氟康唑

氟康唑作为抗真菌药物具有广泛的用途。本文介绍了几项国外氟康唑及其中间体的合成专利。国内主要生产厂家有海南曼克星制药厂、广东太阳神集团荔城制药厂、上海信谊药业有限公司等,国外公司有Pfi-zer等。国内生产氟康唑的成本为4000元/kg,市场销售价格为6000元/kg,国外最新的合成工艺可以将其原料成本降低到1600元/kg。据悉,国际社会已要求拥有氟康唑专利的公司允许其他公司免费使用其专利,以减低治疗爱滋病的费用。     

几类抗真菌药物的研发进展及市场情况

现阶段，活跃在国内抗真菌药物市场上的主要品种仍为唑类抗真菌药，包括氟康唑、伊曲康唑和两性霉素B（amphotericinB，AmB）等。根据全国16大重点城市样本医院的统计数据显示，2005年进入医院统计的抗真菌药共有12种，仅前3个品种就占了九成多的市场，只剩不足3％的市场供其余产品分食。其中，氟康唑一枝独秀，以1．3亿元的用药金额占了抗真菌药65％的市场份额；其次为伊曲康唑，拥有26．5％的份额；两性霉素B排第三位，所占比例为6％；而棘球白素类抗真菌药卡泊芬净的用药金额为205万元，占有份额仅为1％；伏立康唑占0．5％；咪康唑和酮康唑各占0．3％。下面就简单介绍一下排名前几种的药物进展及市场情况。     

配合物{[Co（HFlu）2Cl2】·2C2H5OH}n的合成、结构及体外抗真菌活性

新合成了1种钴-氟康唑配合物{[Co（HFlu）2Cl2】·2C2H5OH}n，利用X-射线单晶衍射仪等对配合物进行了结构分析，并研究了该配合物的体外抗真菌活性，标题化合物对丝状真菌的抗菌效果明显优于氟康唑，对酵母菌的体外抗真菌活性与氟康唑相当，     

UPLC-MS/MS法同时测定化妆品中8种抗真菌药物的含量

以电喷雾离子源(ESI)为电离源,在正离子采集模式下建立了化妆品中8种抗真菌药物(氟康唑、酮康唑、萘替芬、联苯苄唑、克霉唑、益康唑、咪康唑、灰黄霉素)含量测定的超高效液相色谱-串联质谱(UPLC-MS/MS)方法,得到了8种抗真菌药物在0.02～0.60μg/mL范围内线性关系良好;平均回收率为91.71％ ～101....     

1，3─二氯丙酮合成方法的改进

１，３─二氯丙酮合成方法的改进傅建龙，丁光月，马道明（华南理工大学应用化学系，广州５１０６４１）１，３－二氯丙酮是重要的有机和药物合成中间体，是高效低毒深部抗真菌新药氟康唑的重要原料之一，它的合成方法主要有丙酮的直接氯化［１］和１，３－二氯－２－两醇...     

导向有机化合物对氟康唑发明的贡献

以降低化合物的亲脂性、提高代谢稳定性为出发点,在导向化合物的基础上勇于改进,脱颖而出新一代的高效抗真菌药—氟康唑。     

卡泊芬净的临床应用及化学合成的研究进展

卡泊芬净是一种由Glarealozovensis发酵产物纽莫康定B0经半合成而来的环六肽化合物，是一种棘白霉素类抗真菌药物，可用于治疗对其它抗真菌药物治疗反应不佳的念珠菌引起的感染，介绍了卡泊芬净的临床应用及化学合成方法。     

香精香料信息13则

<正>1、精油的抗真菌活性,对于抗药性的烟曲霉和红色发癣菌,精油和氟康唑具有协同增效作用印度Aligarh Muslim大学农业微生物学系学者Mohd.Sajjad Ahmad Khan等人在"Applied Microbiology and Biotechnology"杂志2011,90(3),1083~1094页上用英文发表的文章报道本研究的目的是筛选某些精油和活性成分的抗真菌活性,并研究它们与氟康唑(fluconazole)体外交互作用以对付具有抗药性的致病真菌。     

小檗碱的抗真菌活性及其分子探针的合成研究进展

真菌的耐药性是近年来临床面临的一大严峻挑战。小檗碱对抗真菌方面表现出的较好耐药消减作用及各种植物病原真菌对其表现出较强的敏感性,使的小檗碱具有作为真菌感染临床治疗或抗真菌药物开发的巨大潜力。综述了小檗碱的抗真菌活性、作用机理及其分子探针的研究,预期为小檗碱类抗真菌药物的开发及相关研究提供参考。     

新型抗真菌药物的研究现状

综述了新型抗真菌药物三唑类抗真菌药物、多烯类药物和棘白霉素类药物的研究现状。指出抗真菌药物的研究主要集中在研发新型三唑类抗真菌药物、降低多烯类药物的毒副作用以及筛选具有新作用位点的抗真菌药物,其研究向高效、广谱、低毒的方向发展。     

Structural Optimization of Berberine as a Synergist to Restore Antifungal Activity of Fluconazole against Drug‐Resistant Candida albicans

We have conducted systematic structural modification, deconstruction, and reconstruction of the berberine core with the aim of lowering its cytotoxicity, investigating its pharmacophore, and ultimately, seeking novel synergistic agents to restore the effectiveness of fluconazole against fluconazole‐resistant Candida albicans. A structure–activity relationship study of 95 analogues led us to identify the novel scaffold of N‐(2‐(benzo[d][1,3]dioxol‐5‐yl)ethyl)‐2‐(substituted phenyl)acetamides 7 a – l , which exhibited remarkable levels of in vitro synergistic antifungal activity. Compound 7 d (N‐(2‐(benzo[d][1,3]dioxol‐5‐yl)ethyl)‐2‐(2‐fluorophenyl)acetamide) significantly decreased the MIC₈₀ values of fluconazole from 128.0 μg mL^?1 to 0.5 μg mL^?1 against fluconazole‐resistant C. albicans and exhibited much lower levels of cytotoxicity than berberine toward human umbilical vein endothelial cells.     

Solvent-induced supramolecular isomers: Two dimensional coordination polymers constructed by Cu(II) and fluconazole

Two Cu(II)–fluconazole supramolecular isomers 1 and 2 formulated as (flu)₂Cu(SCN)₂ (flu = fluconazole) have been synthesized and structurally characterized by single crystal X-ray diffraction. Different solvent media lead to the different binding modes of anion SCN⁻ and the flexible C–C chain of fluconazole has been rotated in the two isomers. Complex 1 exhibits a two dimensional square grid-like layer and complex 2 exhibits a two dimensional framework with a parquet motif. Different H-bonds and stacking modes are observed in the two isomers. Complex 1 is nonemissive, whereas complex 2 exhibits photoluminescence property.     

How dense are cylindrical brushes grafted from a multifunctional macroinitiator?

A series of cylindrical brushes with poly(methyl methacrylate) (PMMA) and poly(n-butyl acrylate) (PBA) side chains of different lengths was studied to understand the grafting density of brush molecules prepared by the ‘grafting from’ approach. Molecules with PMMA side chains were prepared by grafting MMA from a multifunctional macroinitiator, poly(2-(2-bromoisobutyryloxy)ethyl methacrylate). Molecules with PBA side chains were prepared with poly(2-(2-bromopropionyloxy)ethyl methacrylate) as a macroinitiator. Analysis of the detached side chains showed an incomplete initiation process resulting in longer side chains than expected for complete initiation. Limited initiation (40-80%) was also observed for short PMMA chains using a low molar mass initiator ethyl 2-bromoisobutyrate with CuCl catalyst systems. The lower initiation efficiency was confirmed via visualization of individual molecules by atomic force microscopy. The larger distance between adsorbed brush molecules was consistent with <50% initiation efficiency.     

Synthesis and characterization of LC side chain AB blockcopolymers

Summary The synthesis of liquid crystalline side chain A-B blockcopolymers, prepared by living anionic polymerization in combination with a polymeranalogous reaction is reported. Thereby the A-block was formed from a non mesogenic monomer (styrene, butadiene and n-butylmethacrylate) and the B-block from a monomer with a lateral active group (2-(trimethylsiloxy)-ethylmethacrylate), used for introduction of the side chain mesogens (cholesterylformyl- and 2-(4-[5-hexylpyrimidin-2-yl]-benzoyloxy)-groups). The obtained copolymers show mostly phase separation phenomenons. In dependence of the content of LC side groups a mesomorphic behaviour was observed.     

Potent Synergy between Spirocyclic Pyrrolidinoindolinones and Fluconazole against Candida albicans

A spiroindolinone, (1S,3R,3aR,6aS)‐1‐benzyl‐6′‐chloro‐5‐(4‐fluorophenyl)‐7′‐methylspiro[1,2,3a,6a‐tetrahydropyrrolo[3,4‐c]pyrrole‐3,3′‐1H‐indole]‐2′,4,6‐trione, was previously reported to enhance the antifungal effect of fluconazole against Candida albicans. A diastereomer of this compound was synthesized, along with various analogues. Many of the compounds were shown to enhance the antifungal effect of fluconazole against C. albicans, some with exquisite potency. One spirocyclic piperazine derivative, which we have named synazo‐1, was found to enhance the effect of fluconazole with an EC₅₀ value of 300 pM against a susceptible strain of C. albicans and going as low as 2 nM against some resistant strains. Synazo‐1 exhibits true synergy with fluconazole, with an FIC index below 0.5 in the strains tested. Synazo‐1 exhibited low toxicity in mammalian cells relative to the concentrations required for antifungal synergy.     

头孢克肟侧链(甲酯)活性硫酯的合成

从头孢克肟侧链酸(甲酯)合成头孢克肟侧链活性酯,收率82.8%,具有工业生产价值。     

头孢呋辛酸侧链——（Z）-2-甲氧亚氨基-2-（呋喃-2-基）乙酸铵

介绍了头孢呋辛酸的侧链——— (Z) 2 甲氧亚氨基 2 (呋喃 2 基 )乙酸铵的结构和性质 ,及以呋喃乙酰和 2 呋喃 (羰基 )乙酸为起始原料的 3条不同的合成路线 ,得知以乙酰呋喃与亚硝酸进行肟化反应的路线是适合工业化生产的。最后简介了头孢呋辛酯 (钠 )的市场现状。     

Synthesis and Antimicrobial Activity Evaluation of Imidazole-Fused Imidazo[2,1-b][1,3,4]thiadiazole Analogues

Three series of new imidazole-fused imidazo[2,1-b][1,3,4]thiadiazole analogues (compounds 20 a – g , 21 a – g , and 22 a – g ) have been synthesized, and their antibacterial and antifungal activities have been evaluated. All the target compounds showed strong antifungal activity and high selectivity for the test fungus Candida albicans over Gram-positive and -negative bacteria. N-((4-(2-Cyclopropyl-6-(4-fluorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazol-2-yl)methyl)aniline ( 21 a ) showed the highest activity against C. albicans (MIC₅₀=0.16 μg/mL), 13 and three times that of the positive control compounds gatifloxacin and fluconazole, respectively. Compounds 21 a and 20 e did not show cytotoxicity against human foreskin fibroblast-1 cells, and compound 21 a was as safe as the positive control compounds in hemolysis tests. These results strongly suggest that some of the compounds produced in this work have value for development as antifungal agents.     

Design, synthesis, and biological evaluation of 1-[(biarylmethyl)methylamino]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ols as potent antifungal agents: new insights into structure-activity relationships

We recently reported the design and synthesis of azole antifungal agents with a focus on modifications to the side chain appended to the propanol group. Herein we have identified a series of new 1-[(biarylmethyl)methylamino] derivatives with broad-spectrum antifungal activities against the most prevalent human pathogenic fungi (Candida spp. and Aspergillus fumigatus). Compounds containing a flexible benzylamine moiety were clearly shown to yield the best antifungal activities, without the need for a hydrogen-bond acceptor substituent directly attached to the para position. We were also able to determine that selected compounds are able to overcome gene overexpression and point mutations that lead to reduced susceptibility or resistance against current treatments, such as fluconazole. As the minor differences observed with small structural modifications cannot be explain with only a three-dimensional model of CYP51, adequate physicochemical parameters must be evaluated in terms of antifungal potency, bioavailability, and toxicity. Therefore, structure-activity relationship studies such as these reveal new insights for the development of future antifungal therapies.     

An efficient synthesis of quinoxalinone derivatives as potent inhibitors of aldose reductase

A novel and facile synthesis of quinoxalinone derivatives was developed in which a wide range of 3-chloroquinoxalin-2(1H)-ones as key intermediates can be generated chemo- and regioselectively in good yields from corresponding quinoxaline-2,3(1H,4H)-diones. This new protocol is arguably superior, as it allows the design and preparation of a variety of bioactive quinoxaline-based compounds, which are particularly effective in the treatment of diabetes and its complications. Through this procedure, a new class of quinoxalinone-based aldose reductase inhibitors were synthesized successfully. Most of the inhibitors, with an N1-acetic acid head group and a substituted C3-phenoxy side chain, proved to be potent and selective. Their IC(50) values ranged from 11.4 to 74.8 nM. Among them, 2-(3-(4-bromophenoxy)-7-fluoro-2-oxoquinoxalin-1(2H)-yl)acetic acid and 2-(6-bromo-3-(4-bromophenoxy)-2-oxoquinoxalin-1(2H)-yl)acetic acid were the most active. Structure-activity relationship and molecular docking studies highlighted the importance of the ether spacer in the C3-phenoxy side chains, and provided clear guidance on the contribution of substitutions both at the core structure and the side chain to activity.