Severe liver injury and clinical characteristics of occupational exposure to 2-amino-5-chloro-N,3-dimethylbenzamide: A case series

Background:The 2-amino-5-chloro-N,3-dimethylbenzamide is a key intermediate in the synthesis of pesticides and pharmaceuticals.However,no literature currently exists on 2-amino-5-chloro-N,3-dimethylbenzamide poisoning in humans.This study aimed to reveal the health hazard of this chemical for humans and summarize the clinical characteristics of patients with occupational 2-amino-5-chloro-N,3-dimethylbenzamide poisoning.Methods:This observational study included four patients with 2-amino-5-chloro-N,3-dimethylbenzamide poisoning from June 2022 to July 2022.The entire course of the incidents was described in detail.Blood 2-amino-5-chloro-N,3-dimethylbenzamide concentrations were detected by a mass spectrometer.Hema-toxylin and eosin staining was performed to assess liver injury,and immunofluorescence was used to evaluate hepatic mitophagy.Results:The 2-amino-5-chloro-N,3-dimethylbenzamide powder(99%purity)entered the human body mainly via the skin and respiratory tract due to poor personal protective measures.The typical course of 2-amino-5-chloro-N,3-dimethylbenzamide poisoning was divided into latency,rash,fever,organic dam-age,and recovery phases in accordance with the clinical evolution.Rash and fever may be the important premonitory symptoms for further organ injuries.The chemical was detected in the blood of all patients and caused multiple organ injuries,predominantly liver injury,including kidney,myocardium,and micro-circulation.Three patients recovered smoothly after comprehensive treatments,including artificial liver therapy,continuous renal replacement therapy,glucocorticoids,and other symptomatic and supportive treatments.One patient survived by liver transplantation.The postoperative pathological findings of the removed liver showed acute liver failure,and immunofluorescence staining confirmed the abundance of mitophagy in residual hepatocytes.Conclusions:This study is the first to elaborate the clinical characteristics of patients with 2-amino-5-chloro-N,3-dimethylbenzamide poisoning.The chemical enters the body through the respiratory tract and skin during industrial production.The 2-amino-5-chloro-N,3-dimethylbenzamide poisoning causes multiple-organ dysfunction with a predominance of liver injury.Liver transplantation may be an effective option for patients with severe liver failure.The mechanisms of liver injury induced by 2-amino-5-chloro-N,3-dimethylbenzamide might involve abnormal mitochondrial function and mitophagy.

Acute Toxicity and Cardio-Respiratory Effects of 2-Deoxy-D-Glucose: A Promising Radio Sensitiser

Objective To evaluate the acute toxicity of 2-deoxy-D-glucose （2DG） by oral （p.o.） and intravenous （i.v.） routes, and also the cardio-respiratory effects following high doses of 2DG in animal models. Methods The LD50 of 2DG （in water） was determined in rats and mice by p.o. route and in mice by i.v. route. The effect of 2-DG （250 mg/kg, 500 mg/kg, and 1000 mg/kg, i.v.） was studied on various cardio-respiratory parameters viz., mean arterial blood pressure, heart rate and respiratory rate in anaesthetised rats. The effect of 2DG （500 mg/kg, 1000 mg/kg, and 2000 mg/kg, p.o.） was also studied on various respiratory parameters viz., respiratory rate and tidal volume in conscious rats and mice using a computer program. Results The p.o. LD50 of 2DG was found to be 〉8000 mg/kg in mice and rats, and at this dose no death was observed. The LD50 in mice by i.v. route was found to be 8000 mg/kg. At this dose 2 out of 4 mice died and the death occurred within 6 h. A significant increase in the body weight was observed after p.o. administration of 2DG in rats at 500 mg/kg, 1000 mg/kg, and 2000 mg/kg doses. There was no significant change in the body weight at 4000 mg/kg and 8000 mg/kg by the p.o. route in rats and up to 8000 mg/kg by p.o. as well as i.v. routes in mice. Intravenous administration of 2DG （250 mg/kg, 500 mg/kg, and 1000 mg/kg） in anaesthetised rats showed a time-dependent decrease in the mean arterial blood pressure. There was no change in the heart rate in any of the treatment groups. The tidal volume was not changed significantly by p.o administration in conscious rats, but a significant decrease in the respiratory frequency at 500 mg/kg and 1000 mg/kg doses was observed. In the mice also there was no change in the tidal volume after p.o, administration, but the respiratory frequency decreased significantly at 2000 mg/kg dose. Conclusion 2DG is a safe compound but can cause a fall in the blood pressure and a decrease in respiratory frequency at high doses.

Chronic Dietary Administration of 2-Deoxy-D-Glucose Does Not Compromise Neurobehavioral Functions at Tumor Preventive Doses in Mice

Beneficial effects of dietary energy restriction (DER), including extension of life-span, reduction in cancer risk, anti-cancer effects and decrease in age related neurodegenerative diseases have been well established. Given that DER is difficult to implement in humans due to practical constraints, development of energy restriction mimetics (ERMs) is considered as a suitable alternative. Our recent studies have established the anti-tumor effects of the dietary administration of the glycolytic inhibitor 2-deoxy-D-glucose, a potential ERM, an alternative to DER;without any adverse effects on general physiology. Since functioning of the brain is critically dependent on glucose, we investigated the effects of chronic dietary 2-DG administration on the behavioural outcome in mice. Our findings based on a battery of neuro-behavioural tests clearly suggest that the chronic dietary administration of 2-DG that appreciably impairs the process of tumorigenesis has no adverse effect on the cognitive, affective and sensory-motor functions. Together with the maintenance of normal physiology reported by us earlier, these observations strengthen the potential of dietary 2-DG as a safe cancer preventive strategy.

Pharmacokinetic,Physicochemical and Medicinal Properties of N-glycoside Anti-cancer Agent More Potent than 2-Deoxy-D-Glucose in Lung Cancer Cells

Acetylated N-xyloside of 1-naphthylamine(K8A)has been shown to be more potent than 2-deoxy-D-glucose in lung cancer cells and has therapeutic potential for further drug development.In this paper we evaluate and report cytotoxicity,pharmacokinetic,physicochemical and medicinal properties of this D-Xylose derivative(K8A)as a lead anticancer agent with greater therapeutic potential than 2-deoxy-D-glucose(2-DG).2-DG has been in clinical trials for treatment of solid tumors and other types of cancer.We demonstrate using virtual tools that K8A has better“drug-likeness”than 2-DG and does not violate any Lipinski,Ghose,Veber,Egan or Muegge rules.On the other hand,2-DG violates Ghose and Muegge rules.A“BOILEDegg evaluation”,predicts that K8A has higher gastrointestinal absorption(HIA)than 2-DG and is not effluxed by P-glycoprotein(P-gp).Additionally,K8A does not penetrate the blood brain barrier(BBB)and is not a substrate of most Cytochrome P450(CYP)enzymes.Importantly,K8A did not show false positive alert from PAINS screening enabling us to narrow down and rule out false targets.Importantly,K8A is more potent than 2-DG in H1299 and A549 lung cancer cells.

Regeneration of 2-amino-2-methyl-1-propanol used for carbon dioxide absorption

To improve the efficiency of the carbon dioxide cycling process and to reduce the regeneration energy consumption, a sterically hindered amine of 2-amino-2-methyl-1- propranol （AMP） was investigated to determine its regeneration behavior as a CO2 absorbent. The CO2 absorption and amine regeneration characteristics were experimentally examined under various operating conditions. The regeneration efficiency increased from 86.2% to 98.3% during the temperature range of 358 to 403 K. The most suitable regeneration temperature for AMP was 383 K, in this experiment condition, and the regeneration efficiency of absorption/regeneration runs descended from 98.3% to 94.0%. A number of heat-stable salts （HSS） could cause a reduction in CO2 absorption capacity and regeneration efficiency. The results indicated that aqueous AMP was easier to regenerate with less loss of absorption capacity than other amines, such as, monoethanolamine （MEA）, diethanolamine （DEA）, diethylenetriamine （DETA）, and N-methyldiethanolamine （MDEA）.

Microwave-assisted reactions:Three-component process for the synthesis of 2-amino-2-chromenes under microwave heating

2-Amino-2-chromenes are class of heterocycles that posses considerable interest as pigments, cosmetics, potential agrochemicals and being the main constituents of many natural products. Although, they are generally prepared either under conventional heating, benign reagents or very recently, a three component condensation in polyethylene glycol-water in the presence of nanosized magnesium oxide, most of these methods require prolonged reaction time, reagents in stoichiometric amounts and generate moderate yields of products. Microwave technique performs a better yield in a short reaction time （85-94%; 5-8 min）. Also, three-component one step reaction is of great interest for cost savings from the point of raw materials, energy and time, A combination between both techniques will be attractive for researchers in that field.

Synthesis and Structural Characterization of a Tetranuclear Copper Complex with 2-Amino-1,3-thiazole

The title tetranuclear complex,（μ4-oxo）-hexakis（μ2-chloro）-tetrakis（2-amino-1,3-thiazole-N）-tetra-copper（ii） [Cu4（μ4-O）（μ-Cl）6L4]（1,L=2-amino-1,3-thiazole） was synthesized by the reaction of CuCl2·2H2O with 2-amino-1,3-thiazole in methanol and characterized by IR spectra and X-ray diffraction.Complex 1 crystallizes in triclinic,space group P1 with a=9.7137（2）,b=10.7005（2）,c=14.6505（2）,α=83.9550（10）,β=82.0930（10）,γ=67.1640（10）°,V=1387.84（4）3,Mr=883.43,Z=2,μ=3.927 mm-1,Dc=2.1144 g/cm3,F（000）=868,R=0.0332 and wR=0.0814.The complex contains a tetrahedron of four CuII atoms coordinating to a central μ4-O atom,with the six edges of the tetrahedron bridged by six Cl atoms.The Cu-O bond distances range from 1.910（2） to 1.918（2）,Cu-Cl from 2.3501（11） to 2.5924（10）,and Cu-Cu from 3.1003（6） to 3.1663（6）.The coordination geometries of the four coppers distort from trigonal bipramid to tetragonal pyramid with different distortion factors.The free animo groups of the ligands result in a lot of N-H···Cl and N-H···N intra-and intermolecular hydrogen bonds.

Synthesis and antiangiogenic activities of 5-amino-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanoic acid derivatives

Based on the structure-activity relationships and antiangiogenic mechanism of RGD-containing peptides, a series of 5-amino- 1,3-dihydro-1,3-dioxo-2H-isoindole derivatives were synthesized. The structures were characterized by ^1H NMR, MS and elementary analysis. There ability to inhibit angiogenesis were evaluated by chick embryo chorioallantoic membrane assay at 10^-5 mol/L. Compounds 7a and 7b displayed obvious antiangiogenic activity.

Synthesis,Crystal Structure and Plant Growth Regulatory Activity of 1-(3-Amino-[1,2,4]triazol-1-yl)-3,3-dimethyl-butan-2-one

The title compound 1-（3-amino-[1,2,4]triazol-1-yl）-3,3-dimethyl-butan-2-one（3） was synthesized by Hofmann-alkylation reaction of 1-chloro-3,3-dimethyl-butan-2-one（1） and ~1H-[1,2,4]triazol-3-ylamine（2） with equal amount of K_2CO_3 as acid acceptor. The structure of compound 3 was characterized by ~1H NMR, 13 C NMR, HRMS and single-crystal X-ray diffraction. The compound crystallizes in the monoclinic system, space group P21/n with a = 5.7227（8）, b = 27.924（4）, c = 6.2282（7） ？, β = 101.892（11）°, V = 973.9（2） ？~3, Z = 4, T = 180.00（10） K, μ（MoKα） = 0.087 mm^（-1）, Dc = 1.243 g/cm^3, 3832 reflections measured（3.648≤θ≤26.022°）, 1916 unique reflections（Rint = 0.0359, Rsigma = 0.0572） used in all calculations. The final R = 0.0557（I 〉 2σ（I）） and w R = 0.1276（all data）. Bioassay showed that 3 displayed excellent activity as plant growth regulator with inducing lateral root formation and enhancing primary root elongation at 0.27 mmol/L（50 ppm） in soybeen（He Feng-50）. Good water solubility was found with 50 mg in 1 m L of water. Therefore, application of 3 in agriculture is more environmentally friendly due to cosolvent-free condition, and results in improved abiotic-stress tolerance by affecting the root growth. And furthermore, it can be used as a precursor to investigate the function of regulating plant root growth.

Microwave promoted one-pot synthesis of 3-(2′-amino-3′-cyano-4′-arylpyrid-6′-yl)coumarins

A facile procedure for the synthesis of 3-（2′-amino-3′-cyano-4′-arylpyrid-6′-yl） coumarins are being reported starting from 3- acetylcoumarin, aromatic aldehydes and malononitrile. The reactions were carried out on microwave irradiation in good yield with short time and easy work-up. The structures of all the compounds have been confirmed on the basis of their analytical, IR, ^1H NMR, and mass spectral data.

An Efficient and Rapid Synthesis of 2-amino-4-arylthiazoles Employing Microwave Irradiation in Water

A facile, high yielding green chemical synthetic protocol adaptable to the parallel synthesis of a library of potentially bioactive 2-amino-4-arylthiazoles is reported herein. The methodology involves the condensation of various aracyl bromides with N-arylthioureas under MWI using water as solvent, to yield pure products (81%-97%) in very short reaction times (1-20 min).

An improved synthesis of (-)-7-isopropyl-cis-l-amino-2-indanol the chiral auxiliary for 6π-azaelectrocyclization

（-）-7-Isopropyl-cis-l-amino-2-indanol, a key chiral auxiliary and ligand in the highly stereo-selective asymmetric 6π- azaelectrocyclization, has been prepared previously by two methods. Each however involved using of one extreme condition, i.e. high temperature or high pressure, for the respective reaction. A modified reaction route employed mild condition for synthesis was presented in this report.

Removal of 5-Amino-2-chlorotoluene-4-sulfonic and Chlorhydric Acids From Wastewater by Weakly Basic Resin: Equilibrium and Kinetics

Objective To study the adsorption of 5-Amino-2-chlorotoluene-4-sulfonic (CLT) and chlorhydric (HCl) acids from wastewater by weakly basic resin. Methods The kinetics and isotherm were studied. Thermodynamic parameters for the adsorption of acids were calculated and discussed. Results The adsorption of CLT and HCl acids followed Langmuir isotherm and the first-order kinetics model. Conclusion The adsorptive affinity of the two acids on D301R is in the order of CLT acid 〉 HCl acid. CLT and HCl acids can be separated.

Preparation and Standard Formation Enthalpy of 2-Amino-4,6-dimethylpyrimidine and Its Related Complexes of Copper

The complexes of hydrous copper chloride and copper nitrate with 2-amino-4,6-dimethylpyrimidine(ADMP) were prepared via reflux in alcohol. The compositions of the complexes were identified as Cu(ADMP) 2Cl 2·2H 2O(b) and Cu(ADMP)(NO 3) 2·H 2O(c) by chemical and elemental analyses. The complexes were characterized by IR, XPS, 1H NMR and TG-DTG techniques. The constant-volume combustion energies of ADMP and the complexes, Δ c E , were determined by a precise rotating-bomb calorimeter at 298 15 K. They were (-3664 53±1 18), (-4978 47±2 72) and (-1696 70±1 36) kJ/mol, respectively. Their standard enthalpies of combustion, Δ c H 0 m, and standard enthalpies of formation, Δ f H 0 m, were calculated to be (-3666 39±1 18), (-4977 23±2 72), (-1691 12±1 36) kJ/mol and (19 09±1 43), (-2041 80±3 29), (-2397 24±1 65) kJ/mol, respectively.

Synthesis and Cytotoxicity of Novel Diaryl Ureas Containing 2-Amino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl Group

A series of 2-amino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl substituted diaryl urea derivatives was designed and synthesized. Their in vitro cytotoxicities against two cancer cell lines（Bel-7402 and A549） were evaluated by standard MTT assay. Six of tested compounds 6, 8, 10, 17, 21 and 22 exhibited more potent cytotoxicity superior to sorafenib. The structure activity relationship（SAR） study indicates that 2-amino-5,6,7,8-tetrahydropyrido- [4,3-d]pyrimidinyl group was an option for cytotoxic potency.

Synthesis of 2-Amino-4,6-dimethoxypyrimidine(ADM)

Using malononitrile as the raw material, a novel synthesis route of 2-amino-4,6-dimethoxypyrimidine(ADM) was put forward, in order to solve the instability in first step reaction of industrial synthesis. The influence of reactant ratio, temperature and time on product quality and yield was explored. The results showed that ADM was successfully prepared through acetyl chloride route, the yield was higher than that of industrial production process, and the process stability was good, with the product purity over 99%. Therefore, the new synthesis route is suitable for industrial production.

Theoretical Study on the Reaction Mechanism of 2-Methoxybenzaldehyde,4-Bromo-indanone,Malononitrile and Ammonium Acetate One-pot to Form 6-(2-Methoxyphenyl)-2-amino-6-bromo-5H-indeno[1,2-b]pyridine-3-carbonitrile

The reaction mechanism of 2-methoxybenzaldehyde, 4-bromo-indanone, malononitrile and ammonium acetate one-pot to form 6-（2-methoxyphenyl）-2-amino-6-bromo-5 Hindeno[1,2-b]pyridine-3-carbonitrile was studied by density functional theory. The geometries of the reactants, transition states, intermediates and products were optimized at the PW91/DNP level. Vibration analysis was carried out to confirm the transition state structure. Reaction pathways were investigated in this study. The result indicates that the reaction Re→ TSB1→IMB1→ TSB2→ IMB2→TSB3→IMB3→TSB4→IMB4→TSB5→IMB5→TSB6→IMB6→TSB7→IMB7→ TSB8→IMB8→TSB9→IMB9→P2 is the main pathway, the activation energy of which is the lowest. The dominant product predicted theoretically is in agreement with the experiment results.

Syntheses and Characterization of Two New Alkaline Earth Metal-organic Topological Frameworks with 3-Amino-1H-1,2,4-triazole-5-carboxylate

Two new alkaline earth metal coordination polymers constructed from the deriva-tive of 1,2,4-triazole are presented herein,namely,{[Sr（AmTAZAc）2（H2O）]}（1） and {[Ba（AmTAZAc）2（H2O）]}（2）（AmTAZAc = 3-amino-1H-1,2,4-triazole-5-carboxylate）,which have been synthesized by using the layering method and structurally characterized by elemental analysis,IR,and single-crystal X-ray diffraction.Complexes 1 and 2 are isostructural,and both crystallize in the orthorhombic system,space group Fdd2.X-ray structural analysis shows that 1 or 2 has an intriguing 3-D infinite network of（318.438.510） topology based on a 2-D sheet structure of（4,4） net.The result shows that noncovalent interactions play an important role in strengthening the whole structures of the compounds.

Mechanism of Excited State Double Proton Transfer in 2-Amino-3-Methoxypyridine and Acetic Acid Complex

The excited-state double-proton transfer （ESDPT） mechanism of 2-amino-3-methoxypyridine and acetic acid com- plex is studied by the density functional theory （DFT） and time-dependent DFT with CAM-B3LYP functional. The complex is connected through two different types of inter-molecular hydrogen bonds. After photo-excitation, both hydrogen bonds get strengthened, which can facilitate the ESDPT reaction. The scanned potential energy curve along the proton transfer coordinate indicates that the ESDPT reaction proceeds in a stepwise pattern.

Synthesis and Crystal Structure Analysis of 2-Amino-4,6-bis(diphenoxyl phosphoramide)-1,3,5-triazine

A disubstituted triazine compound, namely, 2-amino-4,6-bis（diphenoxyl phosphorramide）-1,3,5-triazine, which is an inherent flame retardant monomer, was synthesized specifically, and its structure was characterized by using NMR spectrum and X-ray single-crystal diffraction. Unit cell parameters： space group P21/c, Z=4, a=8.7494（15）, b=27.518（5）, c=12.511（2）,β=109.323（16） , Z=4, V=2842.7（9）β3 , Dc=1.380 g/cm3 , F（000）=1224 and Mr=590.46. All the atoms are in the general positions.