新型2-苯基苯并呋喃-3-酰胺衍生物的设计、合成及对Sortase A的抑制活性

以金黄色葡萄球菌转肽酶Sortase A与底物LPXTG的结合构象为模板,设计合成了12个具有L-shape构象的2-苯基苯并呋喃-3-酰胺衍生物作为Sortase A抑制剂,并经核磁共振和高分辨质谱确认结构,其中10个目标化合物未见文献报道。体外抑制活性结果显示,9个目标化合物对Sortase A具有较好的抑制活性[IC50=(22.2~62.3)μmol/L]。构效关系分析结果表明,苯并呋喃3-位上的取代基为-CONHCH2CH(CH3)2时抑制活性较好,而为-COOH时则抑制活性丧失;2-位苄基上带有吸电子基如氰基时抑制活性较好,而为供电子基如羟基时抑制活性较差;苯并呋喃其他位置上的取代基对抑制活性未见明显影响。     

α-取代肉桂酰苯乙胺类化合物的合成及其生物活性

目的 设计合成未见文献报道的α-取代肉桂酰苯乙胺类化合物，并对其进行生物活性筛选。方法 在肉桂酸部分的苯环上，分别引入p-Cl、3，4-OCH2O、p-NO2等取代基，而在苯乙胺部分的苯环上，对邻位和间位用甲氧基进行取代，先后合成了18个α-取代肉桂酰苯乙胺类化合物．结构经元素分析、HREIMS、EI-MS、1H-NMR、IR确认。结果 目标化合物具有明显的免疫及舒张血管的活性。结论 该类化合物作为药物先导化合物，具有进一步研究的价值。     

3-取代-1(3H)-异苯并呋喃酮光学异构体的合成及抗血小板活性初步研究

目的为开发高效、低毒的新型抗脑卒中药物,设计一系列3-取-代1(3H)-异苯并呋喃酮衍生物,研究这类化合物的抗血小板活性。方法以邻苯二甲酸酐为起始原料合成了一系列3-取代-1(3H)-异苯并呋喃酮6a-g以及7a-g,拆分了化合物6a-g。使用Born氏法体外实验评价了这类化合物的抗血小板活性。结果抗血小板活性强弱顺序为:l-异构体>dl消旋体>d-异构体;烷基苯酞的活性要强于相应的烯基苯酞。所合成的目标化合物活性均弱于正丁基苯酞(NBP,6c)及阿司匹林(Asp)。结论异苯并呋喃酮类化合物抗血小板活性可能与分子大小及构型有关,不同取代基作用强度总体趋势随取代基增大而减弱,体内生物大分子可能对该类化合物存在立体选择性。     

绿原酸酰胺二聚体的合成及体外抗脂质代谢紊乱活性研究

目的设计合成绿原酸的酰胺二聚体衍生物,并对其进行体外抗脂质代谢紊乱活性的研究.方法以绿原酸为起始原料经3步反应制得目标化合物,利用HepG2细胞株评价该类化合物的调血脂活性.结果 设计并合成8个绿原酸酰胺二聚体衍生物CGA-2a~2d及CGA-3a~3d,均经波谱技术确证结构.药理实验结果表明,衍生物CGA-2d和CGA-3a~3d具有不同程度的调血脂活性.结论 绿原酸二聚体化合物CGA-2a~2d及CGA-3a~3d均为未见文献报道的新化合物,部分化合物具有潜在的调脂生物活性,具有深入研究价值.     

N-取代-3-吲哚乙酰胺类α1-肾上腺素受体拮抗剂的合成及生物活性

目的设计合成新型吲哚乙酰胺类α1-肾上腺素受体拮抗剂,评价其α1-肾上腺素受体拮抗活性.方法 结合α1-肾上腺素受体拮抗剂的构效关系和计算机辅助药物设计方法所构建的药效团模型,设计合成了19个N-取代-3-吲哚乙酰胺类化合物,并测定拮抗参数pA2值.结果 18个化合物未见文献报道,其结构均经1H-NMR、IR及ESI-MS(HRMS)确证.结论 初步生物活性测试表明:所合成的目标化合物多数具有较好的α1-肾上腺素受体拮抗活性.     

苯并呋喃衍生物扩冠活性研究

目的：对合成的苯并呋喃衍生物进行药理活性的研究。方法：采用Langendorff法,进行豚鼠体外灌流实验。结果：包括5个化合物有较好的扩冠活性,其中4个化合物未见文献报道。结论：氯原子的引入增强苯并呋喃类化合物的扩冠活性,硝基、氨基、苄基等基团的引入会影响化合物的活性。     

新活性红霉素衍生物的研究进展

目的综述新活性红霉素衍生物的研究进展。方法依据国内外近期公开发表的30篇文献,对新活性红霉素衍生物的研究进展进行分类、归纳与总结。结果长期以来,红霉素及其衍生物作为抗菌药物被广泛使用。临床与实验数据显示,该类化合物还具有一些新的生物活性,例如促进消化道运动活性、抗炎与免疫调节活性、拮抗黄体生成素释放激素活性以及抑制磷酸二酯酶-3活性等。在提高红霉素的新活性并降低其抗菌作用的研究中,已设计、合成了多种类型的新结构的红霉素衍生物。结论利用红霉素衍生物的新活性研制、开发新药,已逐步成为红霉素衍生物研究的重要内容,呈现良好的发展势头。     

2-取代苯基-1,2,4-三氮唑[5,1-a]并吡啶类衍生物的合成及其溶黄体活性

目的研究2－取代苯基－1，2，4－三氮唑[5,1-a]并吡啶类衍生物的合成及其抗早孕活性。方法 甲基取代吡啶胺化后，通过和取代苯甲腈缩合反应合成目标化合物，利用离体培养大鼠黄体细胞试验进行抗早孕活性筛选。结果 设计合成了14个未见文献报道的2－取代苯基－1，2，4－三氮唑[5,1-a]并唑啶类衍生物，均为新化合物。生物活性实验结果表明：除化合物7k以外，新合成的化合物都有一定溶黄体细胞的作用，其中化合物7b,71的作用更强，它们的ED50分别为0.5μg/mL和1.6μg/mL。结论 新合成的化合物具有一定的损伤黄体细胞的活性，值得进一步研究。     

非抗菌活性红霉素衍生物研究进展

目的综述非抗菌活性红霉素衍生物的研究进展。方法依据国内外近期公开发表的40篇文献,对非抗菌活性红霉素衍生物的研究进展进行分类、归纳与总结。结果长期以来,红霉素及其衍生物作为抗菌药物被广泛使用。在临床实践中人们发现,该类化合物还具有一些新的生物活性,例如促进消化道运动、抗炎/免疫调节、抗寄生虫、抗肿瘤、拮抗黄体生成素释放激素、以及抑制磷酸二酯酶-3等活性。为提高新活性降低其抗菌作用,已经设计、合成了多种类型的新结构红霉素衍生物。结论利用红霉素衍生物的新活性研制、开发新药已经成为研究热点。     

4′-脂肪胺基烷基取代槲皮素衍生物的合成

目的 探索制备新槲皮素的抗肿瘤化合物。方法 以槲皮素为起始原料，在碱性条件下与卤代脂肪胺反应，制备目标化合物。结果 对槲皮素4′-羟基进行结构改造，合成8个4′-脂肪胺基烷基取代槲皮素衍生物，均未见文献报道。结论 目标化合物的结构经核磁共振氢谱、紫外光谱分析确证。对该类化合物的抗癌活性研究仍在进行中。     

2-Methoxyphenylethanolamines, potential beta-adrenergic blocking agents.

The effect of the introduction of a 2-methoxy substituent on the beta-adrenergic antagonistic properties of a series of 3- and 4-substituted phenylethanolamines (1) was studied. Both the series of bromo- and methyl-substituted compounds behaved similarly, indicating that electronic forces are not significant in determining beta-adrenergic antagonist activity. When compared with the corresponding phenylethanolamines without a 2-methoxy substitutent, the 2-methoxy-4-substituted derivatives (3a and 3d) had enhanced potency and selectivity but the 2,3- (3b and 3e) and the 2,5-disubstitution patterns (3c and 3f) showed a loss of activity. The inconsistent changes in activity prevented any firm conclusions being made about the effect of the ether oxygen and the beta-adrenoceptor antagonistic activity of phenoxypropanolamines.     

Structure-activity relationships in cinnamamides. 1. Synthesis and pharmacological evaluation of some (E)- and (Z)-N-alkyl-alpha,beta-dimethylcinnamamides.

Two series of (E)- and (Z)-N-alkyl-alpha,beta-dimethylcinnamamide derivatives were prepared and the biological activity of these compounds was investigated in a series of pharmacological tests. All compounds tested had clear activity on the CNS; generally, this was depressant with E isomers, while Z isomers always caused marked stimulation (tremors and convulsions). Some of the E isomers also had a clear-cut anticonvulsant activity as shown by the antagonistic effect on pentylenetetrazole-induced seizures in the mouse. The NMR spectra of these compounds, which confirm their configurations, are discussed.     

An update on benzofuran inhibitors: a patent review

ABSTRACT

Introduction: Benzofuran is a fundamental unit in numerous bioactive heterocycles. They have attracted chemists and medical researchers due to their broad range of biological activity, where some of them possess unique anticancer, antitubercular, antidiabetic, anti-Alzheimer and anti-inflammatory properties. The benzofuran nucleus is present in a huge number of bioactive natural and synthetic compounds. Benzofuran derivatives have potent applications in pharmaceuticals, agriculture, and polymers. The recent developments considering the biological activities of benzofuran compounds are reported. They have a vital role as pronounced inhibitors against a number of diseases, viruses, fungus, microbes, and enzymes.

Areas covered: This review covers the recent developments of biological activities of benzofurans during the period 2014–2019. The covered areas here comprised antimicrobial, anti-inflammatory, antitumor, antitubercular, antidiabetic, anti-Alzheimer, antioxidant, antiviral, vasorelaxant, anti-osteoporotic and enzyme inhibitory activities.

Expert opinion: In addition to the already commercialized 34 benzofurans-based drugs in the market, this chapter outlines several potent benzofuran derivatives that may be useful as potential pro-drugs. It is also focused on providing details of SAR and the effect of certain functional groups on the activity of the benzofuran compounds. The presence of -OH, -OMe, sulfonamide, or halogen contributed greatly to increasing the therapeutic activities comparing with reference drugs.     

Synthesis of new 8-(5-substituted amino-1,3,4-oxadiazol-2-yl) and 8-(5-substituted amino-1,3,4-thiadiazol-2-yl) methoxyquinolines with antibilharzial activity

Several 5-substituted amino-1,3,4-oxadiazol-2-yl and 5-substituted amino-1,3,4-thiadiazol-2-yl derivatives with different 8-hydroxyquinoline moieties in the 2-position were prepared and tested for their antiparasitic activity. Preliminary biological tests on mice experimentally infested with Schistosoma mansoni revealed that the new compounds show moderate schistosomicidal activity.     

Antihypertensive thiadiazoles. 1. Synthesis of some 2-aryl-5-hydrazino-1,3,4-thiadiazoles with vasodilator activity

Some 2-aryl-5-hydrazino-1,3,4-thiadiazoles have been synthesized and screened for antihypertensive activity. In general, compounds with a 2-substituted phenyl ring had higher activity than their 3- or 4-substituted counterparts or those containing heteroaryl groups. The 2-methylphenyl and 2-ethylphenyl derivatives 7 and 18 were the most potent members of the series. Preliminary studies indicated that the hypotensive action of these compounds was due to a direct relaxant effect on vascular smooth muscle.     

Antiparkinsonian effects of novel adenosine A(2A) receptor antagonists

The present work describes the synthesis of a pyrazinopurinedione derivative which was together with a series of pyrimidopurinedione derivatives tested for potential antiparkinsonian activity in two tests: the "oxotremorine" and the "reserpine" test. For the studies compounds which had shown affinity for the adenosine A(2A) receptor were chosen. One compound, a pyrazinopurinedione derivative, without affinity for A(2A) receptors, but showing adenosine A(1) receptor affinity was also investigated. The performed preliminary tests indicated that, contrary to the pyrazinopurinedione all pyrimidopurinediones demonstrated antiparkinsonian effects. As a result of present studies it may be concluded that antiparkinsonian effects of the examined compounds are correlated with the antagonistic activity toward adenosine A(2A) receptors in this class of compounds. However a direct correlation of the potency of both effects was not observed possibly due to different pharmacokinetic properties of the compounds. The most active derivatives of the present series were aryl-substituted pyrimidopurinediones.     

5'-O-alkyl ethers of N,2-substituted adenosine derivatives: partial agonists for the adenosine A1 and A3 receptors

New N,5'-di- and N,2,5'-trisubstituted adenosine derivatives were synthesized in good overall yields. Appropriate 5-O-alkyl-substituted ribose moieties were coupled to 6-chloropurine or 2,6-dichloropurine via Vorbrüggen's glycosylation method. Subsequent amination and deprotection of the intermediates yielded compounds 18-35. Binding affinities were determined for rat adenosine A1 and A2A receptors and the human A3 receptor. The ability of compounds 18-35 to inhibit forskolin-induced (10 microM) cyclic AMP (cAMP) production and their ability to stimulate guanosine 5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding, via either the adenosine A1 receptor or the adenosine A3 receptor, were assessed. N-Cyclopentyl-substituted adenosine derivatives displayed affinities in the low nanomolar range for the adenosine A1 receptor, whereas N-(3-iodobenzyl)-substituted derivatives had high affinity for the adenosine A3 receptor. Compound 22 had the highest affinity for the adenosine A1 receptor (K(i) value of 16 nM), and compounds 20 and 26 had the highest affinities for the adenosine A3 receptor (K(i) values of 4 and 3 nM, respectively). A chlorine substituent at the 2-position either did not affect or slightly increased the adenosine A1 receptor affinity, whereas the A3 receptor affinity was affected differently, depending on the N-substituent. Furthermore, the introduction of chlorine slightly increased the A3/A1 selectivity ratio. At the 5'-position, an O-methyl substituent induced the highest adenosine A1 receptor affinity, whereas an O-ethyl substituent did so for the A3 receptor. All compounds showed partial agonistic effects in both the cAMP and [35S]GTPgammaS assays, although more marked in the latter assay. In general, the 2-chloro derivatives seemed to have lower intrinsic activities compared to the 2-H-substituted compounds on both the adenosine A1 and the adenosine A3 receptors. The compounds with an N-(3-iodobenzyl) substituent displayed the lowest intrinsic activities. Finally, all compounds also showed partially antagonistic behavior in the [35S]GTPgammaS assay.     

Structure-activity studies of diazabicyclo[3.3.0]octane-substituted pyrazines and pyridines as potent α4β2 nicotinic acetylcholine receptor ligands

A series of diazabicyclo[3.3.0]octane substituted pyridines and pyrazines was synthesized and characterized at the α4β2 neuronal nicotinic acetylcholine receptor (nAChR). The compounds were designed to mimic the profile of ABT-089, high affinity binding ligand for the α4β2 nAChR, with limited agonist activity. Carboxamide derivatives of 3-(diazabicyclo[3.3.0]octane)-substituted pyridines or 2-(diazabicyclo[3.3.0]octane)-substituted pyrazines were found to have the desired binding and activity profile. The structure-activity relationship of these compounds is presented.     

From tyrosine to glycine: synthesis and biological activity of potent antagonists of the purinergic P2X7 receptor

The characterization of the native and recombinant P2X7 receptor continues to be hindered by the lack of specific and subtype-selective antagonists with a "druglike" profile. However, a tyrosine derivative named KN-62 exhibits selective P2X7 receptor-blocking properties. As a molecular simplification of KN-62, the present study was designed to evaluate the functional antagonistic properties of a novel series of glycine derivatives characterized by the presence of different phenyl-substituted piperazine moieties. Antagonistic activity of these glycine derivatives was tested on HEK293 cells transfected with the human P2X7 receptor. The most potent P2X7 receptor antagonist identified in this study (compound 4g) contains an o-fluorine substituent on the phenylpiperazine moiety and had an IC50 of 12.1 nM. The biological responses investigated were ATP-dependent Ca2+ influx across the plasma membrane and ethidium bromide uptake.     

Purine and deazapurine nucleosides: synthetic approaches,molecular modelling and biological activity

A number of ligands for the adenosine binding sites has been obtained by using nucleoside convergent and divergent synthesis. Most of our nucleosides have been synthesized by coupling 2,6-dichloropurine (1), 2,6-dichloro-1-deazapurine (2), 2,6-dichloro-3-deazapurine (3) with ribose, 2- and 3-deoxyribose and 2,3-dideoxyribose derivatives. The use of these versatile synthons allowed the introduction of various substituents in 2- and/or 6-positions. The glycosylation site and the anomeric configuration of the obtained nucleosides were assigned on the basis of spectroscopic studies and confirmed by molecular models. A series of potent adenosine receptor ligands has been obtained by using divergent approaches, mostly starting from guanosine. Substitutions in 2, 6, 8, and 5' position of adenosine molecule led to ligands selective for the different adenosine receptor subtypes. Furthermore, we investigated the molecular bases of the different behavior of 2- and 8-alkynyl adenosines, by means of NMR experiments and molecular modeling studies. With docking experiments, we demonstrated that the two class of molecules should have different binding modes that explain their different degree of affinity and the shift of their activity from agonistic (2-substituted derivatives) to antagonistic (8-substituted derivatives).