The antifungal activities of some 6-[N-(halophenyl)amino]-7-chloro-5,8-quinolinediones againstCandida species

A series of 6-[N-(halophenyl)amino]-7-chloro-5,8-quinolinedione derivatives 1-10 were tested for antifungal susceptibilities, in vitro, against pathogenic Candida species such as C. albicans, C. glabrata, C. krusei, C. parapsilosis and C. tropicalis. The MICs were determined by the standard macrodilution techniques, according to the NCCLS 1992 guidelines. The 6-[N-(halophenyl)amino]-7-chloro-5,8-quinolinedione derivatives showed generally potent antifungal activities against pathogenic Candida species. Among them, derivative 1, 2, 5 and 7 showed more potent antifungal activities than ketoconazole. All derivatives 1-10 had specially potent activities against C. tropicalis. Derivative 1 and 2 containing (N-3,4-dihalo-phenyl)amino moiety exhibited the potent antifungal activities. Derivative 2 with (3,4-dichlorophenyl)amino substituent was the most effective in preventing the growth of Candida species at MICs 4 micrograms/ml respectively.     

Antibacterial and antifungal compounds. VIII. Synthesis and antifungal activity of pyrrol derivatives similar to trichostatin A

Some p-methylbenzolpyrrole acrylic acids and related compounds were synthesized. The new pyrrole derivatives have structural features in common with trichostatin A, an antifungal antibiotic. The above acids and derivatives were tested against Candida albicans and Candida sp in comparison with miconazole, pyrrolnitrin and amphotericin B and showed very weak antifungal activities. Occasionally some activity was found against a few strains of Candida albicans and against Candida pseudotropicalis.     

2-(2,4-二氟苯基)-3-(N-甲基-N-取代基酰胺基)-1-(1H 1,2,4-三唑-1-基)-2-丙醇类化合物的合成及抗真菌活性的研究

目的:寻找新的高效、低毒、广谱的抗真菌药物。方法:设计合成了21 个三唑类化合物作为真菌细胞色素P450 14α-去甲基化酶的抑制剂,并通过体外抗真菌实验测定其抗真菌活性。结果:21 个化合物均为新化合物。体外抗真菌试验表明所有目标化合物对试验真菌均有不同程度的抑制作用,特别是对白色念珠菌和近平滑念珠菌具有很好的活性。结论:所有化合物都不同程度地对真菌细胞色素P450 14α-去甲基化酶有抑制作用,化合物15 对8 种不同真菌均显示了较高的活性,有进一步研究价值。     

Synthesis of some hydroxamic acid derivatives of benzimidazole and their antibacterial and antifungal activities.

A number of 1H-benzimidazole-2-propanoic acid derivatives have been synthesized by Phillips method, and their antibacterial and antifungal activities have been tested. The chemical structures of the synthesized compounds were elucidated by spectroscopic (IR, NMR, mass) and elementary analysis. Investigation of antimicrobial activity of the compounds was done by agar dilution technique using bacteria (Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Mycobacterium smegmatis ATCC 607) and yeast-like fungi (Candida albicans, Candida tropicalis, Candida pseudotropicalis, Candida kruzei, Candida globrata). Among the compounds tested N-hydroxy-3-(1H-benzimidazol-2-yl)-propionamide (Compound 6) showed considerable activity against both Candida albicans and Candida tropicalis.     

In vitro antifungal activity of itraconazole: a comparative study with ketoconazole]

In vitro antifungal activities of itraconazole (ITZ), a new oral triazole antifungal agent, were studied against a wide range of medically important fungi including 16 genera, 37 species and 51 strains stocked in this center. The test was carried out using the agar dilution method on Sabouraud dextrose agar. ITZ showed equal or superior antifungal activities to ketoconazole against most strains of pathogenic yeasts, dimorphic fungi, non-pigmented hypomycetes, dermatophytes and dematiacious fungi. Although some strains of Candida albicans and Candida tropicalis were not completely inhibited by ITZ at concentrations up to 80 micrograms/ml, partial growth inhibitions were observed even at drug concentrations as low as 0.04 microgram/ml. The antifungal activity of ITZ against C. albicans was markedly influenced by medium composition, medium pH, inoculum size and incubation time.     

Fungicidal activity of human lactoferrin-derived peptides based on the antimicrobial αβ region

Owing to the increasing number of infections in hospitalised patients caused by resistant strains of fungi, there is a need to develop new therapeutic agents for these infections. Naturally occurring antimicrobial peptides may constitute models for developing such agents. A modified peptide sequence (CFQWKRAMRKVR; HLopt2) based on amino acid residues 20-31 of the N-terminal end of human lactoferrin (hLF) as well as a double-sized human lactoferricin-like peptide (amino acid residues 16-40; HLBD1) were investigated for their antifungal activities in vitro and in vivo. By in vitro assay, HLopt2 was fungicidal at concentrations of 12.5-25 μg/mL against Cryptococcus neoformans, Candida albicans, Candida krusei, Candida kefyr and Candida parapsilosis, but not against Candida glabrata. HLopt2 was demonstrated to have ≥ 16-fold greater killing activity than HLBD1. By inducing some helical formation caused by lactam bridges or by extending the assay time (from 2h to 20 h), HLBD1 became almost comparable with HLopt2 in its fungicidal activity. Killing of C. albicans yeast cells by HLopt2 was rapid and was accompanied by cytoplasmic and mitochondrial membrane permeabilisation as well as formation of deep pits on the yeast cell surface. In a murine C. albicans skin infection model, atopic treatment with the peptides resulted in significantly reduced yields of Candida from the infected skin areas. The antifungal activities of HLopt2 in vitro and in vivo suggest possible potential as a therapeutic agent against most Candida spp. and C. neoformans. The greatly improved antifungal effect of the lactam-modified HLBD1 indicates the importance of amphipathic helix formation for lethal activity.     

叔丁基三唑衍生物的合成及抗真菌活性研究

目的研究具有叔丁基结构的三唑醇类化合物的抗真菌活性以及各种4-(4-烷氧基苯基)哌嗪侧链的引入对抗真菌活性的影响.方法以一氯频那酮、三氮唑为原料,经多步反应合成目标化合物,化合物结构经IR、1H-NMR谱确证;选择8种真菌为实验菌株,按国际标准抗真菌敏感性实验方法测定其体外抗真菌活性.结果设计合成了10个新化合物.10个目标化合物对8种真菌均具有一定的抑制活性,其中,有4个化合物对白色念珠菌的MIC80值小于或等于0.125 mg·L-1,是氟康唑的4倍以上,与伊曲康唑相当.结论可以通过引入更多的疏水基团设计三唑醇类化合物,立体化学因素对该类化合物的体外抑菌活性有较大影响.     

In vitro antifungal activity of itraconazole, a new triazole antifungal agent, against clinical isolates from patients with systemic mycoses]

The in vitro antifungal activity of itraconazole (ITZ), a new oral triazole antifungal agent, against clinical isolates from patients with systemic mycoses were compared with those of existing systemic antifungals, viz. ketoconazole (KCZ), miconazole or amphotericin B. The studies were performed with 65 isolates of pathogenic yeasts and 13 isolates of Aspergillus spp. using the agar dilution method on casitone agar. ITZ showed the most potent antifungal activities against isolates of pathogenic yeasts including several Candida spp. (Candida parapsilosis, Candida krusei, Candida guilliermondii), Cryptococcus neoformans, Trichosporon cutaneum (MIC less than or equal to 0.08 micrograms/ml) and Aspergillus spp. including Aspergillus fumigatus (MIC less than or equal to 5 micrograms/ml). On the other hand, activities of ITZ against isolates of other Candida spp. such as Candida albicans and Candida glabrata were lower than those of KCZ and other reference drugs. Some isolates of C. albicans and C. tropicalis were not completely inhibited by ITZ even at concentrations above 10 micrograms/ml on casitone agar. However, in the micro-broth dilution method using synthetic amino acid medium, fungal as the test medium, ITZ completely inhibited the growth of all these isolates at drug concentrations of less than or equal to 0.20 micrograms/ml.     

新型含哌嗪侧链三唑类化合物的设计、合成和抗真菌活性研究

目的 基于唑类药物与靶酶相互作用模式,设计新型三唑类化合物,并测试其对常见致病真菌的抑制活性.方法 采用酰化反应合成目标化合物,通过1H NMR和MS确证其化学结构,经微量液基稀释法测试体外抗真菌活性.结果 合成了12个含C1甲基和哌嗪侧链的新型唑类化合物,它们均显示了中度至良好的抗真菌活性.结论 部分目标化合物对白色念珠菌的活性优于对照药氟康唑,值得进一步深入构效关系研究.     

没食子酰哌嗪类化合物的合成及抗真菌作用研究

目的 设计合成没食子酰哌嗪衍生物,考察其对耐药真菌的抗菌活性。方法 以三甲氧基没食子酸为原料,在PyBOP/DIEA存在下与哌嗪反应得到中间体,在脱保护后与相应的酸缩合,最后脱甲基得到目标化合物。采用美国国家临床实验室标准委员会（CLSI）推荐方法,将目标化合物对2株临床分离的耐药白色念珠菌株进行体外抗真菌活性试验,进而与氟康唑（8 μg/ml）联用,开展协同抗真菌活性试验。结果 共合成了11个化合物,其中6个化合物表现出优于没食子酸的抗真菌活性。结论 没食子酰哌嗪可以提高没食子酸的抗真菌活性,没食子酸酰结构是重要的药效团,若引入桂皮酸或2,3-二氯苯甲酸可以进一步提高活性。     

Studies of Antimicrobial Activities of some 4-Thiazolidinone Fused Pyrimidines, [1,5]-Benzodiazepines and their Oxygen Substituted Hydroxylamine Derivatives

Thiazolidin-4-one fused pyrimidines, [1,5]-benzodiazepines and their oxygen substituted hydroxylamine derivatives have been screened for antibacterial, antifungal and antimalarial activity. Bacillus subtilis, Escherichia coli, Proteus mirabilis and Salmonella typhi were used for antibacterial screening. Aspergillus fumigatus and Candida albicans were used for antifungal screening and Plasmodium species were used for antimalarial screening. The antibacterial and antifungal activities are expressed in terms of zone of inhibition and antimalarial activity is expressed in IC(50) value. Fifteen compounds 2Xa, 2Xb, 2Xc, 2Xs, 3IV, 3Va, 3Vc, 3VIIIa, 3VIIIh, 3IXa, 3IXb, 3IXc, 3Xa, 4IXa and 4Xa were tested for antibacterial as well as antifungal activity and seven compounds 2IXb, 2Xb, 3VIIIc, 3Xc, 4IXa, 4Xa and 4IXw were tested for antimalarial activity. Streptomycin, griseofulvin and chloroquine were taken as standard drugs in antibacterial, antifungal and antimalarial activity, respectively. The compound 2Xs was found significant antimicrobial against Bacillus subtilis, E. coli, Aspergillus fumigatus and Candida albicans as well as compound 3Xa was significant antimicrobial against Bacillus subtilis, E. coli, Salmonella typhi, Aspergillus fumigatus and Candida albicans. The compound 2Xb showed significant antimalarial activity.     

Synthesis, characterization and evaluation of mannich bases as potent antifungal and hydrogen peroxide scavenging agents

In the present study, (E)-2-{ [-2-(2,4-Dinitrophenyl)hydrazono]methyl} phenol (3) was synthesized and used as key intermediate for the synthesis of new Mannich bases. All the synthesized compounds were evaluated for their antifungal activity against three fungal strains Candida albicans, Candida tropicalis and Aspergillus niger and antioxidant activity. The structure of these compounds was confirmed by IR, 1H NMR and 13C NMR studies. Most of the compounds exhibited moderate to significant activities.     

新型三唑类化合物的设计、合成和抗真菌活性研究

目的 基于唑类药物合理优化的分子设计模型,设计新型三唑类化合物,并测试其对常见致病真菌的抑制活性。方法 采用环氧化物开环法合成目标化合物,通过¹H NMR和MS确证其化学结构,经微量液基稀释法测试体外抗真菌活性。结果 合成了2个含三唑酮侧链的新型唑类化合物,它们均显示了优秀的广谱抗真菌活性。结论 目标化合物对白色念珠菌的活性优于对照药氟康唑和酮康唑,值得进一步深入构效关系研究。     

含硫的三唑类化合物的合成及抗真菌活性研究

目的设计合成含有二硫代甲酸酯侧链的新型三氮唑类化合物,并研究其体外抗真菌活性。方法通过与二硫化碳的加成及取代反应合成了9个新型三氮唑类化合物,其结构通过1 H NMR和MS确证,并选择8种真菌为实验菌株,对其体外抗真菌活性进行测试。结果所有化合物对实验菌株均有一定的抗菌活性,尤其对白色念珠菌活性较好,化合物6d对白假丝酵母菌的MIC80值<0.125μg/ml,是伊曲康唑的64倍。结论引入丙基、硫元素和取代苄基侧链对目标化合物的抗真菌活性影响较大;二硫代甲酸酯结构的引入有利于提高三唑类化合物的体外抗真菌活性。     

1-[2-(N-甲基-N-取代苄基)氨基-2-(2,4-二氟苯基)乙基]-1H-1,2,4-三唑类化合物的合成及抗真菌活性

目的:1-[2-(N-甲基-N-取代苄基)氨基-2-(2,4-二氟苯基) 乙基]-1H-1,2 ,4-三唑类化合物的合成及抗真菌活性研究。方法:通过付-克反应、三唑烷基化、酮亚胺还原和Leuckart 反应,得到关键中间体,然后通过N-烷基化反应制得目标化合物,并用二倍稀释法测定了体外抑菌活性。结果:合成了23 个1-[2-(N-甲基-N-取代苄基) 氨基-2-(2,4-二氟苯基)乙基]-1H-1 ,2,4-三唑类化合物,均为首次报道。所有目标化合物对8 种致病真菌均有不同程度的抗真菌活性。大部分化合物对Candida.albicans 和Candida.parapsilosis 的抗菌活性明显高于布替萘芬,其中1 ,2 ,6 ,13,14 ,19 对Candida.albicans 的抗菌活性是益康唑的8～32 倍,2,13 对Cryptococcu.neoformans 的抗菌活性是布替萘芬的4～8 倍,是益康唑64 ～128 倍。所有化合物对Microsporum .canis 的抗菌活性均高于或相当于益康唑。结论:其中一些化合物显示了较强抗真菌的活性,值得进一步研究。     

念珠菌引起深部感染的病原学特征与药敏试验

目的了解近年来深部念珠菌感染的病原学特征和医院内深部真菌感染现状,为临床提供病原学诊断和合理使用抗真菌药物的依据。方法血培养使用BacT ALERT 3D血培养检测仪,其他各种临床标本用沙堡培养基培养,科玛嘉念珠菌显色培养基分离鉴定念珠菌;用ATB Fungus 2药敏卡对菌株进行体外药物敏感试验。结果3年间从深部标本中共分离出念珠菌2256株,菌种分布依次为:白色念珠菌(72.61%)、光滑念珠菌(10.28%)、克柔念珠菌(9.40%)、热带念珠菌(4.97%)、其他念珠菌(2.74%);162株念珠菌药敏结果:5-氟胞嘧啶、两性霉素对所有念珠菌敏感度都很高,但各种真菌对4种抗真菌药物均出现了不同程度的耐药。结论白色念珠菌仍为主要的致病真菌,但非白色念珠菌所占比例有逐年上升的趋势。不同念珠菌对常用抗真菌药物敏感性存在差异,准确分离鉴定和药敏试验,对指导临床医生合理用药有重要意义。     

Synthesis,antifungal activity,and molecular modeling studies of new inverted oxime ethers of oxiconazole

Some new oxime ethers of types 7 and 8, in which the methyleneaminoxy group, C=N-O, of oxiconazole 6 is in an inverted atomic sequence, were synthesized and tested for their antifungal activities. Among them, the type 7 compounds, such as the N-ethoxy-morpholino-substituted derivatives 7l-o (Table 1), showed good antifungal properties against the Candida strains tested, with minimum inhibitory concentration (MIC) values similar to those of the reference drug 6. A remarkable result was obtained with these types of azoles, which had shown a cidal character against Candida albicans, while the reference drug oxiconazole was only fungistatic in the same tests. This fact may be seen from a comparison of the MIC values with those of the minimum fungicidal concentration (MFC) values for most of the type 7 compounds assayed that have shown differences between the MIC and the MFC, which are lower than three double diluitions. A simple molecular modeling of the P450 14-alpha-sterol demethylase from C. albicans (Candida P450DM) was built in order to understand how the structural differences between type 7 compounds and oxiconazole 6 can induce different antifungal profiles. The results of this work seem to confirm that it is possible to reverse the atomic sequence of the methyleneaminoxy group, C=N-O, of 6, obtaining new imidazoles possessing good antifungal properties.     

Substances with antibacterial and antifungal activity. VII. Synthesis and microbiologic activity of new derivatives of 1,5-diarylpyrrole

The synthesis and antifungal activities of new 1,5-diarylpyrrole derivatives are reported. Antimicrobial data in comparison with pyrrolnitrin show that N-methylpiperazinylamides exhibit very poor activity against Candida albicans and Candida sp. while acid and ester derivatives are inactive. Vice-versa many acid or amide derivatives show interesting antibacterial activity. The results obtained are discussed on the basis of structure-activity relationships.     

Synthesis and antifungal activity of 5,8-quinazolinedione derivatives modified at positions 6 and 7

5,8-Quinazolinediones modified at positions 6 and 7 were synthesized and tested for in vitro antifungal activities against Candida species and Aspergillus niger. Most of 5,8-quinazolinediones 3-5 generally exhibited potent antifungal activity. 6-Arylamino-7-chloro-5,8-quinazolinediones (3) generally showed more potent antifungal activity than 7-arylthio-5,8-quinzolinediones (4) and 6,7-bis-(arylthio)-5,8-quinazolinediones (5).     

Researches on antibacterial and antifungal agents, X. Synthesis and antifungal activities of 1-(p-methyl-alpha-[4-(1H-pyrrol-1-yl)phenyl]benzyl)azoles and some related products

The synthesis and antifungal activities against Candida albicans and Candida spp. of some pyrrole analogues of bifonazole are reported. 1-(p-Methyl-alpha-[4-(1H-pyrrol-1-yl)phenyl]benzyl)imidazole was found to be equipotent or sometimes superior to bifonazole and ketoconazole, and lightly inferior to miconazole. Substitution of the imidazole moiety with other azoles retained some activities. No activity was shown when the azole aromatic rings were replaced by the heteroalicyclic ones.