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。     

7-(取代-5-氮杂螺[2,4]庚烷-5-基)喹诺酮类化合物的合成与抗菌作用

为寻找新的广谱、高效、低毒喹诺酮类抗菌药物,本文设计合成了9个7-(7-甲基氨甲基-5-氮杂螺2,4庚烷-5-基)-1-环丙基-6-氟-1,4-二氢-4-氧代-1,8-萘啶-3-羧酸及其类似物,其结构均经1H-NMR、MS所确证,并测定了它们的体外抗菌活性。结果表明,9个目标物均具有广谱活性,其中化合物23、26、27对10株革兰氏阳性菌的MIC值为0.01～0.12μg/ml,其活性远优于对照药加替沙星(MIC值为0.12～1μg/ml)和环丙沙星(MIC值为0.25～4μg/ml)。对10株革兰氏阴性菌的MIC值为0.01～2μg/ml,其活性基本与对照药相当或更优。     

5-氨基-8-甲氧基-喹诺酮类的合成及其体外抗菌作用

以1-环丙基-6，7-二氟-8-甲氧基-1，4-二氢-4-氧代喹啉-3-羧酸乙酯为起始原料依次经过硝化、还原和水解三步反应制得5-氨基-1-环丙基-6，7-二氟-8-甲氧基-1，4-二氢-4-氧代喹啉-3-羧酸，然后分别与2（R）-（-）／2（S）-（＋）或2（R，S）-甲基哌嗪缩合，得到3种目标化合物（5a、5b和5c）。测定它们对20株临床分离和标准革兰阴性菌和标准革兰阳性菌的最低抑菌浓度。结果表明，5a和5b的体外抗菌活性与外消旋体5c基本相当。     

5-芳基-1,2-二氢-1-吡咯里嗪酮类化合物的合成及抗炎镇痛作用

目的 研究5-芳基-1，2-二氢-1-吡咯里嗪酮类化合物的抗炎镇痛作用构效关系，寻找高效低毒、具有抗炎镇痛活性的新型吡咯里嗪酮衍生物。方法 以吡咯里嗪酮为母体，设计并合成了5-芳基-1，2-二氢-1-吡咯里嗪酮类化合物。用二甲苯致小鼠耳肿胀法和小鼠醋酸扭体法测定了该类化合物的抗炎及镇痛活性。结果 用两条路线合成了10个目标化合物，经1H-NMR和MS确证其结构。小鼠试验表明，一些所合成的化合物具有明显的抗炎和／或镇痛作用。结论 化合物Ⅲ1及Ⅲ5的抗炎活性优于对照药布洛芬；化合物Ⅲ5的镇痛活性优于对照药布洛芬；其中化合物Ⅲ5的抗炎及镇痛活性均强于对照药布洛芬，值得进一步研究。     

莫西沙星8-二氟甲氧基类似物的合成与体内外抗菌作用

1-环丙基-6，7-二氟-8-甲氧基-1，4-二氢．4-氧代喹啉．3-羧酸乙酯依次经醚键断裂、酯化、二氟甲基醚化得1．环丙基-6，7-二氟-8-二氟甲氧基-1，4-二氢-4-氧代喹啉．3-羧酸乙酯，然后经过螫合、与[1S，6S]-2．叔丁氧羰基．2，8．二氮杂双环[4，3，0]壬烷缩合、最后脱除叔丁氧羰基保护得到1-环丙基．8．二氟甲氧基-7-[（1S，6S）．2，8．二氮杂双环[4，3，0]壬烷．8．基]-6-氟．1，4-二氢-4-氧代喹啉-3-羧酸。目标化合物的结构经核磁共振氢谱和质谱（ESI）所确证，并测定了其体内外抗菌作用，结果表明该化合物优于对照药环丙沙星，与莫西沙星相当或略优，尤其对肺炎链球菌29074的体内活性突出，值得深入评价。     

2-氯喹啉-3-甲醛缩氨基胍衍生物的合成及其抗炎活性研究

目的设计合成具有抗炎活性的2-氯喹啉-3-甲醛缩氨基胍类化合物。方法以6-羟基-3,4-二氢-2-喹啉酮为原料,与氯苄进行亲核取代反应得到中间体6-取代苄氧基-3,4-二氢-2-喹啉酮,该中间体经VilsmeierHaack反应得到2-氯-6-苄氧基-喹啉-3-醛类化合物,最后与氨基胍碳酸盐反应得到目标化合物;采用二甲苯诱导小鼠耳肿胀实验测定目标化合物的抗炎活性。结果与结论共合成了13个化合物,其中5个是未见报道的新化合物,其结构均经MS、IR、~1H-NMR和~(13)C-NMR谱确证。活性评价结果显示,该系列化合物均具有较好的抗炎活性。其中,化合物5a活性最好,在100 mg·kg~(-1)剂量下,腹腔注射给药时抑制率达到94.01%,优于阳性对照药布洛芬(39.56%)。     

新型二氢呋喃类化合物的合成及抑制血小板聚集活性研究

目的 研究2-（4-甲氧基苯基）-4-乙烯基-2,5-二氢呋喃-3-羧酸及其衍生物的合成及抗血小板凝集活性.方法 设计合成未见报道的目标化合物17个,应用1H-NMR、MS对得到的目标化合物进行结构鉴定,采用Born方法对目标化合物进行体外抗凝血活性测试.结果 合成得到2-（4-甲氧基苯基）-4-乙烯基-2,5-二氢呋喃-3-羧酸及其衍生物17个,所有目标化合物均具有优于对照药MCI-154的抗血小板凝集活性.结论 2-（4-甲氧基苯基）-4-乙烯基-2,5-二氢呋喃-3-羧酸及其衍生物具有较好的抗凝血药理活性,其中化合物（3）,（6）和（10）的活性分别是到对照药MCI-154的22.2,12.8和8.6倍,具有很强的开发应用前景.     

5-取代苯氧基及2,5-双取代苯氧基伯喹衍生物的合成及其抗疟作用

一般认为8-氨基喹啉类化合物的抗疟作用与其在宿主体内转化成活性代谢物-喹啉醌有关。扑疟喹5,6-二醌在体外的抗疟活性比扑疟喹强16倍。在8-氨基喹啉类化合物的5-位引入苯氧基或烷氧基因在体内仍可代谢成醌式化合物而保持较高的抗疟活性,如5-对氟苯氧基和5-甲氧基伯喹的猴疟根治效果都优于伯喹,此外,喹啉类化合物经生物转化可生     

5-氨基苯并咪唑酮类衍生物的设计、合成及其乙酰胆碱酯酶抑制活性的研究

以5-氨基苯并咪唑酮为原料,经过酰化和取代反应合成了目标化合物,并采用Ellman分光光度法,考察了它们对乙酰胆碱酯酶的体外抑制活性。结果表明部分目标化合物具有一定的乙酰胆碱酯酶抑制活性,其中化合物4d的抑制活性最好,其IC50=7.2μmol·L-1,优于对照药利斯的明;同时它对丁酰胆碱酯酶几乎没有抑制活性。5-氨基苯并咪唑酮类化合物对乙酰胆碱酯酶的抑制活性值得进一步研究。     

吡酮酸类抗茵药物的研究XVI．6-氟-1-（2-氟-5-吡啶基）-7-（1一哌嗪基）-1，4-二氢-4-氧代喹啉-3-羧酸及其类似物的合成与抗茵作用

合成了14个6-氟-1-(2-氟-5-吡啶基)-5．7．8-不同取代-1．4-二氢-4-氧代喹啉-3-羧酸及其类似物．测定了它们对14株革兰氏阳性和革兰氏阴性细菌的MIC值．并与环丙沙星对照。结果表明,这些化合物的抗菌活性均很弱。     

Synthesis, analgesic and antiinflammatory properties of certain 5-/6-acyl-3-(4-substituted-1-piperazinylmethyl)-2-benzoxazolinones derivatives

The synthesis of a novel series of Mannich bases of 5-/6-acyl-5-methyl-2-benzoxazolinones has been described. The structures attributed to compounds 2a, 3a, 4a, 4b, 9a, 9b, 5a-5g, 6a-6g, 10a, 10g, 11a, 11g have been elucidated using IR and (1)H NMR spectroscopic techniques besides elemental analysis. The compounds have been evaluated for their in vivo analgesic and antiinflammatory activities using the p-benzoquinone-induced writhing test and the carrageenan hind paw oedema test in mice, respectively. In addition, the ulcerogenic effects of the compounds were determined. Among the tested derivatives most promising results were obtained for the compounds bearing a 6-(4-chlorobenzoyl) at C-6 position and 2-/4-fluorophenyl at C-3 position of 2-benzoxazolinone ring (11c, 11d).     

Synthesis and in vitro antifungal evaluation of 1,3,5-trisubstituted-2-pyrazoline derivatives

Pyrazolines, the well-known five-membered nitrogen-containing heterocyclic compounds, have received considerable interests in the fields of medicinal and agricultural chemistry because of their broad spectrum of biological activities. To discover more potent antifungal compounds, a series of structurally related 1,3,5-trisubstituted-2-pyrazoline derivatives have been synthesized by introducing furan rings regarded as bioactive substructure into the scaffold of pyrazolines and tested for their activities against six plant pathogenic fungi in vitro. The preliminary bioassays indicated that almost all synthesized compounds had displayed variable growth inhibitory effects on the tested pathogenic fungi. In particular, compounds 4, 7, 9, 12, 18, 19, and 38 displayed excellent antifungal activities against Rhizoctonia solani and their inhibition of growth reached 100% at the concentration of 20 mg/L. Additionally, compounds 9 and 19 bearing two furan rings, respectively, at site 3 and site 5 of the pyrazoline cycle showed the strongest activities against R. solani (the EC(50) were 3.46 mg/L and 3.20 mg/L). The bioactivity results provide good starting templates for further structural optimization of pyrazoline derivatives.     

Synthesis and antiinflammatory evaluation of 9-anilinoacridine and 9-phenoxyacridine derivatives

Mast cells, neutrophils, and macrophages are important inflammatory cells that have been implicated in the pathogenesis of acute and chronic inflammatory diseases. To explore a novel antiinflammatory agent, we have synthesized two types of acridines, 9-anilinoacridine and 9-phenoxyacridine derivatives, for evaluation on the grounds that acridine is a versatile heterocycle possessing a wide variety of biological properties. The title compounds were synthesized by reaction of 9-chloroacridine with appropriate Ar-NH(2) and Ar-OH, and their antiinflammatory activities on inhibitory effects on the activation of mast cells, neutrophils, and macrophages were studied. Three acridine derivatives 4, 10, and 11 were proved to be more potent than the reference inhibitor mepacrine for the inhibition of rat peritoneal mast cell degranulation with similar IC(50) values (16-21 microM). Compound 3 also showed potent inhibitory activity (IC(50) = 8.2 and 4.4 microM, respectively) for the secretion of lysosomal enzyme and beta-glucuronidase from neutrophils. Moreover, compounds 5 and 9 were shown to be efficacious inhibitors of TNF-alpha production in macrophage-like cell lines RAW 264.7. Compounds 2 and 12 were the potent inhibitors of TNF-alpha production in murine microglial cell lines N9. To further explore the cytotoxic properties of these acridine derivatives, (E)-12 was selected for NCI's in vitro disease-oriented tumor cells screen. The results indicated that this compound had no significant cytotoxicity with a mean GI(50) of 58.0 microM. These results indicated that the antiinflammatory effects of acridine derivatives were mediated, at least in part, through the suppression of chemical mediators released from mast cells, neutrophils, and macrophages and that these compounds have the potential to be novel antiinflammatory agents with no significant cytotoxicity.     

Molecular analysis of hexahydro-1H-indeno[1,2-b]pyridines: potential antidepressants

Biological tests indicate hexahydro-1H-indeno[1,2-b]pyridines to be potential human antidepressants with additional stimulating properties. Two diastereomeric series with H4a,H5-trans,H4a,H9b-cis and H4a,H5-cis,H4a,H9b-cis configurations have been tested biologically. The results revealed that the H4a,H5-cis,H4a,H9b-cis series and the ortho-substituted 5-phenyl H4a,H5-trans,H4a,H9b-cis compounds lack activity. Neither the conformation with lowest potential energy nor any other electron-derived parameter correlate with these data. The only relevant difference between the active and the inactive compounds detected thus far is the rotational barrier of the phenyl in the 5-position. The conclusion was reached that certain conformations, which do not resemble those of lowest potential energy, cannot be adopted by the inactive compounds. Therefore, the interaction of the drug with the binding site, responsible for its biological activity, appears to be governed by a dynamic process. This process is characterized by a transformation of the conformation of lowest potential energy to one with an energy content above the minimum.     

吡考他胺结构类似物的合成及其抗血小板聚集活性研究

目的通过对抗血小板聚集药物picotamide(吡考他胺)分子的1,3-侧链进行结构修饰和改造来合成新的类似物,以期找到活性更强的抗血小板聚集剂。方法以苯甲醚为原料,经3步反应制得中间体4-甲氧基-1,3-苯二甲酰氯,经与不同芳胺类化合物进行亲核取代反应制得目标化合物,用Born比浊法对制得的目标化合物进行体外抗血小板聚集活性的初筛。结果与结论共制得13个目标化合物,其结构经IR、1H-NMR和MS确证。其中9个化合物P2和P5~P12未见文献报道。以picotamide为阳性对照药物,对13个化合物进行了体外抗血小板聚集活性初筛,试验结果表明,化合物P8、P9和P12的抗血小板聚集活性很高,明显优于picotamide。     

Bioenhancing and antimycobacterial agents from Ammannia multiflora

The methanolic extract of Ammannia multiflora (Lythraceae) showed significant bioenhancing activity with the antibiotic nalidixic acid. Bioassay-guided fractionation of MeOH extract resulted in the isolation of a novel compound, 2,5-bis-(3,3'-hydroxyaryl)tetrahydrofuran, named as ammaniol (5), along with 9 other known compounds (1-4, 6-10). Furthermore, compound 4-hydroxy- α-tetralone (1) was converted into five semisynthetic acyl derivatives, 1A-1E, which were evaluated along with compounds 1, 5, 6, 9, and 10 for their bioenhancing activity in combination with nalidixic acid against the two strains, CA8000 and DH5 α, of Escherichia coli. The results showed that the methanolic extract of A. multiflora and compounds 1 and 9 possessed significant bioenhancing activity and reduced the dose of nalidixic acid fourfold while compounds 5, 6, 10 and semisynthetic derivatives 1A- 1E reduced the dose of nalidixic acid twofold. Compound 5 was also tested for antimycobacterial activity against Mycobacterium H37Rv and was found to show moderate activity (MIC 25?μg/mL) against this pathogen.     

Discovery of New Acid Ceramidase-Targeted Acyclic 5-Alkynyl and 5-Heteroaryl Uracil Nucleosides

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Syntheses of tolrestat analogues containing additional substituents in the ring and their evaluation as aldose reductase inhibitors. Identification of potent, orally active 2-fluoro derivatives

A series of aldose reductase inhibitors were prepared which were analogues of the potent, orally active inhibitor tolrestat (1). These compounds (5, 7, 9, and 10) have an extra substituent on one of the unoccupied positions on the naphthalene ring of 1. Primary amide prodrugs of several members from the series 5 and 7, namely 6 and 8, respectively, were also prepared. These compounds were evaluated in two in vitro systems: an isolated enzyme preparation from bovine lens to assess their intrinsic inhibitory activity and an isolated sciatic nerve assay to determine their ability to penetrate membranes of nerve tissue. These compounds were also evaluated in vivo as inhibitors of galactitol accumulation in the lens, sciatic nerve, and diaphragm of galactose-fed rats. In general, compounds in series 5, 7, 9, and 10 were potent inhibitors of bovine lens aldose reductase. 2-Halo-substituted analogues from the series 5, 7, and 9 exhibited high activity in the nerve of the 4-day-galactose-fed rat, and in several instances, the primary amide prodrug 8 enhanced the in vivo potency of the respective carboxylic acid 7. Two 2-fluoro-derivatives, 8a and 9a, had especially high activity in vivo and were chosen for additional studies. These compounds were found to be approximately equipotent to tolrestat in the sciatic nerve of the galactose-fed rat and the STZ rat, as judged by their ED50's in these assays. Although primary amide analogue 8a did not have intrinsic inhibitory activity toward aldose reductase, it was metabolized to an active form in vivo and also in vitro within the sciatic nerve.     

Synthesis and anti-DNA -virus activity of the 5'-monophosphate and the cyclic 3',5'-monophosphate of 9-(beta-D-xylofuranosyl) guanine.

9-(beta-TD-xylofuranosyl)guanine (xylo-G) was converted chemically to the 9-(beta-D-xylofuranosyl)guanine 5'-monophosphate (xylo-GMP) and 9-(beta-D-xylofuranosyl)guanine cyclic 3',5'-monophosphate (c-xylo-GMP). These compounds were tested against a variety of DNA viruses in tissue culture in parallel with 9-(beta-D-arabinofuranosyl)adenine (ara-A). This evaluation revealed that xylo-G, xylo-GMP, and c-xylo-GMP were all moderately active but less effective than ara-A. When the four compounds were administered intracerebrally as a treatment for herpes virus, type 1 induced encephalitis in mice, c-xylo-GMP exhibited superior activity to that shown by the other three. When administered intraperitoneally, c-xylo-GMP was found to have a therapeutic index of about 4, which is less than that for ara-A (approximately 30) in the same system.     

2,4,5-三芳基-1H-吡唑-3(2H)-酮类化合物的合成与生物活性评价

目的 设计合成2,4,5-三芳基-1H-吡唑-3(2H)-酮类化合物,并研究其对ALK5信号通路、COX-1和COX-2信号通路的抑制活性,以期发现新型的ALK5或COX抑制剂。方法 关键中间体3-氧代-2,3-芳基丙酸甲酯（6）可以由两种方法制备：一是由芳基醛（1）与芳基乙酸甲酯（2）Aldol缩合后经Swern氧化的方法得到;二是通过芳基酰氯（5）与芳基乙酸甲酯的钠盐（4）直接缩合得到。化合物6与4-腈基苯肼（7）缩合得到4-（3,4-二芳基-5-氧代吡唑啉-1-基]）苯腈（8）,将化合物8的腈基水解为酰氨得到化合物（9）。应用基于细胞的TGF-Smad2检测评价化合物的ALK5抑制活性; 采用化学发光法测试化合物对COX1和COX2的抑制活性;采用MTT法检测化合物的细胞毒性。结果与结论 本文所合成的化合物和中间体均为新化合物,所有目标化合物和大部分中间体的结构经过了核磁与质谱的确证,其中目标化合物18个。多个化合物显示具有很好的对ALK5信号通路、COX信号通路的抑制活性,并且细胞毒性较小。