6-[(N-2,3-dichlorophenyl)amino]-7-chloro-5,8-quinolinedione treatment of candidiasis in normal mice

6-[(N-2,3-Dichlorophenyl)amino]-7-chloro-5,8-quinolinedione (RCK11) was tested forin vivo antifungal activities in the treatment of systemic infection withCandida albicans in normal mice compared with ketoconazole. The therapeutic potential of RCK11 had been assessed by evaluating their activities (survival rates) against systemic infections in normal mice. ED₅₀ of intraperitoneally administered RCK11 was 0.10±0.01 mg/kg but that of ketoconazole had 8. 00±0.73 mg/kg respectively. When RCK11 was administered intravenously at the ED₅₀ (0.10 mg/kg), the colony counts ofCandida albicans in the liver after 7 days and 14 days were reduced as likely as ketoconazole at the ED₅₀ (8.00 mg/kg), and the better survival rates than ketoconazole were achieved after 14 days. The results suggest that RCK11 may be a potent antifungal agent.     

Synthesis and antifungal evaluation of 6-(N-arylamino)-7-methylthio-5,8-quinolinediones

A series of 6-(N-arylamino)-7-methylthio-5,8-quinolinedione derivatives4a-4l was newly synthesized for the evaluation of antifungal activity. 6-(N-Arylamino)-7-methylthio-5,8-quinolinediones were prepared by regioselective nucleophilic substitution of 6,7-dichloro-5,8-quinolinediones with arylamines in the presence of Ce³⁺, and Na₂S/dimethylsulfate. The MIC values of4a-4l were determined for antifungal susceptibilityin vitro againstCandida species by agar streak method. The derivatives4a-4l had generally potent antifungal activities against all human pathogenic fungi. Especially they had the most potent activity againstC. krusei at 12.5≈0.8 μg/ml. Compounds4d, 4g, 4h, 4j and4k had more potent antifungal activities than fluconazole. Compounds4g and4h completely inhibited the fungal growth at 0.8≈6.3 μg/ml against allCandida species, while fluconazole inhibited the growth at 25 μg/ml. The compounds such as4g and4h containing an N-(4-bromo-2-methylphenyl)- or N-(4-bromo-3-methylphenyl)amino substituent exhibited the most potent antifungal activities.     

The synthesis of 6-(N-Arylamino)-7-chloro-5,8-quinolinedione derivatives for evaluation of antifungal activities

A series of 6-(N-arylamino)-7-chloro-5,8-quinolinedione derivatives was newly synthesized for the evaluation of antifungal activities. 5-Amino-8-hydroxy-quinoline (II) was treated with KClO₃ in HCl to give 6,7-dichloro-5,8-quinolinediones (III). 6-(N-arylamino)-7-chloro-5,8-quinolinediones1–12 were prepared by regioselective nucleophilic substitution of III with arylamines. In the presence of CeCl₃, the N-arylamino groups were introduced at the 6-position of 5,8-quinolinedione ring by the regioselective substitution. These derivatives1–12 were tested for antifungal and also antibacterial activities,in vitro, againstCandida albicans, Aspergillus niger, Tricophyton mentagrophytes, Bacillus subtilis, Pseudomonas aeruginosa, Staphylococcus aureus andEscherichia coli. The MIC values were determined by the two-fold agar/streak dilution method. Newly obtained 6-(N-arylamino)-7-chloro-5,8-quinolinedione derivatives showed potent antifungal and antibacterial activities. Among these derivatives,1, 3, 5, 7, 8 and9 showed more potent antifungal activities than fluconazole and griseofulvin. Also most of derivatives were found to be more active than ampicillin against gram-positive bacteria.1 and7 showed the very potent antifungal activities.1 was the most effective in preventing the growth ofCandida albicans, Aspergillus niger, Tricophyton mentagrophytes, Bacillus subtilis andStaphylococcus aureus at MIC 1.6 μg/ml.     

In vitro andin vivo antifungal activities of 6-[(N-4-bromophenyl) amino]-7-chloro-5,8-quinolinediones

Antifungal activities of 6-[(N-4-bromophenyl)amino]-7-chloro-5,8-quinolinedione (RCK7) were tested. The MIC values of RCK7 were determined for antifungal suceptibility,in vitro againstAspergillus niger, Cryptococcus neoformans andTrichophyton mentagrophyte by standard agar streak method.In vitro, RCK7 showed more potent antifungal activity than fluconazole and ketoconazole. Also, RCK7 was tested forin vivo antifungal activity in the treatment of systemic infection withCandida albicans in normal mice. The therapeutic potential of RCK7 had been assessed by evaluating their survival rate against systemic infections compared with that of ketoconazole. ED₅₀ of intraperitoneally administered RCK7 was 2.05±0.30 mg/kg but that of ketoconazole was 8.00±0.73 mg/kg, respectively. When RCK7 was administered intravenously at the ED₅₀ (2.05 mg/kg), the colony counts ofCandida albicans in the liver after 7 days and 14 days were reduced as likely as ketoconazole at the ED₅₀ (8.00 mg/kg), and the better survival rates than ketoconazole’s were achieved after 14 days. The results suggest that RCK7 may be a potent antifungal agent.     

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).     

Synthesis and antifungal activity of 6,7-bis-[S-(aryl)thio]-5,8-quinolinediones

6,7-Bis-[S-(aryl)thio]-5,8-quinolinediones 4 and 5 were synthesized by the substitution of 6,7-dichloro-5,8-quinolinediones with appropriate arylthiols. Their antifungal activity were tested in vitro for their growth inhibitory activities against pathogenic fungi in comparison with flucytosine. The antifungal activities were significantly improved by S-(aryl)thio moieties of the compounds 4 and 5. The all tested compounds 4 and 5 showed generally good activities against C. albicans and A. niger ranging from 0.8 to 25 microg/ml. Among them, compounds 4d-4h and 5a-5c exhibited also good activities against C. krusei and C. tropicalis. The activities of compounds 4j and 4l were comparable to those of flucytosine against all tested fungi.     

1-(1H-1,2,4-三唑-1-基)-2-(2,4-二氟苯基)-3-取代-2-丙醇的合成及抗真菌活性研究

１（１Ｈ１，２，４三唑１基）２（２，４二氟苯基）３取代２丙醇的合成及抗真菌活性研究张大志周廷森吴义杰刘超美麻铭川冯向庭（第二军医大学药学院，上海２００４３３）氮唑类化合物是目前抗真菌药物研究最为活跃的领域之一。该类化合物可分...     

Synthesis and antimicrobial activity evaluation of some new adamantane derivatives

In this study, some new Schiff bases were synthesized as antimicrobial agents using benzaldehyde derivatives and 1- or 2-aminoadamantane. The structures of the synthesized compounds were confirmed by IR, 1H-NMR and elementary analysis. Antimicrobial activities of the synthesized compounds were tested against some bacteria and yeast-like fungi. The antimicrobial activity of the compounds was investigated by broth microdilution method using two Gram positive (Staphylococcus aureus ATCC 25923, Enterococcus faecalis ATCC 29212) and two Gram negative (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853) bacteria and yeast-like fungi (Candida albicans ATCC 90028, Candida krusei ATCC 6258, Candida parapsilosis ATCC 22019). The antifungal activity of 1-((2-chloro-3,4-dimethoxybenzylidene) amino(adamantane (compound 3) against C. krusei and C. parapsilosis (minimal inhibitory concentration 32 micrograms/ml) was higher than that of the other tested compounds.     

Synthesis and characterization of (Z)-N-(1-[2-{3-[(dimethylamino)methyl)]-2-methoxyphenyl}-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl]ethylidene) benzenamine derivatives as potent antifungal agents

In the present study, a series of (Z)-N-(1-[2-{3-[(dimethylamino)methyl)]-2-methoxyphenyl}-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl]ethylidene)benzenamine derivatives have been synthesized and characterized by IR, 1H NMR and 13C NMR spectra. All the synthesized compounds were evaluated for their antifungal activity and were compared with the standard drug, clotrimazole. The compounds demonstrated excellent to weak antifungal activity. Among the synthesized derivatives, 4f and 4h showed significant activity and 4c exhibited moderate activity against Candida albicans, Candida tropicalis and Aspergillus niger as compared with the standard antifungal agent - clotrimazole. The minimum inhibitory concentration of the compounds was in the range of 1.62-25 microg/mL against fungi. Furthermore, the substitution of chloro, nitro and methoxy groups at para position of benzene moiety play an important role in enhancing the antifungal activity of this class of compounds.     

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.     

1-(1H-1,2,4-三唑-1-基)-(2,4-二氟苯基)-3-取代-2-丙醇类化合物的合成及其抗真菌活性

目的研究不同取代哌啶和环仲胺侧链的引入对三唑醇类化合物抗真菌活性的影响。方法以氟康唑为先导化合物,设计合成了9个三唑醇类新化合物,化合物的结构均通过核磁、红外光谱确证;选择8种真菌为实验菌株,根据美国国家临床实验室标准委员会(NCCLS)推荐的标准化抗真菌敏感性实验方法,进行体外抑菌活性测试。结果目标化合物对8种真菌特别是深部真菌均有一定的抑制作用,其中化合物4、5对白色念珠菌的MIC80值小于或等于0.125μg.mL-1,是氟康唑活性的4倍以上,与伊曲康唑活性相当。结论立体化学因素的改变对该类化合物体外抑菌活性有较大影响。     

Bioactive steroidal saponins from Smilax medica

Two new spirostanol saponins ( 1 and 2) were isolated from the roots of Smilax medica, together with the known smilagenin 3-O-beta-D-glucopyranoside (3). Their structures were determined by spectroscopic methods including 1D- and 2D-NMR experiments. Compounds 1 and 2 exhibited antifungal activity against the human pathogenic yeasts Candida albicans, C. glabrata and C. tropicalis (MICs between 6.25 and 50 microg/mL) whereas 3 was inactive.     

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

A number of new benzimidazole derivatives were synthesized by the reaction of benzimidazole with appropriate alkyl halides. The compounds synthesized were intensified by 1H-NMR, Fourier Transformation Infrared (FT-IR) and micro analysis. All new and related compounds studied in this work were screened for their in vitro antimicrobial activities against the standard strains: Enterococcus faecalis (ATCC 29212), Staphylococcus aureus (ATCC 29213), Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853) and the yeasts Candida albicans and Candida tropicalis. Eleven of the compounds were found effective to inhibit the growth of Gram-positive bacteria (E. faecalis and S. aureus) at MIC values between 12.5-400 micrograms/ml. None of the compounds exhibited antimicrobial activity against Gram-negative bacteria (E. coli and P. aeruginosa) at the concentrations studied (6.25-800 micrograms/ml). All compounds (except compound 3) were significantly effective against C. tropicalis with MIC values of 6.25-400 micrograms/ml. Eight of the tested compounds showed an antifungal activity against C. albicans with a range of the MICs between 50 and 400 micrograms/ml.     

Synthesis and antifungal activity of 1-[(2-benzyloxy)phenyl]-2-(azol-1-yl)ethanone derivatives: exploring the scaffold flexibility

Based on the N-(phenethyl)azole backbone of azole antifungals, we designed 1-[(2-benzyloxy)phenyl]-2-(azol-1-yl)ethanone derivatives 2 and 3, containing benzyloxyphenyl scaffold of croconazole. Also these compounds can be considered as flexible analogs, resulted from C2-C3 disconnection of 3'-chloro-3-imidazolylflavanone 1, recently described as antifungal agent. Thus, in this report, we describe the synthesis of 1-[(2-benzyloxy)phenyl]-2-(azol-1-yl)ethanone derivatives 2 and 3 and their biological evaluation against different pathogenic fungi. By comparing the antifungal activity profile of flexible compounds 2 and 3 with that of rigid analog 1, it can be inferred that lower susceptibilities (higher minimum inhibitory concentrations) were observed with flexible compounds. However, among the synthesized compounds, 1-[2-(2,4-dichlorobenzyloxy)phenyl]-2-(1H-imidazol-1-yl)ethanone hydrochloride (2g) showed comparable or more potent antifungal activity in comparison with fluconazole as a standard drug.     

Synthesis and antimicrobial activity of new 2-[p-substituted-benzyl]-5-[substituted-carbonylamino]benzoxazoles

A series of 23 new 2-[p-substituted-benzyl]-5-[p-substituted-phenyl/benzyl-carbonylamino]benzoxazole derivatives has been synthesized by reacting 5-amino-2-[p-substituted-benzyl]benzoxazoles with the appropriate carboxylic acid chlorides. The structures of the synthesized compounds were confirmed by IR and (1)H-NMR spectral data. Antimicrobial activities of the compounds were investigated using the twofold serial dilution technique against two gram-positive and two gram-negative bacteria and three Candida species in comparison with standard drugs. Microbiological results indicated that the newly synthesized 2-[p-substituted-benzyl]-5-[p-substituted-phenyl/benzyl-carbonylamino]benzoxazole derivatives (3-25) possessed a broad spectrum of activity, showing MIC values of 6.25-200 microg/mL against the gram-positive and gram-negative microorganisms tested. Moreover, they showed significant antifungal activity with MIC values of 3.12-100 microg/mL against the Candida species tested. Especially, with a MIC value of 3.12 microg/mL, 2-benzyl-5-[p-bromobenzyl-carbonylamino]benzoxazole 9 displayed the same activity against C. glabrata as the standard drug myconazol.     

1-[(3-Aryloxy-3-aryl)propyl]-1H-imidazoles, new imidazoles with potent activity against Candida albicans and dermatophytes. Synthesis, structure-activity relationship, and molecular modeling studies

New 1-[(3-aryloxy-3-aryl)propyl]-1 H-imidazoles were synthesized and evaluated against Candida albicans and dermatophytes in order to develop structure-activity relationships (SARs). Against C. albicans the new imidazoles showed minimal inhibitory concentrations (MICs) comparable to those of ketoconazole, miconazole, and econazole, and were more potent than fluconazole. Several derivatives ( 10, 12, 14, 18- 20, 24, 28, 29, 30, and 34) turned out to be potent inhibitors of C. albicans strains resistant to fluconazole, with MIC values less than 10 microg/mL. Against dermatophytes strains, compounds 20, 25, and 33 (MIC 相似文献   

N-〔3-(1H-1,2,4-三唑-1-基)-2-(2,4-二氟苯基)-2-羟基-丙基〕-氨基乙酸及其衍生物的合成和抗真菌活性

设计合成了Ｎ〔３（１Ｈ１，２，４三唑１基）２（２，４二氟苯基）２羟基丙基〕氨基乙酸及其９个衍生物，均为未见文献报道的新化合物，初步药理试验表明：部分化合物对浅部真菌有一定的活性，除卡氏枝孢霉菌外，对其它深部真菌活性较弱，其中化合物（５ｅ），（５ｈ）对某些真菌的体外活性较强，明显优于氟康唑，但稍弱于酮康唑     

1-(1H-1,2,4-三唑-1-基)-2-(2,4-二氟苯基)-3-[(4-取代)-哌嗪-1-基]-2-丙醇的合成及其抗真菌活性

目的研究不同取代哌嗪侧链的引入对三唑醇类化合物抗真菌活性的影响.方法设计合成了13个三唑醇类新化合物;选择8种真菌为实验菌株,进行体外抑菌活性测试.结果目标化合物对8种真菌特别是深部真菌均有一定的抑制活性,其中有8个化合物对白色念珠菌的MIC80值小于或等于0.125μg/mL,是氟康唑活性的4倍以上,与酮康唑活性相当.结论脂水分配系数和立体化学因素的改变对该类化合物体外抑菌活性有较大影响.     

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.     

1-{2-[(4-取代苯基)甲氧基]-2-(取代苯基)乙基}-1H-氮唑类化合物的合成及抗真菌活性

根据氮唑类抗真菌化合物的构效关系和作用机理,设计合成了29个1-{2-[(4-取代苯基)甲氧基]-2-(取代苯基)乙基}-1H-氮唑类化合物,其中九个为首次报道。初步体外抑菌试验结果表明,大多数目标化合物对八种试验菌株都有不同程度的抗真菌活性。化合物14对白念珠菌的活性与克霉唑及益康唑相当,对其它七种试验菌株的活性明显强于克霉唑及益康唑。化合物4,12对白念珠菌活性差,对其它七种试验菌株的活性也强于克霉唑和益康唑。化合物5,6和23除对白念珠菌外,对其它七种试验菌株,也有较强活性。