Microbial detoxification of chlorpyrifos, profenofos, monocrotophos, and dimethoate by a multifaceted rhizospheric Bacillus cereus strain PM38 and its potential for the growth promotion in cotton.

Bacillus genera, especially among rhizobacteria, are known for their ability to promote plant growth and their effectiveness in alleviating several stress conditions. This study aimed to utilize indigenous Bacillus cereus PM38 to degrade four organophosphate pesticides (OPs) such as chlorpyrifos (CP), profenofos (PF), monocrotophos (MCP), and dimethoate (DMT) to mitigate the adverse effects of these pesticides on cotton crop growth. Strain PM38 exhibited distinct characteristics that set it apart from other Bacillus species. These include the production of extracellular enzymes, hydrogen cyanide, exopolysaccharides, Indol-3-acetic acid (166.8 µg/mL), siderophores (47.3 µg/mL), 1-aminocyclopropane-1-carboxylate deaminase activity (32.4 µg/mL), and phosphorus solubilization (162.9 µg/mL), all observed at higher concentrations. This strain has also shown tolerance to salinity (1200 mM), drought (20% PEG-6000), and copper and cadmium (1200 mg/L). The amplification of multi-stress-responsive genes, such as acdS, ituC, czcD, nifH, sfp, and pqqE, further confirmed the plant growth regulation and abiotic stress tolerance capability in strain PM38. Following the high-performance liquid chromatography (HPLC) analysis, the results showed striking compatibility with the first kinetic model. Strain PM38 efficiently degraded CP (98.4%), PF (99.7%), MCP (100%), and DMT (95.5%) at a concentration of 300 ppm over 48 h at 35 °C under optimum pH conditions, showing high coefficients of determination (R2) of 0.974, 0.967, 0.992, and 0.972, respectively. The Fourier transform infrared spectroscopy (FTIR) analysis and the presence of opd, mpd, and opdA genes in the strain PM38 further supported the potential to degrade OPs. In addition, inoculating cotton seedlings with PM38 improved root length under stressful conditions. Inoculation of strain PM38 reduces stress by minimizing proline, thiobarbituric acid-reactive compounds, and electrolyte leakage. The strain PM38 has the potential to be a good multi-stress-tolerant option for a biological pest control agent capable of improving global food security and managing contaminated sites.

How the chemical structure of phosphoramides affect the fire retardancy and mechanical properties of polylactide?

Phosphoramides, as a kind of high-efficient fire retardants, have been designed in many structures and endowed exceptional fire retardancy to polylactide (PLA). However, due to ignorance of the structure-property correlation, the effect of phosphoramides' structure on the fire retardancy and mechanical properties of PLA is still unclear. Herein, a series of biobased phosphoramides (phosphoramide (V1), linear polyphosphoramide (V2) and hyperbranched polyphosphamide (V3)) were designed and incorporated into PLA, and the structural effect of phosphoramides on the fire-retardant and mechanical properties of PLA was deeply researched. Among three kinds of phosphoramides, the hyperbranched polyphosphoramide is more effective than the corresponding linear polyphosphoramide and phosphoramide in improving the fire-retardant and anti-dripping properties of PLA, and only linear polyphosphoramide shows a positive effect in the mechanical strength of PLA. This work provides a feasible strategy for creating mechanically robust and fire-retardant polymer composites by molecularly tailoring the structure of fire retardants and uncovering their structure-property relationship.

Phosphoramidate Azole Oligonucleotides for Single Nucleotide Polymorphism Detection by PCR.

Detection of the Kirsten rat sarcoma gene (KRAS) mutational status is an important factor for the treatment of various malignancies. The most common KRAS-activating mutations are caused by single-nucleotide mutations, which are usually determined by using PCR, using allele-specific DNA primers. Oligonucleotide primers with uncharged or partially charged internucleotide phosphate modification have proved their ability to increase the sensitivity and specificity of various single nucleotide mutation detection. To enhance the specificity of single nucleotide mutation detection, the novel oligonucleotides with four types of uncharged and partially charged internucleotide phosphates modification, phosphoramide benzoazole (PABA) oligonucleotides (PABAO), was used to prove the concept on the KRAS mutation model. The molecular effects of different types of site-specific PABA modification in a primer or a template on a synthesis of full-length elongation product and PCR efficiency were evaluated. The allele-specific PCR (AS-PCR) on plasmid templates showed a significant increase in analysis specificity without changes in Cq values compared with unmodified primer. PABA modification is a universal mismatch-like disturbance, which can be used for single nucleotide polymorphism discrimination for various applications. The molecular insights of the PABA site-specific modification in a primer and a template affect PCR, structural features of four types of PABAO in connection with AS-PCR results, and improvements of AS-PCR specificity support the further design of novel PCR platforms for various biological targets testing.

Anti-cancer Activity of New Phosphoramide-functionalized Graphene Oxides: An Experimental and Theoretical Evaluation.

BACKGROUND: Graphene oxide (GO)-based systems are among the drug delivery systems and have drawn a lot of interest in the field of medicine. METHODS: In this work, two novel phosphoramides with the formulas of (NHCHCH2C(CH3)2NHC(CH3)2CH2P(S)(OEt)2 (L1) and (NHCHCH2C(CH3)2 NHC (CH3)2CH2P (O) (NHC6H5) (OC5H6) (L2) were synthesized and characterized by spectroscopic methods. Then, graphene oxide (GO) was functionalized by L1 and L2. FT-IR, XRD, FE- SEM/ MAP, and Zeta potential analyses were applied to confirm the synthesis of phosphoramide-functionalized graphene oxides (GO-L1 and GO-L2). Cytotoxicity of synthesized compounds was evaluated against breast cancer cell line (SK-BR-3) using MTT assay. Moreover, the flow cytometry assay was performed to evaluate the cell death mechanisms. RESULTS: The results showed that GO-L1 and GO-L2 had a more inhibitory effect against cancer cells than that of L1 and L2, and GO-L2 showed the highest cytotoxicity with an IC50 value of 38.13 µg/ml. Quantum calculations were employed to optimize structures. HOMO and LUMO energy values and physical adsorption of synthesized compounds were obtained by the DMol3 module in the Material Studio 2017. The docking studies were used to investigate the binding of L1, L2, GO-L1, and GO-L2 to DNA polymerase IIα. CONCLUSION: Anticancer activity of phosphoramide compounds was increased after attachment on the GO surface, and the docking studies' results were in good accordance with the experimental cytotoxicity results.

Standardized Field Trials in Cotton and Bioassays to Evaluate Resistance of Tobacco Thrips (Thysanoptera: Thripidae) to Insecticides in the Southern United States.

Foliar-applied insecticide treatments may be necessary to manage thrips in cotton (Gossypium hirsutum L.) under severe infestations or when at-planting insecticide seed treatments do not provide satisfactory protection. The most common foliar-applied insecticide is acephate. Field observations in Tennessee suggest that the performance of acephate has declined. Thus, the first objective was to perform leaf-dip bioassays to assess if tobacco thrips, Frankliniella fusca (Hinds) (Thysanoptera: Thripidae), in cotton production regions have evolved resistance to foliar-applied insecticides. A second objective was to assess the performance of commonly applied foliar insecticides for managing thrips in standardized field trials in Arkansas, Tennessee, Mississippi, and Texas. For both objectives, several insecticides were evaluated including acephate, dicrotophos, dimethoate, lambda-cyhalothrin, imidacloprid, and spinetoram. Field trials and bioassays were completed from 2018 to 2021. Dose-response bioassays with acephate were performed on tobacco thrips field populations and a susceptible laboratory population. Bioassay results suggest that tobacco thrips have developed resistance to acephate and other organophosphate insecticides; however, this resistance seems to be most severe in Arkansas, Tennessee, and the Delta region of Mississippi. Resistance to other classes of insecticides were perhaps even more evident in these bioassays. The performance of these insecticides in field trials was variable, with tobacco thrips only showing consistent signs of resistance to lambda-cyhalothrin. However, it is evident that many populations of tobacco thrips are resistant to multiple classes of insecticides. Further research is needed to determine heritability and resistance mechanism(s).

New poly(ether-phosphoramide)s sulfides based on green resources as sensitive films for the specific impedimetric detection of nickel ions.

For the development of selective and sensitive chemical sensors, we have developed a new family of poly(ether-phosphoramide) polymers. These polymers were obtained with satisfactory yields by nucleophilic aromatic polycondensation using isosorbide as green resources, and bisphenol A with two novel difluoro phosphinothioic amide monomers. Unprecedented, the thiophosphorylated aminoheterocycles monomers, functionalized with two heterocyclic amine, N-methylpiperazine and morpholine were successfully obtained by nucleophilic substitution reaction of P(S)-Cl compound. The resulting polymers were characterized by different analytical techniques (NMR, MALDI-ToF MS, GPC, DSC, and ATG). The resulting partially green polymers, having tertiary phosphine sulfide with P-N side chain functionalities along the main chain of polymers are the sensitive film at the surface of a gold electrode for the impedimetric detection of Cd, Ni, Pb and Hg. The bio-based poly(ether-phosphoramide) functionalized with N-methylpiperazine modified sensor showed better analytical performance than petrochemical based polymers for the detection of Ni2+. A detection limit of 50 pM was obtained which is very low compared to the previously published electrochemical sensors for nickel detection.

Enantioseparation and dissipation of acephate and its highly toxic metabolite methamidophos in pakchoi by supercritical fluid chromatography tandem mass spectrometry.

Acephate is widely used in crops as racemate. However, the enantioselective dissipation of acephate enantiomers has not been investigated in pakchoi. A sensitive and effective approach was established for determining residues of acephate and its highly toxic metabolite methamidophos enantiomers by supercritical fluid chromatography tandem mass spectrometry. Baseline separations for their enantiomers were achieved by using a Chiralcel OD-H column. The optimal chromatographic conditions were obtained as follows: CO2 /ethanol (95/5) as mobile phase; flow rate, 3.0 mL/min; column temperature, 40°C. The mean recoveries (RSDs) of analytes were in the range of 77-83.1% (6.1-9.9%), 75.4-87.5% (9.3-13.2%), and 81.5-84.2% (7.1-13.4%) at three fortification levels (0.005, 0.05, and 0.5 mg/kg for each enantiomer) for interday assay (n = 18). The method was used to evaluate the enantioselective dissipation of acephate and methamidophos in pakchoi. S-acephate dissipated faster than R-acephate, while the concentration of R-methamidophos was higher than that of S-methamidophos during the entire study period. The results indicated that the R-enantiomer of acephate and methamidophos was preferentially enriched in pakchoi. The established analysis approach and the study data provided useful information for the rational use of acephate in agriculture.

New phosphoramides containing imidazolidine moiety as anticancer agents: An experimental and computational study.

In this study, two new phosphoramides containing imidazolidine; diphenyl (2-imidazolidinone-1-yl)phosphonate (DIOP) and diphenyl (2-Imidazolidinethione -1-yl)phosphonate (DITP) as cytotoxic agents, were synthesized and characterized by using IR, 1H NMR, 13C NMR, 31P NMR, Mass spectroscopy and elemental analysis. The target products were obtained in moderate to good yields (69-86%) by using the time (3 h) and solvent (MeCN). The crystal structure of DIOP was investigated using X-ray crystallography. The main non-covalent intermolecular interactions were also studied by Hirshfeld surface analysis and fingerprint plots. The anticancer and growth inhibitory activities of the synthesized compounds were investigated against human breast cancer cell line MDA-MB-231 using MTT assay; DITP was found to be a better cytotoxic agent than DIOP. The cytotoxicity results were supported by a molecular docking study and in order to know the structure-activity relationship (SAR) of synthesized compounds, the values of HOMO and LUMO energies, dipole moments, hardness, softness, and electrophilicity index were investigated computationally by DFT method. These results were in good accordance with those of in vitro investigation and molecular docking study.

Synthesis, characterization, cytotoxicity studies, theoretical approach of adsorptive removal and molecular calculations of four new phosphoramide derivatives and related graphene oxide.

In this study, four novel phosphoramide ligands (L1-L4) are synthesized and characterized by 31PNMR, 1HNMR, MASS, and FT-IR spectroscopies. In vitro cell growth inhibition is studied by the MTT assay to evaluate the cytotoxicity of ligands against MCF-7 cell line; the result of the assay demonstrates that all ligands significantly suppress the proliferation of breast cancer cells in a concentration-dependent manner. The calculated IC50 values are in the range of 3.6-10.77 µg ml-1, of which the lowest value is attributed to L1. Then a facile approach was developed to functionalize graphene oxide (GO) surface by L1. The data which are obtained by XRD, FT-IR, and EDX analysis confirmed the deposition of phosphoramide on the surface of GO. The cell viability of GO-L1 compound at different concentrations is investigated in 24 h experiment. Excellent synergistic antitumor effects of GO and L1 lead to a decrease in IC50 value up to 2.13 µg ml-1. The Quantum calculations of compounds are used to study energies and HOMO and LUMO values, dipole moments (µ), global hardness (η), global softness (σ), and electrophilicity index (ω) using DMol3 module in Material studio2017. The docking calculations are performed to describe the mode of the binding to DNA and DNA polymerase IIα. Adsorption calculations of ligands (L1-L4) on GO sheet in the presence of water showed that L1 and L2 were located on GO via π electrons of anisole ring. While, L3 and L4 were located on GO by π - π interactions of aniline ring.

Avoidance behavior of Eisenia fetida and Metaphire posthuma towards two different pesticides, acephate and atrazine.

The avoidance behavior is regarded as the method that provides first hand information about the behavior of an organism in the presence of contaminants in the soil. Very little data is found in literature regarding the effect of pesticides on tropical earthworms. Two pesticides, acephate and atrazine which are widely used in Indian tropical area were investigated for their avoidance behavior on standard species, E. fetida (ISO 2007) and on a tropical species, M. posthuma. The avoidance tests are rarely replicated on tropical species, M. posthuma in comparison to standard species, E. fetida or E. andrei. The standard avoidance test (ISO 2007) was taken into consideration for two different species of earthworm. Significant difference in the distribution of earthworms in the control and test soils was found depicting that soil composition plays a vital role in affecting the distribution of worms. The results also show higher sensitivity of E. fetida in comparison to M. posthuma in terms of avoidance response for both the pesticides. For risk assessment, the soil types and indigenous soil species of earthworms must be taken into consideration for evaluation of soil contamination. Avoidance tests forms the basis to study the molecular mechanisms underlying the receptor proteins responsible for the process of chemesthesis in annelids.

AT-527, a Double Prodrug of a Guanosine Nucleotide Analog, Is a Potent Inhibitor of SARS-CoV-2 In Vitro and a Promising Oral Antiviral for Treatment of COVID-19.

The impact of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, is global and unprecedented. Although remdesivir has recently been approved by the FDA to treat SARS-CoV-2 infection, no oral antiviral is available for outpatient treatment. AT-527, an orally administered double prodrug of a guanosine nucleotide analog, was previously shown to be highly efficacious and well tolerated in hepatitis C virus (HCV)-infected subjects. Here, we report the potent in vitro activity of AT-511, the free base of AT-527, against several coronaviruses, including SARS-CoV-2. In normal human airway epithelial cells, the concentration of AT-511 required to inhibit replication of SARS-CoV-2 by 90% (EC90) was 0.47 µM, very similar to its EC90 against human coronavirus (HCoV)-229E, HCoV-OC43, and SARS-CoV in Huh-7 cells. Little to no cytotoxicity was observed for AT-511 at concentrations up to 100 µM. Substantial levels of the active triphosphate metabolite AT-9010 were formed in normal human bronchial and nasal epithelial cells incubated with 10 µM AT-511 (698 ± 15 and 236 ± 14 µM, respectively), with a half-life of at least 38 h. Results from steady-state pharmacokinetic and tissue distribution studies of nonhuman primates administered oral doses of AT-527, as well as pharmacokinetic data from subjects given daily oral doses of AT-527, predict that twice daily oral doses of 550 mg AT-527 will produce AT-9010 trough concentrations in human lung that exceed the EC90 observed for the prodrug against SARS-CoV-2 replication. This suggests that AT-527 may be an effective treatment option for COVID-19.

A novel phosphoramide compound, DCZ0847, displays in vitro and in vivo anti-myeloma activity, alone or in combination with bortezomib.

Multiple myeloma (MM) is an incurable hematological malignancy, for which novel effective therapies are urgently needed. We synthesized a novel phosphoramide compound, DCZ0847, showing a potent anti-myeloma activity both in vitro and in vivo. DCZ0847 showed high cytotoxicity towards primary MM cells but had no effect on normal cells and was well tolerated in vivo. The anti-myeloma activity of DCZ0847 was associated with inhibition of cell proliferation; promotion of cell apoptosis via mitochondrial transmembrane potential collapse and caspase-mediated extrinsic or intrinsic apoptotic pathways; and the induction of G2/M phase arrest via downregulation of CDC25C, CDK1, and cyclin B1. In particular, DCZ0847 induced DNA damage and triggered a DNA-damage response by enhancing the levels of γ-H2A.X, phosphorylated (p)-ATM, p-ATR, p-Chk1, and p-Chk2. Additionally, DCZ0847 was able to overcome the bone marrow stromal cells-induced proliferation of MM cells and blocked JAK2/STAT3 signaling. Importantly, DCZ0847 acted synergistically with bortezomib, with the combination exerting greater cytotoxic effects in vitro and in vivo. Together, our results indicate that DCZ0847, alone or in combination with bortezomib, may represent a potential new therapy for patients with MM.

Acephate interferes with androgen synthesis in rat immature Leydig cells.

Acephate is an organophosphate pesticide. It is widely used. However, whether it inhibits androgen synthesis and metabolism remains unclear. In the current study, we investigated the effect of acephate on the inhibition of androgen synthetic and metabolic pathways in rat immature Leydig cells after 3-h culture. Acephate inhibited basal androgen output in a dose-dependent manner with the inhibition starting at 0.5 µM. It significantly inhibited luteinizing hormone and 8-Br-cAMP stimulated androgen output at 50 µM. It significantly inhibited progesterone-mediated androgen output at 50 µM. Further study demonstrated that acephate down-regulated the expression of Hsd3b1 and its protein at ≥ 0.5 µM, Lhcgr at 5 µM and Star at 50 µM. Acephate directly blocked rat testicular HSD3B1 activity at 50 µM. Acephate did not affect other androgen synthetic and metabolic enzyme activities as well as ROS production, proliferation, and apoptosis of immature Leydig cells. In conclusion, acephate targets LHCGR, STAR, and HSD3B1, thus blocking androgen synthesis in rat immature Leydig cells and HSD3B1 is being the most sensitive target of acephate.

Dynamic surface-enhanced Raman spectroscopy for the detection of acephate residue in rice by using gold nanorods modified with cysteamine and multivariant methods.

Dynamic surface-enhanced Raman spectroscopy (D-SERS) was employed for the rapid detection of acephate in rice with simply regulated gold nanorods. Gold nanorods modified with cysteamine were prepared to circumvent the weak affinity of acephate molecules to the gold surface for a gigantic and stable enhancement. D-SERS was adopted to measure spectra of acephate residue at a range of 100.2-0.5 mg/L in rice samples, and the low residue of 0.5 mg/L can be still detected. Multivariant methods in machine or deep learning were used to develop the regression models for the automatic analysis of acephate residue level. Partial least squares regression and principal component analysis obtained the optimal performance with the root-mean-square error (RMSE) of validation of 5.4776, coefficient of determination (R2) of validation of 0.9560, RMSE of prediction of 6.2845, and R2 of prediction of 0.9541. Thus, the proposed method provides accurate and sensitive detection for acephate in rice.

Rapid monitoring of pesticides in tomatoes (Solanum lycopersicum L.) during pre-harvest intervals by paper spray ionization mass spectrometry.

A rapid analysis of acephate, chlorpyrifos, and cyazofamid in tomato peels during pre-harvest intervals using paper spray ionization mass spectrometry (PSI-MS) has been demonstrated. LODs of 0.01 ppm and LOQs of 0.03 ppm were achieved. Relative standard deviations were below 9%, and recoveries close to 100%. For pesticides monitoring, samples were separated into stored and field groups. Stored group contained fruits that were harvested and stored at low temperature during the pre-harvest interval, and the field group contained fruits that were on the agricultural field over the pre-harvest interval. The decrease in pesticide amounts was lower for the stored samples. At the end of the pre-harvest intervals, acephate, chlorpyrifos, and cyazofamid were determined at 0.86, 0.96, and 0.23 ppm in the stored group, and at 0.26, 0.37, and 0.09 ppm in the field group, respectively. This work demonstrates the utility of PSI-MS for performing rapid quality control of fruit harvesting.

Method development for simultaneous determination of polar and nonpolar pesticides in surface water by low-temperature partitioning extraction (LTPE) followed by HPLC-ESI-MS/MS.

During this research, chemometric approaches were applied for optimization of the low-temperature partitioning extraction (LTPE) for the simultaneous analysis of the pesticides: acephate, difenoconazole, fenamidone, fluazifop, fluazinam, methamidophos, and thiamethoxam from surface water samples and determination by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. It was used the 23 full factorial and the Doehlert experimental designs. The extraction technique was optimized by evaluating the effects of the three variables: sample pH, ionic strength (addition of Na2HPO4), and organic solvent volume. Considering the interest to find an optimal condition for all analytes simultaneously, the best extraction parameters found were as follows: pH = 5.33, concentration of Na2HPO4 = 0.0088 mol L-1 and organic phase volume = 4.5 mL. The optimized methodology showed LOD and LOQ levels from 0.33 to 8.13 ng L-1 and from 1.09 to 26.84 ng L-1, respectively. The recovery values ranged from 38.37 and 99.83% and the RSD values varied from 2.33 to 18.92%. The method was applied to surface water analysis sampled in areas with intensive agricultural practices in Ouro Branco City, Minas Gerais, Brazil. The difenoconazole was detected in concentrations between 12.53 and 94.76 ng L-1.

A high-specificity immunoassay for the therapeutic drug monitoring of cyclophosphamide.

Personalized medicine is pushing forward new diagnostic techniques to aid in controlling drug therapeutic levels and their toxic effects. This study aims to develop a high-throughput screening method for therapeutic drug monitoring (TDM) and occupational exposure of cyclophosphamide (CP), an alkylating agent used as a chemotherapeutic and immunosuppressive drug. In order to achieve this goal, an immunizing hapten that exposes the cyclophosphamide moiety has been designed for the first time. Antibodies produced against this hapten have been used to develop an indirect competitive ELISA for the quantification of CP with high specificity and low cross-reactivity with some metabolites and other anticancer drugs. The assay obtained showed a LOD of 22 ± 6 nM in serum samples, with concentrations much below the blood CP levels of patients treated with the drug. A new tool for the detection and quantification of CP is provided which could be relevant for future pharmacokinetic studies and for therapeutic index improvement.

In Silico Study of the Resistance to Organophosphorus Pesticides Associated with Point Mutations in Acetylcholinesterase of Lepidoptera: B. mandarina, B. mori, C. auricilius, C. suppressalis, C. pomonella, H. armígera, P. xylostella, S. frugiperda, and S. litura.

An in silico analysis of the interaction between the complex-ligands of nine acetylcholinesterase (AChE) structures of Lepidopteran organisms and 43 organophosphorus (OPs) pesticides with previous resistance reports was carried out. To predict the potential resistance by structural modifications in Lepidoptera insects, due to proposed point mutations in AChE, a broad analysis was performed using computational tools, such as homology modeling and molecular docking. Two relevant findings were revealed: (1) Docking results give a configuration of the most probable spatial orientation of two interacting molecules (AChE enzyme and OP pesticide) and (2) a predicted ΔGb. The mutations evaluated in the form 1 acetylcholinesterase (AChE-1) and form 2 acetylcholinesterase (AChE-2) structures of enzymes do not affect in any way (there is no regularity of change or significant deviations) the values of the binding energy (ΔGb) recorded in the AChE-OPs complexes. However, the mutations analyzed in AChE are associated with a structural modification that causes an inadequate interaction to complete the phosphorylation of the enzyme.

Synthesis and Anti-HCV Activities of 4'-Fluoro-2'-Substituted Uridine Triphosphates and Nucleotide Prodrugs: Discovery of 4'-Fluoro-2'- C-methyluridine 5'-Phosphoramidate Prodrug (AL-335) for the Treatment of Hepatitis C Infection.

We report the synthesis and biological evaluation of a series of 4'-fluoro-2'- C-substituted uridines. Triphosphates of the uridine analogues exhibited a potent inhibition of hepatitis C virus (HCV) NS5B polymerase with IC50 values as low as 27 nM. In an HCV subgenomic replicon assay, the phosphoramidate prodrugs of these uridine analogues demonstrated a very potent activity with EC50 values as low as 20 nM. A lead compound AL-335 (53) demonstrated high levels of the nucleoside triphosphate in vitro in primary human hepatocytes and Huh-7 cells as well as in dog liver following a single oral dose. Compound 53 was selected for the clinical development where it showed promising results in phase 1 and 2 trials.

Differential impacts of pesticides on Euschistus heros (Hem.: Pentatomidae) and its parasitoid Telenomus podisi (Hym.: Platygastridae).

Euschistus heros (Fabricius) (Hemiptera: Pentatomidae) primarily attack the pods and seeds of soybean plants, causing severe economic losses in Neotropical Region, and chemical control is essential to avoid these losses. Thus, insecticides more effective against this pest and less toxic to Telenomus podisi Ashmead (Hymenoptera: Platygastridae) - the main biological control agent of E. heros - should be used. In this report, we studied the differential acute impacts of pesticides used in Brazilian soybean against E. heros and T. podisi and evaluated their sublethal effects on the parasitoid to identify effective pesticides towards the pest with less harmful effect to the natural enemy. The LC50 of the insecticides to E. heros ranged from 1.20 to 533.74 ng a.i./cm2; the order of toxicity was thiamethoxam + lambda-cyhalothrin > acetamiprid + fenpropathrin > zeta-cypermethrin > acephate > imidacloprid. All pesticides were classified as slightly to moderately toxic to T. podisi based on the risk quotient. The exposure of T. podisi females to imidacloprid and the insecticide pre-formulated mixtures reduced the emergence of the offspring parasitoids by up to 40% whereas zeta-cypermethrin and the insecticides pre-formulated mixtures reduced offspring survival. The preferred order of choice of insecticides for the management of E. heros according to agronomic, toxicological, and environmental feasibility was the following: thiamethoxam + lambda-cyhalothrin > zeta-cypermethrin > acetamiprid + fenpropathrin > acephate > imidacloprid. Our study provides important and pioneer information to select insecticides for effective control of E. heros with lower impacts on T. podisi.