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To compare the efficacy of lidocaine administered intravenously, intranasally or as an infraorbital nerve block in dogs undergoing rostral rhinoscopy. Randomized clinical trial. A total of 43 client-owned dogs. After premedication with medetomidine 0.01 mg kg–1 and methadone 0.2 mg kg–1 intramuscularly, anaesthesia was induced with propofol and maintained with isoflurane in oxygen. Dogs were randomly allocated to receive 2 mg kg–1 of 2% lidocaine as a bilateral infraorbital nerve block (INB) via the caudal intraoral approach, via bilateral topical intranasal administration (TIA) or as an intravenous bolus (IVB). At 5 minutes following lidocaine administration, responses to rhinoscopy (RR) and biopsies (RB) were evaluated using a simple scoring system (0: no reaction; 1: reaction). Response to the rhinoscopy in the recovery period (RE) was recorded. Recovery quality was scored using a simple descriptive score. Heart rate, respiratory rate and noninvasive arterial blood pressure were recorded. Intravenous (IV) fentanyl 0.001 mg kg-1 was administered if an increase > 20% in any variable occurred. Gross movement was attenuated using propofol 0.5 mg kg–1 IV. Scores were analysed using the Chi-square test with Monte Carlo method. Cardiorespiratory changes among and overtime between groups were compared using one-way anova and one-way anova for repeated measures, respectively, or the correspondent non-parametric tests; p < 0.05. Of the 43 dogs, 42 completed the study. No statistically significant differences were detected in either physical reactions or changes in cardiorespiratory variables for RR, RB, RE or recovery quality, although RB tended to be higher in group TIA (7/10 versus 1/10 INB and 3/13 IVB).Various cardiorespiratory variables changed overtime within groups. In dogs, all three investigated techniques attenuated responses during rostral rhinoscopy in dogs, although INB and IVB were more efficacious when biopsies were taken. [ABSTRACT FROM AUTHOR]

[Display omitted] • Reaction of enones having a leaving group at the β-position with aryl nitrile oxides. • One-pot 1,3-dipolar cycloaddition at room temperature to give the corresponding isoxazole. • No oxidation treatment is required. A facile synthetic route to isoxazole is reported. Through examination of the reaction of stable nitrile oxides, β-substituted cyclohexenones, particularly sulfinyl and sulfonyl derivatives, show excellent regioselectivity in the 1,3-dipolar cycloaddition, forming isoxazoline cycloadducts, which undergo in-situ 1,2-elimination either with the assistance of a base (for the β-sulfonyl derivative) or without the need for a base (for the β-sulfinyl derivative), enabling a direct, high-yield access to isoxazoles. [ABSTRACT FROM AUTHOR]

• Fluralaner can be successfully microencapsulated in yeast for use as a larvicide, despite its molecular weight approaching the maximum for encapsulation. • The novel larvicide formulation is effective against late stage Musca domestica, Aedes albopictus , and Culicoides sonorensis larvae in laboratory-based dose response assays. • A single application of microencapsulated fluralaner controlled Ae. albopictus for five weeks and C. sonorensis for eight weeks. 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 LC 50 at 24 h was estimated using probit analyses. YME fluralaner was highly effective against all species tested (Ae. albopictus LC 50 = 0.000077 mg/mL; C. sonorensis LC 50 = 0.00067 mg/mL; M. domestica LC 50 = 2.58 mg/mL). Additionally, laboratory assays were conducted to determine product reapplication rates using LC 50 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. [Display omitted] [ABSTRACT FROM AUTHOR]

• Lewis acid assisted carbon–fluorine (C-F) bond cleavage reaction of fluorinated isoxazolines. • Construction of quaternary carbon center by introducing O -, S -, or N -nucleophiles onto isoxazoline ring. • Stabilized carbocation intermediate by the adjacent oxygen atom and/or benzene ring. A substitution reaction of O -, S -, or N -nucleophiles onto fluorinated isoxazolines via carbon–fluorine (C-F) bond cleavage was achieved. The C-F bond at the C5 position of fluorinated isoxazolines was dissociated by using SnCl 4 for the generation of a carbocation intermediate in this reaction. Subsequently, various nucleophiles such as alcohols, thiols, and amines were introduced, enabling the conversion to C O, C-S, or C N bonds and the formation of a new quaternary carbon center. [Display omitted] [ABSTRACT FROM AUTHOR]

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. [Display omitted] • The weather determined how 'hot' the tick paralysis season was in eastern Australia: 2018–2024. • The weather in summer predicted the prevalence of tick paralysis with an error of 1.3 %. • The weather in winter predicted the start of the tick paralysis season with an error of 1.7 weeks. • Predictions for the tick paralysis season of 2024 were made. [ABSTRACT FROM AUTHOR]

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. • Lotilaner treatment achieved a 100 % reduction in Otodectes cynotis mites in ferrets. • Oral lotilaner seems to be safe in ferrets. • Lotilaner is the first oral treatment option for otodectic mange in ferrets. [ABSTRACT FROM AUTHOR]

• A galactosyl isoxazoline has been prepared by phenyl nitrile oxide cycloaddition. • The two diastereomeric isoxazolines have been spontaneously resolved by crystallization. • Conformational behavior of both diastereomers has been studied in solution and the crystalline form. In this study, a glycosyl isoxazoline has been prepared by cycloaddition of phenyl nitrile oxide to 6- O -allyl galactopyranose. Crystallization of the galactosyl isoxazoline resulted in the spontaneous resolution of its two diastereomers. Their conformational behavior has been studied in solution and in crystalline form by NMR and X-ray diffraction analysis showing that both diastereomers have essentially the same O S 2 conformation. To complete the study of the diastereomeric isoxazolines, Density Functional Theory was applied. The theoretical and experimental 1H NMR, as well as 13C NMR chemical shifts, showed very good correlation. Furthermore, structures resulting from X-ray analysis provided excellent starting points for DFT calculations. [Display omitted] Spontaneous resolution of diastereomeric glycosyl isoxazolines: a combined theoretical and experimental study in solution and in the crystalline form. [ABSTRACT FROM AUTHOR]

Antiparasitics acting on endo- or ectoparasites represent the second largest segment of the global animal health market, accounting for 23% of market share. However, relatively few novel antiparasitic agents have been introduced into the market during recent decades. One exception, and a groundbreaking 21st century success story, are the isoxazolines, whose full potential has not yet been entirely explored. Unfortunately, resistance issues are present across most parasitic diseases, which generates a clear market need for novel resistance-breaking antiparasitics with new modes/mechanisms of action. Recent advances in science and technologies strongly suggest that the time is right to invest in new modalities such as parasitic vaccines or in environmentally friendly interventions. Antiparasitics for the treatment of companion animals and livestock is one of the largest global market segments in the animal health industry. Parasitic infections caused by endo- and ectoparasites – the latter also transmitting vector-borne diseases – are among the most significant diseases worldwide, in both animals and humans. Most of the antiparasitic active pharmaceutical ingredients were developed more than 20 years ago. Isoxazolines, which first entered the market in 2014, are one of the very rare exceptions and a true success story. Currently, the four leading animal health companies market four isoxazolines in diverse dog and cat products. Drug and multidrug resistance is increasingly common across all parasites. In livestock, it is a significant and widespread problem. In dogs and cats, drug resistance is as yet less serious. The discovery of novel antiparasitics is of utmost importance to overcome resistance and to fill the development pipeline. [ABSTRACT FROM AUTHOR]

Otodectes cynotis , commonly known as "the ear mite," is a highly contagious ectoparasite and a significant cause of otitis externa in canines. The objective of the current study was to determine the efficacy of the isoxazoline afoxolaner (Nexgard®), and the combination of afoxolaner with milbemycin oxime (Nexgard Spectra®), in dogs naturally infested with O. cynotis. In total, 32 infested client-owned dogs from two different sites in Greece were included. The animals were randomly divided into four equal groups based on their infestation score. Group 1 served as the negative control, group 2 received one oral administration of Nexgard (Day 0), group 3 received two monthly oral administrations of Nexgard (Days 0, 30), and group 4 received two monthly oral administrations of Nexgard Spectra (Days 0, 30), according to label instructions. Otoscopic examinations for mites and observations on debris/cerumen in the ears were carried out on Days 0, 15, 30, and 45. A quantitative assessment of ear mites by ear duct flushing and live mite counts was performed on Day 45. The results demonstrated that a single oral dose of afoxolaner and two monthly doses of afoxolaner or afoxolaner with milbemycin oxime resulted in a 99.9% reduction in live mite counts compared to the untreated control group by Day 45. Additionally, treated dogs showed improved clinical symptoms, such as ear cerumen/debris decrease, while untreated dogs experienced worsening symptoms over the study duration. No adverse events were reported. Overall, these results support the use of afoxolaner-based products to treat O. cynotis infestation in dogs. • Afoxolaner and afoxolaner with milbemycin reduce Otodectes cynotis mites in dogs by 99.9%. • Treatments with afoxolaner reduce ear cerumen and debris in naturally infested dogs. • Both treatments are safe, well-tolerated by the dogs and with no adverse events. [ABSTRACT FROM AUTHOR]

• 20 absolute-configuration and 20 relative-configuration isoxazoline fused dihydrobenzofuran derivatives were synthesised. • Single crystal incubation and x-ray diffraction were carried out on compound 3aa. • Performed gram-scale amplification experiments. • All compounds were screen tested for antifungal activity in vitro. The first catalytic enantioselective [3+2] cyclization between 4-amino-isoxazoles and quinone monoimines was achieved by using a chiral phosphoric acid catalyst. This transformation afforded a series of isoxazoline fused dihydrobenzofuran derivatives with two sequential chiral centers in high yields and outstanding enantioselectivities. The absolute configuration of the title compounds was determined by X -ray crystal structure analysis. The subsequent application of the obtained products displayed good antifungal activity against five plant pathogenic fungi further demonstrates the versatility of this transformation.This approach provided an excellent alternative strategy for the synthesis of corresponding bioactive molecules containing an isoxazoline fused dihydrobenzofurans skeleton. [ABSTRACT FROM AUTHOR]

Influenza remains a health problem to humans. Peramivir is a FDA approved anti-influenza drug targeting the virus neuraminidase. The (3 + 2) cycloaddition reaction of 2-ethylbutanenitrile oxide with the cyclopentene dipolarophile derived from Vince lactam is a key step in the conventional synthesis of peramivir. Our study showed that conducting the (3 + 2) cycloaddition reactions with either aliphatic or aromatic nitrile oxide in hexane solution provided high percentage of the desired regioisomer, and the N -substituent having electron-withdrawing property is also beneficial to the regioselectivity. This study also demonstrated an alternative synthetic pathway of (−)-peramivir and the analog having a phenyl group in place of the 3-pentyl moiety. Image 1 • Peramivir is an anti-influenza drug targeting the virus neuraminidase. • The synthesis involves (3 + 2) cycloaddition of nitrile oxide with alkene derived from Vince lactam. • The regioselectivity of cycloaddition is improved by conducting in hexane solution. • The cycloaddition with N -CF 3 CO-cyclopentene derivative gives 94% desired regioisomer. • Alternative syntheses of (−)-peramivir and the phenyl analog are demonstrated. [ABSTRACT FROM AUTHOR]

• Cavalier King Charles Spaniels with Chiari-like malformation/syringomyelia can have neuropathic pain. • Pregabalin has efficacy in humans with neuropathic pain, and similarly affected dogs could potentially benefit from the drug. • Pregabalin-treated dogs showed improved owner-recorded daily pain scores using a numerical rating scale. • Pregabalin improved mechanical hyperalgesia, cold hyperalgesia at 0 °C and cold allodynia at 15 °C. • Pregabalin was efficacious for the treatment of neuropathic pain caused by Chiari-like malformation and syringomyelia in dogs. Pregabalin is the first-line treatment for neuropathic pain (NeP) in humans. Dogs with Chiari-like malformation and syringomyelia (CM/SM) associated with NeP could benefit from pregabalin. The aim of this study was to evaluate the efficacy of pregabalin for NeP in dogs with CM/SM. Eight dogs with symptomatic CM/SM were included in a double-masked, randomised, crossover placebo–controlled clinical trial. All dogs received anti-inflammatory drugs as base-line treatment during placebo or pregabalin phase of 14 ± 4 days each. Analgesic efficacy was assessed with a daily numerical rating scale (NRS) recorded by dog owners (0–10, 10 = worst pain) and quantitative sensory testing at baseline, placebo and pregabalin phases. Blood samples were collected to report pregabalin exposure and to assess renal function. Daily NRS scores recorded by dog owners in the pregabalin group were lower than in the placebo group (P = 0.006). Mechanical thresholds were higher with pregabalin compared to baseline or placebo (P = 0.037, P < 0.001). Cold latency at 15 °C was prolonged on the neck and humeri with pregabalin compared to baseline (P < 0.001 for both) or placebo (P = 0.02, P = 0.0001). Cold latency at 0 °C was longer on pregabalin compared to baseline and placebo (P = 0.001, P = 0.004). There was no pregabalin accumulation between first and last dose. This study demonstrates the efficacy of pregabalin for the treatment of NeP due to CM/SM on daily pain scores recorded by dog owners. Pregabalin significantly reduced mechanical hyperalgesia, cold hyperalgesia (0 °C) and allodynia (15 °C) compared to placebo. Pregabalin was non-cumulative and well tolerated with occasional mild sedation. [ABSTRACT FROM AUTHOR]

A number of isoxazole, 1,2,3-triazole, tetrazole, and 1,2,4-oxadiazole derivatives of [17(20) E ]-21-norpregnene comprising 3β-hydroxy-5-ene and 3-oxo-4-ene fragments were prepared. Among the key steps for the synthesis of isoxazoles, 1,2,3-triazoles, and tetrazoles were (i) 1,3-dipolar cycloaddition of nitrile oxides or azides to acetylenes or nitriles and ii) dehydration of 17β-hydroxy-17α-methylene-azoles to [17(20) E ]-21-norpregnene derivatives. 1,2,4-Oxadiazoles were prepared through the formation of acetimidamides. Potency of the synthesized compounds to inhibit CYP17A1 and to suppress growth of prostate carcinoma cells was investigated. Among the new azole derivatives, four compounds were found possessing high anti-proliferative activity. [ABSTRACT FROM AUTHOR]

• Two clinical field studies were conducted in cats in the United States. • Selamectin (6–12 mg/kg) plus sarolaner (1–2 mg/kg) provided >95% control of fleas after a single treatment. • >99% control of fleas was attained after 2 or more monthly treatments. • Treatment reduced the clinical signs of flea allergy dermatitis. • 94.4% of cats were free of ear mites within one month of treatment. • There were no serious adverse reactions to treatment with selamectin (6–12 mg/kg) plus sarolaner (1–2 mg/kg). Two randomised, single-masked, multi-center field studies were conducted in the United States in cats presented as veterinary patients. The first study evaluated the efficacy and safety of a topically applied formulation of selamectin plus sarolaner (Revolution® Plus/Stronghold® Plus, Zoetis) against natural flea infestations; the second study evaluated its efficacy against natural ear mite infestations. The product was administered topically by the cats' owners at the dose range provided in the market product of 6.0–12.0 mg selamectin and 1.0–2.0 mg sarolaner per kg bodyweight. Imidacloprid plus moxidectin (Advantage® Multi for Cats, Bayer) was used as a positive control in both studies at the label dosage. In the flea study, treatments were administered on Days 0, 30, and 60. Efficacy was calculated based on the mean percent reduction of live flea counts on Days 30, 60, and 90 relative to the pre-treatment count. In the ear mite study, a single treatment was applied on Day 0 and efficacy was determined on Days 14 and 30 based on the presence or absence of ear mites. In both studies, patients were randomly allocated to treatments in the ratio of 2:1, selamectin plus sarolaner: imidacloprid plus moxidectin. In the two studies, 405 cats received treatment with selamectin plus sarolaner; of these, 256 cats received three monthly treatments in the flea study. There were no serious adverse reactions to treatment with selamectin plus sarolaner; health issues noted were typical of the normal ailments or minor traumatic injuries expected in the general cat population and were similar in both treatment groups. Efficacy against fleas based on geometric (arithmetic) means was 97.2% (95.9%), 99.5% (99.4%), and 99.8% (99.8%) in the selamectin plus sarolaner group and was 79.7% (70.5%), 91.4% (77.3%), and 95.5% (87.4%) in the imidacloprid plus moxidectin group on Days 30, 60, and 90, respectively. Flea counts for the selamectin plus sarolaner group were significantly lower than the counts for the imidacloprid plus moxidectin group at all time-points after treatment administration on Day 0 (P < 0.001). Treatment reduced the clinical signs of flea allergy dermatitis (alopecia, dermatitis/pyodermatitis, erythema, pruritus, scaling, and papules) in affected cats by 86.7%–100% in the selamectin plus sarolaner group and by 66.7%–100% in the imidacloprid plus moxidectin group. In the ear mite study, a single application of selamectin plus sarolaner resulted in the clearance of mites from 87.5% of cats within 14 days and 94.4% of cats within 30 days of treatment. The respective percentages of mite-free cats in the imidacloprid plus moxidectin group were 64.0% and 72.0%. There were significantly more cats with no mites noted in the selamectin plus sarolaner group than in the imidacloprid plus moxidectin group on Day 14 and Day 30 (P ≤ 0.018). Selamectin plus sarolaner (Revolution® Plus/Stronghold® Plus) administered topically at monthly intervals for three months was well tolerated and highly effective for the treatment and prevention of natural infestations of fleas on cats presented as veterinary patients. Clinical signs of flea allergy dermatitis improved in affected cats following treatment administration. A single topical treatment was also safe and highly effective for the treatment of ear mite infestations in naturally infested cats. [ABSTRACT FROM AUTHOR]

• Efficacy was assessed against three ticks found on cats in the US. • Treatment with selamectin plus sarolaner resulted in >90% control of existing infestations. • Persistent efficacy of >90% was achieved for at least 4 weeks. • Treatment with selamectin alone provided little if any efficacy. The efficacy of a single topical application of a combination product containing selamectin and sarolaner (selamectin/sarolaner; Revolution® Plus/Stronghold® Plus) was evaluated in seven laboratory studies against Ixodes scapularis (three studies), Dermacentor variabilis (two studies), or Amblyomma maculatum (two studies). In each study, cats were randomly allocated to treatment groups based on pre-treatment host-suitability tick counts. On Days -2, 5, 12, 19, 26 and 33, the cats were infested with unfed adult ticks. On Day 0, cats were treated with either a placebo (vehicle control) or with the spot-on solution at the minimum dose of 6.0 mg selamectin and 1.0 mg sarolaner/kg bodyweight. In one study with I. scapularis and one with D. variabilis an additional group of cats was treated with selamectin alone (Revolution®, Zoetis) at 6.0 mg/kg bodyweight. Tick counts were conducted after treatment and after each weekly re-infestation and efficacy determined relative to placebo-treated animals. There were no treatment-related adverse reactions in any of the studies. Geometric mean live tick counts were significantly (P < 0.05) lower in the selamectin/sarolaner-treated groups compared to the geometric mean tick counts in the placebo-treated groups at all time-points in all studies. For all species, a single topical administration of the selamectin/sarolaner combination resulted in>90% efficacy against existing infestations based on geometric means. Efficacy against weekly re-infestations was >90% based on geometric means for at least 5 weeks for I. scapularis and D. variabilis , and for at least 4 weeks against A. maculatum. Selamectin alone had no efficacy against I. scapularis , where counts on selamectin-treated cats were not significantly different from placebo at all time points (P > 0.05), and for D. variabilis , counts were not significantly different from placebo at 2, 3 and 5 weeks after treatment (P > 0.05) and efficacy was never greater than 85%. Thus, the activity of the sarolaner against three common tick species found on cats in the US is complementary to the existing broad-spectrum parasite control of selamectin. The inclusion of sarolaner with selamectin in a combination product (Revolution® Plus/Stronghold® Plus) provides for the treatment of existing tick infestations and gives at least one month of control against re-infestation following a single topical application. [ABSTRACT FROM AUTHOR]

A new topical formulation of selamectin plus sarolaner (Revolution® Plus/Stronghold® Plus, Zoetis) was evaluated in the treatment and control of naturally occurring infections of Ancylostoma tubaeforme and Toxocara cati in cats presented as veterinary patients in the United States. Three thousand three hundred three (3303) cats were screened in 25 veterinary practices in 15 states and 153 hookworm-positive cats (A. tubaeforme and/or A. braziliense), mainly from Alabama, Mississippi, Texas, and Hawaii, were identified; 135 cats met all the criteria for enrollment and were included on study. The cats were randomly assigned to treatment with Revolution® (at the label dosage, to provide a minimum dosage of 6 mg/kg selamectin) or selamectin plus sarolaner (at a dosage of 6–12 mg/kg plus 1–2 mg/kg, respectively). Treatments were administered at the time of enrollment and repeated 30 days later. Fecal samples were collected for differential fecal egg count prior to the first treatment (Day 0), prior to the second treatment (Day 30), and approximately 30 days later (Day 60). Efficacy was based on the percentage reductions in geometric mean fecal egg count for A. tubaeforme on Day 30 and Day 60 compared with Day 0. Where cats were co-infected with T. cati , efficacy against this species was also evaluated. Efficacy data were evaluated for A. tubaeforme for 40 cats on both Day 30 and Day 60 for the group treated with the selamectin/sarolaner combination and reductions in geometric mean fecal egg counts of 99.4% and 99.7% were demonstrated for Day 30 and Day 60, respectively. For the group treated with selamectin alone, 44 and 40 cats were evaluated and percent reductions for Day 30 and Day 60 were 99.5% and 99.9%, respectively. For T. cati , 14 cats were evaluated in the selamectin/sarolaner-treated group for Day 30 and for Day 60, and the reduction in geometric mean fecal egg count was 100% for both days. There were 11 and 9 cats evaluated for Day 30 and Day 60, respectively, for the selamectin-treated group and the reduction was again 100% for both days. The geometric mean fecal egg counts post-treatment were significantly lower than pre-treatment for both A. tubaeforme and T. cati , for both treatments, and for both periods of interest (P < 0.0001). No serious adverse events related to treatment with either product occurred during the study. Thus, both selamectin alone and the combination product of selamectin/sarolaner were safe and effective when administered on a monthly basis for the treatment and control of natural infections of A. tubaeforme and T. cati. The addition of sarolaner to the formulation did not interfere with the efficacy of selamectin against these nematodes. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • PhI(OAc) 2 -promoted dioxygenation of allyl oximes, including one alkoxylation. • Giving isoxazoline products bearing two contiguous tetrasubstituted carbons. • Mild conditions and operationally simple. Abstract A PhI(OAc) 2 -promoted dioxygenation of allyl oximes, including one alkoxylation, has been developed. This reaction can give isoxazoline products bearing two contiguous tetrasubstituted carbons. Various oximes substrates bearing different aryl groups and tetrasubstituted-olefin moieties were compatible with the mild reaction conditions. A two-electron oxidation pathway was proposed based on results of preliminary mechanistic studies. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Novel spirobiisoxazoline dibenzoquinone derivatives were synthesized. • [3 + 2] Double 1,3-dipolar cycloaddition was performed using allenoate and nitrile oxide. • The new molecules were successfully separated and characterized. Abstract " A series of novel spirobiisoxazoline dibenzoquinone derivatives were synthesized starting from 2,5-dimethoxybenzaldehyde in a six-step synthetic sequence". The key step [3 + 2] double 1,3-dipolar cycloaddition of oxime chloride with allenoate was performed under mild reaction conditions using sodium carbonate at ambient temperature. This is the first innovative synthesis of Spirobiisoxazoline Dibenzoquinone system where quinone ring is alkylated to isoxazoline moiety. [ABSTRACT FROM AUTHOR]

Graphical abstract 2-Isoxazolines were synthesized efficiently at ambient temperature from a formal [4+1] cycloaddition of nitrosoalkenes and sulfur ylides, which were generated in situ from α-haloketone oximes and dimethyl sulfonium salts. This approach provides a new method to synthesize a range of 2-isoxazolines in high yields and high regioselectivity. Highlights • A formal [4+1] cycloaddition of nitrosoalkenes and sulfur ylides. • Efficient synthesis of 2-isoxazolines. • 2-Isoxazolines can be further converted to other well-functionalized building blocks. Abstract 2-Isoxazolines were synthesized efficiently from a formal [4+1] cycloaddition of nitrosoalkenes and sulfur ylides, which were generated in situ from α-haloketone oximes and dimethyl sulfonium salts. This approach provides a new method to synthesize a range of 2-isoxazolines in high yields and high regioselectivity. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • A novel series of new coumarin tethered isoxazolines were synthesized via 1,3-cyclo addition reaction. • Compound 7c is active against human melanoma cancer line without toxic to normal human cells at tested concentration. • Compound 7c is effective in Ehrlich Ascites Carcinoma animal model in in-vivo. Abstract A series of new coumarin tethered isoxazolines (7a-l) were synthesized and evaluated for their cytotoxic potency against human melanoma cancer cell line (UACC 903) as well as fibroblast normal cell line (FF2441). Preliminary results revealed that some of these coumarin tethered isoxazolines 7b , 7c , 7f and 7j exhibited significant antiproliferative effect against human melanoma cancer (UACC 903) with IC 50 values of 8.8 , 10.5 , 9.2 and 4.5 μM respectively. However, compound 7c was non-toxic to normal human cells at the tested concentration. Further, we have chosen compound 7c to check its efficacy in Ehrlich Ascites Carcinoma animal model in-vivo for its antitumor and antiangiogenic properties. Our lead compound significantly reduced the cell viability, body weight, ascites volume and downregulated the formation of neovasculature such as regression of tumor volume. The present study indicates the scope of developing into potent anticancer drug in near future. [ABSTRACT FROM AUTHOR]

Eight novel C 60 -BODIPY-Triarylamine electroactive triads have been synthesized and characterized. Using pyrrolidine (PIR and BDPF series) and isoxazoline (ISO series) as linkers between the fullerene and the BODIPY-Triarylamine (-TAA) system, the effect of these linkers along with different functionalization on the TAA on the electronic properties were studied. Moreover, their photophysical and electrochemical properties were investigated by comparing them to the reference substances BDP , 10a , 10b , and C 60. All C 60 -BODIPY-TAA derivatives absorb visible light strongly in a range between 535 and 563 nm, and photoexcitation of the BODIPY unit causes photo-induced electron transfer, producing the corresponding charge-separated species, which was confirmed by solvatochromic effects on fluorescence measurements. The direction of charge transfer was also revealed by their redox potentials. A better electron affinity was observed for the ISO series when compared with PIR and BDPF. Thermogravimetric analysis showed that the pyrrolidine derivatives are more stable than their isoxazoline analogs and the insertion of alkoxy units in the triads triggers a better thermal endurance in the studied compounds. [Display omitted] • Synthesized BODIPY triads were structurally, optically, and electrochemically characterized. • The solvatochromism properties of isoxazoline and pyrrolidine[60]Fullerene-BODIPY-triarylamine compounds were examined. • Photo-induced electron transfer between BODIPY, triarylamines and C 60 moieties. • Alkoxy units in the triads improve thermal endurance in thermogravimetric analysis. [ABSTRACT FROM AUTHOR]

Abstract A mild and efficient copper-catalyzed radical oxytrifluoromethylation reaction of alkenyl oximes was successfully developed. The method provides a straightforward access to a wide range of CF 3 -containing isoxazolines in good to excellent yields. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

We describe the design, synthesis, X-ray studies, and biological evaluation of novel BACE1 inhibitors containing bicyclic isoxazoline carboxamides as the P3 ligand in combination with methyl cysteine, methylsulfonylalanine and Boc-amino alanine as P2 ligands. Inhibitor 3a displayed a BACE1 K i value of 10.9 nM and EC 50 of 343 nM. The X-ray structure of 3a bound to the active site of BACE1 was determined at 2.85 Å resolution. The structure revealed that the major molecular interactions between BACE1 and the bicyclic tetrahydrofuranyl isoxazoline heterocycle are van der Waals in nature. [ABSTRACT FROM AUTHOR]

Meso- Diaminopimelic acid ( meso -2,6-diamino-heptanedioic acid, DAP) is an important component of the cell wall of many bacteria. Meso -diaminopimelate dehydrogenase (m-Ddh) is a critical enzyme in the process of converting tetrahydrodipicolinate to DAP. Here, we are proposing that DAP analogs targeting m-Ddh may be considered as potential antibiotics. Four DAP analogs without significant structural change from DAP have been obtained and their inhibitory potencies against m-Ddh from the P. gingivalis strain W83 show significant differences from that of DAP. However, their inhibitory mechanisms as for how simple structural change influences the inhibitory potency remain unknown. Therefore, we employed molecular modeling methods to obtain insight into the inhibitory mechanisms of DAP and analogs with m-Ddh. The predicted binding mode of DAP was highly consistent with the experimental structural data and disclosed the important roles played by the binding pocket residues. According to our predictions, the isoxazoline ring of compounds 1 and 2 and the double bonds in compounds 3 and 4 had distinct influences on these compounds' binding to m-Ddh. This enriched understanding of the inhibitory mechanisms of DAP and these four analogs to m-Ddh has provided new and relevant information for future rational development of potent inhibitors targeting m-Ddh. [ABSTRACT FROM AUTHOR]

The structural and morphological features of small 3,5-disubstituted isoxazoles/isoxazolines are presented and discussed in the light of thermal analysis by differential scanning calorimetry (DSC), polarized optical microscopy (POM) technique, combined with single crystal X-ray diffraction and molecular modeling. The title compounds obtained were also characterized by 1 H, 13 C and 19 F NMR. Two of the 3,5-diarylisoxazoles reported here contain totally hydrogenated or fluorinated benzene rings on both sides of the heterocycle. Partially hydrogenated and fluorinated molecules were prepared alternating the position of the benzene rings on 3- and 5-position of the isoxazoles. Other isoxazoles were synthesized to compare the influence of fluorine atoms on the transitional properties. They were synthesized in two steps, starting from [3 + 2] 1,3-dipolar cycloaddition reaction of nitrile oxides with alkenes to yield the isoxazolines and subsequent MnO 2 -oxidation process to reach the final isoxazoles. [ABSTRACT FROM AUTHOR]

In continuation of our program aimed at the development of natural product-based pesticidal agents, a series of isoxazoline-containing podophyllotoxin/2′(2′,6′)-(di)halogenopodophyllotoxin derivatives were prepared, and their structures were well characterized by 1 H NMR, IR, optical rotation, HRMS and mp. Especially the structure of compound Ia was further confirmed by 1 H– 1 H COSY and NOESY spectrum. Among them, two compounds showed good insecticidal and acaricidal activities against Mythimna separata and Tetranychus cinnabarinus . Their structure–activity relationships were also observed. [ABSTRACT FROM AUTHOR]

(±)-3-Methoxy-1-oxa-2,7-diaza-7,10-ethanospiro[4.5]dec-2-ene sesquifumarate (±)-1 was previously characterized as the most selective agonist at α7 neuronal nicotinic acetylcholine receptors in a series of spirocyclic quinuclidinyl-Δ 2 -isoxazoline derivatives. In this study, we performed different in vitro biological assays aimed at characterizing the ADMET properties of (±)-1. Then, we tested the compound in vivo in behavioral studies including classical novel object recognition and inhibitory avoidance tests in the rat, and a spatial memory assay in zebrafish involving a rapid T-maze task. The results indicated an overall favorable profile for (±)-1 in view of potential therapeutic applications targeting the central nervous system. [ABSTRACT FROM AUTHOR]

Two new BODIPY-C 60 systems capable of exhibiting photoinduced charge separation have been designed, synthesized and characterized using various techniques. In these derivatives, the electron donor was BODIPY with two alkoxyphenylethynyl substituents and a fulleropyrrolidine ( B2-Pyr ) and isoxazoline linked ( B2-Is ) at the meso -position of the BODIPY ring served as an electron acceptor. As a result of extended conjugation, the BODIPY-C 60 derivatives revealed absorbance and emission covering a wide spectral range. Based on their redox, computational, absorbance and emission data, are suggested that the new B2-Is derivative showed a better electron affinity that B2-Pyr . [ABSTRACT FROM AUTHOR]

[Display omitted] The reaction of 2-azanorbornene derivatives with nitrile oxides (generated in situ by dehydrohalogenation of N -hydroxyimoyl halides) affords two regioisomers with the exo- arrangement of the isoxazoline ring. [ABSTRACT FROM AUTHOR]

A new and easy-to-perform route to 2-oxazolines amd isoxazolines was reported. Using CuBr 2 as both the bromide source and the reaction promoter, bromocyclization of N-allylamides and allyl ketone oximes proceeded readily, leading to oxazolines and isoxazolines in good to excellent yields. [ABSTRACT FROM AUTHOR]

A novel native cyclodextrin (CD) chiral stationary phase (CSP) with single triazole-bridge at CD C2 position (CSP1) was prepared by anchoring mono(2 A -azido-2 A -deoxy)-β-CD onto alkynyl silica via click chemistry. The effect of CD orientation on single layer CD-CSP's enantioseparation was comprehensively investigated using CSP1 (reversed orientation) and our previously reported CSP2 (C6 single triazole-bridge, normal orientation) as well as a commercial CD-CSP (Cyclobond I 2000, hybrid orientation) by separating several groups of analytes in chiral high performance liquid chromatography. It is found that the CD orientation on silica surface plays an important role in separating different racemates. CSP2 with normal CD orientation affords best separation for isoxazolines while CSP1 with reversed CD orientation better separates naringenin, hesperetin and Tröger's base. CSP2 and Cyclobond I 2000 show comparable separation ability for dansyl amino acids while poor separation was found on CSP1. Besides, molecular dynamics simulation was performed under “real” separation conditions using flavanone as model analyte to reveal the essential factors for CD's chiral discrimination behaviors. [ABSTRACT FROM AUTHOR]

A isoxazoline-[60]fullerene derivative has been prepared. Its complex with Zn-tetraporphyrin has been first evidenced by X-Ray diffraction. The solutions studies of the complex show its high stability and demonstrated the coordination have clear influence on the redox behavior of the components. The structure agrees also well with the theoretically calculated one. [ABSTRACT FROM AUTHOR]

Two diastereomeric analogs ( 1 and 2 ) of diaminopimelic acid (DAP) bearing an isoxazoline moiety were synthesized and evaluated for their inhibitory activities against meso -diaminopimelate dehydrogenase ( m -Ddh) from the periodontal pathogen, Porphyromonas gingivalis . Compound 2 showed promising inhibitory activity against m -Ddh with an IC 50 value of 14.9 µM at pH 7.8. The two compounds were further tested for their antibacterial activities against a panel of periodontal pathogens, and compound 2 was shown to be selectively potent to P. gingivalis strains W83 and ATCC 33277 with minimum inhibitory concentration (MIC) values of 773 µM and 1.875 mM, respectively. Molecular modeling studies revealed that the inversion of chirality at the C-5 position of these compounds was the primary reason for their different biological profiles. Based on these preliminary results, we believe that compound 2 has properties consistent with it being a lead compound for developing novel pathogen selective antibiotics to treat periodontal diseases. [ABSTRACT FROM AUTHOR]

This paper describes firstly an effective protocol for the synthesis of a new series of five examples of 3-(trifluoromethyl)-3,3a-dihydrospiro[chromeno[4,3- c ]isoxazole-4,1′-cycloalkan]-3-ols ( 4 ), in which the cycloalkanes — cyclopentane, cyclohexane, cycloheptane, and 4′-methyl- and 4′- t -butyl-cyclohexane — were isolated at yields of 65–84%. The dihydro-isoxazolinols 4 were obtained regioselectively from the reactions of 2,2,2-trifluoro-1-[4-methoxy-spiro(2 H -chromen-2,1′-cycloalkane)-3-yl]ethanones ( 3 ) with hydroxylamine hydrochloride, in the presence of sodium bicarbonate and methanol as solvent, for 24 h at 60 °C. The ethanone precursors 3 were synthesized by trifluoroacetylation reaction, employing trifluoroacetic anhydride and mixtures of enolethers and/or acetals derived from spiro[chroman-2,1′-cycloalkan]-4-ones ( 2 ) (Kabbe’s adducts), which were obtained beforehand from the reaction of cycloalkanones 1 with 2-hydroxyacetophenone and pyrrolidine. Subsequently, dehydration reactions of isoxazolinols 4 , employing thionyl chloride and pyridine, enabled the isolation of another series of five novel spiro-isoxazoles 5 (76–95% yield). The structural features of the two series of new spiro heterocycles ( 4 and 5) were unequivocally determined with the aid of: one-dimensional 1 H, 13 C, and 19 F NMR spectroscopy; two-dimensional 1 H and 13 C NMR spectroscopy (NOESY, gHMBC, and gHMQC); single crystal X-ray diffraction; and GC–MS. [ABSTRACT FROM AUTHOR]

In the present work, we have efficiently synthesized the pyrrole-isoxazoline derivatives ( 4a-d ) by cyclization of substituted 4-chalconylpyrrole ( 3a-d ) with hydroxylamine hydrochloride. The reactivity of substituted 4-chalconylpyrrole ( 3a-d ), towards nucleophiles hydroxylamine hydrochloride was evaluated on the basis of electrophilic reactivity descriptors ( f k + , s k + , ω k + ) and they were found to be high at unsaturated β carbon of chalconylpyrrole indicating its more proneness to nucleophilic attack and thereby favoring the formation of reported new pyrrole-isoxazoline compounds ( 4a-d ). The structures of newly synthesized pyrrole-isoxazoline derivatives were derived from IR, 1 H NMR, Mass, UV–Vis and elemental analysis. All experimental spectral data corroborate well with the calculated spectral data. The FT-IR analysis shows red shifts in v N–H and v C = O stretching due to dimer formation through intermolecular hydrogen bonding. On basis set superposition error correction, the intermolecular interaction energy for ( 4a-d ) is found to be 10.10, 9.99, 10.18, 11.01 and 11.19 kcal/mol respectively. The calculated first hyperpolarizability ( β 0 ) values of ( 4a-d ) molecules are in the range of 7.40–9.05 × 10 −30 esu indicating their suitability for non–linear optical (NLO) applications. Experimental spectral results, theoretical data, analysis of chalcone intermediates and pyrrole–isoxazolines find usefulness in advancement of pyrrole-azole chemistry. [ABSTRACT FROM AUTHOR]

Synthesis of 3-(4-((3-Phenyl-4,5-dihydroisoxazol-5-yl)methyl)piperazin-1-yl) benzoisothiazole derivatives (5a-i) , which constitute a new class of isoxazolines, has been accomplished in regio-selective manner. These derivatives have been prepared by employing the reaction between substituted aldoximes (4a-i) and 3-(4-Allylpiperazin-1-yl) benzoisothiazole in presence of chloramine-T which afforded in good yields. These compounds were screened for cytotoxic activity on tumor cells. Four among the nine synthesized compounds were found to exhibit potent cytotoxic and antineoplastic activities in comparison to tumor necrosis factor-related apoptosis inducing ligand (TRAIL) protein in mammalian cancer cells. The rest of the derivatives showed moderate activity. [ABSTRACT FROM AUTHOR]

An efficient one-pot synthesis of a new class of 3,4,5-trisubstituted isoxazoline N -oxides/isoxazoles and dihydroisoxazoles is developed by a green approach from aromatic and aliphatic aldehydes by controlling the reaction conditions. Aldehydes were reacted with ethyl nitroacetate in the presence of DABCO as a catalyst under ultrasonication. In aromatic aldehydes, isoxazoline N -oxides were obtained exclusively when the reaction was carried out at 40 °C, but raising the temperature to 80 °C isoxazoles were formed selectively. Aliphatic aldehydes, on the other hand, gave a mixture of isoxazoline N -oxides and dihydroisoxazoles where the ratio of these depended on the bulk of the aliphatic chain on the aldehyde. This is the first method for the synthesis of aliphatic 4-substituted-3,5-bis(ethoxycarbonyl)-isoxazoline N -oxides and 4-substituted-3,5-bis(ethoxycarbonyl)-dihydroisoxazoles with good to excellent yields. [ABSTRACT FROM AUTHOR]

Eight spiroacridine derivatives containing the isoxazoline ring were synthesized and characterized using elemental analysis, IR, UV–vis, and NMR measurements. Their interactions with calf thymus DNA were extensively studied by various spectroscopic techniques and gel electrophoresis. The UV–visible and CD measurements implied that these derivatives interact with calf thymus DNA through intercalation. The Stern-Volmer quenching constants were determined and ranged from 0.126 × 10 4 to 1.394 × 10 4 M −1 . A topoisomerase I inhibition assay was performed with the spiroacridine derivatives. [ABSTRACT FROM AUTHOR]

Various novel deep eutectic solvents (DESs) have been prepared by combining different molar ratio of benzalkonium chloride and urea, subsequently characterized for some physical and spectroscopic properties. Among newly formed DESs, one of the mixture (1:2) was employed in combination with ultrasound (US), for the synthesis of selective isoxazoline derivatives. The reactions were also performed by nonultrasonic (NUS)/thermal method using conventional solvent system for comparison purposes. Applying DES, as a reaction medium in either of the thermal and ultrasonic assisted methods, an appreciable improvement in the product yield was achieved in a shorter time. The results show some advantages in terms of reaction time and energy consumption when DES and ultrasound combination was used for the synthesis of isoxazolines. Recyclability attributes of DES were also studied which revealed that a marginal decrease in the yield (%) was recorded up-to four runs. The findings of this study support the use of DES in combination with ultrasound technique as a viable green route for the synthesis of isoxazoline derivatives. [ABSTRACT FROM AUTHOR]

• Click polymerization was used for efficient adsorption of TNT. • Synergistic effect of Lewis acid-base, dipole-π, and π-π interactions was applied. • The maximum adsorption capacity at 25°C was up to 90.7 mg/g within 3 h. • The porous polymer was reversible and could be reused. A series of hydrophobic porous polymer containing isoxazoline and siloxane groups were successfully prepared via catalyst-free click polymerization and freeze-drying technology. In addition to hydrophobicity, synergistic effect of three molecular aborption interactions, namely point-to-point Lewis acid-base, point-to-face dipole-π, and face-to-face π-π interactions, endowed the resulting porous polymer with good 2,4,6-trinitrotoluene (TNT) adsorption efficiency from wastewater. At the same time, the adsorption efficiency of the resulting porous polymer in different natural/polluted water samples was similar to those in laboratory, and about 80% of the initial adsorption capacity remained after five adsorption-desorption cycles. The results showed that hydrophobic porous polymer containing isoxazoline and siloxane groups is a promising adsorbent for the treatment of TNT wastewater. [ABSTRACT FROM AUTHOR]

The diamondback moth Plutella xylostella (L.) (Lepidoptera: Plutellidae) is a devastating pest that infests several cruciferous vegetable crops worldwide and has developed insecticide resistance in most chemical classes. Fluxametamide is a novel neuroactive isoxazoline compound that binds to a unique site on the γ -aminobutyric acid (GABA) receptor and has an exceptional insecticidal activity on a range of lepidopteran caterpillars. The present study aimed to assess the risk of resistance in P. xylostella to fluxametamide under laboratory conditions. After the repeated exposure to fluxametamide for successive 18 generations of P. xylostella , there was 3.095-fold increase in the LC 50. When the realized heritability (h 2 ) of P. xylostella to fluxametamide in the open field was assumed to be the laboratory-estimated value (h 2 = 0.180) and the mortality was 70–90%, only 22.9–33.1 generations were expected to be required to obtain a 10-fold increase in fluxametamide resistance. Compared with the laboratory susceptible strain (F 0), the Flux-SEL (F 18) strain exhibited a very low level of cross-resistance to emamectin benzoate (5.17-fold) and no significant cross-resistance to fipronil or flubendiamide. With the F 0 and the Flux-SEL test strains (F 12 , F 15 and F 18), the specific activities of cytochrome P450 and glutathione S -transferase showed a remarkable increase during selection, while the esterase activity did not differ significantly. The results indicated that a potential risk of resistance development to fluxametamide exists in P. xylostella after continuous exposure. These pieces of information will be crucial in formulating rational fluxametamide application and resistance management guidelines for controlling P. xylostella under field condition. [Display omitted] • First report of laboratory-selected fluxametamide resistance in Plutella xylostella. • P. xylostella carries a potential risk of field-evolved resistance to fluxametamide. • The estimated h 2 of fluxametamide resistance in Flux-SEL (F 18) strain was 0.180. • Flux-SEL (F 18) strain was weakly resistant to emamectin benzoate. • The activities of P450 and GST increased significantly in Flux-SEL strains during selection. [ABSTRACT FROM AUTHOR]

The first synthesis of clavatadine C was achieved in 5 steps and an overall yield of 38%. The key step in the synthesis features a highly efficient one-pot dibromination and oxidative spirocyclization sequence to forge the spiro-2,6-dibromocyclohexadienone isoxazoline scaffold. Clavatadine C was found to possess moderate cytotoxicity against both breast and colon cancer cell lines. [ABSTRACT FROM AUTHOR]

A novel series (13) of isoxazoline functionalized coumarins was synthesized through 1,3-dipolar cyclization of nitrile oxides with Allylated coumarins. Synthesis of effective and target selective immunostimulators through conjugation of diversely substituted isoxazolines and 7-hydroxycoumarins is the focus of the present article. The proposed synthetic scheme was observed to be highly regiospecific yielding attempted conjugates in good yield (>90%). Kinetic resolution of the racemates was carried out by employing lipase B from Candida antarctica (CALB). The synthesized compounds were screened in vitro and in vivo for their biological activities viz . toxicity and impact on splenocyte proliferation (T- and B-cell proliferation), antibody production (HA titre), delayed-type hypersensitivity reaction (DTH), T-cell subtypes (CD4 and CD8), cytokine production (IL-2, IFN-γ, and IL-4) and NO (macrophage) production. Our results establish that isoxazoline functionalized coumarins exhibit excellent immune potentiating activity especially compounds 2 , 4 and 8 whose activity is more than that of Levimasole as standard. The structure activity relations are explained in light of the structural/functional aspects of tested compounds. To the best of our knowledge the presented work is first of its kind and is presaged to prove very useful for the design and synthesis of bis -heterocycle based novel, therapeutically selective and effective immunopotentiators. [ABSTRACT FROM AUTHOR]

The efficacy of oral afoxolaner plus milbemycin oxime combination chewables against induced gastrointestinal nematode infections in dogs was evaluated in six separate studies. Two studies were performed to evaluate the efficacy of the product against Toxocara canis , two studies evaluated the efficacy against Toxascaris leonina , one study evaluated the efficacy against Ancylostoma braziliense , and one study evaluated the efficacy against Ancylostoma caninum. In the A. caninum study, the efficacy of milbemycin oxime alone and afoxolaner alone was also evaluated. Dogs in all studies were inoculated with infective eggs or larvae and confirmed to have patent infections based on a fecal examination prior to allocation to study group and treatment. Each study utilized a randomized block design with blocks based on pre-treatment body weight. All dogs were assigned to blocks based on body weight, and then each dog within a block was randomly assigned to treatment group. There were two groups of 10 dogs each in the T. canis, T. leonina , and A. braziliense studies: 1) an untreated (control) group and 2) a group treated with afoxolaner plus milbemycin oxime chewables (NexGard Spectra ® , Merial). This group was treated at a dose as close as possible to the minimum effective dose of afoxolaner and milbemycin oxime (2.5 mg + 0.5 mg per kg body weight, respectively) once on Day 0 using whole chews. There were four groups of 10 dogs each in the A. caninum study: 1) untreated (control), 2) NexGard Spectra ® as described above, 3) milbemycin oxime alone (dose of at least 0.5 mg per kg of body weight) and 4) afoxalaner alone (dose of at least 2.5 mg per kg body weight). For parasite recovery and counts, dogs were euthanized humanely and necropsied seven days after treatment. The efficacy of the afoxolaner plus milbemycin oxime combination was ≥98% against T. canis, ≥95.8% against T. leonina, and 90.2% against A. braziliense. Efficacy of the combination against A. caninum was 99.7%, while the efficacy of milbemycin oxime alone was 99.6% and the efficacy of afoxolaner alone was 2.1%. Dogs treated with afoxolaner plus milbemycin oxime chewables had significantly (p ≤ 0.0002) fewer nematodes than the untreated controls in all studies. There were no adverse events or other health problems that were related to treatment with Nexgard Spectra ® in these studies. The results of these controlled studies demonstrate the high efficacy of the afoxolaner plus milbemycin oxime chewables against a broad range of canine intestinal nematode infections. [ABSTRACT FROM AUTHOR]

A route for the regiospecific synthesis of 3-(triazol-3-yl)-1,2-isoxazol(in)e-5-yl-aryl derivatives has been developed by intermolecular 1,3-dipolar cycloaddition chemistry, and novel annulated compounds having triazole/isoxazole have been prepared by employing intramolecular nitrile oxide 1,3-dipolar cycloaddition. [ABSTRACT FROM AUTHOR]

Novel isoxazoline amide benzoxaboroles were designed and synthesized to optimize the ectoparasiticide activity of this chemistry series against ticks and fleas. The study identified an orally bioavailable molecule, ( S )- N -((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)-2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamide ( 23 ), with a favorable pharmacodynamics profile in dogs ( C max = 7.42 ng/mL; T max = 26.0 h; terminal half-life t 1/2 = 127 h). Compound 23 , a development candidate, demonstrated 100% therapeutic effectiveness within 24 h of treatment, with residual efficacy of 97% against American dog ticks ( Dermacentor variabilis ) on day 30 and 98% against cat fleas ( Ctenocephalides felis ) on day 32 after a single oral dose at 25 mg/kg in dogs. [ABSTRACT FROM AUTHOR]

Fatty acid amide hydrolase (FAAH) is a membrane anchored serine hydrolase that has a principle role in the metabolism of the endogenous cannabinoid anandamide. Docking studies using representative FAAH crystal structures revealed that compounds containing a novel piperidinyl thiazole isoxazoline core fit within the ligand binding domains. New potential FAAH inhibitors were designed and synthesized incorporating urea, carbamate, alkyldione and thiourea reactive centers as potential pharmacophores. A small library of candidate compounds (75) was then screened against human FAAH leading to the identification of new carbamate and urea based inhibitors ( K i = pM and nM, respectively). Representative carbamate and urea based chemotypes displayed slow, time dependent inhibition kinetics leading to enzyme inactivation which was slowly reversible. However, evidence indicated that features of the mechanism of inactivation differ between the two pharmacophore types. Selected compounds were also evaluated for analgesic activity in the mouse-tail flick test. [ABSTRACT FROM AUTHOR]

Compounds based on the 3-Br-isoxazoline scaffold fully inhibit glyceraldehyde 3-phosphate dehydrogenase from Plasmodium falciparum by selectively alkylating all four catalytic cysteines of the tetramer. Here, we show that, under the same experimental conditions that led to a fast and complete inhibition of the protozoan enzyme, the human ortholog was only 25% inhibited, with the alkylation of a single catalytic cysteine within the tetramer. The partial alkylation seems to produce a slow conformational rearrangement that severely limits the accessibility of the remaining active sites to bulky 3-Br-isoxazoline derivatives, but not to the substrate or smaller alkylating agents. [ABSTRACT FROM AUTHOR]

Two randomised, blinded, multi-centered field studies were conducted in Europe to demonstrate the efficacy and safety of three monthly oral doses of sarolaner (Simparica™, Zoetis) administered at a minimum dosage of 2.0 mg/kg (range 2–4 mg/kg) against natural flea or tick infestation of dogs presented as veterinary patients. In the flea study, the improvement in clinical signs associated with flea allergy dermatitis (FAD) was also investigated. The palatability of the sarolaner chewable tablet formulation was evaluated in both studies. Spinosad (Comfortis ® Chewable Tablets, Elanco) and fipronil (Frontline ® Spot on, Merial) were used as positive controls in the flea and tick study, respectively. Treatments were administered on Days 0, 30 and 60. Efficacy was calculated based on the mean percent reduction of live parasite counts on post-treatment days 14, 30, 60 and 90 versus the pre-treatment count on Day 0. Non-inferiority of sarolaner to the control products was assessed at each time-point using a margin of 15% at the one-sided 0.025 significance level. Dogs were enrolled in a 2:1 ratio (sarolaner:comparator); 285 flea- and 181 tick-infested dogs were assessed for efficacy and safety, and 137 and 48 dogs were assessed for safety only, in the flea and tick study, respectively. There were no treatment-related adverse events. Efficacy against fleas was 98.8%, 99.4%, >99.9% and >99.9% in the sarolaner-treated group and 98.9%, 93.7%, 96.8% and 95.1% in the spinosad-treated group on Days 14, 30, 60 and 90, respectively. Sarolaner was non-inferior to spinosad at all time-points and was superior on Day 30. For the 42 dogs identified as having FAD at enrolment, the clinical signs of FAD improved in all dogs and the incidence was markedly reduced by the end of the study. Efficacy against ticks was 97.4%, 97.6%, 99.8% and 100% in the sarolaner-treated group and 94.1%, 88.5%, 89.9% and 98.1% in the fipronil-treated group on Days 14, 30, 60 and 90, respectively. Sarolaner was non-inferior to fipronil at all time-points, and was superior on Days 30 and 60. Sarolaner tablets were voluntarily and fully consumed within one minute in 93% of the 1280 occasions offered. Sarolaner administered orally at monthly intervals at a minimum dosage of 2 mg/kg was safe and highly effective against natural infestations of fleas and ticks on dogs. In addition, clinical signs FAD improved in dogs treated with sarolaner, and the flavored, chewable tablets were highly palatable. [ABSTRACT FROM AUTHOR]

The efficacy of sarolaner (Simparica™, Zoetis) was evaluated against Demodex spp. in dogs with generalized demodicosis and against Otodectes cynotis (otodectic mange) in dogs with induced infestations. In the first study, 16 dogs with clinical signs of generalized demodicosis and positive for Demodex spp. mites were randomly assigned to treatment with either sarolaner (2 mg/kg) orally on Days 0, 30 and 60, or topical imidacloprid (10 mg/kg) plus moxidectin (2.5 mg/kg) solution every 7 days from Day 0 to Day 81. For sarolaner-treated dogs, pretreatment mite counts were reduced by 97.1% at 14 days and 99.8% by 29 days after the first dose, with no live mites detected thereafter. Weekly imidacloprid plus moxidectin resulted in 84.4 and 95.6% reduction at these two time points, respectively, with no mites detected from Day 74 on. All dogs in both groups showed marked improvement in the clinical signs of demodicosis. In the second study, 32 dogs with induced infestations of O. cynotis were randomly assigned (eight per group) to oral sarolaner (2 mg/kg) as a single treatment on Day 0 or as a two dose regime (Days 0 and 30), or a placebo group for each of the dose regimes. Sarolaner administered at 2 mg/kg as a single oral dose resulted in a 98.2% reduction at Day 30 and two doses of sarolaner, administered one month apart, resulted in a 99.5% reduction in ear mites at Day 60 compared to placebo controls. There were no treatment related adverse events in either study. In these studies, sarolaner at an oral dose of 2 mg/kg was highly effective in reducing the live mite counts associated with a natural infestation of Demodex spp. and an induced infestation of O. cynotis . In addition, the Demodex -infested dogs showed a marked improvement in the clinical signs of generalized demodicosis. [ABSTRACT FROM AUTHOR]