Synthesis and antibacterial activities of phosphonate derivatives containing aminothiazoloxime fragment / 药学学报

Based on the principle of molecular hybridization, fifteen compounds were designed and synthesized through the combination of aminothiazoloxime and phosphonate fragment. The results showed that these compounds had better inhibitory effects on the tested bacteria. In particular, the activities of compounds Ⅲf and Ⅲi against S. aureus, E. coli, methicillin-resistant S. aureus (MRSA) and fluoroquinolone-resistant E. coli (FREC) were the most significant, the minimal inhibitory concentration (MIC) of Ⅲf was 1, 8, 4, 16 μg·mL-1 respectively, and the MIC of Ⅲi was 4, 4, 16, 8 μg·mL-1 respectively, which were slightly lower than that of the control drug oxacillin, and their anti-E. coli, MRSA and FREC activities were superior to that of the control drug oxacillin. Their activities to S. aureus were close to that of oxacillin, and to E. coli, MRSA and FREC were superior to that of oxacillin, which is worthy of further study.

Effect of Wine Processing on Odour Formation of Polygonatum cyrtonema Rhizoma by GC-MS / 中国实验方剂学杂志

ObjectiveBy exploring the volatile components， polysaccharide composition and changes in the contents of five carbohydrate components of Polygonatum cyrtonema rhizoma before and after processing， and then the effect of yellow rice wine on the odour formation of P. cyrtonema rhizoma was investigated. MethodThe volatile components of P. cyrtonema rhizoma before and after processing were detected by headspace gas chromatography-mass spectrometry（HS-GC-MS）， and sample data were subjected to principal component analysis（PCA） and orthogonal partial least squares-discriminant analysis（OPLS-DA） using SIMCA 14.1， then the differences between these components of P. cyrtonema rhizoma before and after processing were screened according to the principle of variable importance in the projection（VIP） value>1. Crude carbohydrate components in raw and wine-processed P. cyrtonema rhizoma were subjected to oxime and silylation， the carbohydrate components were analyzed by gas chromatography-mass spectrometry（GC-MS/MS）， and the relative contents of various components were calculated by peak area normalization， then quantitative analysis of four carbohydrate components was also carried out. ResultA total of 23 volatile components were identified from the raw products and the wine-processed products， including 15 components in raw products and 20 components in wine-processed products. Among them， 2-methylbutyraldehyde and isovaleraldehyde had a sweet odor and their contents increased after processing， but the contents of hexanal and caproic acid decreased， new components such as 2-acetylfuran and 5-methylfuranal were produced after processing. PCA and OPLS-DA results showed that there were significant differences between raw products and the wine-processed products， a total of 13 differential compounds were screened out， of which 7 showed an upward trend in relative content and 6 showed a downward trend. A total of 7 carbohydrate components， including 5 monosaccharides and 2 disaccharides， were identified in raw products and the wine-processed products. The results of determination showed that the contents of fructose， glucose， mannose and sucrose in P. cyrtonema rhizoma increased after wine-processing， and their increases were 4.54， 1.51， 2.93， 3.66 times， respectively. ConclusionAfter processing， the increase of aromatic flavor of P. cyrtonema rhizoma may be related to the increase of the contents of aldehydes such as 2-methylbutyraldehyde and isovaleraldehyde， while the decrease of raw flavor may be related to the decrease of the contents of volatile components such as hexanal and hexanoic acid， the increase of sweet flavor may be related to the increase of the contents of monosaccharides and oligosaccharides such as fructose and sucrose.

Isolation and identification of chemical constituents from Disporum cantoniense / 中草药

Objective: To study the chemical constituents from Disporum cantoniense. Methods: Various column chromatographic techniques were used to separate and purify the chemical constituents and their structures were elucidated by spectral ananlysis. Results: Sixteen compounds were isolated and identified as 3-maleimide-5-oxime (1), 4-methylene-5-oxopyrrolidine-2- carboxylic acid (2), thymine (3), adenosine (4), 5'-deoxy-5'-methylamino-adenosine (5), ethyl-α-L-rhamnose (6), bergenin (7), 4-hydroxy- 2-methoxyphenyl-6-deoxy-α-L-talopyranoside (8), (-)-epicatechin (9), (6R,9R)-roseoside (10), 3-(4-hydroxy-3,5-dimethoxyphenyl) propane-1,2-diol (11), 3-hydroxy-5-(p-hydroxyphenyl) pentanoic acid (12), 1-ribityl-2,3-diketo-1,2,3,4-tetrahydro-6,7-dimethyl-quinoxaline (13), (6S,9R)-vomifoliol (14), 1-(3,4-dihydroxyphenyl)-2-hydroxye-thanone (15), and 1,2-dihydroxy-1-(4-hydroxy-3,5-dimethoxyphenyl)- ethane (16). Conclusion: Compounds 1, 2, 5-9, and 12-16 are isolated from genus Disporum Salisb. for the first time, and compounds 1, 2, 5-10, and 12-16 are isolated from this plant for the first time.

Clinical study of the therapeutic efficacy from different dosages of pralidoxime chloride used in patients with acute organophosphorus pesticide poisoning / 中华急诊医学杂志

Objective To investigate the effect of different doses of pralidoxime chloride on clinical outcome including recovery rate and mortality in patients with acute organophosphorus pesticide poisoning.Methods According to the total amount of pralidoxime chloride administered over the first 24 hours or entire duration of hospitalization,a cohort of 163 organophosphorus pesticide poisoning patients,admitted from February 2004 to December 2014 were assigned to different groups followed by a retrospective analysis.Comparisons of recovery rate,mortality rate,mean length of hospital stay,and duration of mechanical ventilation were made among groups.SPSS 18.0 was used to analyze categorical variables between the data of groups with x2 test/Fisher exact probability method and numerical variables with t test or One-way ANOVA,and statistical significance was set as P ＜ 0.05.Results According to the amount of pralidoxime chloride given over the first 24 hours,the recovery rate and the mortality rate were significantly improved in the experimental group (pralidoxime chloride ＞ 2 g) than in the control group (pralidoxime chloride ＜ 2 g) (P =0.04).There was no significant difference in mean length of hospital stay between the experimental group and the control group (P =0.171),and there were statistically significant differences in recovery rate and mortality rate among the four dose-response subgroups (total dosage administered in 24 hours in group A ＜ 1 g,in group B ＜2 g,in group C ＜4 g and in group D ＞4 g) (P =0.034).Based on the total amount of pralidoxime chloride prescribed in the entire duration of hospital stay,the recovery rate and mortality rate were significantly better in the experimental group than those in control group (P =0.002),and among the three dose-response subgroups,the significant difference in recovery rate and mortality rate were also observed (P =0.006).Conclusions Increased amounts of pralidoxime chloride prescribed in the first 24 hours and in the whole hospitalized period can improve the recovery rate and reduce the mortality rate in organophosphorus pesticide poisoning patients.

Design, virtual screening, synthesis and anti-hepatitis B virus of oxime derivatives / 药学学报

A series of new oxime and oxime ethers compounds were designed and virtually screened with target using the Molecular Operating Environment (MOE) software. Twelve unreported compounds including 4 oximes and 8 oxime ethers were synthesized with benzene, toluene, methoxybenzene and chlorobenzene as initial raw materials. Structures of compounds were elucidated by 1H NMR, 13C NMR and MS. The results of bioactive screening showed that a part of compounds displayed obviously anti-HBV activities. Inhibitory activities of compounds 4B-2 in secretion of HBsAg and HBeAg were IC50 HBsAg=81.15 μmol·L-1, SIHBsAg=9.20 and IC50 HBeAg=90.66 μmol·L-1, SIHBeAg8.24, respectively. Preliminary structure-activity relationship study shows that methyl oxime ethers displayed better anti-HBV activities than the oximes.

Cytotoxic, genotoxic and apoptotic effects of naringenin-oxime relative to naringenin on normal and cancer cell lines

Objective To assess and compare the cytotoxic, genotoxic, apoptotic and reactive oxygen species (ROS) generating effects of naringenin (NG) and its new derived compound naringenin-oxime (NG-Ox) on MCF-7, HT-29, PC-12 cancer and L-929 normal cell lines. Methods The cells were incubated with different doses of NG-Ox and NG (50–1 000 μmol/L) for 24 h. The cell viability was assessed based on ATP cell viability assay. Intracellular accumulation of ROS was determined using the fluorescent probes 2'7'-dichlorodihydrofluorescin diacetate. Genotoxic effects were evaluated by alkaline single cell gel electrophoresis assay (comet assay) and, the apoptotic effect was evaluated by acridine orange staining at below the IC

Cytotoxic, genotoxic and apoptotic effects of naringenin-oxime relative to naringenin on normal and cancer cell lines

Objective: To assess and compare the cytotoxic, genotoxic, apoptotic and reactive oxygen species (ROS) generating effects of naringenin (NG) and its new derived compound naringenin-oxime (NG-Ox) on MCF-7, HT-29, PC-12 cancer and L-929 normal cell lines. Methods: The cells were incubated with different doses of NG-Ox and NG (50–1 000 mmol/L) for 24 h. The cell viability was assessed based on ATP cell viability assay. Intracellular accumulation of ROS was determined using the fluorescent probes 2070-dichlorodihydrofluorescin diacetate. Genotoxic effects were evaluated by alkaline single cell gel electrophoresis assay (comet assay) and, the apoptotic effect was evaluated by acridine orange staining at below the IC50 levels. Results: Both NG-Ox and NG exhibited cytotoxic, genotoxic and apoptotic effects and resulted in increased ROS values in a dose-dependent manner. The effects were more pronounced on cancer cell lines. The cytotoxic, genotoxic and apoptotic effects of NG-Ox were higher than that of NG in all cell lines. Significant correlations were observed be-tween cell viability, DNA damage, apoptosis and ROS, in all cell lines exposed to either NG-Ox or NG. Conclusions: This study showed that both NG-Ox and NG possess cytotoxic, genotoxic and apoptotic activities through the production of ROS on cells, NG-Ox being the more effective one. Therefore, derived compound of NG might be used as antiproliferative agents for the treatment of cancer.

Characterizing drug-metabolizing enzymes and transporters that areCAR-target genes in mouse intestine

Intestine is responsible for the biotransformation of many orally-exposed chemicals. The constitutive androstane receptor (CAR/Nr1i3) is known to up-regulate many genes encoding drug-metabolizing enzymes and transporters (drug-processing genes/DPGs) in liver, but less is known regarding its effect in intestine. Sixty-day-old wild-type andmice were administered the CAR-ligand TCPOBOP or vehicle once daily for 4 days. In wild-type mice,mRNA was down-regulated by TCPOBOP in liver and duodenum.mice had altered basal intestinal expression of many DPGs in a section-specific manner. Consistent with the liver data (Aleksunes and Klaassen, 2012), TCPOBOP up-regulated many DPGs (, and) in specific sections of small intestine in a CAR-dependent manner. However, the mRNAs ofandwere previously known to be up-regulated by TCPOBOP in liver but were not altered in intestine. Interestingly, many known CAR-target genes were highest expressed in colon where CAR is minimally expressed, suggesting that additional regulators are involved in regulating their expression. In conclusion, CAR regulates the basal expression of many DPGs in intestine, and although many hepatic CAR-targeted DPGs wereCAR-targets in intestine, pharmacological activation of CAR in liver and intestine are not identical.

Synthesis and Characterization of Novel Hydrazone Based Anti-mutagenic and Antioxidative Agents.

The present study was designed to produce novel hydrazine and evaluate their biological properties including antioxidant, antityrosinase and antimutagenic. 4-allyloxybenzoyl hydrazine (1) reacts with 5-acetyl-1,3-dimethyl barbituric acid (2) and 2-Isonitrosoacetophenone (3) in the presence of acetic acid as a catalyst to produce the hydrazone derivatives 4 and 5 in high yields respectively. The new hydrazone derivatives 4 and 5 have been fully characterized by using multinuclear NMR (1H, 13C) spectroscopy and elemental analysis. The compounds 4 and 5 were studied for their antioxidant and tyrosinase enzyme inhibition activity. In addition the mutagenic and antimutagenic activities were evaluated by Ames Salmonella/ microsome mutagenicity test. The results showed that both of compounds exhibited significant antioxidative and antimutagenic activity and compound 5 has shown moderate tyrosinase inhibition activity. This study suggested that these compounds could be considered as novel bioactive agents in pharmaceutical area.

Isolation and Structure Determination of an Imidazo-pyrimidine, 5-Chlorocavernicolin, Maleimide oximes and Nucleosides from a Marine Sponge Extract

In a continuation of our studies to discover bioactive secondary metabolites from marine sources, we further investigated samples from a tryptamine and phenyl-alkane producing sponge, which resulted in the isolation of four uncommon small molecules and five nucleosides. Their structures were determined to be 7,8-dihydroimidazo[1,5-c]pyrimidin-5(6H)-one (1), 5-chlorocavernicolin (2), maleimide-5-oxime (3), 3-methylmaleimide-5-oxime (4), uridine (5), 2'-deoxyuridine (6), thymidine (7), adenine (8), and adenosine (9) by spectroscopic analyses. The isolated compounds were evaluated for inhibitory activity against soluble epoxide hydrolase (sEH) as well as the Wnt/beta-catenine signaling pathway.

Effects and mechanisms of chloro-oxime derivatives on spatial learning and memory dysfunction in two dementia animal models / 中国药理学通报

Aim To explore the effects and mecha-nisms of choro-oxime derivatives on spatial learning and memory impairment in Kunming mice and SD rats induced by scopolamine and Aβ1-42 , respectively. Methods 40 Kunming mice were randomly divided into 5 groups: control group, model group, donepezil treatment group, arimoclomol treatment group and TCO-2 treatment group. There were 8 mice in each group. Mice of control group were established by intra-peritoneal injection of saline, and mice of other groups were injected with scopolamine and caused memory im-pairment. Both control group and model group were treated with solvent by intraperitoneal administration;donepezil treatment group received donepezil by intra-gastric administration; arimoclomol treatment group and TCO-2 treatment group were given the correspond-ing drugs by abdominal injection, respectively. The solvent and drugs were given at the same time every morning for 8 days. Spatial learning and memory abili-ty were tested by Morris water maze from the fifth day of the drugs administration. 40 SD rats were divided into 5 groups the same as the dementia model men-tioned above. Mice of control group were established by intracerebroventricular injection of saline, and mice of other groups were injected with insoluble Aβ1-42 to be induced of memory impairment. Solvent and drugs were also delivered as mentioned above. Morris water maze was carried out from the fifth day of the drug de-livery. After that, acetyl cholinesterase activity of hip-pocampus was tested with acetyl cholinesterase reagent kit; the content of Aβ1-42 in hippocampus was meas-ured by ELISA assay kit;the expression of phosphoryl-ated tau proteins was detected by Western Blot. Re-sults In both two dementia models, choro-oxime de-rivatives could improve the spatial learning and memory ability, shorten the escape latency and increase the times of crossing the former platform. Choro-oxime de-rivatives could also inhibit the acetyl cholinesterase ac-tivity in animal brain, decrease the concentration of Aβ1-42 and the expression of phosphorylated tau pro-teins in the dementia rats’ hippocampus. Conclusions Spatial learning and memory deficits induced by sco-polamine and Aβ1-42 could be reversed by choro-oxime derivatives. It may be concerned with enhancement of the cholinergic system functions and reduction of the levels of Aβ1-42 and phosphorylated tau proteins in the brain.

Synthesis of saxagliptin intermediate N-BOC-3-hydroxyadamantylglycine / 中国药学杂志

OBJECTIVE: To explore a new synthesis method of the saxagliptin intermediate of the dipeptidyl peptidase IV (DPP-IV)inhibitor saxagliptin, N-BOC-3-hydroxy-1-adamantylglycine, to reduce the synthesis cost of saxagliptin. METHODS: The synthesis used 1-adamantane carboxylic acid (1) as the starting material. Through achlorination, substitution, and decarboxylation afford 1-adamantyl methyl ketone (2) was obtained, which was then converted into 2-(3-hydroxy-1-adamantyl)-2-oxoacetic acid (3)by oxidation with potassium permanganate in aqueous NaOH. Compound 3 reacted with hydroxylamine hydrochloride to give the 2-(3-hydrox-1-adamantyl)-2-hydroxyimino acetic acid(4), and then oxime 4 was reduced, and got the amino with BOC2O to afford dipeptidyl peptidase IV (DPP-IV)inhibitor saxagliptin intermediate N-BOC-3-hydroxyadamanty- lglycine(5). RESULTS: We got a new compound 4 which had not been reported. The 36% overall yield was reached. CONCLUSION: This synthetic route is simple, its reaction conditions are mild, and the raw materials are cheap and readily available, so it is suitable for manufacturing purposes.

Synthesis and β-adrenergic blocking activity of oxime ether hybrids derived from a natural isochroman-4-one / 中国天然药物

AIM@#In a search for new cardiovascular drug candidates, a series of novel oxime ethers derived from a natural isochroman-4-one were synthesized.@*METHOD@#Compounds 3 and 6, derived from the natural antihypertensive compound 7, 8-dihydroxy-3-methyl-isochroman-4-one (XJP), were designed and synthesized. Subsequently, a series of novel isochroman-4-one oxime ether hybrids were prepared by hybridizing various N-substituted isopropanolamine functionalities to isochroman-4-one oxime. Furthermore, β1-adrenergic blocking activities of the synthesized compounds were assayed using the isolated rat left atria.@*RESULTS@#Twenty target compounds were obtained, and the preliminary structure-activity relationships were deduced. The most promising compound Ic exhibited β1-adrenoceptor blocking activity (inhibition: 52.2%) at 10(-7) mol·L(-1), which was superior to that of propranolol (inhibition: 49.7%).@*CONCLUSION@#The results suggested that natural product XJP/isopropanolamine moiety hybrids may provide a promising approach for the discovery of novel cardiovascular drug candidates.

Síntesis y evaluación in vitro de la actividad antifúngica de oximas, éteres de oxima e isoxazoles / Síntese e avaliação in vitro da atividade antifúngica de oximas, éteres de oxima e isoxazóis / Synthesis and in vitro assessment of antifungal activity of oximes, oxime ethers and isoxazoles

Objetivo. Sintetizar y realizar la evaluación preliminar de la actividad antifúngica in vitro de oximas, éteres de oxima e isoxazoles. Materiales y métodos. Las oximas se sintetizaron a partir de aldehídos o cetonas con NH2OH.HCl y K2CO3. Los éteres de oxima se obtuvieron mediante alquilación de oximas con bromuro de propargilo o bromuro de 2-bromobencilo, empleando como base NaOH y acetona como solvente. Los isoxazoles se obtuvieron mediante cicloadiciones 1,3-dipolares empleando nitrato cérico amónico (NAC), cloramina-T (CAT) y NaOCl. Los productos fueron identificados y/o caracterizados por resonancia magnética nuclear (RMN) y espectrometría de masas (EM). Se realizaron pruebas de inhibición de crecimiento radial sobre Aspergillus niger y Fusarium roseum. Resultados. Se obtuvieron cinco oximas, siete éteres de oxima, cuatro de ellos nuevos y cuatro nuevos isoxazoles. Las sustancias evaluadas presentaron actividad antifúngica a cantidades de 1,5 mg y 3,0 mg. Conclusiones. Aunque las cicloadiciones 1,3-dipolares permitieron obtener los isoxazoles esperados, se observó que ésta metodología generó una amplia variedad de subproductos lo que disminuyó los rendimientos e hizo difícil la purificación del producto de interés. Cuatro de las sustancias evaluadas presentaron porcentajes de inhibición superiores al 80%...

Synthesis and in vitro assessment of antifungal activity of oximes, oxime ethers and isoxazoles. Objective. To synthesize and carry out a preliminary evaluation of the in vitro antifungal activity of oximes, oxime ethers and isoxazoles. Materials and methods. Oximes were synthesized from aldehydes or ketones with NH2OH.HCl and K2CO3. Oxime ethers were prepared by alkylation of oximes with propargyl bromide or 2-bromobenzyl bromide, using NaOH as base and acetone as solvent. The isoxazoles were obtained by 1,3-dipolar cycloadditions using ceric ammonium nitrate (CAN), chloramine T (CAT) and NaOCl. Products were identified or characterized using nuclear magnetic resonance (NMR) and mass spectrometry (MS). Radial growth inhibition assays against Aspergillus niger and Fusarium roseum were carried out. Results. Five oximes, seven oxime ethers, four of them new, and four new isoxazoles were obtained. The assessed substances exhibited antifungal activity in amounts of 1,5 mg and 3,0 mg. Conclusions. Although 1,3-dipolar cycloadditions allowed to obtain the desired isoxazoles, this methodology produced a wide variety of side products that reduced yields and made difficult the purification of the target products. Four of the tested compounds showed inhibition percentages greater than 80%...

Síntese e avaliação “in vitro” da atividade antifúngica de oximas, éteres de oxima e isoxazóis. Objetivo. Sintetizar e realizar a avaliação preliminar da atividade antifúngica in vitro de oximas, éteres de oxima e isoxazóis. Materiais e métodos. As oximas foram sintetizadas a partir de aldeídos ou cetonas com NH2OH.HCl e K2CO3. Os éteres de oxima foram obtidos pela alquilação de oximas com brometo de propargilo ou brometo de 2-bromobenzilo, utilizando NaOH como base e acetona como solvente. Os isoxazóis foram obtidos por cicloadição 1,3-dipolar usando nitrato cérico de amônio (NCA), cloramina-T (CAT) e NaOCl. Os produtos foram identificados e / ou caracterizados por ressonância magnética nuclear (RMN) e espectrometria de massas (EM). Foram realizados testes de inibição sobre o crescimento radial de Aspergillus niger e Fusarium roseum. Resultados. Foram obtidas cinco oximas, sete éteres de oxima, quatro deles novos e quatro novos isoxazóis. As substâncias testadas apresentaram atividade antifúngica em quantidades de 1,5 mg e 3,0 mg. Conclusões. Embora as cicloadições 1,3-dipolares permitiram obter os isoxazóis esperados, observou-se que esta metodologia resultou numa grande variedade de subprodutos que reduziram os rendimentos e tornaram difícil a purificação do produto de interesse. Quatro das substâncias testadas apresentaram porcentagens de inibição acima de 80%...

Organophosphate poisoning : A review.

Organophosphate pesticides are used extensively worldwide, and poisoning by these agents, particularly in developing nations is a public health problem. Organophosphorous nerve agents are still considered as potential threat in both military or terrorism situations. The mechanism of toxicity is the inhibition of acetylcholinesterase, resulting in accumulation of the neurotransmitter acetylcholine and continued stimulation of acetylcholine receptors both in central and peripheral nervous systems. Beside acute cholinergic crisis, organophosphates are capable of producing several subacute or chronic neurological syndromes. The well described intermediate syndrome (IMS) emerges 1-4 days after an apparently well treated cholinergic crisis. The standard treatment consists of reactivation of inhibited acetylcholinesterase with an oxime antidote (pralidoxime, obidoxime, HI-6 and Hlo7) and reversal of the biochemical effects of acetylcholine with atropine. The newer oximes HI-6 and Hlo& are much more suitable and efficacious acetylcholinesterase reactivator for severe acute nerve agent induced poisoning than currently used pralidoxime or obidoxime. Patients who receive treatment promptly usually recover from acute toxicity but may suffer from neurologic sequelae.

SYNTHESIS AND ANTIFUNGAL ACTIVITY OF SOME IMIDAZOLYL OXIME ETHER DERIVATIVES / 第二军医大学学报

Oxiconazole, a new broad-spectrum antifungal agent, was synthesized accordi ng to the method reported by Mixich G et al and some improvement was made in the preparation of N- (2, 4-dichlorobenzoylmethyl) imidazole, an important intermediate.In an effort to search for more effective antifungal drugs by chemical modification, several imidazolyl oxime ether derivatives were synthesized.The structures of the synthetic products were proved by elemental analysis.In vitro fungistatic tests showed that compounds Ⅰ-Ⅷ were more effective than clotri-mazole against most of the fungal strains tested and that compound Ⅲ possessed antifungal action against Aspergillus while others didn't.The structure of compound I(oxiconazole)was confirmed by UV, IR, 1H-NMR and MS.Its X-ray powder diffraction data are also provided.In a clinical trial,94.10% of the patients with tinea cruris were cured after a two-week oxiconazole treatments cure rate significantly higher than that of econazole(84.24%, P