Residual estimation of spirotetramat and its metabolites in chilli and soil by LC-MS/MS.

Two applications of spirotetramat were done to study the dissipation and persistence of spirotetramat and its four different metabolites in chilli and soil at 10 days interval. Total spirotetramat residues were estimated by LC-MS/MS instrument. The mean initial deposits of total spirotetramat after application of spirotetramat 15.31 OD @ 60 (X dose), 75 (1.25 × dose) and 120 (2 × dose) g a.i. ha-1 on green chilli were found to vary from 0.38 to 0.83 mg kg-1 during the initial year. Spirotetramat and its metabolite residues in green chilli were found to be below limit of quantification (0.01 mg kg-1) after 15 days of application. The spirotetramat cis enol (the major metabolite) was formed in both the soil and the plant. The residues of spirotetramat-monohydroxy were below LOQ irrespective of any substrate during the estimation. In soil, the total initial spirotetramat deposits for the 1st year were found 0.09 for X dose, 0.12 for 1.25 × dose and 0.20 mg kg-1 for 2 × dose. After 3 days for both X and 1.25 × doses and 5 days for 2 × dose, the total spirotetramat residues were below LOQ. The spirotetramat's half-life values have been determined to be between 3.19 and 3.93 days and 1.00 and 1.59 days, respectively, in soil and green chilli fruits. One day waiting period is proposed for the safe consumption of green chilli when the spirotetramat was applied irrespective of the dose.

Residue behavior and consumer risk assessment of spirotetramat and chlorpyrifos on cabbage heads and cropped soil.

A field experiment following good agricultural practices was laid out to study the dissipation of spirotetramat (90 g a.i. ha-1 and 180 g a.i. ha-1) and chlorpyrifos (400 g a.i. ha-1 and 800 g a.i. ha-1) on cabbage heads and soil. Samples were processed using quick, easy, cheap, effective, rugged, and safe (QuEChERS) method for residue estimation of spirotetramat and chlorpyrifos, which were further detected using HPLC-PDA and GC-FPD respectively. The residues of spirotetramat on cabbage heads reached below detection limit (BDL) (< 0.05 mg kg-1) on 7th and 10th day and for chlorpyrifos, BDL (< 0.01 mg kg-1) was achieved on 10th and 15th day for X and 2X dose, respectively. On 20th day after second spray, residues in soil were found to be BDL for both the pesticides. Half-life of spirotetramat and chlorpyrifos was found to be 3 and 2 days, respectively while a safe pre-harvest interval (PHI) of 9 days for spirotetramat and 10 days for chlorpyrifos is suggested on cabbage. The dietary risk assessment studies for various age groups of Indian population, ascertained safety of treated cabbage heads for consumption, as current study revealed that hazard quotient (HQ) < 1 and theoretical maximum dietary intake (TMDI) < maximum permissible intake (MPI) for both the pesticides at respective PHI.

Insights into spirotetramat-induced thyroid disruption during zebrafish (Danio rerio) larval development: An integrated approach with in vivo, in vitro, and in silico analyses.

Spirotetramat (SPT), a tetronic acid-derived insecticide, is implicated in reproductive and lipid metabolism disorders, as well as developmental toxicity in fish. While these effects are documented, the precise mechanisms underlying its developmental toxicity are not fully elucidated. In this study, zebrafish embryos (2 h post-fertilization, hpf) were exposed to four concentrations of SPT (0, 60, 120, and 240 µg/L) until 21 dpf (days post-fertilization). We delved into the mechanisms by examining its potential disruption of the thyroid endocrine system, employing in vivo, in vitro, and in silico assays. The findings showed notable developmental disturbances, including reduced hatching rates, shortened body lengths, and decelerated heart rates. Additionally, there was an increase in malformations and a decline in locomotor activity. Detailed analyses revealed that SPT exposure led to elevated thyroid hormone levels, perturbed the hypothalamic-pituitary-thyroid (HPT) axis transcript levels, amplified deiodinase type I (Dio1) and deiodinase type II (Dio2) activities, and both transcriptionally and proteomically upregulated thyroid receptor beta (TRß) in larvae. Techniques like molecular docking and surface plasmon resonance (SPR) confirmed SPT's affinity for TRß, consistent with in vitro findings suggesting its antagonistic effect on the T3-TR complex. These insights emphasize the need for caution in using tetronic acid-derived insecticides.

Dissipation, residues, and evaluation of processing factor for spirotetramat and its formed metabolites during kiwifruit growing, storing, and processing.

Spirotetramat is widely used around the world to control sucking pests and may form in agricultural products. In the current study, the dissipation, residues, and evaluation of processing factor (PF) for spirotetramat and its formed metabolites were investigated during kiwifruit growing, storing, and processing. The residue analysis method was established based on high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) combined with a QuEChERS method to detect the residues of spirotetramat and its metabolites in kiwifruit and its processed products. The method provided recoveries of 74.7-108.7%, and the relative standard deviations (RSDs) were 0.6-13.1%. The LOQs of spirotetramat and its four metabolites were 1 µg kg-1. The degradation of spirotetramat was best fitted for the first-order kinetics model with a half-life of 9.90-10.34 days in the field and 24.75-30.13 days during storage. Residues of spirotetramat and its formed metabolites in kiwifruit would not pose dietary risk to consumers. Moreover, the peeling and fermentation were the highest removal efficiency for the spirotetramat and its formed metabolite residues during processing. The PF values calculated after each individual process were < 1, indicating a significant reduction of residues in different processing processes of kiwifruit. The spirotetramat was degraded during kiwifruit wine-making process with half-lives of 3.36-4.91 days. B-enol and B-keto were the main metabolites detected in kiwifruit and its processed products. This study revealed the residues of spirotetramat and its formed metabolites in kiwifruit growing, storing, and processing, which helps provide reasonable data for studying the dietary risk factors of kiwifruits and products.

Synthesis, cytotoxic activity evaluation and mechanistic investigation of novel 3,7-diarylsubstituted 6-azaindoles.

A number of new disubstituted 6-azaindoles have been designed and synthesized bearing a crucial structural modification in respect to an analogous antiproliferative hit compound. The synthesis was performed using 2-amino-3-nitro-4-picoline, that was suitably modified and converted to 7-chloro-3-iodo-6-azaindole and this central scaffold was used for successive Suzuki-type couplings, to result in the target compounds. The evaluation of the cytotoxic activity was performed against four human cancer cell lines, as well as a normal human fibroblast strain. Certain compounds possessed strong anticancer activity without affecting normal cells. At subcytotoxic concentrations for cancer cells, these compounds displayed an anti-proliferative effect by arresting the cells at the G2/M phase of the cell cycle, which could be associated with the observed decrease in the phosphorylation levels of the MEK1- ERK1/2 pathway and/or the activation of the p53-p21WAF1 axis.

Systemic insecticides for control of stem gall wasp in highbush blueberry.

The gall wasp, Hemadas nubilipennis Ashmead, is a pest of highbush and lowbush blueberry and can pose a challenge to control with foliar sprays due to adult activity being during bloom and because larval development is within plant tissues. We hypothesized that systemic insecticides that move within the blueberry vascular system would reach areas where H. nubilipennis eggs are laid, causing larval mortality. Three application methods, crown injection, soil drench, and foliar spray were applied to potted 'Jersey' blueberry bushes at 50% and 100% rates to quantify systemic residue concentrations in shoots and leaves. Additionally, systemic insecticides were evaluated for control of gall wasps using single-shoot bioassays and measuring larval mortality at 0.01%, 0.1%, 1%, and 10% of field rate provided within a floral pick. Systemic insecticides tested in both studies included imidacloprid, flupyradifurone, and spirotetramat. The potted bush residue study determined that insecticides moved from three tested sites of entry: the roots, crown cavity, and foliage. Results from the shoot bioassays found that the mean percent larval survival of H. nubilipennis was negatively correlated with the concentration of AI detected in galls. Imidacloprid and spirotetramat were found to have the greatest potential for control of H. nubilipennis due to mortality in the shoot bioassays and similar residue concentrations in the potted bush studies to shoot bioassays. Future research should evaluate systemic insecticides applied in highbush blueberry plantings for control of H. nubilipennis using the bioassay mortality assessment method developed in this study.

Lethal and sublethal effects of flubendiamide and spirotetramat against the leaf worm, Spodoptera litura(Fabricius) under laboratory conditions.

The leaf worm, Spodoptera litura (Fabricius) (Lepidoptera: Noctuidae) is a notorious insect pest of many economically important cultivated crops like cotton, maize, tobocco and vegetables causing severe economic losses from 50-100%. In most crops, damage arises due to voracious feeding by the larvae and leads to the skeletonizing of leaves. Toxicological studies were performed to estimate lethal and sublethal levels of flubendiamide and spirotetramat against S. litura. Effects of these estimated values were assessed on different biological traits of S. litura including life duration, survival and next generation potential. Both flubendiamide and spirotetramat showed toxic responses against second instar larvae of S. litura under laboratory conditions. Larval duration and survival rate of S. litura to were significantly different. Exposure to test insecticides resulted in negative effect on the demography of S. litura as longer life cycle and decreased fecundity. Changes in net reproductive rate and intrinsic rate of increase also helped to decide the fate of these insecticides. Low reproductive potential and low hatching percentage due to exposure to test insecticides can help to manage next generation of target pest. These two new chemistry insecticides can be recommended for their effective and long-term utilization against this important leaf feeder which may help its management and decrease economic losses faced by the growers. Their impact on larval duration and low survival rate at lethal levels guides about their potential in pest control.

HNODThia: A Promising Chelator for the Development of 64Cu Radiopharmaceuticals.

Herein, we present the synthesis and coordination chemistry of copper(II) and zinc(II) complexes of two novel heterocyclic triazacyclononane (tacn)-based chelators (HNODThia and NODThia-AcNHEt). The chelator HNODThia was further derivatized to obtain a novel PSMA-based bioconjugate (NODThia-PSMA) and a bifunctional photoactivatable azamacrocyclic analogue, NODThia-PEG3-ArN3, for the development of copper-64 radiopharmaceuticals. 64Cu radiolabeling experiments were performed on the different metal-binding chelates, whereby quantitative radiochemical conversion (RCC) was obtained in less than 10 min at room temperature. The in vitro stability of NODThia-PSMA in human plasma was assessed by ligand-challenge and copper-exchange experiments. Next, we investigated the viability of the photoactivatable analog (NODThia-PEG3-ArN3) for the light-induced photoradiosynthesis of radiolabeled proteins. One-pot photoconjugation reactions to human serum albumin (HSA) as a model protein and the clinically relevant monoclonal antibody formulation MetMAb were performed. [64Cu]Cu-7-azepin-HSA and [64Cu]Cu-7-azepin-onartuzumab were prepared in less than 15 min by irradiation at 395 nm, with radiochemical purities (RCP) of >95% and radiochemical yields (RCYs) of 42.7 ± 5.3 and 49.6%, respectively. Together, the results obtained here open the way for the development of highly stable 64Cu-radiopharmaceuticals by using aza-heterocyclic tacn-based chelators, and the method can easily be extended to the development of 67Cu radiopharmaceuticals for future applications in molecularly targeted radio(immuno)therapy.

Synthesis, Characterization, Antimicrobial and Antimalarial Activities of Azines Based Schiff Bases and their Pd(II) Complexes.

Herein, we report synthesis, characterization, antimicrobial and antimalarial activities of azines Schiff base ligands (L1 -L4 ) and their palladium (II) complexes (C1 -C4 ) of [Pd(L)(OAc)2 ] type. The azine ligands (L1 -L4 ) were prepared by condensation of carbonyl compounds with hydrazine hydrate and their complexes by the reaction of palladium acetate with L1 -L4 ligands in 1 : 1 molar ratio. The prepared ligands and their complexes were characterized by spectral characterization using 1 H &13 C-NMR, FT-IR and mass spectral studies, which revealed that the ligands coordinates via azomethine nitrogen and heteroatom or aryl carbon with palladium. Moreover, Schiff bases and their palladium (II) complexes have been screened for their antibacterial (S. aureus, B. subtillis, and S. typhi, P. aeruginosa), antifungal (C. albicans, A. niger, and A. clavatus) and antimalarial (P. falciparum) activities. The Schiff base L4 showed good results for antibacterial against S. aureus (MIC, 50 µg/mL) and antimalarial against P. falciparum (IC50 , 0.83 µg/mL). The complex C1 showed best antibacterial activity (MIC, 62.5 µg/mL) against S. typhi and the complex C4 exhibited remarkable antimalarial activity (IC50 , 0.42 µg/mL) among the tested compounds. Thus, azines based ligands and their Pd complexes can be good antimicrobial and antimalarial agents if explored further.

In-Class Cross-Reactivity among Hospitalized Patients with Hypersensitivity Reactions to Fluoroquinolones.

Results from this large, multicenter study suggest that patients with a confirmed ciprofloxacin, moxifloxacin, or levofloxacin hypersensitivity reaction are likely to tolerate other fluoroquinolones. Avoiding different fluoroquinolones in patients labeled with a ciprofloxacin, moxifloxacin, or levofloxacin allergy may not always be mandatory. This was a study of patients with a ciprofloxacin, moxifloxacin, or levofloxacin hypersensitivity reaction and a documented electronic medical record administration of a different fluoroquinolone. Numerically, the most common reaction risk occurred with a challenge to moxifloxacin (2/19; 9.5%), followed by ciprofloxacin (6/89; 6.3%), and levofloxacin (1/44; 2.2%).

Development of spirotetramat nanoparticles based on mesoporous silica: improving the uptake and translocation of spirotetramat in plants.

As an ideal nanocarrier, mesoporous silica nanoparticles (MSNs) have the characteristics of high specific surface area, adjustable pore size, and good biocompatibility, which are excellent carriers for improving the stability and sustained-release performance of pesticides and improving the utilization rate of pesticides In this study, three kinds of particle size MSNs (100 nm, 200 nm, and 400 nm) were prepared by hydrothermal synthesis method, and then, the spirotetramat (Stm) was loaded into MSNs with different particle sizes by solvent volatilization method to prepare Stm nanoparticles with different particle sizes (Stm@MSNs). The results of Stm@MSNs characterization showed that the three particle sizes of MSNs were 112.5, 200.1, and 439.4 nm, respectively. Besides, the pore sizes of the three MSNs were all in the range of 2~50 nm. And the FTIR spectra showed that the Stm was successfully loaded into the channel of MSNs. TGA analysis showed that Stm@MSNs-100, Stm@MSNs-200, and Stm@MSNs-400 had good thermal stability in the range of 200°C. The drug loads of Stm@MSNs-100, Stm@MSNs-200, and Stm@MSNs-400 to Stm were 38%, 21%, and 53%. The release test showed that all of them showed the characteristics of slow release. After 3 days of application on cucumber plants, Stm was detected in both upper and lower leaves of cucumber. Compared with MSNs-200 and MSNs-400, the nanocarrier MSNs-100 were more easily absorbed by cucumber plants and could carry more Stm into cucumber plants. This study provided a theoretical basis for the development and application of nanocarriers and the improvement of pesticide utilization rate by discussing the effects of different particle size MSNs on the slow release and systemicity of pesticides.

The spirotetramat inhibits growth and reproduction of silkworm by interfering with the fatty acid metabolism.

Spirotetramat is a novel insecticide and acaricide that can effectively control many species of piercing-sucking pests by inhibiting lipid synthesis. The silkworm is an economically important insect and a model organism for genetics and biochemical research. However, the toxic effect on their development and reproduction remain unclear. In this study, we demonstrated the negative effects of spirotetramat on the development, vitality, silk protein synthesis, and fecundity of silkworm. We also compared expression changes of silkworm genes using digital gene expression (DGE). A total of 1567 differentially expressed genes (DEGs) were detected, of which 874 genes were downregulated and 693 genes were upregulated. Gene Ontology (GO) enrichment analysis showed that the DEGs were enriched in the oxidation-reduction process, oxidoreductase activity, and fatty-acyl-CoA reductase activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the DEGs were mainly enriched in fatty acid metabolism and lysosome pathways. We detected the relative expression of silkworm genes related to fatty acid synthesis and decomposition pathways and the degradation pathway of juvenile hormone by quantitative real-time PCR. The expression levels of Acetyl CoA carboxylase (ACC), fatty acyl-CoA reductase (FACR), Enoyl-CoA hydratase (ECH), very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase (LCHAD), juvenile hormone epoxide hydrolase (JHEH), and phytanoyl-CoA dioxygenase (PCD) genes were downregulated. These data demonstrate the effects of spirotetramat on silkworm and its effects on genes involved in fatty acid metabolism.

Accelerated and Concerted Aza-Michael Addition and SuFEx Reaction in Microdroplets in Unitary and High-Throughput Formats.

The sulfur fluoride exchange (SuFEx) reaction is significant in drug discovery, materials science, and chemical biology. Conventionally, it involves installation of SO2 F followed by fluoride exchange by a catalyst. We report catalyst-free Aza-Michael addition to install SO2 F and then SuFEx reaction with amines, both occurring in concert, in microdroplets under ambient conditions. The microdroplet reaction is accelerated by a factor of ∼104 relative to the corresponding bulk reaction. We suggest that the superacidic microdroplet surface assists SuFEx reaction by protonating fluorine to create a good leaving group. The reaction scope was established by performing individual reactions in microdroplets of 18 amines in four solvents and confirmed using high-throughput desorption electrospray ionization experiments. The study demonstrates the value of microdroplet-assisted accelerated reactions in combination with high-throughput experimentation for characterization of reaction scope.

Two-photon absorption and triplet excited state quenching of near-IR region aza-BODIPY photosensitizers via a triphenylamine moiety despite heavy bromine atoms.

Aza-BODIPY compounds with methoxy groups at -3 and -5 and triphenylamine moieties at -1 and -7 positions with and without heavy bromine atoms at -2 and -6 positions have been designed and synthesized. The chemical structures of the novel compounds were fully characterized using 1H NMR, 13C NMR, FTIR, and HRMS-TOF-ESI techniques. Steady-state absorption and emission features were investigated to analyze ground-state interactions. The effects of triphenylamine moieties and bromine atoms on charge transfer dynamics and two-photon absorption (TPA) properties were investigated using femtosecond transient absorption spectroscopy measurements and open-aperture (OA) Z-scan experiments, respectively. Contrary to popular belief, the compound containing heavy bromine atoms and triphenylamine moieties did not demonstrate any triplet transition. Since the triphenylamine moiety has high electron-donating properties and a long conjugation length, it exhibited intramolecular charge transfer (ICT) features from electron-donating moieties to the aza-BODIPY core. Additionally, it is concluded that the excited-state lifetime is shortened in the presence of a bromine atom with triphenylamine moieties. This result is rather interesting since the triplet excited state is quenched by the triphenylamine moiety despite the presence of a heavy bromine atom. The performed OA Z-scan experiments revealed that the aza-BODIPY compound containing bromine atoms has a higher TPA cross-section value (116 GM) due to efficient intramolecular charge transfer compared to that without bromine atoms (89 GM). Additionally, in the theoretical calculations, it was found that the charge transfer percentage (CT%) was the strongest in compounds containing bromine atoms.

Palladium-catalyzed annulative π-extension of o-halobiphenyls with o-chloropyridinecarboxylic acids to access azatriphenylenes.

A palladium-catalyzed bay-region annulative π-extension reaction of o-halobiphenyls with o-chloropyridinecarboxylic acids was developed. The reaction was carried out with a 1 : 1 ratio of substrates. A variety of azatriphenylene derivatives could be synthesized by this approach. This transformation could be applied to the synthesis of ionic liquid-crystalline molecules.

Identification, isolation, characterization, and synthesis of impurities of pesticide spirotetramat.

Research work featured in this article describes the impurity profile of spirotetramat, a widely used broad-spectrum pesticide targeting acetyl-CoA carboxylase. Technical grade spirotetramat from four different sources were analyzed and compared with commercial Movento using UPLC-MS. Seven potential impurities were detected and six of them except for the trans-isomer of spirotetramat were subsequently isolated using preparative HPLC. All impurities were characterized mainly by MS and NMR spectroscopy and their structures were further confirmed by chemical synthesis. The formation of the impurities was described in this report as well.

Regioselectivity in inhibition of peptide deformylase from Haemophilus influenzae by 4- vs 5-azaindole hydroxamic acid derivatives: Biochemical, structural and antimicrobial studies.

Ribosome assisted protein synthesis in all prokaryotes begins with a formylated methionine. Deformylation and demethionylation of these newly synthesized proteins are critical co-translational events carried out by peptide deformylase (PDF) and methionine aminopeptidase (MetAP) in all living cells. Since the mechanism of N-terminal modification is common between the infectious microbes and the host human cells, it is a challenge to identify selective inhibitors. Given that both MetAP and PDF are metalloenzymes, and have strong affinity for hydroxamic acids, we reasoned that the azaindole-based hydroxamic acids could inhibit the PDF enzymes. In the present study we describe the screening of a 17-compound library with 4- and 5- substituted azaindole hydroxamic acid derivatives against PDF enzyme from H. influenzae (HiPDF), M. tuberculosis (MtPDF) and human PDF (HsPDF). Several of these molecules showed nanomolar inhibition against HiPDF enzyme, best at 21 nM (15). On the other hand, none of these compounds inhibited the human enzyme while only two molecules showed moderate inhibition against Mtb enzyme. Surprisingly only 5-substituted azaindole derivatives inhibited the PDF enzymes. Some of the 5-substituted azaindole compounds inhibited the growth of different microbes indicating their potential application in antimicrobial therapy. Crystallographic and modeling studies provided the mechanistic view of regioselective inhibition.

Design, synthesis, and antitumor study of a series of novel 1-Oxa-4-azaspironenone derivatives.

A series of 1-oxa-4-azaspiro[4,5]deca-6,9-diene-3,8-dione derivatives containing structural fragments of conjugated dienone have been synthesized previously by our group, however the Michael addition reaction between conjugated dienone and nucleophilic groups in the body may generate harmful and adverse effects. To reduce harmful side effects, the authors started with p-aminophenol to make 1-oxo-4- azaspirodecanedione derivatives, then utilized the Michael addition and cyclopropanation to eliminate α, ß unsaturated olefinic bond and lower the Michael reactivity of the compounds in vivo for optimization. At the same time, heteroatoms are put into the molecules in order to improve the hydrophilicity of the molecules and the binding sites of the molecules and the target molecules, establishing the groundwork for improved antitumor activity. The majority of the compounds had moderate to potent activity against A549 human lung cancer cells, MDA-MB-231 breast cancer cells, and Hela human cervical cancer cells. Among them, the compound 6d showed the strongest effect on A549 cell line with IC50 of 0.26 µM; the compound 8d showed the strongest cytotoxicity on MDA-MB-231 cell line with IC50 of 0.10 µM; and the compound 6b showed the strongest activity on Hela cell line with IC50 of 0.18 µM.

Spirotetramat resistance in Myzus persicae (Sulzer) (Hemiptera: Aphididae) and its association with the presence of the A2666V mutation.

BACKGROUND: Chemicals are widely used to protect field crops against aphid pests and aphid-borne viral diseases. One such species is Myzus persicae (Sulzer), a global pest that attacks a broad array of agricultural crops and transmits many economically damaging plant viruses. This species has evolved resistance to a large number of insecticide compounds as a result of widespread and repeated chemical use in many parts of the world. In this study, we investigated the evolution of resistance to a new plant protection product, spirotetramat, following reported chemical control failures. RESULTS: Our study provides clear phenotypic and genotypic evidence of spirotetramat resistance in populations of M. persicae from Australia. We show there is cross-resistance to other insecticides within the same chemical group, namely spiromesifen and spirodiclofen. We also demonstrate that resistance is associated with the previously reported mutation, A2226V in the target site of spirotetramat, acetyl-CoA carboxylase. Our genetic analysis found all resistant M. persicae populations belong to the same multi-locus clonal type and carry the A2226V mutation, which appears to be inherited as a dominant trait in this species. CONCLUSION: Our findings provide new insight into the resistance conferred by A2226V and have implications for the control of M. persicae in Australia and worldwide. A diagnostic assay developed in this study should serve as a valuable tool for future resistance monitoring and to support the implementation of pest management strategies. © 2022 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.