3-羟基-6-O-甲基红霉素-9-肟基衍生物的合成及体外抗菌活性

目的　寻找并合成抗耐药菌活性的3位羟基红霉素衍生物。方法　以红霉素A为原料,经9位酮基肟化,9位肟羟基,2′位羟基和3′位二甲胺基同时苄基化,6位羟基甲基化,水解去3位克拉定糖,氢化还原脱苄基,对甲基苄基或邻氯苄基取代9位肟羟基等6步反应,制得3-羟基-6-O-甲基红霉素-9-肟基衍生物,其结构经¹³CNMR ,FAB MS确证。结果　共制得7个化合物,对其中4个(5 - 8)未见报道的化合物进行了体外抗菌活性测定。结论　5 ,7,8对部分红霉素诱导耐药菌有一定的活性     

3-羟基-6-O-甲基红霉素-9-肟基衍生物的合成及体外抗菌活性

目的　寻找并合成抗耐药菌活性的 3位羟基红霉素衍生物。方法　以红霉素A为原料 ,经 9位酮基肟化 ,9位肟羟基 ,2′位羟基和 3′位二甲胺基同时苄基化 ,6位羟基甲基化 ,水解去 3位克拉定糖 ,氢化还原脱苄基 ,对甲基苄基或邻氯苄基取代 9位肟羟基等 6步反应 ,制得 3 羟基 6 O 甲基红霉素 9 肟基衍生物 ,其结构经1 3 CNMR ,FAB MS确证。结果　共制得 7个化合物 ,对其中 4个 (5 - 8)未见报道的化合物进行了体外抗菌活性测定。结论　 5 ,7,8对部分红霉素诱导耐药菌有一定的活性     

红霉素类大环内酯抗生素结构改造和抗菌活性研究的最新 …

对耐酸和抗耐药菌的新型红霉素衍生物的结构改造及其抗菌作用关系研究的最新进展进行综述,红霉素衍生物新品种作用特点显示,其不仅提高了血药浓度,延长了半衰期,增强了疗效,减少了副作用,而且某些酮基红霉素衍生物对大环内酯耐药菌有较强抗菌作用。     

红霉素类大环内酯抗生素结构改造和抗菌活性研究的最新进展

对耐酸和抗耐药菌的新型红霉素衍生物的结构改造及其抗菌作用关系研究的最新进展进行综述,红霉素衍生物新品种作用特点显示,其不仅提高了血药浓度,延长了半衰期,增强了疗效,减少了副作用,而且某些酮基红霉素衍生物对大环内酯耐药菌有较强抗菌作用。     

酮内酯类抗生素的研究进展（下）

在此基础上通过6—O-丙烯基13与各种芳基卤反应，合成了一系列(3-芳基取代)丙-2-烯-衍生物14。13通过反应得到系列6—O-取代丙胺衍生物15。其中3-喹啉基取代物14显示出与红霉素具有相当的抗菌活性。并且显示改善了对各种红霉素耐药菌的抗菌活性。对诱导MLSB耐药     

新红霉素衍生物结构修饰与抗菌活性研究进展

综述了近年来红霉素衍生物的结构修饰与抗菌活性关系研究的最新进展,结果显示,该红霉素类衍生物新药品种具有组织和血药浓度高,半衰期长和抗耐药菌等药代动力学新特性。     

抗菌活性红霉素衍生物研究进展

目的综述具有抗菌活性红霉素衍生物的研究进展。方法依据国内外近期公开发表的53篇文献,对具有抗菌活性红霉素衍生物的研究进展进行分类、归纳与总结。结果长期以来,红霉素及其衍生物作为抗菌药物被广泛使用。20世纪80年代后期问世的第二代大环内酯类抗生素,具有药代动力学性质好、毒性及不良反应小的特点,现已广泛应用于临床。目前,红霉素化学修饰研究的主要目标是研制对大环内酯耐药菌有效的第三代大环内酯类药物。结论利用具有抗菌活性红霉素衍生物研制开发新药,已逐步成为红霉素衍生物研究的重要内容,呈现良好的发展势头。     

红霉素衍生物的成环修饰

半合成红霉素衍生物是临床上一类重要的抗感染药物,但细菌对现有品种产生日益严重的耐药性,因此急需研发出对耐药菌有效的新型大环内酯类抗生素。在深入研究抗菌作用机制的基础上,对红霉素的化学结构进行修饰与改造,特别是通过环状体系的引入与变换这一有效的药物设计方法,已获得了很多结构新颖且具有较强抗菌活性的红霉素衍生物。综述近年来在红霉素衍生物成环修饰方面的进展,重点介绍若干具有优良抗菌活性的新化合物以及相关的构效关系信息。     

2’，4＂-二乙酰基红霉素-9-O-杂环烷基肟衍生物的合成及体内抗菌活性

目的设计合成2’，4＂-二乙酰基红霉素-9-O-杂环烷基肟衍生物，并对其体内抗菌活性进行评价。方法以红霉素为原料，经9位羰基肟化、肟羟基烷基化、2’，4＂-二羟基乙酰化3步反应制得目标化合物；选取有代表性的8个化合物评价其对小鼠感染所致败血症的治疗作用。结果与结论共制得18个未见文献报道的目标化合物，经MS,^1H—NMR确证结构；该类化合物具有较好的抗菌活性，其中化合物9n的活性优于对照药罗红霉素和克拉霉素。     

新一代红霉素衍生物及其构效关系研究进展

综述国内外关于十四元大环内酯类抗生素红霉素的结构修饰和所得衍生物抗菌活性的研究近况,介绍了若干个有较好抗菌活性的先导化合物。大环内酯类抗生素广泛应用于临床的同时,细菌对其产生耐药性的问题也愈发突出。以酮内酯为代表的新一代大环内酯类红霉素衍生物具有良好的药动学性质,且对耐药菌有很好的活性,成为近年来大环内酯类抗生素研发的重点。     

新活性红霉素衍生物的研究进展

目的综述新活性红霉素衍生物的研究进展。方法依据国内外近期公开发表的30篇文献,对新活性红霉素衍生物的研究进展进行分类、归纳与总结。结果长期以来,红霉素及其衍生物作为抗菌药物被广泛使用。临床与实验数据显示,该类化合物还具有一些新的生物活性,例如促进消化道运动活性、抗炎与免疫调节活性、拮抗黄体生成素释放激素活性以及抑制磷酸二酯酶-3活性等。在提高红霉素的新活性并降低其抗菌作用的研究中,已设计、合成了多种类型的新结构的红霉素衍生物。结论利用红霉素衍生物的新活性研制、开发新药,已逐步成为红霉素衍生物研究的重要内容,呈现良好的发展势头。     

Synthesis and Antibacterial Activity of Novel 4″‐O‐Carbamoyl Erythromycin‐A Derivatives

Novel 4″‐O‐carbamoyl erythromycin‐A derivatives were designed, synthesized, and evaluated for their in‐vitro antibacterial activities. All of the 4″‐O‐carbamoyl derivatives showed excellent activity against erythromycin‐susceptible Staphylococcus aureus ATCC25923, Streptococcus pyogenes, and Streptococcus pneumoniae ATCC49619. Most of the 4″‐O‐arylalkylcarbamoyl derivatives displayed potent activity against erythromycin‐resistant S. pneumoniae encoded by the mef gene and greatly improved activity against erythromycin‐resistant S. pneumoniae encoded by the erm gene or the erm and mef genes. In particular, the 4″‐O‐arylalkyl derivatives 4c–4e and 4g were found to possess the most potent activity against all the tested erythromycin‐susceptible strains, which were comparable to those of erythromycin, clarithromycin, or azithromycin. 4″‐O‐Arylalkyl derivatives 4e and 4g were the most effective against erythromycin‐resistant S. pneumoniae encoded by the mef gene (0.25 and 0.25 µg/mL). 4″‐O‐Arylalkyl derivatives 4a and 4b exhibited significantly improved activity against erythromycin‐resistant S. pneumoniae encoded by the erm gene. In contrast, the 4″‐O‐alkylcarbamoyl derivatives hardly showed improved activity against all the tested erythromycin‐resistant strains.     

9,11-cyclic acetal derivatives of (9S)-9-dihydroerythromycin A

A series of 9,11-cyclic acetal derivatives of (9S)-9-dihydroerythromycin A (4) have been prepared and their antibacterial activities compared to those of erythromycin A and 9-dihydroerythromycin A. Many of the cyclic acetal derivatives showed better antibacterial activity than their parent 4. In particular, the acetaldehyde acetal (9-O,11-O-ethylidene-9-dihydroerythromycin A) (8b) showed good antibacterial activity in comparison with erythromycin A but was not sufficiently improved in vivo to warrant progression.     

New research in macrolides and ketolides since 1997

Macrolide and ketolide antibacterials remain a very dynamically active group. To overcome erythromycin A resistance within Gram-positive cocci and bacteria, novel compounds have been semi-synthesised, such as ketolides and C-4' carbamate erythromycylamine derivatives. The continual efforts of those studying macrolides have led to molecular level investigations into the mechanism of action of these antibacterials. Among all novel derivatives, only telithromycin and AB-773 are currently under development. No real novel developments have been seen with the 15- and 16-membered ring macrolides, however, research is also continuing in this area. This review is an update of our knowledge in the field of macrolides.     

(9S)-9-羟基-12-亚甲基红霉素A衍生物的合成

为了合成具有抗菌活性的红霉素衍生物,本文以红霉素A为原料,合成了6-位烯丙基取代中间体12,21-双键-2′-O,4″-O-二苯甲酰基-(9S)-9-O,11-O-异丙基-6-O-烯丙基红霉素A 12,得到(9S)-9-羟基-12-亚甲基衍生物6和6,7-去氢-(9S)-9-羟基-12-亚甲基衍生物11。经¹³C NMR,FAB-MS确证产物结构。所得化合物进行了体外抗菌活性测定。6和11均显示出较弱的抑菌活性。     

Biotransformation of lankamycin, darcanolide, and 11-acetyllankolide by a blocked mutant of the erythromcyin producing organism Streptomyces erythreus

The biotransformation of lankamycin and congeners darcanolide and 11-acetylankolide by a blocked mutant of the erythromycin-producing organism Streptomyces erythreus, which cannot synthesize erythromycin without supplementation with erythromycin precursors, was investigated. Darcanolide and 11-acetyllankolide were converted into the corresponding 15-deoxy-15-oxo derivatives. Lankamycin was transformed to 15-deoxy-15-oxolankamycin, 4'-deacetyl-15-deoxy-15-oxolankamycin and 3'-de-O-methylankamycin. None of the derivatives possessed high antimicrobial activity.     

Structure-activity relationship studies on 4'-O-acyltylosin derivatives: significance of their 23-O-mycinosyl and 4'-O-acyl moieties in antimicrobial activity against macrolide-resistant microbes

Essential roles for both the 23-O-mycinosyl and 4'-O-acyl moieties of 4'-O-acyltylosin derivatives in the expression of antimicrobial activity against multiple macrolide-resistant strains of Staphylococci and mycoplasmas were demonstrated by in vitro comparison of the MICs of erythromycin, josamycin, tylosin and its 3- and 4'-O-acyl derivatives, demycinosyltylosin (DMT) and its 3- and 4'-O-acyl derivatives and 23-modified 3-O-acetyl-4'-O-isovaleryl-DMT derivatives.     

Chemical modification of erythromycins. II. Synthesis and antibacterial activity of O-alkyl derivatives of erythromycin A

A series of O-alkyl erythromycin A derivatives have been synthesized and their antibacterial activities compared with those of erythromycin A (1) and 6-O-methylerythromycin A (3). Methylation of the hydroxyl groups of erythromycin A analogue proceeded stepwise by the two main pathways beginning at the C-6 and C-11 positions, individually. O-Alkylation, other than methylation, took place at the C-11 hydroxyl group exclusively. Among O-alkyl derivatives, 6,12-di-O-methylerythromycin A (5) showed comparable in vitro antibacterial activity to those of 1 and 3. 11-O-Methylerythromycin A (8) was slightly less active than 1. O-Methylation at the C-4" position resulted in a decrease of antibacterial activity.     

红霉素衍生物抗菌活性构效关系研究进展

为解决抗生素的耐药性问题，近年来在红霉素化学结构修饰方面开展了大量的研究，并发现了诸如酮内酯、酰内酯、双环内酯等多种具有良好抗耐药菌活性的新型大环内酯类化合物。该文对红霉素衍生物抗菌活性研究成果做一概括，并对构效关系研究的某些重要结论加以探讨。