喹诺酮类抗菌药物的临床应用

喹诺酮类(4-Quinoiones)又称吡酮酸类或吡啶酮酸类,是一类以1,4-二氢-4-氧-3-氧-3-喳啉羧酮为基本结构的全合成抗菌药物。由于其抗菌谱广、抗菌作用强、安全等特点,故近年来发展十分迅速,临床应用非常广泛。下面就其构效关系及作用原理简述如下: 1 构效关系 喹诺酮类抗菌药含有1-取代-1.4-二氢-4氧-吡啶-3-羧酸部分,萘啶酸(IVA)是第一个喹诺酮抗菌药,它不仅对革兰氏阴性菌有较强的活性,与其他抗生素无交叉耐药性。在喹诺酮研究的基础上,又发现了喹啉,毗啶和萘啶的基本环系4-氧代-3-羧酸骨架、具有抗菌活性所必需的。在1—位之间具有环形取代的化合物,具有生理活性。据报道合成的含有异噻毗环的化合物,其中酸的烯酮式羧基与4-酮是平面的,它具有抗各种革兰氏阳性菌和阴性菌的优异活性。     

新的1—特丁基—7—取代氟吡酮酸的合成和构效关系

自萘啶酸发现以来,已经合成了大量的6-氟吡酮酸类化合物,其中几个7位带有哌嗪取代基的成为良好的抗菌剂。如氟哌酸、氟啶酸、环丙氟哌酸、氟嗪酸和双氟哌酸(Difloxacin)。这些吡甜酸类抗菌剂的1位取代基不同。最近已经报道在吡酮酸的1位可能取代基中,特丁基(化合物7a和7b)取代增加了抗菌活性,特别是抗革兰氏阳性菌的活性。本文报道7-(取代氨基)-6-氟-1-特丁基-1,4-二氢喹诺酮和1,8-萘啶-3-羧酸衍生物     

吡酮酸类抗菌药物的研究——Ⅱ.7-氨基-1-乙基-6-氟-l,4-二氢-4-氧掛喹啉-3-羧酸乙酯的合成

已报道了一系列2,6-取代的8-乙基-5,8-二氢-5-氧攒吡啶[2,3-d]嘧啶类化合物的合成与抗菌活性。最近Hiroshi Koga等通过构效关系的研究,指出6-位氟取代的吡酮酸类化合物不仅扩大了抗菌谱,而且增强了抗菌作用。为了进一步了解其构效关系并筛选更有效的抗菌药物,我们从4-氟-3-硝基苯胺(Ⅳ)出发,合成了7-氨基-1-乙基-6-氟-1,4-二氢-4-氧掛喹啉-3-羧酸乙酯(Ⅸ)。 为了用最简便的方法得到(Ⅳ),我们企图用工业原料(Ⅰ)进行部分还原而获得。关     

喹诺酮类抗菌药选评

<正> 概述喹诺酮类抗菌药是由萘啶酸发展起来的合成抗菌药,它们都具有吡啶酮酸的共同结构,通过抑制DNA旋转酶和拓扑异构酶Ⅳ而产生抗菌作用。这种作用一般对细菌的选择性高,对人相对安全。喹诺酮类(Quinolones)抗菌药是指喹啉酮酸类化合物,但现在习惯上把萘啶类和嘧啶并吡啶等化合物都统称为喹诺酮类,所以严格一点,应称为吡啶酮酸类(Pyridonecarboxylic acids)。目前临床广泛应用的主要是喹啉类化合物和少数萘啶类药物及1个嘧啶并吡啶类药物。     

喹啉酮结构整合酶抑制剂的设计、合成及其抗HIV-1活性研究

目的设计合成含有喹啉环的二酮酸类化合物,并探讨此类化合物抗HIV-1活性的构效关系。方法以已上市的HIV-1整合酶抑制剂elvitegravir(埃替格韦)和RDS-1997为先导化合物,改造喹啉酮苯环上的取代基,设计各种不同的酰胺取代物。首先,对氨基苯甲酸乙酯与2-乙氧亚甲基乙酰乙酸乙酯缩合得到喹啉酮环化合物;然后,经取代、水解和缩合得到酰胺取代的喹啉酮化合物;最后,与草酸二乙酯反应,水解后得到目标化合物。测定目标化合物对HIV-1假病毒的抑制活性。结果与结论合成了11个未见文献报道的新化合物,其结构经核磁共振氢谱、质谱确证;体外细胞活性评价结果表明,目标化合物在质量浓度10μg·m L-1时对HIV-1假病毒细胞有抑制活性,其中,化合物7d、7f和7i的抑制率大于或等于95%。     

抗菌药氟哌酸的合成

氟哌酸(1,Norfloxacin,AM-715),化学名1-乙基-6-氟-1,4-二氢-4-氧代-7-(1-哌嗪基)喹啉-3-羧酸,是日本学者1978年合成、1980年完成药理和临床评价的新药,为较好的吡啶酮酸类抗菌药物之一。本品对革兰氏阳性菌、特别是对包括绿脓杆菌在内的革兰氏阴性菌有很强的抗菌作用。培养基的pH值、接种菌量等外界因素对其抗菌作用无     

苄基四氢异喹啉类生物碱的药理作用及其研究进展

目的 介绍苄基四氢异喹啉生物碱的主要药理作用及其研究进展。 方法 综述苄基四氢异喹啉类化合物的生物活性、作用机制及其临床应用。 结果 苄基四氢异喹啉类生物碱具有多方面的药理学活性,尤其在抗肿瘤、抗氧化、抗炎、抗病原微生物等方面的研究进展迅速,且临床应用较为广泛。 结论 苄基四氢异喹啉类化合物具有丰富的生物学活性,研究其药理作用便于更深入地了解该类化合物的作用特点及应用前景,为该领域药物开发提供思路和启示。     

1-(4-酰胺基)苄基四氢异喹啉类化合物的合成与生物活性

异喹啉类化合物有较强的抗高血压、抗心律失常、抗血栓活性。以往对苄基异喹啉的结构改造主要集中于１位和２位，１位取代基为取代的苄基或萘甲基，结构变化不大，而针对２位进行分子设计，合成了许多化合物。研究结果表明，异喹啉母环与１位次甲基连接的芳环在空间构象上...     

合成苄基二氢异喹啉类化合物时一特例反应

<正> 苄基二氢异喹啉类化合物是合成具有特殊药理活性的阿朴菲类、吗啡二烯酮等生物碱的重要中间体,且本身也有很强的药理活性,因此,我们经Bischler-Napieraski法合成一系列的苄基二氢异喹啉类化合物,其中发现一特列反应即:(±)N-(3,4-甲二氧基苯乙基)-α-甲氧基-邻-氯苯乙酰胺(Ⅰ)在成环时α-甲氧基氧化成羰基氧。反应后得到产物Ⅱ,未得到预计产物Ⅱ’.反应式如下:     

1—（4—胺乙酰胺基）苄基四氢异喹啉类化合物的合成及其心血管活性

研究发现某些异喹啉类化合物具有较好的心血管活性，Ｎ胺乙酰基取代的苄基四氢异喹啉化合物对二氢吡啶（ＤＨＰ）受体有较好的亲和力〔１〕．据报道〔２〕化合物１（２乙胺基乙酰胺基３，４二甲氧基）苄基异喹啉具有较强的抗心律失常作用，毒性远低于利多卡因．...     

Protection of carrageenin edema and trypsin hydrolysis of bovine serum albumin by naphthylthiosemicarbazides and their cyclized oxadiazoles.

Seven 1-(naphth-1-ylacetyl)-4-substituted thiosemicarbazides were synthesized and cyclized to the corresponding 2-(naphth-1-ylmethyl)-5-arylamino-1,3,4-oxadiazoles. All compounds, with the exception of two slbstituted oxadiazoles, possessed low anti-inflammatory activity. The protection afforded by these compounds against carrageen-in-induced edema ranged from 3 to 43% where cyclization, in general, decreased anti-inflammatory activity. All compounds (1 mM), possessed antiproteolytic activity where in vitro protection of trypsin-induced hydrolysis of bovine serum albumin, in most cases was greater with oxadiazoles.     

The synthesis and antibacterial activities of quinolones containing five- and six-membered heterocyclic substituents at the 7-position

A series of 6-fluoro-7-substituted-1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids were prepared. The substituents at the 7-position included five- and six-membered heterocyclic rings such as oxazoline and oxazine as well as five-membered heteroaromatic rings such as oxazoles and imidazoles. The structure--activity relationships (SAR) of these compounds indicated that oxazole substituents containing a 2-methyl group had the greatest in vitro potency. The compounds showed greater in vitro antibacterial activity against Gram-positive organisms than against Gram-negative organisms.     

Synthesis and in vitro and in vivo structure-activity relationships of novel antifungal triazoles for dermatology

In search for new compounds with potential for clinical use as antifungal agents in dermatology, a series of 12 azole compounds were synthesized stereospecifically and investigated specifically for their activity against dermatophyte fungal infections in animal models. This panel of azoles was studied in vitro and compared with itraconazole and terbinafine for their antifungal activity using a panel of 24 Candida spp. and 182 dermatophyte isolates. Three azoles (1c, 2c, and 4c) showed in vitro antifungal potency equivalent to itraconazole, but superior to terbinafine, against a panel of 24 Candida spp. with comparable or lower activity than that of itraconazole and terbinafine against 182 dermatophyte isolates and only rare activity against other pathogenic fungi. However, in vivo 1c and 4c, both given orally, demonstrated antifungal activity at least three times greater than itraconazole and were superior compared to terbinafine in M. canis infected guinea pigs. In a mouse model infected by T. mentagrophytes, again 4c, but not 1c, showed 5-fold superior activity over itraconazole and terbinafine. Compound 2c was effective in both models but less effective than itraconazole in these models. On the basis of these promising results, 4c is currently being clinically investigated for its potential as a novel antifungal agent against dermatophytosis.     

Synthesis and antimicrobial activities of some new tetrahydro-2H-1,3,5-thiadiazine-2-thione derivatives of cefadroxil.

Eleven new 7-[2-(dihydro-5-substituted-6-thioxo-2H-1,3,5-thiadiazine-3( 4H)-yl)-2- (4-hydroxyphenyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid derivatives were synthesized by the reaction of cefadroxil monohydrate, formaldehyde and substituted potassium dithiocarbamate. Their structures have been elucidated by spectral data and elementary analysis. The title compounds were tested for antimicrobial activity in vitro against gram-positive bacteria (Staphylococcus aureus, Streptococcus faecalis), gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa) and yeast-like fungi (Candida albicans, C. parapsilosis, C. stellatoidea, C. pseudotropicalis) in comparison with cefadroxil monohydrate. The activity of compounds 1 and 10 against S. aureus (MBC: 37.5 micrograms/ml) and compound 1 against E. coli (MBC: 75 micrograms/ml) were found to be the same as cefadroxil monohydrate. Compounds 1 and 10 were more effective than cefadroxil monohydrate against S. faecalis with 25 and 37.5 micrograms/ml MBC values, respectively. None of the compounds and cefadroxil monohydrate proved to be effective against P. aeruginosa (MBC: greater than 100 micrograms/ml). While cefadroxil monohydrate had no activity against yeast-like fungi, compounds 9 and 10 were significantly effective against yeast-like fungi (MFC: 37.5 micrograms/ml).     

Synthesis and antitumor activity of preactivated isophosphamide analogues bearing modified alkylating functionalities

In search of cancer chemotherapeutic agents with greater efficacy than cyclophosphamide, 4-hydroperoxyisophosphamide analogues bearing modified alkylating functionalities such as 2-bromoethyl, 2-iodoethyl, 2-methyl-sulfonyloxyethyl, and 2-ethylsulfonyloxyethyl groups were prepared by ozonolytic cyclization reaction of N,N'-substituted 3-butenyl phosphorodiamidates. Comparative cytotoxicity against L1210 cells and antileukemic life-span activity against L1210 implanted BDF1 mice of the newly synthesized compounds were tabulated. The 4-hydroperoxyisophosphamide analogues which have different alkylating groups in a molecule showed slightly greater cytoxicity in vitro than those with the same alkylating groups. Most of the compounds having different alkylating groups also showed high antileukemic activity in vivo. Among them, the highest efficacy was found for 2-[N-methyl-n-(2-chlorethyl)]amino-3-(2-methylsulfonyloxyethyl)-4-hydroperoxy-1,3,2-oxazaphosphorinane 2-xoide (NSC 280122D) whos life-span activity was also greater than that of 4-hydroperoxyisophosphamide, cyclophosphamide, and isoposphamide. The superiority of this compound was especially apparent by oral administration.     

Thiophenes and furans derivatives: a new class of potential pharmacological agents

A new class of potential pharmacological thiophenes and furans compounds has been prepared. The obtained thiophenes and furans derivatives were screened for anti-inflammatory, antinociceptive and antioxidant activity in rats. In vitro hepatic ALA-D activity was also evaluated. Thiophene 2 exhibited higher anti-inflammatory effect than thiophenes 1 and 3. However, compound 1 demonstrated lower IC(50) for lipid peroxidation than 2 and 3 in liver and brain. Furan compounds 4-6 presented similar anti-inflammatory activity. The acetylenic furans 4 and 5 inhibited scarcely lipid peroxidation at low concentration as 10 μM. Conversely, furan compound 6 was the most effective against lipid peroxidation in liver. Furans 4 and 5 inhibited lipid peroxidation, in brain, only in high concentrations. In contrast, furan 6 protected (90%) against lipid peroxidation at 10 μM. Thiophene 1 was devoid of anti-inflammatory activity but was efficient in reducing acetic acid-induced constriction. Conversely, it analogue furan 4 presented anti-inflammatory and antinociceptive activity. Thiophene and furan inhibited hepatic ALA-D only at high concentrations. All compounds displayed antioxidant activity however the anti-inflammatory activity is not related to antioxidant potential.     

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。     

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。     

Microwave-assisted synthesis and anti-bacterial activity of some 2-amino-6-aryl-4-(2-thienyl)pyrimidines

Some novel 2-amino-6-aryl-4-(2-thienyl)pyrimidines were synthesized from 3-aryl-1-thien-2-ylprop-2-en-1-ones and guanidine hydrochloride in presence of alkali by conventional heating in alcoholic medium and microwave heating in solvent-free conditions. The compounds were evaluated for in vitro anti-bacterial activity. The anti-bacterial data revealed that compounds 5a-e had better activity against tested gram-positive organisms than the reference ciprofloxacin and norfloxacin. However, the compounds were nearly inactive against gram-negative bacteria. Compounds 5c and e were the most active compounds against gram-positive bacteria.     

Antiproliferative activity in vitro of new malatoplatinum(ll) complexes

The results of studies on antiproliferative activity in vitro of nine new platinum(II) complexes against cells of eight human and six murine neoplastic cell lines are described. New complexes with the anionic rest originating from enantiomeric forms of hydroxydicarboxylic malic acid were synthesized to obtain agents with increased water solubility and decreased toxicity. Three compounds, coded 1-3, with ethylenediamine as a neutral ligand, showed cytotoxic activity against 12 out of 14 target cell lines. Their cytotoxic activity was similar or even slightly higher than that of the reference carboplatin. The remaining six compounds, coded 4-9, with 1-alkylimidazole as a neutral ligand, revealed rather low cytotoxic activity, and only against the cells of the human bladder cancer cell line Hu1703He, ovarian cancer cell line OAW-42 and mouse leukemia P388. Most of them appeared to be negative against all other cell lines. No compounds, including reference carboplatin, showed any cytotoxicity against the cells of the T47D human breast cancer cell line or B16F-10 mouse melanoma cell line. The results obtained are in accordance with common opinion, i.e. that the presence of neutral amine ligands with NH groups is required for the cytotoxic activity of platinum complexes. Compounds with a primary amine (ethylenediamine) showed higher cytotoxic activity in vitro than complexes with a tertiary amine (1alkylimidazole).