Synthesis of 4‐Aryl‐2‐Quinolones via Copper‐Catalyzed Hydroarylation of (o‐Aminophenyl)propiolates with Arylboronates

4‐Aryl‐2(1H)‐quinolones were efficiently synthesized via copper‐catalyzed hydroarylation of (o‐aminophenyl)propiolates with arylboronic acid neopentyl glycol esters. The substrate propiolates were prepared from the corresponding silylalkynes with carbon dioxide by Kondo’s carboxylation method using N,N‐dimethylformamide as a solvent. Hydroarylation was performed in the presence of 3 mol% copper(II) acetate in methanol at 28 °C for 12 h and subsequent deprotection using trifluoromethanesulfonic acid (3.0 equiv.) at 65 °C for 2 h in the same pot to afford the desired 4‐aryl‐2(1H)‐quinolones in 39–89% yields.

     

A Phytochemical–Halogenated Quinoline Combination Therapy Strategy for the Treatment of Pathogenic Bacteria

With the continued rise of drug‐resistant bacterial infections coupled with the current discouraging state of the antibiotic pipeline, the need for new antibacterial agents that operate through unique mechanisms compared with conventional antibiotics and work in synergy with other agents is at an all‐time high. We have discovered that gallic acid, a plant‐derived phytochemical, dramatically potentiates the antibacterial activities of several halogenated quinolines (up to 11 800‐fold potentiation against Staphylococcus aureus) against pathogenic bacteria, including drug‐resistant clinical isolates. S. aureus demonstrated the highest sensitivity towards gallic acid–halogenated quinoline combinations, including one halogenated quinoline that demonstrated potentiation of biofilm eradication activity against a methicillin‐resistant S. aureus (MRSA) clinical isolate. During our studies, we also demonstrated that these halogenated quionlines operate through an interesting metal(II) cation‐dependent mechanism and display promising mammalian cytotoxicity.     

超高效液相色谱-质谱串联法测定蜂蜜中喹诺酮类药物残留

目的建立超高效液相色谱-质谱串联法测定蜂蜜中喹诺酮类药物残留的分析方法。方法分析采用Thermo Fisher Gold Hypersil柱(50 mm×2.1 mm, 1.9μm);流动相A为甲醇,流动相B为0.1%甲酸水溶液,流动相流速:0.2 mL/min,柱温:35℃,梯度洗脱;电喷雾离子源正离子扫描(electron spray ionization, ESI+),选择反应监测模式检测(selected reaction monitoring,SRM)。结果 6种喹诺酮类药物在各自范围内线性关系良好,相关系数r均大于0.998,平均加样回收率在82.47%～105.06%,相对标准偏差(relative standard deviation,RSD)均小于5.62%。12批次样品中有2批次检出诺氟沙星。结论该方法前处理简单、快捷、测定灵敏度高、结果准确,可适用于蜂蜜中喹诺酮类药物残留量的检测,为监督检验提供了更为简单准确的方法。     

UPLC-MS/MS检测鸡蛋中22种喹诺酮类药物残留方法的研究

应用超高效液相色谱串联质谱建立鸡蛋中加雷沙星、曲伐沙星、莫西沙星、奥比沙星、吉米沙星、加替沙星、培氟沙星和环丙沙星等22种喹诺酮类药物残留检测方法。样品经过2%甲酸乙腈提取、正己烷分步去脂,Oasis HLB柱净化后,经Acquity UPLC BEH Shield RP18(100 mm×2.1 mm,1.7μm)分离,以甲醇和0.1%甲酸水溶液为流动相进行梯度洗脱,双通道MRM信号采集模式,22种喹诺酮类药物能在11 min完好分离,方法的最低定量限均低于1.0μg/kg,在2.0~100.0μg/L浓度范围内,22种喹诺酮类药物线性良好,相关系数均在0.99以上;通过2、10、20 g/kg三个浓度的加标回收实验表明,回收率为60.1%~96.2%,RSD%值为1.44%~11.1%。该方法相比现有国标检测药物种类多,新型药物多,对更全面筛查和确证鸡蛋中喹诺酮类药物残留,防范非法添加造成安全隐患具有一定的参考价值。     

超高液相色谱-串联质谱法测定猪肉中8种喹诺酮类兽药残留的不确定度评定

目的评定超高液相色谱-串联质谱法测定猪肉中8种喹诺酮类兽药残留量的不确定度。方法根据JJF 1135-2005《化学分析测量不确定度评定》和JJF 1059.1-2012《测量不确定度评定与表示》中的有关规定,建立不确定度的数学模型,逐层对不确定度进行分析。结果添加量为1.0μg/kg时,8种喹诺酮类兽药残留量测定的相对标准不确定度为2.77%~6.65%;添加量为2.0μg/kg时,8种喹诺酮类兽药残留量测定的相对标准不确定度为1.69%~6.67%;添加量为4.0μg/kg时,8种喹诺酮类兽药残留量测定的相对标准不确定度为1.31%~5.43%。结论在实际检测中,提高天平精度及定容精度,控制标准溶液配制过程,提高检验员工作质量和效率均可降低引入的不确定度,使检测结果更可靠。     

液相色谱-串联质谱法检测蜂蜜中15种喹诺酮类和17种磺胺类药物残留

目的建立同时测定蜂蜜中15种喹诺酮和17种磺胺类药物残留的液相色谱-串联质谱(liquid chromatography-tandem mass spectrometry,HPLC-MS/MS)检测方法。方法样品经过磷酸盐缓冲溶液(pH=8)提取,过HLB(hydrophile-lipophile balance)固相萃取柱净化。以CORTECS C18色谱柱(2.1 mm×100 mm,1.6μm)分离,以5 mmol乙酸铵、0.1%甲酸水(A)和0.1%甲酸-乙腈(B)作为流动相进行梯度洗脱。质谱分析以电喷雾为离子源(electrospray ionization,ESI+),采用多反应监测(multiple reaction monitoring,MRM)。结果本方法在15 min内完成32种目标化合物的分离。15种喹诺酮和17种磺胺类药物在1.0、5.0和10.0μg/kg添加水平的回收率为54.9%~122.5%,相对标准偏差(relative standard deviation,RSD)小于18.7%(n=6),方法检出限为0.4μg/kg,定量限为1.0μg/kg。结论该方法快速、准确、灵敏,适合测定蜂蜜中喹诺酮和磺胺类药物残留。     

Regioselective Synthesis of 1,2‐ and 1,4‐Dihydroquinolines by Palladium‐Catalyzed Intramolecular N‐Arylation

A series of 1,2‐ and 1,4‐dihydroquinolines has been successfully prepared. The Pd‐catalyzed intramolecular N‐arylation of Z‐enamines, formally prepared by the Horner–Wadsworth–Emmons olefination, proceeded efficiently to furnish the cyclized products. Depending on the cyclization conditions, substituted 1,4‐dihydroquinolines and further isomerized 1,2‐dihydroquinolines were independently obtained in high yields with an excellent control of isomerization of the double bond.

     

Design, synthesis, and in vitro antibacterial activity of fluoroquinolone derivatives containing a chiral 3-(alkoxyimino)-2-(aminomethyl)azetidine moiety

A series of novel (R)/(S)-7-(3-alkoxyimino-2-aminomethyl-1-azetidinyl)fluoroquinolone derivatives were synthesized and evaluated for their in vitro antibacterial activity against representative strains. Our results reveal that 12 of the target compounds generally show better activity (MIC: <0.008-0.5 μg mL(-1)) against the tested Gram-positive strains including MRSA and MRSE than levofloxacin (LVFX, MIC: 0.125-8 μg mL(-1)). Their activity is similar to that of gemifloxacin (GMFX, MIC: <0.008-4 μg mL(-1)). However, they are generally less active than the two reference drugs against Gram-negative strains. Moreover, against clinical strains of S. aureus including MRSA and S. epidermidis including MRSE, the MIC(50) values (0.06-16 μg mL(-1)) and MIC(90) values (0.5-32 μg mL(-1)) of compounds 16 w, y, and z are 2-8- and 2-16-fold less than LVFX, respectively, and 16 w (MIC(90) range: 0.5-4 μg mL(-1)) was also found to be more active than GMFX (MIC(90) range: 1-8 μg mL(-1)).     

Rapid determination of 19 quinolone residues in spiked fish and pig muscle by high-performance liquid chromatography (HPLC) tandem mass spectrometry

A multiresidue method has been developed for the confirmation and quantification of 19 quinolones (enrofloxacin, ciprofloxacin, norfloxacin, ofloxacin, flumequine, oxolinic acid, difloxacin, sarafloxacin, sparfloxacin, danofloxacin, fleroxacin, marbofloxacin, enoxacin, orbifloxacin, pefloxacin, nalidixic acid, pipemidic acid, lomefloxacin and cinoacin) in pig and fish by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The samples were extracted with acetonitrile, analytes separated by LC on a C₁₈ column using 0.1% formic acid–methanol with a linear gradient elution programme, and detected by MS/MS. The linear range was 0.3–50 µg kg^–1 with correlation coefficients (r) more than 0.9956. The limits of detection were 0.1 µg kg^–1. Mean recoveries for each analyte in pig muscle and fish ranged from 75.3% to 96.3% and from 79.7% to 94.2% with relative standard deviations below 10%. The method is fast, safe, sensitive and precise, and can be used simultaneously to analyse residual quinolones.