唑烷酮类抗耐药菌新药--康替唑胺

多重耐药革兰阳性菌是致细菌性感染的重要病原菌之一,其感染具有高发病率和高病死率。临床最为关注的革兰阳性病原菌为耐甲氧西林金黄色葡萄球菌(MRSA),耐甲氧西林凝固酶阴性葡萄球菌(MRCNS)和耐万古霉素肠球菌(VRE)。当前治疗上述耐药菌感染的抗菌药物,包括糖肽类、唑烷酮类等多种药物已用于临床,然而既安全又有效的抗菌药物仍未能满足临床需求。

聚异氰氨酸酯唑烷酮的高应变动态响应研究

通过基本力学性能测试和Kolsky杆(SHPB)方法,测试聚异氰氨酸脂唑烷酮(POZD)在高应变率下的非线性力学行为。结果表明,防爆新材料POZD应力应变关系能够较好地用Mooney-Rivlin模型来表示,该模型采用左柯西张量不变量表示的应变能函数来描述POZD材料的力学响应特性,以便对其防爆性能进行进一步设计和优化。

卫生技术评估在新型唑烷酮药物康替唑胺遴选评价中的应用

目的通过卫生技术评估新型唑烷酮类抗菌药康替唑胺,为医院遴选、临床合理使用新型噁唑烷酮药物提供循证依据。方法按照药品目录遴选评价管理指南评估细则对国产康替唑胺片进行量化评估,通过检索中国知网、万方、维普、Pub Med、Metstr等中外文数据库及相关政府网站获得康替唑胺的适应证、药理作用、指南推荐情况、药品价格等信息,按照药学特性、有效性、安全性、经济性及其他属性量化评价,汇总得分并根据评分划分推荐级别。结果综合评估结果显示,康替唑胺药学特性18.8分,有效性15分,安全性14.2分,经济性14分,其他属性10分,总得分72分,可推荐进入医疗机构用药目录。结论康替唑胺作为新品种可以推荐进入医疗机构用药目录,对于临床上利奈唑胺无法治愈的耐甲氧西林金黄色葡萄球菌(MRSA)感染,康替唑胺片有望成为更加安全的抗菌药物选择。

噁唑烷酮类新药MRX-Ⅰ在人血浆、尿液浓度超高效液相色谱串联质谱测定方法的建立及验证

目的建立及验证超高效液相色谱串联质谱（UPLC-MS,/MS）的方法用于测定人血浆和尿液中恶唑烷酮类新药MRX-I药物浓度。方法 UPLC-MS/MS液相条件为色谱柱Waters ACQUITY UPLC BEH C8;流动相为乙腈：水（40：60,v/v）。质谱采用ESI源正离子多反应监测（MRM）。内标为利奈唑胺,以乙酸乙酯液-液萃取法清除血浆及尿液样本中杂质。方法学验证包括基质效应、绝对回收率、精密度和准确度及MRX-I在人血浆及尿液样本中放置稳定性。结果 UPLC-MS/MS法检测MRX-I在人血浆和尿液中的线性范围均为（0.005 00～1.00）mg/L,最低检测浓度均为0.005 00 mg/L。MRX-I与内标在血浆和尿液中的保留时间小于1.5 min。本方法学验证结果显示MRX-I在人血浆和尿液基质效应因子分别为90.4%±8.2%和82.7%±7.9%;血浆和尿液中MRX-I提取回收率分别为112.8%±13.4%和105.6%±13.4%。MRX-I血浆样本的测定方法日内、日间准确度分别为98.9%～105.0%和96.5%～102.6%;尿液样本的测定方法日内、日间准确度分别为92.7%～98.6%和95.1%～105.7%。MRX-I在人血浆和尿液样本室温放置24 h、预处理后自动进样器放置48 h、-40℃冰箱冻融3次、-40℃冰箱分别放置8个月和6个月仍然保持稳定。结论本研究建立的UPLC-MS/MS检测人血浆及尿液中MRX-I浓度方法的灵敏度高,专属性强。其方法学验证结果均符合生物样品分析的要求。

氮杂环丙烷与CO_2反应的最新研究进展

二氧化碳既是温室气体的主要成分,也是储量丰富的碳资源,研究二氧化碳的转化与利用有着重要的意义。总结了近几年各种催化体系催化氮杂环丙烷与CO_2的环加成反应,包括不可回收催化剂、可回收催化剂和无催化剂体系,以及各体系对氮杂环丙烷与CO_2环加成反应产物收率和区域选择性的影响。

PPG/PTMG基单组分聚脲的制备及性能研究

采用预聚体法,分别以聚氧化丙烯二醇(PPG)、聚四氢呋喃二醇(PTMG)和两者共混物为软段,甲苯二异氰酸酯(TDI)和唑烷潜固化剂为硬段制备单组分聚脲。并通过红外光谱、差式量热、吸水率、力学性能、硬度、表干时间和实干时间等表征手段研究了组合聚醚配比对单组分聚脲结构与性能的影响。结果表明:随着PTMG比例的增加,表干时间和实干时间缩短,拉伸强度、断裂伸长率、粘结强度和硬度逐渐增加,吸水率降低。当多元醇PTMG比例为100%时,单组分聚脲的综合性能达到最优。

HKUST-1单位点铜催化CO2/CS2成环耦合三氟甲基化反应

以烯丙基胺类化合物为底物,Togni′s ReagentⅡ〔1-(三氟甲基)-1,2-苯碘酰-3(1H)-酮〕为三氟甲基源,CO2或CS2为C1合成子,高稳定性金属有机框架HKUST-1的Cu2(O2C)4双轮桨节点的单位点铜为催化剂,在温和条件下耦合CO2/CS2成环与三氟甲基化反应。对碱性添加剂、溶剂、反应温度、催化剂负载量等反应条件进行了优化。结果表明,在5%的HKUST-1〔以底物N-苄基-2-苯基丙烯-2-烯-1-胺(1a)的物质的量为基准计算得到。HKUST-1的添加量基于Cu2(O2C)4双轮桨节点(催化剂最简分子结构式为Cu2(BTC)4/3·2H2O,摩尔质量为439.28g/mol)的摩尔质量计算,下同〕、CO2压力为101.325kPa、45℃的最佳反应条件下,含不同取代基的底物能以69%~87%的产率得到三氟甲基-唑烷酮医药中间体。自由基捕获实验验证了该反应可能的反应机理。催化剂HKUST-1可循环使用4次仍保持良好催化活性和晶态结构。使用CS2替代CO2时,可得到具有中枢神经调节作用的三氟甲基-噻唑烷硫酮衍生物,体现出该体系对硫毒化的耐受性。

Synthesis and Antibacterial Activity of (S)-5-(Heterocycle Methylene) -3-(3-Fluoro-4-morpholin-4-yl-phenyl)-Oxazolidin-2-one Derivatives

Aim To study the structure-activity relationship of antibacterial oxazolidinone derivatives. Methods Seven （S） -5- （ heterocycle methylene） -3- （3-fluoro-4-morpholin-4-yl-phenyl） -oxazoli- din-2-ones were synthesized by the substitution of （S）-[ 3-（3-fluoro-4-morpholin-4-yl-phenyl）-oxazohdin-2-one-5-yl]-methanol mesylate with some secondary amines and the structures of the product were confirmed by ^1H NMR and elemental analyses or MS. Results None of the seven compounds showed potent activity against the tested 20 strains of bacteria in vitro. Conclusion The replacement of 5- acetylaminometyl of Linezolid by 5-（heterocycle methylene） lost the antibacterial activity.

Synthesis of Tazobactam,β-Lactamase Inhibitor

Tazobactam,β lactamase inhibitor, was synthesized from 6 aminopenicillanic acid through eleven steps, including diazotization, bromination, oxidation, chlorization, cyclization, deprotection and so on. The designed route was examined, particularly the azide substitution and cyclization. In the latter reaction, vinyl acetic ester was employed in place of acetylene.

A Study of the Relationship Between the Chemical Structure and the Anticonvulsant Activity of the 3-Pyrazolidinones

The Hansch approach was used in the quantitative structure anticonvulsant activity studies of the previously synthesized 1-substituted-and 1.5-disubstituted-3-pyrazo- lidinones.Correlation analysis predicted that 1.5-disubstituted-3-pyrazoljdinones in which 1- substituent is n-propyl but not benzyl.with the total hydrophobic constant of 1-and 5-sub- stituents(∑л)equals to 4.5(optimum value)will have the most potent activity.On the basis of this analysis eleven 5-substituted and I-n-butyl-5-substituted-3-pyrazolidinones were syn- thesized.Pharmacological tests indicated that the prediction of the Hansch analysis of the 3- pyrazolidinones is correct.The Hansch analysis,by including these 11 compounds,gives an almost identical correlation with that previously obtained.

(Z)-5-(4-methoxybenzylidene)thiazolidine-2,4-dione protects rats from carbon tetrachloride-induced liver injury and fibrogenesis

AIM： To evaluate the hepatoprotective roles of （Z）- 5-（4-methoxybenzylidene）thiazolidine-2,4-dione （SKLB010） against carbon tetrachloride （CCI4）-induced acute and chronic liver injury and its underlying mecha- nisms of action.

Synthesis of two new thiazolidines and their hepatoprotective effects

Two new 2-substituted thiazolidine-4（R）-carboxylic acids （TCAs）, 2-glusosaminal-TCA （GIcNH2Cys） and 2-N-acetyl-glueosanlinal-TCA （GlcNAeCys）, were synthesized. Their protective effects against liver toxicity induced by acetaminophen （APAP） were investigated in a mice model. The resuits demonstrate that administration of TCAs （ i. p. , 800 mg/kg） 30 min after APAP challenge efficiently decrease ALF, AST, and LDH levels in liver. GlcNAcCys shows the best proteetive eftects, decreasing ALT, AST and LDH levels to 63%, 18.4% and 37% of the APAP group respectively. Comparison with the control showed that APAP greatly decreases total sulfhydlyl （T-SH） levels （43%）, non-protein hound sulfhydryl （NP-SH） levels （50%） and total antioxidative capabilities （57%） in the liver 24 hr after challenge. TCAs treatments 30min after APAP challenge significantly elevate sulfhydryl levels and total antioxidative capabilities. APAP administration also markedly （P 〈 0.05） increases liver lipid peroxidation to 1.65 and 1.17 times that of the control 4 hr and 24 hr after APAP administration respectively. TCAs treatments can inhibit lipid peroxidation as measured by decreased malondialdehyde （MDA） contents in liver. The histopathological results also further confirm the hepatoprotective effects of TCAs. In conclusion, our data show that TCAs, GleNAcCys particularly, have hepatoprotective anti antioxidant etfects.

Efficient approach to thiazolidinones via a one-pot three-component reaction involving 2-amino-1-phenylethanone hydrochloride,aldehyde and mercaptoacetic acid

A highly efficient three-component reaction has been developed for the synthesis of thiazolidinones involving the reaction of 2-amino-l-phenylethanone hydrochloride with an aromatic aldehyde and mercaptoacetic acid in the presence of diisopropylethylamine in a single pot.Critically,this reaction exhibited excellent chemoselectivity,with the nitrogen atom of the 2-amino-l-phenylethanone component reacting selectively with the aromatic aldehyde to give the corresponding Schiff base.Nucleophilic attack at the carbon of the Schiff base by the sulfur atom of mercaptoacetic,followed by a cyclocondensation reaction between the nitrogen and the carboxylic acid moiety afforded the desired thiazolidinones,which were fully characterized by spectroscopic techniques.

Synthesis and antifungal activity of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-(4-substituted acyl piperazin-1-yl)-2-propanols

Objective: To study the effect of fluconzole derivatives from a side chain containing 4-substituted acyl piperazin-1-yl on antifungal activity. Methods: Fourteen title compounds were synthesized and confirmed by the elementary analysis, 1HNMR and IR spectra. Five deep fungal strains and 3 shallow fungal strains were chosen as the experimental strains.Minimum inhibitory concentrations(MICs) of all title compounds were determined by the method recommended by the National Committee for Clinical Laboratory Standards (NCCLS) using RPMI 1640 test medium. Results: Among the 14 title compounds, 12 were first reported. The results of preliminary antifungal test showed that all the title compounds exhibited potent antifungal activities to a certain extent. The activity of 4 compounds were more than 4 times as high as that of fluconazole and equal to that of ketoconazole against Candida albicans in vitro(MIC 80 value≤0.125 μg/ml). Conclusion: Introduction of a side chain containing 4-substituted acyl piperazin-1-yl into the main part of fluconazole has important influence on antifungal activities of title compounds.

Role of renal proximal tubule transport in thiazolidinedioneinduced volume expansion

Thiazolidinediones （TZDs）, pharmacological activa-tors of peroxisome-proliferator-activated receptors γ （PPARγ）, significantly improve insulin resistance and lower plasma glucose concentrations. However, the use of TZDs is associated with plasma volume expansion, the mechanism of which has been a matter of contro-versy. Originally, PPARγ-mediated enhanced transcrip-tion of the epithelial Na channel （ENaC） γ subunit was thought to play a central role in TZD-induced volume expansion. However, later studies suggested that the activation of ENaC alone could not explain TZD-induced volume expansion. We have recently shown that TZDs rapidly stimulate sodium-coupled bicarbonate absorp-tion from renal proximal tubule （PT） in vitro and in vivo. TZD-induced transport stimulation was dependent on PPARγ/Src/EGFR/ERK, and observed in rat, rabbit and human. However, this stimulation was not observed in mouse PTs where Src/EGFR is constitutively activated. Analysis in mouse embryonic fbroblast cells confrmed the existence of PPARγ/Src-dependent non-genomic signaling, which requires the ligand binding ability but not the transcriptional activity of PPARγ. The TZD-in-duced enhancement of association between PPARγ and Src supports an obligatory role for Src in this signal-ing. These results support the view that TZD-induced volume expansion is multifactorial. In addition to the PPARγ-dependent enhanced expression of the sodium transport system（s） in distal nephrons, the PPARγ-dependent non-genomic stimulation of renal proximal transport may be also involved in TZD-induced volume expansion.

Removal of Trace Olefins from Aromatics by Catalytic Alkylation Using 1-Alkyl-3-methylimidazolium Bromochloroaluminate Catalyst

Removal of trace olefins from aromatic liquids had been investigated in the presence of various ionic liquids like 1-ethyl-3-methylimidazoliurn bromochloroaluminate （EMIMBr-AlCl3）, 1-butyl-3-methylimidazolium bromochloroaluminate （BMIMBr-AlCl3）, l-hexyl-3-methylimidazolium bromochloroaluminate （HMIMBr-AlCl3）, and 1-octyl-3-methylimidazolium bromochloroaluminate （OMIMBr-A1C13）. It was found that the longer the alkyl chain of ionic liquid cations was, the higher the olefins conversion would be. OMIMBr-AlCl3 （with 0.67 molar fraction of AlCl3） had an obvious performance on olefins removal. The influences of various reaction parameters such as the dosage of catalyst, the reaction temperature, and the reaction time on the reaction catalyzed by OMIMBr-AlCl3 were investigated. Under optimum reaction conditions, a higher than 99% conversion of olefins was achieved. The preliminary results revealed that the process could save time, consume less energy, separate products easier, and cause less pollution to the environment.

Gas-phase Thermolysis of 1,2,3-triazole and 1,2,3-triazine Derivatives

Gas-phase thermolysis of 1-ethoxycarbonyl-benzotriazole under static, FVP and microwaves condition yielded N^1 and NZ-ethylbenzotriazole, 2-ethoxy-1,3-benzooxazole, biphenylene and oxazolidin-2-one. On the other hand, direct condensation and pyrolysis of naphtho[1,8-de][1,2,3]triazine with ethylisocyanate, phenylisocyanate and their isothiocayanates, benzoylisothiocyanate and thiourea at 150-160 ℃ or under microwaves irradiation produced the corresponding naphthopyrimidin-2-one derivatives.

Effect of interferon and ribavirin combined with amantadine in interferon and ribavirin non-responder patients with chronic hepatitis C (genotype 1)

AIM: To evaluate the efficacy of amantadine plus interferonalpha and ribavirin in non-responder patients with chronic hepatitis C.METHODS: Twenty-six non-responder patients received the regimen of IFN-α-2a at a dose of 6 million units three times a week, 1 000-1 200 mg of ribavirin daily, and 200 mg of amantadine daily in divided doses over 48 wk. After the end of treatment, at the 72nd wk, a sustained viral response rate was determined.RESULTS: An early (after 12 wk of therapy) response was seen in 34.6% (9/26) of patients. Response rate at the 24th wk was 42.3% (11/26). End of treatment response (ETR) was 53.8% (14/26). Sustained viral response (SVR) was 42.3% (11/26). There was a statistically significant difference between 0 and 12 wk (P = 0.04), 0 and 24 wk (P = 0.01), 0 and 48 wk (P = 0.00), and 0 and 72 wk (P = 0.001). No patient had severe adverse effects during the treatment.CONCLUSION: Combination regimen of interferon-α,ribavirin and amantadine can enhance sustained viral response on IFN-α and ribavirin non-responder patients with HCV. Triple therapy with amantadine should be evaluated in further studies.

ASYMMETRIC HYDROSILYLATION CATALYZED BY POLYMER-SUPPORTED THIAZOLIDINE RHODIUM CATALYSTS

Asymmetric hydrisilylation catalyzed by polymeric thiazolidine rhodium catalystswas conducted. Almost the same optical yields have been obtained when comb-shapedpolymeric ligands and their corresponding monomer complexed rhodium cataltystswere used to asymmetric hydrosilylation of acetophenone. Optical yield of chira 1- methylbenzyl alcohol reaches as high as 71.5%. Temperature dependence of enantio- selective hydrosilylation of acetophenone was discussed.

DFT-Study on Antioxydant of 3-Alkyl-4-P henylacetylam i no-1H-1,2,4-Triazol-5-O nes and Its Derivatives

In this article, we have performed B3LYP/6-31＋G（d） calculations of geometrical and reaction enthalpies of antioxidant mechanisms for ADPHT 1-4 （3-alkyl-4-phenylacetylamino-lH-1,2,4-triazol-5-ones） and its derivatives： HAT （hydrogen atom transfer）, SET-PT （single electron transfer-proton transfer） and SPLET （sequential proton-loss electron transfer） were investigated in gas and solution-phases. Solvent contribution to enthalpies was computed employing integral equation formalism IEF-PCM （integral equation formalism method） method. It turned out that the lowest BDEs （bond dissociation energies） is obtained for C-H bonds due to captodative effect in various media. Results indicate that HAT mechanism represents the most anticipated process in gas-phase from thermodynamic point of view. But, the SPLET represents the thermodynamically preferred reaction pathway in solvents （2-propanol, acetonitrile, DMF （N,N-dimethylformamide） and water）. The authors showed that bond dissociation energies, IP （ionization potential） and PA （proton affinity） are sufficient to evaluate the thermodynamically preferred mechanism.