氨基噻唑衍生物的合成与药理活性研究

目的:合成氨基噻唑类衍生物并研究其抗流感病毒活性。方法:以氨基噻唑类化合物为母核,合成一系列神经氨酸酶抑制剂,通过在体方法检测其对流感病毒的抑制活性。结果与结论:合成了6个新化合物,其中部分化合物具有一定的抗流感病毒活性。     

新型4-噻唑烷酮衍生物及其抗病毒活性研究进展

4-噻唑烷酮是一个具有重要生物学活性的化学结构,其衍生物具有广泛的药理活性,包括抗病毒活性。目前4-噻唑烷酮类抗病毒药的研究开发已取得长足进展。综述具有不同取代的新型4-噻唑烷酮衍生物及其抗人类免疫缺陷病毒、抗丙型肝炎病毒和抗流感病毒活性以及构效关系研究进展。     

噻唑烷二酮和芳酮酸类PPARγ激动剂三维定量构效关系研究

目的建立PPARγ激动剂-噻唑烷二酮和芳酮酸类化合物的三维定量构效关系,为设计高活性PPARγ激动剂提供结构信息。方法与结果用比较分子力场分析方法得到噻唑烷二酮和芳酮酸类化合物CoMFA模型,其交叉验证相关系数R²=0.656,非交叉验证相关系数R²=0.982,F_10,37=201.1,绝对误差SE=0.115。结论从CoMFA系数等势图中揭示芳酮酸类化合物较噻唑烷二酮类化合物活性更高的原因,提示芳酮酸类化合物与PPARγ结合时形成了不同于BRL-PPARγ复合物晶体的结合腔。     

噻唑并三嗪类化合物的合成及其基于U2OS-EGFP细胞的抗肿瘤活性

目的探讨7H-噻唑并[3,2-b]-1,2,4-三嗪类化合物的体外肿瘤细胞增殖抑制活性,及初步的构效关系和作用机理。方法以3,4-二氢-6-芳基-3-硫代-1,2,4-三嗪-5(2H)-酮为原料,经环合反应、Williamson反应,合成7H-噻唑并[3,2-b]-1,2,4-三嗪类化合物,考察目标化合物体外肿瘤细胞增殖抑制作用。结果与结论合成了10个7H-噻唑并[3,2-b]-1,2,4-三嗪类化合物,经MS、1H-NMR确证结构。体外抗肿瘤活性研究显示,有4个化合物在50μmol·L~(-1)时对骨肉瘤细胞U2OS-EGFP抑制率高于50%。其中,活性最好的化合物4 d对U2OS-EGFP细胞抑制活性的IC50值为9.824μmol·L~(-1)。分子模拟结果显示,这类化合物作用于ERK1/2,应是一种ERK1/2抑制剂。     

新型乙酰胆碱酯酶抑制剂5H-噻唑并[3,2-a]嘧啶类化合物的设计、合成与生物活性研究

目的 寻找作为乙酰胆碱酯酶抑制剂的具有新化学结构类型的化合物。方法 采用分子对接的虚拟筛选方法寻找新型乙酰胆碱酯酶抑制剂，设计了10个5H-噻唑并[3,2-a]嘧啶类化合物。以芳醛、硫脲等为起始原料，通过Biginelli反应生成二氢嘧啶类化合物，再与氯代苯乙酮作用经Hantzsch环合反应制得目标化合物，其结构经红外光谱、质谱、核磁共振氢谱和碳谱确证。采用Ellman方法进行体外抑制乙酰胆碱酯酶活性测试。 结果 合成了10个5H-噻唑并[3,2-a]嘧啶类化合物，体外抑制乙酰胆碱酯酶活性测试结果显示，所有目标化合物均具有乙酰胆碱酯酶抑制活性，其中3个目标化合物在10 μmol.L^-1时抑制活性均超过50%。结论5H-噻唑并[3,2-a]嘧啶类化合物是潜在的乙酰胆碱酯酶抑制剂。将计算机辅助药物分子设计、有机合成和生物活性测试相结合是发现和设计新型乙酰胆碱酯酶抑制剂的有效途径。     

黏球菌产生的活性天然产物

从化学结构、生物学活性、生物合成、应用开发等角度,综述了已有文献报道的黏球菌活性天然产物,重点介绍了作用于肌动蛋白的大环内酯类化合物rhizopodin、作用于呼吸链的肽类化合物myxothiazol和多烯类化合物myxalamid、作用于核酸的芳香类化合物myxopyronin和saframycin Mx1,以及作用于细胞壁的大环类化合物myxovirescin,阐明了黏球菌次级代谢产物的化学结构多样性和生物活性多样性,为进一步开发黏球菌活性天然产物提供线索。     

2-氨基噻唑类化合物的合成

目的合成2-氨基噻唑类化合物。方法溴化铜在乙酸乙酯/氯仿中分别溴化芳基烷基酮及脂肪酮,得到的α-溴化产物,不经分离直接与硫脲环合制得相应的2-氨基噻唑类化合物。结果合成收率为87.4%~98.9%。目标物2-氨基噻唑类化合物的结构经红外光谱、核磁共振谱和质谱确证。结论该合成路线可行,收率高,得到的10个化合物中有4个是未见报道的新化合物。     

β-咔啉化合物结构修饰与抗肿瘤活性及生化作用研究进展

β-咔啉类化合物是一大类具有不同程度芳香性的天然存在或人工合成的吲哚类生物碱,广泛分布于自然界,包括多种植物、各类海洋生物和人的组织和体液当中。该类化合物有多种生物学活性,其中抗肿瘤活性明显。为了提高肿瘤细胞毒性,大量文献报道了不同β-咔啉衍生物与抗肿瘤活性的构效关系研究。本文针对有明显抗肿瘤活性β-咔啉生物碱及其衍生物和它们的生化作用进展作一综述,旨在为今后β-咔啉类化合物进一步开发提供一定的参考。     

苯并硫氮杂(艹卓)类化合物的研究进展

在寻找先导化合物的过程中，苯并硫氮杂革类化合物占有非常重要的位置。按照结构类型，苯并硫氮杂革类主要包括1，3-、1,4-、4，1-和1，5-苯并硫氮杂革四大类。它们可以作用于许多不同家族的靶点，显示出了广泛的生物学活性。在苯并硫氮杂革类化合物中，1，5-苯并硫氮杂革类化合物的生物学活性最为广泛，可以作为钙离子通道拮抗剂、某些蛋白激酶的抑制剂、一些G蛋白偶联受体的拮抗剂以及缓激肽激动剂等。作者对苯并硫氮杂革类化合物的研究进展进行了综述。     

噻唑化合物作为酶和受体抑制剂研究新进展

噻唑类化合物作为酶和受体抑制剂具有广泛的生物活性,在医药领域发展迅速。本文结合我们的研究工作,参考国内外近年文献综述了噻唑作为酶和受体抑制剂在抗菌、抗癌、抗病毒、消炎镇痛、降血糖、治疗神经退行性疾病和抗寄生虫等领域的研究新进展。     

Structural improvement of new thiazolidinones compounds with antinociceptive activity in experimental chemotherapy‐induced painful neuropathy

Chemotherapy‐induced neuropathy is a disabling pain condition resulting from chemotherapy for cancers. Up to now, no drug is available to cure chemotherapy‐induced neuropathy. In the present study, we describe the structural design, synthesis, chemical and pharmacological characterization of 15 thiazolidinones, a class of potential analgesic compounds. The synthesis of new thiazolidinones was achieved by using the thiazolidinone heterocyclic as main structural pharmacophoric group and varying the substituents attached to the phenyl near to the iminic bond. The analgesic potential of the compounds was investigated in a mice model of oxaliplatin‐induced neuropathic pain, using von Frey, rota‐rod and open‐field tests. Except for compound 14 , these thiazolidinones exhibited antinociceptive property without causing motor impairment. Thiazolidinones 12 , 15 and 16 displayed a dose‐dependent antinociceptive effect, with similar efficacy and enhanced potency than gabapentin, the gold standard drug used for neuropathic pain. In addition, the antinociceptive activity of 16 lasted longer than gabapentin. The antinociceptive effect of thiazolidinones was prevented by GW9662, a PPARγ antagonist. The main antinociceptive compounds exhibited positive Lipinski's index, predicting their oral bioavailability. In conclusion, the structural design performed here led to the identification of new compounds endowed with potent antinociceptive activity, potentially useful to treat chemotherapy‐induced neuropathic pain.     

Synthesis antimicrobial and antifungal activity of some new 3 substituted derivatives of 4-(2,4-dichlorophenyl)-5-adamantyl-1H-1,2,4-triazole

The synthesis of a series of substituted hydrazones and thiazolidinones is described, starting from N-[4-(2,4-dichlorophenyl)-5-adamantyl-1H-1,2,4-triazol-3-ylmercaptoacetyl]hydrazine. The new compounds were tested for antimicrobial and antifungal activity and some of them exhibited moderate activity against Candida albicans.     

Synthesis antimicrobial and antifungal activity of some new 3-substituted derivatives of 4-(2,4-dichlorophenyl)-5-adamantyl-1H-1,2,4-triazole

The synthesis of a series of substituted hydrazones and thiazolidinones is described, starting from N-[4-(2,4-dichlorophenyl)-5-adamantyl-1H-1,2,4-triazol-3-ylmercaptoacetyl)hydrazine. The new compounds were tested for antimicrobial and antifungal activity and some of them exhibited moderate activity against Candida albicans.     

Preparation and Characterization of Ergoline Thiazolidinones and an Ergoline Imidazolidinone

The preparation of the ergoline thiazolidinones 2,3 and the ergoline imidazolidinone 5 is described. The ¹³C- and ¹⁵N-NMR spectra of the ¹⁵N-labelled compounds ¹⁵N- 2a and ¹⁵N- 3a allow the distinction of the two isomers.     

Synthesis of new 4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine derivatives with an incroporated thiazolidinone moiety and testing their possible serine protease and cercarial elastase inhibitory effects with a possible prospective to block penetration ofSchistosoma mansoni cercariae into the mice skin

5-Substituted 4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine were synthesized by interaction of 4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-sulfonylhydrazide with some aldehydes to give the corresponding Schiff-bases, which after cyclization gave corresponding thiazolidinones. For some of the thiazolidinones, Mannich bases reaction was carried out. All the derivatives were tested for their possible inhibitory effect on Schistosoma mansoni cercarial elastase (CE). Only, N-(4-methylbenzyledine)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-sulfonylhydrazide was found to have potent inhibitory effect on the CE activity with IC50 = 264 microM. Upon its use as a paint for mice tails before infection with S. mansoni cercariae, the compound formulated in jojoba oil caused a significant reduction (93%; P-value = 0.0002) in the worm burden. IgG & IgM in mice sera were measured by using several S. mansoni antigens by ELISA. Sera from treated infected mice (TIM) 2, 4, and 6 weeks (W) post infection (PI) showed 1.2 folds lower, 1.2 folds higher, 1.7 folds lower IgM reactivity against soluble cercarial antigenic preparation (CAP), respectively, when compared with sera collected from infected untreated mice (IUM). Sera from TIM 2, 4, and 6WPI showed 1.3, 1.6, and 1.7 folds higher IgG reactivity, respectively against CAP than the IgG reactivity from IUM. Sera from TIM 2, 4 and 6WPI showed 1.5, 1.2 folds lower and 1.4 folds higher IgM reactivity, respectively against soluble worm antigenic preparation (SWAP) when compared with sera collected from IUM. Sera from TIM 2, 4, and 6WPI showed 1.4, 1 folds lower and 1 fold higher IgG reactivity, respectivley to SWAP when compared with sera from IUM. Sera from TIM 2, 4, and 6WPI had generaly lower IgM and IgG reactivities against soluble egg antigen (SEA) when compared with sera from IUM.     

Synthesis and biological investigations of new thiazolidinone and oxadiazoline coumarin derivatives

Ethyl (coumarin-4-oxy)acetate 1 was prepared through the reaction of 4-hydroxycoumarin with ethyl bromoacetate. Compound 1 was allowed to react with hydrazine hydrate to produce coumarin-4-oxyacetic hydrazide 2. The synthesis of N-(arylidene and alkylidene)-coumarin-4-oxyacetic hydrazones 3-20 was performed. The preparation of 2-substituted-3-[(coumarin-4-oxy) acetamido]thiazolidinones 21-26 and 2-[(coumarin-4-oxy)methyl]-4-acetyl-5-substituted-delta2-1,3,4-oxadiazolines 27-33 was performed by the reaction of the hydrazones 3, 4, 7, 9, 12, 14 with mercaptoacetic acid and the hydrazones 3, 4, 5, 7, 12, 15, 16 with acetic anhydride, respectively. The antiviral activities, cytotoxicities and structure-activity relationship (SAR) towards different microorganisms of the prepared compounds were studied.     

Antidiarrhoeal Activity of New Thiazolidinones Related to Loperamide

A series of thiazolidinones related to loperamide was synthesized and evaluated for antidiarrhoeal activity in mice, using the castor oil test. Of five compounds tested, antidiarrhoeal activity was found only for 2?(p-nitrophenyl)?3?{3?[(4?(p-chloro-phenyl)-4?hydroxy)piperidino]ethyl}-1,3?thiazolidin?4?one. The compound was less active than loperamide (ED50 values = 48.7 (24.8?95.6) and 0.91 (0.24?3.40) mg kg^?1, respectively), but was also less toxic (LD50 values = 745.9 (545.2?929.8) and 108.9 (85.5?138.7) mg kg^?1, respectively). Its antidiarrhoeal activity was counteracted by naloxone. Our results support the hypothesis that this compound, like loperamide, is an opiate-receptor agonist.     

Synthesis and pharmacological activity of 2-(substituted)-3-{2-[(4-phenyl-4-cyano)piperidino]ethyl}-1,3-thiazolidin-4-ones

Loperamide is a well-known peripherally acting opiate used for the treatment of diarrhoea. To gain more knowledge on the structure-activity relationships of antidiarrhoeal drugs and to develop new active molecules, a series of aryl-cyano-piperidinoalkyl-thiazolidinones related to Loperamide was synthesized and screened for antidiarrhoeal activity in mice by castor oil test. To characterize the potency and toxicity of the synthesized compounds ED50 and LD50 values were also determined. The thiazolidinones 2-6 displayed antidiarrhoeal activity at doses ranging between 15 and 82 mg/kg. Although the results show that the synthesized compounds are 15- to 80-fold less active respect to the reference compound, Loperamide, they are much less toxic (> or = 1000 mg/kg and 108.9 mg/kg, respectively). Besides, to evaluate the involvement of opioid receptors in antidiarrhoeal activity, Naloxone was administered prior to test the 2-phenyl-3-{2-[(4-phenyl-4-cyano)piperidino]ethyl}-1,3-thiazolidin-4-one (2), the more active compound of this series. The results obtained by this study, suggest that the antidiarrhoeal activity of this series of thiazolidinone derivatives could involve the opioid receptors.     

Synthesis, partition coefficients and antibacterial activity of 3'-phenyl (substituted)-6'-aryl-2' (1H)-cis-3',3'a-dihydrospiro [3-H-indole-3,5'-pyrazolo (3',4'-d)-thiazolo-2-(1H)-ones

Condensation of isatin with primary aryl amines gave a series of Schiff bases (1) which on reaction with thioglycolic acid in 1,4-dioxane afforded the formation of the corresponding 4- thiazolidinones (2). Compound 2 on condensation with substituted benzaldehydes in anhydrous sodium acetate furnished 3-aryl -5'-phenyl (substituted) spiro [3H-indole-3,2'-thiazolidines]-2-(1H), 4'(5'H)-diones (3). The latter (3) on reaction with hydrazine hydrochloride in anhydrous sodium acetate gave 3'-phenyl (substituted) -6'-aryl-2'(1H)-cis-3',3'a-dihydrospiro [3H-indole-3,5'-pyrazolo (3',4'-d)-thiazolo-2-(1H)-ones] (4). The structure has been established on the basis of spectral data. The partition coefficient for n-octanol/water solvent system and in vitro antibacterial activity of the 2'(1H)-cis-3',3'a-dihydrospiro [3H-indole-3,5'-pyrazolo (3',4'-d)-thiazolo-2-(1H)-one] derivatives have been evaluated.