy and hyperthermia, 7 days after oral fluralaner administration. Dermatopathological and microbiological evaluations were consistent with a pustular acantholytic dermatitis. A 4-month course of immunosuppressive therapy resulted in complete remission of lesions, which did not recur after therapy was withdrawn.

Un chien croisé âgé de 9 mois a développé une dermatite pustuleuse généralisée, accompagnée de léthargie et d'hyperthermie, 7 jours après l'administration orale de fluralaner. Les évaluations dermatopathologiques et microbiologiques sont compatibles avec une dermatite acantholytique pustuleuse. Un traitement immunosuppresseur de 4 mois induit une rémission complète des lésions, qui n'ont pas récidivé après l'arrêt du traitement.

Um cão mestiço de nove meses de idade desenvolveu uma dermatite pustular generalizada, acompanhada de letargia e hipertermia, 7 dias após administração de fluralaner. As avaliações dermatohistopatológicas e microbiológicas foram consistentes com uma dermatite pustular acantolítica. Um curso de quatro meses com terapia imunossupressiva resultou em remissão completa das lesões, que não recidivaram após o fim do tratamento.

Un perro mestizo de 9 meses desarrolló dermatitis pustulosa generalizada, acompañada de letargo e hipertermia, 7 días después de la administración oral de fluralaner. Las evaluaciones dermatopatológicas y microbiológicas fueron compatibles con una dermatitis pustulosa acantolítica. Un tratamiento inmunosupresor de 4 meses dio como resultado la remisión completa de las lesiones, que no reaparecieron después de retirar el tratamiento.

Efficacy and Safety of Lotilaner Ophthalmic Solution 0.25% in the Treatment of Demodex Blepharitis: A Systematic Review and Meta-Analysis.

PURPOSE: To evaluate the safety and efficacy of Lotilaner ophthalmic solution 0.25% in the treatment of demodex blepharitis. METHODS: PubMed, Web of Science, Scopus, and Embase databases were searched. RCTs comparing lotilaner with placebo or any other standard treatments were included. Outcomes of mean collarette grade (MCG), mite density (Md), meaningful collarette reduction (MCR), mite eradication (ME), were pooled as mean difference (MD), and the outcomes of erythema cure (EC), collarette cure (CC) adverse events (AE) as risk ratio (RR) with their 95% confidence interval (CI) between the two groups from baseline to the endpoint. Review Manager (Version 5.4.1) software was used to conduct all statistical analyses. RESULTS: Four RCTs (947 patients) were included in this study. The overall effect favored the lotilaner group in terms of mean collarette grade upper lid (MD -0.99, 95% CI [-1.26, -0.72]), MCG lower lid (MD -0.57, 95% CI [-1.03, -0.11]), Md (MD -1.13, 95% CI [-1.47, -0.79]), MCR (MD 2.07, 95% CI [2.27, 3.21]), ME (MD 3.46, 95% CI [2.96, 4.04]). EC (RR 3.16, 95% CI [2.18 to 4.59]) and CC (RR 4.17, 95% CI [2.97 to 5.85]). No significant difference between the two groups in terms of AE (RR 1.25, 95% CI [0.75 to 2.06]). However, these findings are limited by significant heterogeneity in some of the reported outcomes. CONCLUSIONS: Our findings show that lotilaner might effectively treat Demodex blepharitis. However, further RCTs with larger and more diverse populations are needed to confirm these findings as some outcomes show significant heterogeneity.

Design, synthesis and insecticidal activity of novel Isoxazoline Acylhydrazone compounds.

BACKGROUND: Nowadays, the diamondback moth has ascended to become one of the most formidable pests plaguing cruciferous vegetables. Consequently, the exigency for the development of efficacious pesticide candidates for crop protection has never been more paramount. In response to this pressing need, this study presents a compendium of novel isoxazoline derivatives, incorporating acylhydrazone moieties, synthesized with the express purpose of serving as potential insecticides. RESULTS: The structures of these derivatives were confirmed using Proton nuclear magnetic resonance (1 H NMR), Carbon-13 nuclear magnetic resonance (13 C NMR), and high-resolution mass spectrometry (HR-MS). Most of these derivatives demonstrated effective insecticidal activities against Plutella xylostella. Notably, compound E3 exhibited exceptional insecticidal activity against Plutella xylostella (LC50 = 0.19 mg L-1 ), surpassing the effectiveness of ethiprole (LC50 = 3.28 mg L-1 ), and comparable to that of fluxametamide (LC50 = 0.22 mg L-1 ). Interestingly, compound E3 also displayed potent insecticidal activity against Pyrausta nubilalis (LC50 = 0.182 mg L-1 ) and Chilo suppressalis (LC50 = 0.64 mg L-1 ), and the LC50 values of fluxametamide were 0.23 mg L-1 (P. nubilalis) and 2.26 mg L-1 (C. suppressalis), respectively. The molecular docking results revealed that the compound E3 can form a hydrogen bond and two Pi-Pi bonds with the active sites of GABA receptors. In addition, the DFT calculations were also performed to study the relationship between insecticidal activities. The structure-activity relationships suggested that the identity of the R substituent was crucial for their pesticidal activities. CONCLUSION: The results of the present study suggest that isoxazoline acylhydrazone derivatives could be promising candidates against P. xylostella and other Lepidopteran pests. © 2023 Society of Chemical Industry.

Comparison of the initial and residual speed of Ixodes scapularis kill on dogs treated with a single dose of Bravecto® Chew (25 mg/kg fluralaner) or Simparica TRIO® (1.2 mg/kg sarolaner, 24 µg/kg moxidectin, 5 mg/kg pyrantel).

BACKGROUND: Compliant ectoparasiticide product use is a comprehensive way to control ticks and reduce the risk of tick-borne pathogen transmission to dogs. Because the systemically acting isoxazoline ectoparasiticides require tick attachment for drug delivery, fast speed of kill is essential to minimize tick-borne pathogen transmission risk. METHODS: Dogs of satisfactory tick-carrying capacity were randomly allocated to treatment groups and administered, per label instructions, Bravecto® Chews (minimum 25 mg/kg fluralaner), Simparica TRIO® (minimum 1.2 mg/kg sarolaner, 24 µg/kg moxidectin, 5 mg/kg pyrantel), or no treatment. Dogs were infested with approximately 50 unfed adult (35 female, 15 male) Ixodes scapularis on Day -2, 21 and 28. Live tick counts were performed at 4, 8, 12 and 24 h post-treatment (Day 0) and post-infestation on Day 21 and 28. Tick control efficacy was determined by comparing live tick means for each product-treated group to the untreated control group and each other at all time points using a linear mixed model. The percent of dogs free of live ticks was analyzed using the Fisher's exact test for treatment group comparison. RESULTS: The untreated control group maintained adequate tick infestations throughout the study. Using geometric means, an existing I. scapularis infestation was controlled by 99.7% and 93.0% 12 h post-treatment and by 100% and 99.5% 24 h post-treatment, for Bravecto® and Simparica TRIO®-treated dogs, respectively. Ixodes scapularis infestations were controlled more quickly for Bravecto®- compared to Simparica TRIO®-treated dogs on Day 21 at 8 h (efficacy 74.0% vs. 0.0%, p = 0.003) and 12 h (efficacy 99.2% vs. 39.4%, p < 0.001) post-infestation and Day 28 at 8 h (efficacy 92.2% vs. 0.0%, p < 0.001) and 12 h (efficacy 99.6% vs. 27.7%, p < 0.001) post-infestation. On Day 28 post-treatment, the efficacy of Bravecto® and Simparica TRIO® to control a new I. scapularis infestation was 100% and 96.6%, respectively, by 24 h post-infestation. Of product-treated dogs, 100% of Bravecto®-treated dogs were free of live ticks by 24 h post-treatment or post-infestation. No treatment-related adverse reactions occurred during the study. CONCLUSIONS: Ixodes scapularis infestations are controlled more quickly 21 and 28 days post-treatment for dogs administered a single dose of Bravecto® compared to dogs administered a single dose of Simparica TRIO®.

Design, Synthesis, Insecticidal Activity, and SAR of Aryl Isoxazoline Derivatives Containing Pyrazole-5-carboxamide Motif.

It is important to develop new insecticides with a new mode of action because of increasing pesticide resistance. In this study, a series of novel aryl isoxazoline derivatives containing the pyrazole-5-carboxamide motif were designed and synthesized. Their structures were confirmed by 1H NMR, 13C NMR, and HRMS. Bioassays indicated that the 24 compounds synthesized possessed excellent insecticidal activity against Mythimna separate and no activity against Aphis craccivora and Tetranychus cinnabarinus. Among these aryl isoxazoline derivatives, 3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydrozol-3-yl)-N-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxamide (IA-8) had the best insecticidal activity against M. separate, which is comparable with the positive control fluralaner. The molecular docking results of compound IA-8 and fluralaner with the GABA model demonstrated the same docking mode between compound IA-8 and positive control fluralaner in the active site of GABA. Molecular structure comparisons and ADMET analysis can potentially be used to design more active compounds. The structure-activity relationships are also discussed. This work provided an excellent insecticide for further optimization.

Green synthesis and anti-biofilm activities of 3,5-disubstituted isoxazoline/isoxazole-linked secondary sulfonamide derivatives on Pseudomonas aeruginosa.

The search for new classes of antibiotics is a real concern of public health due to the emergence of multi-resistant bacteria strains. We report herein the synthesis and characterization of a new series of 13 molecules combining isoxazoline/isoxazole sulfonamides and hydrazides motives. These molecules were obtained according to a costless eco-friendly procedure, and a one-pot three-step cascade synthesis under ultrasonic cavitation. All the synthesized compounds were fully characterized by HRMS, 1H NMR, 13C NMR spectroscopy and HPLC analysis. These new molecules have been evaluated against the major human opportunistic pathogen Pseudomonas aeruginosa to determine their potential to affect its growth and biofilm formation or dispersion. Two derivatives (5a and 6a) demonstrated their ability to destabilize a mature biofilm by about 50 % within 24 h. This may pave the way to the development of a new class of compounds affecting biofilm, which are easy to synthesize according to green chemistry processes.