7-(7-氨甲基-5-氮杂螺［2,4］庚烷-5-基)-1-环丙基-6-氟-8-甲氧基-1,4-二氢-4-氧代喹啉-3-羧酸及其类似物的合成与抗菌作用7-(7-氨甲基-5-氮杂螺［2,4］庚烷-5-基)-1-环丙基-6-氟-8-甲氧基-1,4-二氢-4-氧代喹啉-3-羧酸及其类似物的合成与抗菌作用

目的寻找新的广谱、高效、低毒喹诺酮类抗菌药物。方法设计合成7-(7-氨甲基-5-氮杂螺［2,4］庚烷-5-基)-1-环丙基-6-氟-8-甲氧基-1,4-二氢-4-氧代喹啉-3-羧酸及其类似物,测定其体内外活性。结果共合成了20个新化合物,经¹HNMR,MS和HRMS确证其结构。其中5个目标化合物(22～26)有广谱活性,尤其对革兰氏阳性菌具有很强的活性。其中化合物24对所试的13株革兰氏阳性菌的MIC值均0.03 mg·L^-1,其活性优于对照药克林沙星和加替沙星,对所试的6株革兰氏阴性菌,其活性相当于或低于对照药。结论化合物(22～26)值得进一步评价。     

哌拉西林/舒巴坦对临床分离菌的体外抗菌活性研究

目的　比较研究哌拉西林、舒巴坦、哌拉西林与舒巴坦不同比例联合及阿莫西林 /舒巴坦 (2∶1) ,对临床分离 3 0 9株需氧菌和 3 0株厌氧菌的体外抗菌活性及其影响因素 (研究哌拉西林 /舒巴坦 (2∶1)对金葡球菌、大肠埃希氏菌和铜绿假单胞菌的的杀菌曲线 )。方法　采用琼脂平板稀释法及肉汤稀释法测定MIC值 ,Nitrocefin纸片法测定细菌产生的 β 内酰胺酶 ,时间杀菌曲线采用肉汤 10倍稀释法。结果　对临床分离的3 3 9株需氧菌及厌氧菌体外抗菌活性研究结果显示 ,哌拉西林及其与舒巴坦联合时 ,对革兰氏阳性球菌及厌氧菌的体外抗菌活性MIC50 为 1～ 4μg/ml,MIC90 多数低于 12 8μg/ml,优于革兰氏阴性杆菌 ,其MIC50 为 1～12 8μg/ml ,MIC90 多数高于 12 8μg/ml;单用舒巴坦对各种细菌的体外抗菌活性极差 ,多数菌的MIC50 及MIC90 分别为 64及 2 5 6μg/ml。对革兰氏阴性杆菌及厌氧菌 ,哌拉西林与舒巴坦联合时体外抗菌活性明显优于单用哌拉西林 ;对于革兰氏阳性球菌 ,哌拉西林联合舒巴坦后体外抗菌活性改善不如革兰氏阴性杆菌及厌氧菌。哌拉西林对产酶株的MIC高于非产酶株 ,联合舒巴坦后 ,产酶株MIC降低而非产酶株MIC变化不明显。不同比例联合的体外抗菌活性比较发现 ,以哌拉西林 /舒巴坦 2∶1联合时效果较好。     

甲磺酸左氧氟沙星的体外抗菌活性研究

甲磺酸左氧氟沙星(Levofloxacin Mesylate,MSALVFX)是本所研制的一种新的氟喹诺酮类抗菌药,是氧氟沙星左旋体的甲磺酸盐。我们测定了甲磺酸左氧氟沙星的体外抗菌活性,并与同类药比较。实验结果表明,MSALVFX是一种广谱、抗菌活性强的喹诺酮类抗菌药,对革兰阳性菌的MIC为0.12～1μg/ml,对革兰阴性菌的MIC为0.002～1μg/ml。对临床分离致病菌871株的活性均与左氧氟沙星相似,是氧氟沙星的2倍。接种量、马血清、培养基pH值等因素对MSALVFX的抗菌活性无明显影响。MSALVFX的杀菌作用与左氧氟沙星、环丙沙星相当,比氧氟沙星强2倍。     

1-取代苄基喹啉酮酸衍生物的合成与抗菌活性

喹啉酮酸类化合物是近年来研究发展十分迅速的广谱、高效、低毒的抗菌药物。作者合成并测定了近三十个6-氟-7-取代氨基取代的1-取代苄基喹啉酮酸类化合物,对金黄色葡萄球菌25923,大肠杆菌25922以及绿脓杆菌的MIC(μg/ml)值。结果表明,这类化合物的体外抗菌活性均较低,对革兰氏阳性菌的作用相对强于对革兰氏阴性菌的作用。1-取代苄基抗菌活性顺序一般为:苄基>对氯苄基>对硝基苄基。     

对革兰氏阳性菌有优良活性的新喹诺酮WIN57273的体内外活性

作者用体内外模型对新的7-二甲基吡啶取代的喹诺酮类化合物 WIN57273 进行了抗菌活性的评价。用琼脂和肉汤稀释法进行的体外实验表明它对革兰氏阳性菌和阴性菌具有广谱活性,对葡萄球菌抗菌活性最强。对凝固酶阳性葡葡球菌的 MIC_(90)≤0.002μg/ml;对凝固酶阴性葡萄球菌 MIC_(90)为0.008μg/ml;对肠球菌的 MIC_(90)为0.06μg/ml。对链球菌 A 族和 B 族以及肺炎球菌的抗菌活性与前相当。总的来说,它对革兰氏阴性菌的 MIC_(90)≤1μg/ml(除了粘质沙雷氏菌 MIC_(90)为16μg/ml,弗氏柠檬酸细菌 MIC_(90)为4μg/     

利福平和其他抗菌药物之间的协同作用

利福平(甲哌力复霉素)是1965年问世近年盛行而且评价较高的一种新药,其特点是口服吸收快,血浓度高,作用较持久,对革兰氏阳性菌(MIC0.001—0.5μg/ml,ED_(50)0.1-2mg/kg)、革兰氏阴性菌(MIC1—10μg/ml)和分枝杆菌(MIC0.005-1μg/ml)尤其是分枝结核杆菌(MIC<0.25μg/ml)有很强的抗菌作用,其抗菌活性不受血清蛋白和 pH 变     

哌拉西林／舒巴坦对临床分离功的体外抗菌活性研究

目的比较研究哌拉西林、舒巴坦、哌拉西林与舒巴坦不同比例联合及阿莫西林/舒巴坦(21),对临床分离309株需氧菌和30株厌氧菌的体外抗菌活性及其影响因素(研究哌拉西林/舒巴坦(21)对金葡球菌、大肠埃希氏菌和铜绿假单胞菌的的杀菌曲线).方法采用琼脂平板稀释法及肉汤稀释法测定MIC值,Nitrocefin纸片法测定细菌产生的β-内酰胺酶,时间杀菌曲线采用肉汤10倍稀释法.结果对临床分离的339株需氧菌及厌氧菌体外抗菌活性研究结果显示,哌拉西林及其与舒巴坦联合时,对革兰氏阳性球菌及厌氧菌的体外抗菌活性MIC5o为1～4μg/ml,MIC90多数低于128μg/ml,优于革兰氏阴性杆菌,其MIC50为1～128μg/ml,MIC90多数高于128μg/ml;单用舒巴坦对各种细菌的体外抗菌活性极差,多数菌的MICso及MIC90分别为64及256μg/ml.对革兰氏阴性杆菌及厌氧菌,哌拉西林与舒巴坦联合时体外抗菌活性明显优于单用哌拉西林;对于革兰氏阳性球菌,哌拉西林联合舒巴坦后体外抗菌活性改善不如革兰氏阴性杆菌及厌氧菌.哌拉西林对产酶株的MIC高于非产酶株,联合舒巴坦后,产酶株MIC降低而非产酶株MIC变化不明显.不同比例联合的体外抗菌活性比较发现,以哌拉西林/舒巴坦21联合时效果较好.哌拉西林与舒巴坦21联合时,对多数临床分离菌的体外抗菌活性与阿莫西林/舒巴坦(21)的体外抗菌活性相当.本研究中,I临床分离细菌对哌拉西林的耐药率以假单胞菌属最高,达61.5%,其次是肠杆菌属细菌及大肠埃希氏菌,分别为50.8%、50.0%.哌拉西林联合舒巴坦后,所有细菌的耐药率明显下降.体外杀菌效果研究表明,当哌拉西林联合舒巴坦21时,4×MIC浓度作用于金葡球菌、大肠埃希氏菌及铜绿假单胞菌后,细菌数均随时间延长而呈指数级减少,在作用于8h细菌均被杀灭.1×MIC及2×MIC作用于以上细菌后,杀菌效果不及4×MIC.各种细菌的体外抗菌活性主要受培养基pH值及接种菌量的影响,几乎不受小牛血清白蛋白浓度的影响.结论哌拉西林/舒巴坦对β-内酰胺酶产生菌株的体外抗菌活性优于哌拉西林,以21联合效果最好,杀菌效果以4×MIC浓度最好,体外抗菌活性受培养基pH值及接种量的影响.     

7-[3-氨甲基-4-(脲亚氨基)吡咯烷-1-基]喹诺酮衍生物的合成与抗菌作用研究

目的 寻找新的喹诺酮类抗菌药.方法 设计合成7-位具有较强亲水性取代基的7个氟喹诺酮衍生物,测定其体外抗菌活性.结果 化合物10对金葡菌(包括MRSA)和表葡菌(包括MRSE)的活性(MIC:0.06～4μg/mL)与左氧氟沙星和吉米沙星基本相当.化合物11对肺炎链球菌08-2的活性(MIC:0.25μg/mL)分别是左氧氟沙星和吉米沙星的128倍和32倍,化合物12对肺炎克雷伯菌09-22和09-23的活性(MIC:1μg/mL)分别是左氧氟沙星和吉米沙星的16倍和4倍,但目标物对革兰阴性菌的活性普遍弱于对照药.结论 7-位取代基的水溶性并非决定喹诺酮抗菌活性的主要因素.     

6-氟-4-喹诺酮类杂合分子的合成及体外抗菌活性研究

目的 筛选新型抗耐药的具有抗菌活性的6-氟-4-喹诺酮类杂合化合物。方法 以诺氟沙星和6-氟-4-喹诺酮-3-羧酸乙酯为主体，与异烟肼、妥曲珠利、青蒿素衍生物和1,2,4-三唑衍生物等结构单元进行杂合，设计了一系列新杂合分子，通过酰胺缩合、烷基化、Mannich反应以及Schiff反应等得到目标化合物。采用测定最小抑菌浓度法，测定目标化合物对革兰阳性菌-耐甲氧西林金黄色葡萄球菌(MRSA)和革兰阴性菌-铜绿假单胞菌(Pae)的体外抗菌活性。结果与结论合成了11个全新的6-氟-4-喹诺酮类杂合分子，所有目标化合物的结构经ESI-MS、¹H-NMR谱确证。体外抗菌活性测试结果表明绝大部分目标化合物具有一定的抗菌活性，其中化合物D对Pae表现出更好的抗菌活性(MIC值为1.0μg·mL^-1,优于阳性对照药诺氟沙星3.9μg·mL^-1);化合物J对MRSA表现出更好的抗菌活性(MIC值为4.2μg·mL^-1,优于阳性对照药诺氟沙星7.8μg·mL^-1)。结合修饰过的分子结构和反应位点，...     

dl-7-(4,4-二甲基-3-氨甲基-吡咯烷-1-基)-喹诺酮类化合物的合成与抗菌作用

目的寻找新的高效抗革兰氏阳性菌的喹诺酮类药物。方法设计合成了dl-7-(4,4-二甲基-3-氨甲基-吡咯烷-1-基)-1-环丙基-6-氟-8-甲氧基-1,4-二氢-4-氧代喹啉-3-羧酸及其类似物，测定其体外活性。结果共合成10个目标化合物，经¹H NMR，MS确证其结构。目标化合物具有良好的抗革兰氏阳性菌的活性，尤其是化合物22不仅对4株革兰氏阳性耐药菌(两株MRSA，两株MRSE)的活性表现突出，MIC值为0.015～0.5 mg·L^-1，其活性是加替沙星(MIC值为0.125～16 mg·L^-1)的4～128倍，而且，对铜绿假单孢菌03-5的MIC值为0.008 mg·L^-1，其活性是加替沙星(MIC值为0.03 mg·L^-1)的4倍。结论化合物22值得进一步深入评价。     

5-HT5 receptors

The 5-HT(5) receptor family consists of two members designated as 5-HT(5A) and 5-HT(5B). To date the 5-HT(5A) receptor has been identified in the mouse, rat, and human. The 5-HT(5B) receptor also is expressed in the mouse and rat, but not in the human where the coding sequence is interrupted by stop codons. Both receptors are essentially limited in distribution to the central nervous system (CNS), although the 5-HT(5A) receptor has also been found on neurons and neuronal-like cells of the carotid body. Within the CNS the 5-HT(5A) receptor shows a relatively broad distribution, while the 5-HT(5B) receptor has a very restricted distribution. The 5-HT(5A) receptor has been demonstrated to couple to G proteins, and the primary coupling appears to be through Gi/o to inhibit adenylyl cyclase activity. The 5-HT(5) receptors have not been extensively characterized pharmacologically. Both receptors show their highest affinity for LSD, which appears to act as a partial agonist at the 5-HT(5A) receptor. Amongst agonist-like molecules, 5-CT (5-carboxamidotryptamine) also has high affinity and has greater potency and affinity at the 5-HT(5A) receptor than does 5-HT itself. Both [(125)I]LSD and [(5)H]5-CT have been used as radioligands to study the receptors in vitro. Nothing is known about the role of the 5-HT(5B) receptor in vivo. A mouse line has been developed where the 5-HT(5A) receptor has been knocked out and these animals have been shown to have a diminished response to LSD-induced increases in locomotion. The 5-HT(5) receptors remain as two of the least studied and understood of the 5-HT receptor subtypes.     

5-氟胞苷和5''-脱氧-5-氟胞苷的合成

5-氟胞嘧啶经苯甲酰化保护后分别与供糖体四乙酰核糖和5-脱氧三乙酰核糖缩合,再经氨解,以45.7%和42.6%的收率分别制得5-氟胞苷和5'-脱氧-5-氟胞苷.     

5-氟胞苷和5＇-脱氧-5-氟胞苷的合成

5-氟胞嘧啶经苯甲酰化保护后分别与供糖体四乙酰核糖和5-脱氧三乙酰核糖缩合,再经氨解,以45.7%和42.6%的收率分别制得5-氟胞苷和5＇-脱氧-5-氟胞苷。     

Synthesis and biological activities of 5-trifluoromethyl-5'-azido-2',5'-dideoxyuridine and 5-trifluoromethyl-5'-amino-2',5'-dideoxyuridine.

5-Trifluoromethyl-2'-deoxyuridine (1) was tosylated with p-toluenesulfonyl chloride in dry pyridine at 3 degrees to give 5-trifluoromethyl-5'-O-(p-tolylsulfonyl)-2'-deoxyuridine (2), which was converted to 5-trifluoromethyl-5'-azido-2',5'-dideoxyuridine (3) by reacting with lithium azide in N,N-dimethylformamide at 85-90 degrees for 2 h. Compound 3 was then hydrogenated in ethanol-water (1:1, v/v) at room temperature and 35 psi of hydrogen pressure, using 10% palladium on charcoal as cstalyst, to yield 5-trifluoromethyl-5'-amino-2',5'-dideoxyuridine (4). Compound 4 is about fourfold less potent than compound 1 as an antiviral agent but is about 40-fold less toxic to the host Vero cells. Thus the therapeutic index of compound 1 has been improved by a factor of 10 by replacement of the 5'-hydroxyl with an amino group. Compound 1, however, is more than 100-fold more inhibitory to Sarcoma 180 cells in culture relative to compound 4. Compound 3 is markedly less potent than compound 1 or 4 as either an antiviral or an antineoplastic compound.     

5'-deoxy-5'-methylthioadenosine phosphorylase--IV. Biological activity of 2-fluoroadenine-substituted 5'-deoxy-5'-methylthioadenosine analogs

5'-Deoxy-5'-methylthioadenosine phosphorylase (MTAPase) phosphorolyzes 5'-deoxy-5'-methylthioadenosine (MTA) generated during polyamine biosynthesis to adenine and 5-methylthioribose-1-phosphate. Two doubly-substituted, 2-fluoroadenine-containing analogs of MTA, 5'-deoxy-2-fluoroadenosine (5'-dFAdo) and 5'-deoxy-5'-iodo-2-fluoroadenosine (5'-IFAdo), were synthesized and studied as substrates of MTAPase: their reaction with this enzyme resulted in the liberation of the cytotoxic base, 2-fluoroadenine, as well as potentially cytotoxic analogs of 5-methylribose-1-phosphate. The activities of these MTA analogs were compared to that of the singly-substituted analog, 5'-deoxy-5'-methylthio-2-fluoroadenosine (5'-MTFAdo). The cytotoxic action of these MTA analogs depended primarily on their conversion to 2-fluoroadenine-containing nucleotides, as a cell line that contains both MTAPase and adenine phosphoribosyltransferase (APRT) activity (HL-60 human promyelocytic leukemia) readily converted these MTA analogs to 2-fluoroadenine-containing nucleotides (especially 2-fluoroadenosine triphosphate) and was highly sensitive to the growth-inhibitory effects of all three compounds (IC50 values in the 10(-8) M range), whereas cell lines lacking MTAPase (CCRF-CEM human T-cell leukemia) or APRT (HL-60/aprt1 cells) did not form analog nucleotides and were relatively insensitive to these compounds (IC50 values in the 10(-5) M range). The doubly-substituted analogs were not more growth inhibitory than 5'-MTFAdo in wild type HL-60 cells as the potent effects of 2-fluoroadenine may mask the activity of the 5-methylthioribose-1-phosphate analogs generated in the reaction of these compounds with MTAPase. 5'-dFAdo and 5'-IFAdo also were irreversible inhibitors of S-adenosylhomocysteine hydrolase, which may explain in part the weak but observable growth inhibitory action of these compounds against MTAPase-deficient cell lines.