3-取代三唑醇类化合物的合成及抗真菌活性

目的设计合成1-(1H-1,2,4-三唑-1-基)-2-(2,4-二氟苯基)-3-烷氧基苯基哌嗪-2-丙醇和1-(1H-1,2,4-三唑-1-基)-2-(2,4-二氟苯基)-3-取代硫醚-2-丙醇化合物,并进行体外抗真菌活性测试.方法以间二氟苯为起始原料,经多步反应,得到中间体环氧化物甲烷磺酸盐,再与各种烷氧基苯基哌嗪和取代硫醇开环得到目标化合物,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.结果共合成12个(其中11个为新化合物)目标化合物,经元素分析,1H-NMR和IR确证结构,其中4个化合物的抗真菌活性强于对照品氟康唑和酮康唑.结论含烷氧苯基哌嗪侧链的三唑醇类化合物具有较强的抗真菌活性.     

伊曲康唑注射液

[商品名] sporanox,斯皮仁诺 [化学名称] (±)-顺式-4-[4-[4-[4-[[2-(2,4-二氯苯基)-2-(1H-1,2,4-三唑-1-甲基)-1,3-二氧戊环-4-基]甲基] 苯基]-1-哌嗪]苯基]-2,4-二氢-2-(1-甲基丙基)-3H-1,2,4-三唑-3-酮     

新型三氮唑醉籽抗真菌药物合成（I）

在运用比较分子力场分析法(CoMFA)对122个氮唑类抗真菌化合物进行三维定量关系(3D-QSAR)的基础上设计合成了4个1-(1H-1,2,4三唑-1-基)-2-)2,4-二氟苯基)-3-)3-取代-1H-吲哚-1-基)-2-丙醇化合物和4个1-(1H-1,2,4-三唑-1-基)-2-(2,4-二氟苯基)-3)3-取代苯基-4(1H)取代喹啉酮-1-基)-2-丙醇化合物,所有目标化合物均未见文献报道,结构经1H-NMR,IR和MS确证,其体外抑菌实验正在进行中.     

新型三氮唑醇类抗真菌药物合成(Ⅰ)

在运用比较分子力场分析法(CoMFA)对122个氮唑类抗真菌化合物进行三维定量关系(3D－QSAR)研究的基础上设计合成了4个1-(1H-1,2,4-三唑-1-基)-2-(2,4-二氟苯基)-3-(3-取代-1H-吲哚-1-基)-2-丙醇化合物和4个1-(1H-1,2,4-三唑-1-基)-2-(2,4-二氟苯基)-3-(3-取代苯基-4(1H)-取代喹啉酮-1-基)-2-丙醇化合物。所有目标化合物均未见文献报道,结构经     

泊沙康唑

泊沙康唑(posaconazole)是2006年9月15日由美国FDA批准的一种广谱三唑类抗真菌药,用于难治性疾病或其他药物耐药所引起的真菌感染(如曲霉菌病、结核菌病和镰刀菌病等),该药由美国Scher-ing-Plough公司研制上市,商品名为Noxafil[1]。泊沙康唑化学名称:(-)-4-[4-[4-[4-[(2R-顺)-5-(2,4-二氟苯基)四氢-5-(1H-1,2,4-三唑-1-基甲基)呋喃-3-基]甲氧基]苯基]-1-哌嗪基]苯基-2,4-二氢-2-[(S)-1-乙基-2(S)-羟基丙基]-3H-1,2,4-三唑-3-酮;英文化学名称:(-)-4-[4-[4-[4-[(2R-cis)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-yl-met…     

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。     

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（Ⅱ）

基于计算机辅助药物设计系统及靶酶模建的需要。根据氮唑类抗真菌药物的构效关系和作用机理。设计合成了15个1-（1H-1,2,4-三唑-1-基）-2-（2,4-二氟苯基）-3-取代-2-丙醇类化合物,均为首次报道。运用微量注偌倍比稀释法对8种常见致病真菌进行外抑菌试验。化合物Ⅳg具有较强的体外抗真菌活性。     

伏立康唑

[通用名称] voriconazole,伏立康唑 [商品名称] Vfend [化学名称] (2R,3S)-2-(2,4-二氟苯基)-3-(5-氟-4-嘧啶)-1-(1H-1,2,4-三唑-1-基)-2-丁醇     

3-(氨基烷氧基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物的设计、合成与乙酰胆碱酯酶抑制活性

目的初步探讨在7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物母核C-3位苯环侧链中引入二乙胺基团的3-(氨基烷氧基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物的合成及其乙酰胆碱酯酶抑制活性。方法以取代的苯甲醛和乙酰甘氨酸为初始原料,经Erlenmeyer-Plchl反应、缩合反应、水解反应、缩合反应,生成6-芳甲基-3-硫代-1,2,4-三嗪-5(2H)-酮类化合物,再与取代的α-氯代苯乙酮反应,得到6-芳甲基-3-(羟基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物;以芳基乙烯为原料,经温和的氧化反应、缩合反应得到3,4-二氢-6-芳基-3-硫代-1,2,4-三嗪-5(2H)-酮类化合物,再与取代的α-氯代苯乙酮在乙酸中反应得到6-芳基-3-(羟基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物。两条合成路线得到的3-(羟基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物进一步经Williamson反应制备得到10个3-(烷氧基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物。所有目标化合物结构均经质谱、红外光谱和核磁共振氢谱确证。采用Ellman法对目标化合物进行体外乙酰胆碱酯酶抑制活性筛选。结果根据前期已筛选化合物的活性数据和总结出的初步构效关系,设计并合成了10个C-3位苯环侧链中含有二乙胺基团的3-(氨基烷氧基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物。体外乙酰胆碱酯酶抑制活性筛选表明,所有目标化合物均具有乙酰胆碱酯酶抑制活性,其中7个化合物在10μmol.L-1浓度水平抑制活性超过了50%。结论根据体外重组人源AChE(rhAChE)抑制活性的测试结果,发现C-3位苯环侧链中含有二乙胺基团的7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物均具有较好的rh-AChE抑制活性。在这一位置的侧链中引入二乙胺基团,可以增强化合物对rhAChE的抑制活性。     

1-[2-(取代苯基甲硫基)-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

设计合成了21个1-[2-(取代苯基甲硫基)-2-(2,4-二氟苯基)乙基]-1H-1,2,4-三唑类化合物,其中19个为首次报道。体外抑菌试验表明:所有目标化合物对8种试验真菌均有不同程度的抗菌活性,其中化合物1,2,5对絮状表皮癣菌的活性为硫康唑的512倍以上;化合物5对白色念株菌的活性为硫康唑的32倍;化合物2对申克孢子丝菌的活性为硫康唑的32倍;化合物2,14对新型隐球菌的活性分别为硫康唑的64倍,32倍;化合物1,5对熏烟色曲菌的活性分别为硫康唑的16倍以上。     

Synthesis and pharmacological evaluation of novel 4-isopropylthiazole-4-phenyl-1,2,4-triazole derivatives as potential antimicrobial and antitubercular agents

A series of novel 4-isopropylthiazol-4-phenyl-1,2,4-triazol derivatives, N′-(substituted benzylidene)-2-(5-(4-isopropylthiazol-2-yl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)acetohydrazides 4a–e, 4-isopropylthiazol-2-yl-4′-phenyl-4′H-1′, 2′,4′-triazol-3′-ylthio (substituted methyl benzylidene) acetohydrazides 5a–f, 3-(4-isopropylthiazol-2-yl)-4-phenyl-5-(5-substituted-1,3,4-oxadiazol-2-ylthio)-4H-1,2,4-triazole derivatives 6a–f and N-acetyl-5′-(4-isopropylthiazol-2-yl)-4′-phenyl-4′H-1,2,4-triazol-3′-ylthio) acetohydrazide 7 were synthesized and characterized by spectroscopy, elemental, and mass spectral analysis. These compounds were evaluated for their preliminary in vitro antibacterial, antifungal, and antitubercular activity against Mycobacterium tuberculosis (M. tuberculosis) H37Rv strain by broth dilution assay method. All the compounds exhibited moderate to significant antibacterial and antifungal activities. Results of the antitubercular screening against Mycobacterium tuberculosis H37Rv showed that compounds 4c and 6c exhibited good antitubercular activity when compared with first line drug isoniazid.     

Synthesis of 3-(3,4-dimethoxyphenyl)-1 H-1,2,4-triazole-5-thiol and 2-amino-5-(3,4-dimethoxyphenyl)-1,3,4-thiadiazole derivatives exhibiting anti-inflammatory activity

New 1-acylderivatives of 5-alkylthio-3-(3,4-dimethoxyphenyl)-4H-1,2,4-triazole (5c-f, 6d-f) were synthesized by the acylation of 5-alkylthio-3-(3,4-dimethoxyphenyl)-4H-1,2,4-triazoles (3, 4) with acyl chlorides. The compounds 3, 4 were obtained by the alkylation of 3-(3,4-dimethoxyphenyl)-1H-1,2,4-triazole-5-thiol (2) sodium salt with alkyl iodides. Compound 2 and 2-amino-5-(3,4-dimethoxyphenyl)-1,3,4-thiadiazole (8) were prepared by the treatment of 3,4-dimethoxybenzoylthiosemicarbazide (1) with sodium hydroxide or acetyl chloride (and then sodium hydroxide), respectively. Related 2-acylamino-5-(3,4-dimethoxyphenyl)-1,3,4-thiadiazoles (7c, e, f) were synthesized by the acylation of compound 8 with acyl chlorides. 3-(3,4-Dimethoxyphenyl)-4-phenyl-4,5-dihydro-1H-1,2,4-triazole-5-thione (9) was N-acylated with acyl chlorides or S-methylated with iodomethane to give 1-acyl-3-(3,4-dimethoxyphenyl)-4-phenyl-4,5-dihydro-1H- 1,2,4-triazole-5-thiones (10a, b) or 3-(3,4-dimethoxyphenyl)-5-methylthio-4-phenyl-4H-1,2,4-triazole (11) respectively. The synthesized compounds 6d, 7a, c, 10a, b, 11 exhibit anti-inflammatory activity.     

1-(1-取代苯基)-2-(1H-1,2,4-三唑或苯并三唑基)-O-(取代苄基)乙酮肟醚类化合物的合成及抗真菌活性

报道了29个新的1-(1-取代苯基)-2-(1H-1,2,4-三唑或苯并三唑基)-O-(取代苄基)乙酮肟醚类化合物的合成与体外抗菌试验。结果表明,大多数化合物对大部分真菌有抑菌活性,化合物T₁,T₄,T₆,T₁₁,T₁₂,B₁,B₃,B₄和B₆对部分真菌抑菌活性优于或相当于奥昔康唑。     

Synthesis and biological evaluation of [alpha-(1,5-disubstituted 1H-pyrazol-4-yl)benzyl]azoles, analogues of bifonazole.

A series of pyrazole analogues of bifonazole, an antifungal drug used in clinical practice, 2a-h and 4a-h were synthesized and tested in vitro against Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus, with no significant results. Imidazoles 2a-h were also tested in vivo for antiarrhythmic and antihypertensive activities; two of these compounds showed moderate activity against ventricular fibrillation caused by aconitine in rats. The above compounds were prepared by reaction of phenyl-[5 substituted 1-phenyl (or 1-methyl)-1H-pyrazol-4-yl]methanols with N,N'-carbonyldiimidazole (2a-h) or of the respective chloro derivatives with 1H-1,2,4-triazole (4a-h).     

1—[2—（N—甲基—N—取代苄基）氨基—2—（2,4—二氯苯基）乙基]—1H—1,2,4—三唑类化合物的合成及抗真菌活性

根据氮唑粝和苄胺类抗真菌化合物的构效关系和作用机理,合成了22个1-[2-(N-甲基-N-取代苄基）氨基-2-(2,4-二氯苯基）乙基]-1H-1,2,4-三唑类新化合物,所有化合物经元素分析,红外光谱和核磁共振谱确证结构。初步抑菌试验结果表明,所有化合物对9种致病真菌具有不同程度的抑制作用。化合物2,5,6,9,10,12,13,14和18对红色毛癣菌显示较强活性,化合物1,2,5,10,15和18对羊毛样小孢子菌抑制作用较强,它们对该两种真菌的作用优于或相当于益康唑,而化合物2和5对多种真菌均显示较强活性。     

Selective inhibition of virus multiplication by new acylated 1,2,4-triazole derivatives

Six out of 99 new acylated 1,2,4-triazole derivatives specifically inhibited rubella virus replication in RK 13 cell cultures. These are the following: 3-methylthio-5-(2-chlorobenzamido)-1H-1,2,4-triazole; 3-methylthio-5-(2-bromobenzamido)-1H-1,2,4-triazole; 3-methylthio-5-(2-methylbenzamido)-1H-1,2,4-triazole; 3-methylthio-5-(2-nitrobenzamido)-1H-1,2,4-triazole; 3-methylthio-5-(2-methylthiobenzamido)-1H-1,2,4-triazole and 3-ethylthio-5-(2-methylbenzamido)-1H-1,2,4-triazole. The compounds did not directly interfere with the infectivity of the rubella virus particles and the antiviral effect was demonstrable only within cells infected with rubella virus. The active compounds did not inhibit the replication of herpes simplex virus type 1, influenza virus and adenovirus in cell culture systems. Structure-activity relationships are discussed.     

Synthesis and in vitro antimicrobial evaluation of 5-(1-methyl-5-nitro-2-imidazolyl)-4H-1,2,4-triazoles

The increasing clinical importance of drug-resistant pathogens has lent additional urgency to antimicrobial research. Various 5-(1-methyl-5-nitro-2-imidazolyl)-4H-1,2,4-triazoles (4a-6f) were synthesized and tested in vitro for their antibacterial and antifungal activities. Compounds 4a and 4b exhibited significant effects against Bacillus subtilis at MIC ranges of 0.5-1 microg/mL and moderate effects against Staphylococcus aureus.     

Synthesis and antimicrobial activity of some new flavonyl oxime ether derivatives.

The synthesis of a series of 6 compounds related to 2-(4'-formyl-phenyl)-4]H-1-benzopyran-4-one O-substituted oxime and the results of a study of their biological activity are reported. The structural assignments of the compounds is based upon various spectral data. The prepared compounds were screened for their in vitro antibacterial and antifungal activities. Compound F3 exhibited the best antifungal activity compared with ketoconazole and fluconazole.     

Quinoxaline derivatives. Part II: Synthesis and antimicrobial testing of 1,2,4-triazolo[4,3-a]quinoxalines, 1,2,4-triazino[4,3-a]quinoxalines and 2-pyrazolylquinoxalines

Three main classes of quinoxaline derivatives have been synthesized. The first class comprises the synthesis of three novel series of 1,2,4-triazolo[4,3-a]quinoxalines; namely 1-substituted-1,2,4-triazolo[4,3-a]quinoxalines 3a-f, 1-substituted aminomethyl-1,2,4-triazolo[4,3-a]quinoxalines 14a-d and 1-cyano or ethoxycarbonylmethyl-1,2,4-triazolo[4,3-a]quinoxalines 6, 12. The second class involves the synthesis of 2-substituted-1 H-1,2,4-triazino[4,3-a]quinoxalines 4a-d. The third class deals with the synthesis of a variety of 2-pyrazolylquinoxalines, namely 2-(5-amino-3-arylpyrazol-1-yl)-3-phenylquinoxalines 5a-d, 2-[5-hydroxy-3-phenyl-4-(4-substituted sulfamoylphenyl)azopyrazol-1-yl]-3-phenylquinoxalines 15a, b, and 2-(5-hydroxy-4-nitroso-3-phenylpyrazol-1-yl)-3-phenylquinoxalin e (16). The prepared compounds were tested in vitro for their antimicrobial activity. Compounds 13 and 14b exhibited promising antifungal activity against C. albicans (MIC 25, 50 mu/ml respectively). Compound 13 was as active as the antibiotic nystatin.