Design, Synthesis, and Insecticidal Activities of Novel meta-Diamide Compounds Containing Ethyl Acetate and Their Derivatives.

In this study, a series of meta-diamide compounds containing ethyl acetate group and their derivatives were designed and synthesized. Their insecticidal activities against Plutella xylostella, Spodoptera frugiperda and Alfalfa sprouts were evaluated. Preliminary bioassays showed that some of the title compounds exhibited excellent insecticidal activities. Especially compound ethyl N-(3-((2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(4-cyanobenzoyl)glycinate and ethyl N-(3-((2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(6-fluoronicotinoyl)glycinate showed 100 % mortality at 0.1 mg/L against Plutella xylostella and Spodoptera frugiperda, same to broflanilide. Their LC50 against Plutella xylostella is 0.286 mg/L and 0.0218 mg/L, respectively. Moreover, compound ethyl N-(3-((2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(6-fluoronicotinoyl)glycinate displayed faster control efficacy than broflanilide at 0.1 mg/L. The results indicated that meta-diamide compounds containing ethyl acetate group could be developed as novel and promising insecticides.

Synthesis and structure-activity relationships of novel furazan-3,4-diamide analogs as potent anti-cancer agents.

This study describes the synthesis and structure-activity relationships of a series of furazan-3,4-diamide analogs. 1,2,5-Oxadiazole ring and electron-withdrawing substituent on the phenyl ring are proposed to be the important elements which contribute to a significant extent maximal potency of anti-proliferation effect.

Development and validation of a method for the analysis of five diamide insecticides in edible mushrooms using modified QuEChERS and HPLC-MS/MS.

In this study, a new method for simultaneous determination of cyantraniliprole, chlorantraniliprole, tetrachlorantraniliprole, cyclaniliprole and flubendiamide in edible mushrooms by high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) combined with a modified QuEChERS procedure. The samples were extracted using acetonitrile and then cleaned up by primary secondary amine (PSA) and octadecylsilane (C18). The determination of these insecticides was achieved in less than 5 min using an electrospray ionization source in positive mode (ESI+) for cyantraniliprole and chlorantraniliprole, while negative mode (ESI-) for tetrachlorantraniliprole, cyclaniliprole and flubendiamide. The linearities of the calibrations for all target compounds were acceptable (R2 ≥ 0.9922). The limits of detection and quantification were 0.05-2 µg kg-1 and 5 µg kg-1, respectively. Acceptable recoveries (73.5-110.2%) were acquired for these insecticides with RSDs less than 12.7%. The results demonstrated that the proposed method was effective and convenient for the determination of these insecticides in edible mushrooms.

Ryanodine Receptors for Drugs and Insecticides: An Overview.

Ryanodine receptors (RyRs) are calcium channels located on the endo(sarco)plasmic reticulum of muscle cells and neurons. They regulate the release of stored intracellular calcium and play a critical role in muscle contraction. The N-terminal part of these receptors accounts for roughly 80% and contains the binding sites for diverse RyRs modulators. The C-terminal domain contains the transmembrane region. This review summarizes the current knowledge about the molecular biology of insect RyRs, chemicals targeting mammal or insect RyRs, and the reasons for mammal RyR-related diseases and diamides resistances. It may lay the foundation for effective management of mammal RyR-related diseases and diamides resistances.

Synthesis, insecticidal evaluation and 3D-QSAR study of novel anthranilic diamide derivatives as potential ryanodine receptor modulators.

BACKGROUND: Anthranilic diamide insecticides control lepidopteran pests through selectively binding and activating insect ryanodine receptors. In order to search for potential insecticides targeting the ryanodine receptors, a series of anthranilic diamide analogs including trifluoromethyl, nitro, or chloro groups were designed and synthesized by the principle of bioisosterism and structural optimization. RESULTS: Insecticidal data indicated that some compounds displayed good activity against oriental armyworm (Mythimna separata) and diamondback moth (Plutella xylostella). In particular, the larvicidal activity of 6p against P. xylostella was 95% at 0.01 mg L-1 , equivalent to chlorantraniliprole (85%, 0.01 mg L-1 ). The comparative molecular similarity index analysis model obtained indicated that hydrogen bond acceptor and electron-withdrawing groups in the R'3 group are favourable for insecticidal activity against M. separata, which is consistent with the structure-activity relationships. Moreover, the calcium imaging experiment indicated, like chlorantraniliprole, that 6h and 6p are interacting with the ryanodine receptor. CONCLUSION: Introducing trifluoromethyl, nitro, or chloro groups to a specific position in the N-phenylpyrazole could improve or maintain the activity against M. separata and P. xylostella. 6h and 6p could be used as potential lead compounds for ryanodine receptor modulators. © 2018 Society of Chemical Industry.

The mechanism of ureido-pyrimidinone:2,7-diamido-naphthyridine complexation and the presence of kinetically controlled pathways in multicomponent hydrogen-bonded systems.

The kinetics of association of ureido-pyrimidinone (U) dimers, present either in the 4[1H]-keto form or in the pyrimidin-4-ol form, with 2,7-diamido-1,8-naphthyridine (N) into a complementary heterodimer have been investigated. The formation of heterodimers with 2,7-diamido-1,8-naphthyridine from pyrimidin-4-ol dimers is much faster than from 4[1H]-pyrimidinone dimers. Using a combination of simple measurements and simulations, evidence for a bimolecular tautomerization step is presented. Finally, the acquired kinetic knowledge of the different pathways leading from ureido-pyrimidinone homodimers to ureido-pyrimidinone:diamido-naphthyridine (U:N) heterodimers allows the prediction and observation of kinetically determined ureido-pyrimidinone heterodimers which slowly convert back to the corresponding homodimers.

Synthesis and insecticidal activity study of novel anthranilic diamides analogs containing a diacylhydrazine bridge as effective Ca2+ modulators.

Anthranilic diamides is a class of insecticides target at ryanodine receptors (RyRs). To discover potent insecticides targeting at RyRs, a series of novel anthranilic diamides with a diacylhydrazine bridge were designed and synthesized. Their insecticidal activities were evaluated and a preliminary structure-activity relationship (SAR) was summarized. In particular, compound 5g exhibited good lethality against oriental armyworm (Mythimna separata) at a concentration of 5 mg/L. The calcium imaging experimental results indicated that the compound 5g can serve as effective insect Ca2+ level modulators by disrupting the cellular calcium homeostasis in Mythimna separata (Walker) and Spodoptera exigua (Hübner), which probably activated the RyRs on the ER membrane.

Quantifying the intrinsic effects of two point mutation models of proline-proline diamino acid diamide: a first-principle computational study.

Two sites of a Pro-Pro diamide were subjected to individual Pro --> Thr point mutations. The parent diamide Pro-Pro as well as selected conformers of the Pro-Thr and Thr-Pro mutant models were subjected to molecular computations at the B3LYP/6-31G(d) level of theory. At the optimized geometries, thermodynamic functions (S, H, and G) were computed. In order to assess relative stabilities of the mutant models, isodesmic reactions were constructed to calculate DeltaS, DeltaH, and DeltaG, relative to the initial Pro-Pro state. The importance of intramolecular hydrogen bonds, involving the -OH group of the Thr side chain, which emerged after the point mutations were also examined. Our findings suggest a novel approach to analyzing the stability of point mutants in peptide models through the analysis of thermodynamic functions.

Composites of malonic acid diamides and phospholipids--Impact of lipoplex stability on transfection efficiency.

The use of cationic lipids as gene delivery systems is a basic method in gene therapy. Through ongoing research, lipofection is currently the leader of non-viral vectors in clinical trials. However, in order to unleash the full potential of lipofection further intensive investigations are indispensable. In this study, various lipoplex formulations were compared regarding their ability to bind DNA. To obtain information about a possible premature release of DNA at the cell surface, heparin and chondroitin dependent lipoplex destabilization experiments were carried out. Complementary investigations in cell culture were performed to quantify DNA outside the cell. Additionally, DNase I stability was investigated. In this regard a multitude of methods, namely confocal laser scanning microscopy (CLSM), polymerase chain reaction (PCR), cell culture experiments, ethidium bromide assay, gel electrophoresis, Langmuir-isotherm experiments, infrared reflection absorption spectroscopy (IRRAS), Brewster angle microscopy (BAM), zeta-(ζ)-potential measurements, and dynamic light scattering (DLS), were applied. Although the complexation of DNA is a fundamental step, we show that the DNA release by biological agents (proteoglycans) and an unsuccessful cell attachment are major transfection limiting parameters.

Radiosensitization by diamide analogs and arsenicals.

Several analogs of the glutathione (GSH) oxidizing reagent diamide [diazenedicarboxylic acid bis(N,N'-diethylamide)] were tested as radiosensitizers of aerobic cells. In general, radiosensitization correlates with the rate of reaction with cellular reducing agents and occurs only when the reductive capacity of the cell is exceeded. SR-4077, [diazenedicarboxylic acid bis(N,N-piperidide)], is particularly suitable for mechanistic studies, because it is less cytotoxic than diamide, but is equally reactive toward cellular GSH. SR-4077 sensitizes CHO cells to X rays under aerobic conditions, even when the drug is added after irradiation. Radiosensitization is expressed both as a change in the exponential slope of the radiation cell survival curve and as a decrease in the shoulder of the survival curve. Phenylarsine oxide, a dithiol-binding reagent, sensitizes aerobic CHO cells to X rays by modification of the shoulder of the survival curve. The results are consistent with the hypothesis that the shoulder-modifying effect of GSH oxidants is caused by the loss of protein thiols, which might be involved in the repair of X ray-induced DNA damage.

Novel concepts in modification of radiation sensitivity.

PURPOSE: To determine whether biological effects of radiation, such as apoptosis, that differ from classical clonogenic cell killing, can be modified with agents that would not be expected to modify classical clonogenic cell killing. This would expand the range of potential modifiers of radiation therapy. METHODS AND MATERIALS: EL4 murine lymphoma cell apoptosis was determined by electrophoretic analysis of deoxyribonucleic acid (DNA) fragmentation. DNA was extracted 24 h after irradiation or addition of inducing agents. Modifiers of radiation-induced apoptosis were added immediately after irradiation. The effects of radiation on wounded endothelial monolayers were studied by scraping a line across the monolayer 30 min after irradiation. Cell detachment was used as an endpoint to determine the protective effect of prolonged exposure to retinol prior to irradiation. RESULTS: EL4 cell apoptosis can be induced by tert-butyl hydroperoxide or the glutathione oxidant SR-4077. Radiation-induced EL4 cell apoptosis can be inhibited with 3-aminobenzamide, an agent that sensitizes cells to classical clonogenic cell killing. Radiation-induced endothelial cell detachment from confluent monolayers can be modified by pretreatment with retinol. CONCLUSION: These results raise the possibility that radiation could induce apoptosis by an oxidative stress mechanism that is different from that involved in classical clonogenic cell killing. These and other recent findings encourage the notion that differential modification of classical clonogenic cell killing and other important endpoints of radiation action may be possible.

Dicarboxylate diamide dimercaptide (N2S2) technetium-99m complexes: synthesis and biological evaluation as potential renal radiopharmaceuticals.

Novel diamide dimercaptide (N2S2) ligands 4, 5, and 8 have been synthesized and evaluated as potential renal radiopharmaceuticals. The target compounds were prepared in modest overall yields of 22%, 19%, and 20%, respectively, using readily available starting materials. Following in situ deprotection, 99mTc complexes of high radiochemical purity were obtained in excellent yield and were found to be stable for up to 6 h. The 99Tc complex of ligand 8 was isolated as the AsPh4 salt. The X-ray crystallographic data for [99TcO(8)]AsPh4 (space group P2(1)/n: Z = 4, a = 9.342(3) A; b = 18.594(5) A; c = 18.417(7) A; beta, deg = 90.61(3); V, A3 = 3199.1(20)) show that the Tc is bound to both thiolate sulfur atoms and to two deprotonated amide nitrogen atoms. The coordination geometry about the Tc is square-pyramidal with an -yl oxygen atom in the apical position. The Tc-N bond distances (2.002(12) and 1.984(12) A), the Tc-S bond distances (2.300(5) and 2.286(5) A), and the Tc-O bond distance (1.667(11) A) are in good agreement with bond lengths reported for similar complexes. The carboxylate groups are not bonded to the Tc atom in the solid state, nor in CDCl3 solution, as evidenced by X-ray crystal data and solution NMR data, respectively. In the solid state, [99TcO(8)]AsPh4 is monoanionic, therefore, at physiological pH, [99mTcO(8)] is presumably trianionic. Biodistribution studies performed in rats with the 99mTc complexes revealed slow blood clearance and high muscle uptake for these agents. Modest hepatobiliary excretion was observed, and low quantities of the complexes were found in the heart, lungs, and spleen after 1 h. The urinary excretion of the 99mTc complexes of ligands 4, 5, and 8 was found to be slow when compared to the excretion of [131I]OIH in rats (22%, 22%, and 32% vs 85-86%, respectively). Protein binding of 99mTc complexes of ligands 4, 5, and 8 in both rat and monkey plasma was found to be similar to MAG3. While the synthetic schemes reported here supply facile routes to novel N2S2 ligands, biodistribution studies of the 99mTc complexes performed on rats revealed slow renal excretion rates, accompanied by slow blood clearance and high uptake in muscle tissue. Preliminary planar imaging studies in monkeys also revealed slow renal excretion for these agents. The 99mTc complexes evaluated here are poor candidates as renal radiopharmaceuticals.

Radiosensitization, thiol oxidation, and inhibition of DNA repair by SR 4077.

The mechanism of radiosensitization by diazenedicarboxylic acid bis(N),N-piperidide (SR 4077), a less toxic analog of diamide, was studied using Chinese hamster ovary cells. SR 4077 gave an average SER of 1.58 for postirradiation incubations of 0.5, 1.0, or 2.0 h. Intracellular GSH and protein thiols decreased rapidly following drug addition and GSSG increased. The GSH/GSSG ratio shifted to 1/1.6 after SR 4077 addition but returned to greater than 10/1 between 0.5 and 1.0 h. After 4 h, total intracellular GSH was only 58% of pretreatment level and extracellular GSSG increased. Protein thiols decreased to 18% of pretreatment values, recovered most rapidly between 0.5 and 1.0 h, and reached 87% of pretreatment level after 4 h. A decrease in DNA single-strand break repair as measured by alkaline filter elution rate over 0.5 h was seen, and the initial rate of repair was slower than in cells not treated with SR 4077. DNA double-strand break repair as measured by neutral filter elution rate was delayed during the first hour after irradiation when cells were treated with SR 4077. The times for maximum radiosensitization, GSH and protein thiol oxidation and recovery, and DNA strand break repair kinetics were closely linked. We propose that a protein thiol(s) required in repair processes was reversibly oxidized during SR 4077 treatment.

Post-treatment with a novel PARG inhibitor reduces infarct in cerebral ischemia in the rat.

Poly(ADP-ribose) is synthesized from nicotinamide adenine dinucleotide (NAD(+)) by poly(ADP-ribose) polymerase (PARP) and degraded by poly(ADP-ribose) glycohydrolase (PARG). Overactivation of the poly(ADP-ribose) pathway increases nicotinamide and decreases cellular NAD(+)/ATP, which leads to cell death. Blocking poly(ADP-ribose) metabolism by inactivating PARP has been shown to reduce ischemia injury. We investigated whether disrupting the poly(ADP-ribose) cycle by PARG inhibition could achieve similar protection. We demonstrate that either pre- or post-ischemia treatment with 40 mg/kg of N-bis-(3-phenyl-propyl)9-oxo-fluorene-2,7-diamide, a novel PARG inhibitor, significantly reduces brain infarct volumes by 40-53% in a rat model of focal cerebral ischemia. Our result provides the first evidence that PARG inhibitors can ameliorate ischemic brain damage in vivo, in support of PARG as a new therapeutic target for treating ischemia injury.

Identification of oxidative degradates of the thrombin inhibitor, 3-(2-phenethylamino)-6-methyl-1-(2-amino-6-methyl-5-methyleneca rboxamidomethylpyridinyl)pyrazinone, using liquid chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry.

Liquid chromatography/mass spectrometry was used to identify reaction products from a solution of 3-(2-phenethylamino)-6-methyl-1-(2-amino-6-methyl-5-methyleneca rboxamidomethylpyridinyl)pyrazinone (L-375,378) and hydrogen peroxide, a system that generates high levels of the oxidative degradates which form in the tablets and intravenous (i.v.) solutions of L-375,378. Two major hydrogen peroxide reaction products of L-375,378 (m/z 407) with m/z values of 369 and 370 were separated and identified. Both compounds were products of ring opening with elimination of three carbon atoms from the center pyrazinone ring. The structural assignments for these two products were alpha-amidinoamide and alpha-diamide compounds, respectively. In addition, five products (m/z 423) with a molecular weight 16 Da greater than that for L-375,378 were separated. Further liquid chromatography/tandem mass spectrometry experiments indicated that three of these M + 16 products were phenolic derivatives of L-375,378. Among them, the para-hydroxy compound has been verified using an authentic standard. The other two phenolic compounds were believed to be the meta- and ortho-hydroxy derivatives of L-375,378. The fourth M + 16 product was derived from hydroxylation of the methyl group on the center pyrazinone ring. The fifth M + 16 product was derived from oxidation on the aminopyridine moiety, most likely N-oxide of the pyridine ring. Other minor hydrogen peroxide reaction products were not studied in detail because they did not appear in tablets or i.v. formulations.

Synthesis and cytotoxic evaluation of N1,Nm-bis[(tetrahydrobenzo[a]acridin-12-yl)phenyl]alkanediamides and N1,Nm-bi.

The title compounds were synthesized in four steps from 5,5-dimethyl-1, 3-cyclohexanedione as starting material. These compounds were evaluated against 60 tumoral cell lines, whereas the N1,Nm-bis[benzo[c]acridin-7-yl]phenyl]alkanediamides displaying significant cytotoxic activity, the corresponding N1,Nm-bis[benzo[a]acridin-12-yl]phenyl]alkanediamides derivatives were found to be less cytotoxic.

Facile synthesis of a new fluorogenic metal scavenging interpolymeric diamide based on cellulose and alginic acids.

A microwave assisted synthesis of a water soluble fluorogenic interpolymeric diamide has been described involving alginic acid and polyglucuronic acid (PGA) amide of ethylenediamine (EDA), through a monoamide of PGA and EDA, in good yields (>80wt% in each step). PGA was prepared by TEMPO (2,2,6,6-tetramethyl piperidine-1-oxyl radical) mediated oxidation of cellulose of the halophytic plant Salicornia brachiata. The amides were characterized by spectral analyses. The fluorescence emission of the PGA amide was 7-fold greater than that of the interpolymeric diamide. PGA monoamide exhibited superior heavy metal ions [Pb(II) and Hg(II)] uptake properties to the diamide, the former showing optimum adsorptions of ions 398.8 and 282.8mg/g, respectively. These materials may be of utility as potential sensors harnessing their fluorogenic and metal scavenging properties.

Double affinity amplification of galectin-ligand interactions through arginine-arene interactions: synthetic, thermodynamic, and computational studies with aromatic diamido thiodigalactosides.

A series of aromatic mono- or diamido-thiodigalactoside derivatives were synthesized and studied as ligands for galectin-1, -3, -7, -8N terminal domain, and -9N terminal domain. The affinity determination in vitro with competitive fluorescence-polarization experiments and thermodynamic analysis by isothermal microcalorimetry provided a coherent picture of structural requirements for arginine-arene interactions in galectin-ligand binding. Computational studies were employed to explain binding preferences for the different galectins. Galectin-3 formed two almost ideal arene-arginine stacking interactions according to computer modeling and also had the highest affinity for the diamido-thiodigalactosides (K(d) below 50 nM). Site-directed mutagenesis of galectin-3 arginines involved in binding corroborated the importance of their interaction with the aromatic diamido-thiodigalactosides. Furthermore, the arginine mutants revealed distinct differences between free, flexible, and solvent-exposed arginine side chains and tightly ion-paired arginine side chains in interactions with aromatic systems.

On the cytotoxicity and status of oxidative stress of two novel synthesized tri-aza macrocyclic diamides as studied in the V79 cell lines.

Two tri-aza macrocycles as diamide derivatives of macrocyclic compounds possess a hydrophilic cavity surrounded by hydrophobic ring, which enables them to diffuse cell membrane and interfere with different living systems. In this study, we comparatively evaluated cytotoxicity effects of tri-aza dibenzo sulfoxide (TSD) and dibenzo sulfide (TTS) macrocyclic diamides in a range of doses (0.5-8mM) and the role of oxidative stress in V79 cell culture. We assessed the effects of these substances on ROS level, cellular viability, apoptosis events, activity of antioxidant enzymes including superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase (CAT), and on some macromolecules' oxidative damage end-products: malondialdehyde (MDA), dityrosine, and 8-hydroxy-deoxyguanosine (8-OH-dG) that were assessed by spectrometry and HPLC methods. Both compounds revealed cytotoxicity effects on cell culture particularly at doses >1mM after 24-h incubation. They decreased cellular viability and significantly promoted ROS generation, increased enzyme activities, and enhanced oxidative damages in which TSD was more effective. Treatment of cells with each compound alone increased significantly the percent of apoptotic events at 2 and then 4mM. Co-treatment with alpha-tocopherol (alpha-TCP) drastically reduced these events. Cells' exposure with mixture of 30 microM alpha-tocopherol and 8mM of each compound exerted significant decrease in the levels of ROS, enzyme activities, and oxidative damage biomarkers. As conclusion, our study documented the oxidative radical forming ability of the studied compounds and further strengthened the documentation of their cytotoxicity effects through lipids, proteins and DNA oxidation damages.

Catalytic asymmetric desymmetrization of meso-diamide derivatives through enantioselective N-allylation with a chiral pi-allyl Pd catalyst: improvement and reversal of the enantioselectivity.

In the presence of the Trost ligands-Pd catalysts, N-monoallylation of bis(2,4,6-triisopropylbenzne)sulfonylamides derived from meso-1,2-diamines proceeds with good to excellent enantioselectivity (85-96% ee) to give asymmetric desymmetrization products. Under the same conditions, in the reaction with meso-bistolunesulfonylamide derivatives, reversal of the enantioselectivity is observed.