阿奇霉素
描述
阿奇霉素是一种广谱大环内酯类抗生素，用于治疗各种细菌感染。 它是在 1980 年代由克罗地亚制药公司普利瓦发现的，并于 1988 年获准用于医疗用途 。 阿奇霉素以其长的半衰期和高组织穿透性而闻名，使其对呼吸道、肠道和泌尿生殖道感染有效 .
科学研究应用
阿奇霉素在化学、生物学、医学和工业领域具有广泛的科学研究应用。 它用于治疗细菌感染，包括呼吸道、皮肤和性传播感染 。 近年来，阿奇霉素一直在研究其在治疗 COVID-19 中的潜在用途，尽管需要更多研究来证实其疗效 。 此外，已开发出负载阿奇霉素的微乳剂用于治疗细菌性皮肤感染，显示出延长的释放和在皮肤内的积累 .
生化分析
Biochemical Properties
Azithromycin is part of the azalide subclass of macrolides, and contains a 15-membered ring, with a methyl-substituted nitrogen instead of a carbonyl group at the 9a position on the aglycone ring . This allows for the prevention of its metabolism . Azithromycin is a weak substrate for CYP3A4, and is minimally metabolized by the enzyme .
Cellular Effects
Azithromycin is known to have both antiviral and immunomodulatory effects . It interferes with receptor-mediated binding, viral lysosomal escape, intracellular cell-signaling pathways, and enhances type I and III interferon expression . It also disrupts immune and metabolic networks, including down-regulation of mucin production .
Molecular Mechanism
Azithromycin works by decreasing the production of protein, thereby stopping bacterial growth . It binds to the 23S rRNA of the bacterial 50S ribosomal subunit . This inhibits protein synthesis, which is essential for bacterial replication .
Temporal Effects in Laboratory Settings
Azithromycin is used long term for the prevention of exacerbations of bronchiectasis and COPD . The usual dose is 250mg three times a week . It has been demonstrated to maintain azithromycin concentrations at sites of infection and continues to be effective for several days after administration has ceased .
Dosage Effects in Animal Models
In animal models, the effects of azithromycin can vary with different dosages . For example, a single oral dose of 10 to 40 mg/kg provided tissue levels that were proportional to the dose in rats . Two- to 4-fold increases in tissue concentration were observed in rats after being dosed with 20 mg/kg for 7 days .
Metabolic Pathways
Azithromycin is associated with a network of altered energy metabolism pathways and immune subsets, including T cells biased toward immunomodulatory and exhausted profiles . In vitro, azithromycin exposure inhibited T-cell cytotoxicity against tumor cells and impaired T-cell metabolism through glycolysis inhibition .
Transport and Distribution
Azithromycin gains rapid and high concentration in a number of cells including polymorphonuclear leucocytes, monocytes, and macrophages . Extensive and rapid distribution from serum into the intracellular compartments is followed by rapid distribution to the tissues . Tissue concentrations exceed serum concentrations by up to 100-fold following a single azithromycin 500mg dose .
Subcellular Localization
Azithromycin gains entry into cells by both passive and active transport due to its dibasic amphophilic character . It acts by inhibiting protein biosynthesis at the 50S ribosomal level . Intracellular penetration is greatest in the first 24 hours, but continues for up to 72 hours in human fibroblasts .
准备方法
合成路线和反应条件： 阿奇霉素通过一系列化学反应由红霉素 A 合成。该过程包括将红霉素 A 转化为其肟，然后进行贝克曼重排以形成红霉素 A 的氨基醚。 然后将该中间体还原为 9-脱氧-9a-氮杂-9a-高红霉素，最后还原性 N-甲基化得到阿奇霉素 .
工业生产方法： 阿奇霉素的工业生产通常涉及热熔挤出以制备阿奇霉素非晶固体分散体。这种方法提高了药物的溶解度和掩味性。 最佳挤出参数包括 150°C 的温度、75 rpm 的螺杆速度和 25% 的药物百分比 .
化学反应分析
反应类型： 阿奇霉素经历各种化学反应，包括氧化、还原和取代。 例如，在氧化过程中，溴离子连接到阿奇霉素的孤对电子上，形成黄色偶联产物 .
常用试剂和条件： 阿奇霉素反应中常用的试剂包括用于氧化的溴离子，以及用于纳米粒子制备的各种溶剂和表面活性剂 .
相似化合物的比较
阿奇霉素在结构上与红霉素和克拉霉素有关，它们都是大环内酯类抗生素。 阿奇霉素具有一个 15 元环，其中有一个甲基取代的氮原子，这与红霉素的 14 元内酯环不同 。 这种结构差异使阿奇霉素与红霉素相比具有更长的半衰期和更好的组织穿透性 。 其他类似的化合物包括克拉霉素和罗红霉素，它们具有相似的作用机制，但在药代动力学性质上有所不同 .
类似化合物：
- 红霉素
- 克拉霉素
- 罗红霉素
阿奇霉素独特的结构和特性使其成为一种宝贵的抗生素，在医学和研究中具有广泛的应用。
属性
| Azithromycin usually is bacteriostatic, although the drug may be bactericidal in high concentrations against selected organisms. Bactericidal activity has been observed in vitro against Streptococcus pyogenes, S. pneumoniae, and Haemophilus influenzae. Azithromycin inhibits protein synthesis in susceptible organisms by penetrating the cell wall and binding to 50S ribosomal subunits, thereby inhibiting translocation of aminoacyl transfer-RNA and inhibiting polypeptide synthesis. The site of action of azithromycin appears to be the same as that of the macrolides (i.e., erythromycin, clarithromycin), clindamycin, lincomycin, and chloramphenicol. The antimicrobial activity of azithromycin is reduced at low pH. Azithromycin concentrates in phagocytes, including polymorphonuclear leukocytes, monocytes, macrophages, and fibroblasts. Penetration of the drug into phagocytic cells is necessary for activity against intracellular pathogens (e.g., Staphylococcus aureus, Legionella pneumophila, Chlamydia trachomatis, Salmonella typhi). | |
CAS 编号 |
83905-01-5 |
分子式 |
C38H72N2O12 |
分子量 |
749.0 g/mol |
IUPAC 名称 |
(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-(5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl)oxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one |
InChI |
InChI=1S/C38H72N2O12/c1-15-27-38(10,46)31(42)24(6)40(13)19-20(2)17-36(8,45)33(52-35-29(41)26(39(11)12)16-21(3)48-35)22(4)30(23(5)34(44)50-27)51-28-18-37(9,47-14)32(43)25(7)49-28/h20-33,35,41-43,45-46H,15-19H2,1-14H3/t20-,21?,22+,23-,24-,25?,26?,27-,28?,29?,30+,31-,32?,33-,35?,36-,37?,38-/m1/s1 |
InChI 键 |
MQTOSJVFKKJCRP-FHZDSTMTSA-N |
SMILES |
CCC1C(C(C(N(CC(CC(C(C(C(C(C(=O)O1)C)OC2CC(C(C(O2)C)O)(C)OC)C)OC3C(C(CC(O3)C)N(C)C)O)(C)O)C)C)C)O)(C)O |
手性 SMILES |
CC[C@@H]1[C@@]([C@@H]([C@H](N(C[C@@H](C[C@@]([C@@H]([C@H]([C@@H]([C@H](C(=O)O1)C)OC2CC(C(C(O2)C)O)(C)OC)C)OC3C(C(CC(O3)C)N(C)C)O)(C)O)C)C)C)O)(C)O |
规范 SMILES |
CCC1C(C(C(N(CC(CC(C(C(C(C(C(=O)O1)C)OC2CC(C(C(O2)C)O)(C)OC)C)OC3C(C(CC(O3)C)N(C)C)O)(C)O)C)C)C)O)(C)O |
外观 |
Solid powder |
颜色/形态 |
Amorphous solid |
熔点 |
113-115 °C White crystalline powder. mp: 126 °C. Optical rotation: -41.4 deg at 26 °C/D (c = 1 in CHCl3) /Azithromycin dihydrate/ |
| 83905-01-5 | |
物理描述 |
Solid |
Pictograms |
Irritant; Health Hazard; Environmental Hazard |
纯度 |
>98% (or refer to the Certificate of Analysis) |
相关CAS编号 |
117772-70-0 (dihydrate) 121470-24-4 (monohydrate) |
保质期 |
>2 years if stored properly |
溶解度 |
soluble in ethanol and DSMO, minimally soluble in water 5.14e-01 g/L |
储存 |
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years). |
同义词 |
Azadose Azithromycin Azithromycin Dihydrate Azithromycin Monohydrate Azitrocin Azythromycin CP 62993 CP-62993 CP62993 Dihydrate, Azithromycin Goxal Monohydrate, Azithromycin Sumamed Toraseptol Ultreon Vinzam Zentavion Zithromax Zitromax |
蒸汽压力 |
2.65X10-24 mm Hg at 25 °C (est) |
产品来源 |
United States |
Retrosynthesis Analysis
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Strategy Settings
| Precursor scoring | Relevance Heuristic |
|---|---|
| Min. plausibility | 0.01 |
| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
体外研究产品的免责声明和信息
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