四氢吖啶类化合物的合成及其生物活性

以他克林为先导物,设计合成了１４个未见文献报道的新化合物,其中目的物８个。初步药理试验结果表明,所合成的目的物中（３ｂ）、（３ｆ）和（３ｈ）活性较好,显示９－位氨基、巯基和羧基取代物均有神经细胞保护作用,由于化合物（３ｆ）为他克林的苯并类似物,显著苯并他克林可提高他克林的神经细胞保护作用。     

白藜芦醇衍生物及类似物的研究进展

分类综述白藜芦醇衍生物和类似物的生理药理活性及其构效关系，其中包括羟基类似物及甲基化和酯类衍生物等。白藜芦醇衍生物和类似物与白藜芦醇一样具有多种生理药理活性，其中有些化合物的活性、选择性及稳定性均要强于白藜芦醇，故备受关注，成为近些年的研究热点。     

作用于神经系统药物:吡啶并[1,2-a]嘧啶酮系列化合物的合成

加锡果宁(Ⅰ)是中药野花椒的成分之一,具有较强的镇痛作用和中枢抑制作用。为寻找低毒高效的类似物,我们曾对其进行结构改造,设计合成了系列化合物并进行了药理试验。前文报道的是在母核芳环上引入不同取代基而不改变母核结构,本文进一步对不同母核的类似物进行了合成及药理研究。     

环维黄杨星D的结构改造及生物活性环维黄杨星D的结构改造及生物活性

目的通过对植物活性单体环维黄杨星D的结构改造，以寻求疗效更好、治疗安全范围更宽的心血管药物。方法根据合理药物设计原理，设计合成目标化合物，并研究其生物活性。结果获得10个环维黄杨星D新衍生物，经光谱证明了结构。结论选取部分环维黄杨星D新衍生物进行耐缺氧、抗心律失常药理实验，结果表明部分化合物药理活性优于环维黄杨星D。     

环维黄杨星D的前药改造及生物活性研究

目的通过对植物活性单体——环维黄杨星D的前药改造，以寻求疗效更好、治疗安全范围更宽的心血管药物。方法根据前药设计原理，设计合成目标化合物，并研究其生物活性。结果获得7个环维黄杨星D新衍生物，并经光谱证明其结构。结论选取部分环维黄杨星D新衍生物进行抗心律失常药理实验，结果表明部分化合物药理效果优于环维黄杨星D。     

异苯并吡喃并[4,3-C]异恶唑衍生物的合成

带有异苯并吡喃环系结构的天然产物,广泛地存在于自然界中。目前此类化合物的人工合成取得了很大的进展。相当多的异苯并吡喃化合物,都表现出良好地药理性和生理活性。例如,日本化学家所制得的1—卓酚酮取代的异苯并吡喃衍生物,具有明显地抗癌活性。近年来,作者所进行的辛可芬类似物和异色满并吡啶类化合物,以及异喹啉酮的合成,都得到带有异苯并吡喃和N—取代的此环系结构的化合物。药理实验证明,该系列化合物,具有良好地抗炎药     

单羰基姜黄素类似物的结构改造及药理作用研究进展

姜黄素是中药姜黄的主要活性成分,具有抗肿瘤、抗炎、抗氧化等多种药理活性。临床前研究发现,姜黄素具有体内代谢速度快、溶解度不高、生物利用度低等缺陷,因此,其临床应用受到了限制。近年来国内外科学家以姜黄素为先导化合物,设计合成了大量的单羰基姜黄素类似物,并对其药理活性进行了评价,以解决姜黄素存在的缺陷。本文从单羰基姜黄素类似物连接链的角度进行分类,分别对1,4-戊二烯-3-酮类、环酮类和查尔酮类姜黄素类似物的设计合成、活性测试和构效关系等方面进行综述,并对未来姜黄素类似物的设计合成进行展望,为开发更为高效的姜黄素类新药提供参考。     

姜黄素单羰基类似物的研究进展

目的总结近几年来姜黄素单羰基类似物在合成、稳定性及药理活性方面的研究进展。方法通过检索查找相关文献。结果合成的姜黄素单羰基类似物不仅稳定性有所提高,且其药理活性也有所提高。结论姜黄素单羰基类似物具有进一步的研究价值和良好的应用前景。     

β-(3-吲唑基)-乙胺衍生物的合成及其抗放活性

为了寻找有效的辐射防护药,本文报告了有效防护剂5-甲氧基色胺的吲唑类似物及有关衍生物的合成。经药理试验证明5-甲氧基吲唑乙胺及5-羟吲唑乙胺具有明显的抗放活性。     

β-(3-吲唑基)-乙胺衍生物的合成及其抗放活性

为了寻找有效的辐射防护药,本文报告了有效防护剂5-甲氧基色胺的吲唑类似物及有关衍生物的合成。经药理试验证明5-甲氧基吲唑乙胺及5-羟吲唑乙胺具有明显的抗放活性。     

Synthesis of tacrine analogues and their structure-activity relationships

Three man synthetic routes to analogues of tacrine are described: reaction of anthranilonitriles with cyclohexanone and other ketones, reaction of various anilines with alpha-cyanoketones, and reactions involving anilines and cyclic beta-ketoesters. Although tacrine has a wide range of pharmacological effects, it is best known as an inhibitor of cholinesterase enzymes. Many of the analogues that have been made have not been tested against acetylcholinesterase or butyrylcholinesterase activity. Consequently, there is limited information from which a detailed understanding of structure-activity relationships can be derived. However, some halogenated derivatives are not only more potent acetylcholinesterase inhibitors than tacrine, they are also more selective for acetylcholinesterase than for butyrylcholinesterase.     

Multifunctional mercapto-tacrine derivatives for treatment of age-related neurodegenerative diseases

Cooperating mercapto groups with tacrine in a single molecular, novel multifunctional compounds have been designed and synthesized. These mercapto-tacrine derivatives displayed a synergistic pharmacological profile of long-term potentiation enhancement, cholinesterase inhibition, neuroprotection, and less hepatotoxicity, emerging as promising molecules for the therapy of age-related neurodegenerative diseases.     

Pyrrolobenzodiazepines and related systems. 2. Synthesis and biological properties of isonoraptazepine derivatives.

The synthesis of some derivatives and analogues of 12,13,14,14a-tetrahydro-9H,11H-pyrazino-[2,1-c]pyrrolo[1,2- a][1,4]benzodiazepine (isonoraptazepine) is reported. The new derivatives have been subjected to pharmacological tests for evaluation of antidepressant effects. Neurobehavioral assays were also carried out to acquire data on neurotoxicity and sedative action. Isonoraptazepine analogues and derivatives lacked the pharmacological activity of mianserin and aptazepine and showed properties similar to imipramine. Molecular modeling studies revealed structural similarities between isonoraptazepine derivatives and imipramine, thus explaining the similar pharmacological profile found in some of the tests employed. Based on pharmacological data the title compounds cannot be regarded as alpha 2 presynaptic adrenoceptors antagonists. In vitro studies for receptor binding gave support to this observation. The above studies lead us to conclude that isonoraptazepine derivatives are conformationally restricted analogues of imipramine, but their antidepressant activity cannot be correlated to inhibition of 5HT uptake. Among the derivatives tested, 7b and 8e show some affinity for the d-fenfluramine receptor site, a serotonin presynaptic site connected with anorectic activity.     

Design, synthesis, and molecular-modeling study of aminothienopyridine analogues of tacrine for Alzheimer's disease

2-Amino-3-cyanothiophenes were successfully condensed with a number of cycloalkanones to afford tacrine analogues in a one-step reaction mediated with Lewis acid. The newly synthesized compounds have been tested for their ability to inhibit acetylcholine esterase (AChE) activity using tacrine as standard drug. Some of the tested compounds showed moderate inhibitory activity in comparison with tacrine, especially compounds 6a which displayed the highest inhibitory activity. Furthermore, molecular-modeling studies were performed in order to rationalize the obtained biological results.     

Synthesis and biological activity of picobenzide (3,5-dimethyl-N-(pyridin-4-ylmethyl)benzamide) analogues as potential antipsychotic agents

A series of analogues related to picobenzide (CAS 51832-87-2) have been prepared and have been used as starting material to obtain new trisubstituted oxazole derivatives. Two compounds showed a promising pharmacological profile in screening tests of antipsychotic activity, since they affected apomorphine-induced hyperactivity without significant effects on stereotypies.     

New classes of AChE inhibitors with additional pharmacological effects of interest for the treatment of Alzheimer's disease

Alzheimer's disease (AD) is associated to a gradual loss of attention and memory that have been associated to impairment of brain cholinergic neurotransmission, particularly a deficit of cholinergic neurons in the nucleus basalis of Meynert. Thus, it is not surprising that the first therapeutic target that has demonstrated therapeutic efficacy on cognition, behaviour and functional daily activities has been the inhibitors of acetylcholinesterase (AChE), i.e. tacrine, donepezil, rivastigmine and galanthamine. But not all inhibitors of AChE have the same potency to block the enzyme and have a different pharmacological profile. For instance, rivastigmine is a dual inhibitor of AChE and butyrylcholinesterase (BuChE), and galanthamine is a mild inhibitor of AChE and an allosteric potentiating ligand of neuronal nicotinic receptors for acetylcholine (nAChRs). In addition, we have recently found that galanthamine has neuroprotective effects by inducing calcium signals and the induction of the antiapoptotic protein Bcl-2. In this frame, we have been synthesizing new tacrine derivatives that keep their ability to inhibit AChE but that interfere with neuronal calcium overloading and prevent apoptosis. Some of these compounds exhibit neuroprotecting properties and thus, could be useful in the treatment of neurodegenerative and ischaemic brain diseases.     

Conformational effects on the activity of drugs. 7. Synthesis and pharmacological properties of 2-(p-nitrophenyl)-substituted morpholines.

A series of 1-(p-nitrophenyl)-2-aminoethanol derivatives and their morpholine analogues have been synthesized and pharmacologically investigated in order to confirm some pharmacological observations made with the N-isopropyl-substituted compounds. In agreement with the previously obtained results, the weak alpha-adrenergic-stimulating activity and the potentiating effect on the responses to norepinephrine found in the open-chain compounds persist in their corresponding semirigid cyclic analogues. The results are discussed in the light of common knowledge of the structure-activity relationships of alpha-adrenergic drugs.     

A comparative study in rats of the in vitro and in vivo pharmacology of the acetylcholinesterase inhibitors tacrine, donepezil and NXX-066

The in vitro and in vivo effects of the novel acetylcholinesterase inhibitors donepezil and NXX-066 have been compared to tacrine. Using purified acetylcholinesterase from electric eel both tacrine and donepezil were shown to be reversible mixed type inhibitors, binding to a similar site on the enzyme. In contrast, NXX-066 was an irreversible non-competitive inhibitor. All three compounds were potent inhibitors of rat brain acetylcholinesterase (IC50 [nM]; tacrine: 125 +/- 23; NXX-066: 148 +/- 15; donepezil: 33 +/- 12). Tacrine was also a potent butyrylcholinesterase inhibitor. Donepezil and tacrine displaced [3H]pirenzepine binding in rat brain homogenates (IC50 values [microM]; tacrine: 0.7; donepezil: 0.5) but NXX-066 was around 80 times less potent at this M1-muscarinic site. Studies of carbachol stimulated increases in [Ca2+]i in neuroblastoma cells demonstrated that both donepezil and tacrine were M1 antagonists. Ligand binding suggested little activity of likely pharmacological significance with any of the drugs at other neurotransmitter sites. Intraperitoneal administration of the compounds to rats produced dose dependent increases in salivation and tremor (ED50 [micromol/kg]; tacrine: 15, NXX-066: 35, donepezil: 6) with NXX-066 having the most sustained effect on tremor. Following oral administration, NXX-066 had the slowest onset but the greatest duration of action. The relative potency also changed, tacrine having low potency (ED50 [micromol/kg]; tacrine: 200, NXX-066: 30, donepezil: 50). Salivation was severe only in tacrine treated animals. Using in vivo microdialysis in cerebral cortex, both NXX-066 and tacrine were found to produce a marked (at least 30-fold) increase in extracellular acetylcholine which remained elevated for more than 2 h after tacrine and 4 h after NXX-066.     

Comparison of inhibitory activities of donepezil and other cholinesterase inhibitors on acetylcholinesterase and butyrylcholinesterase in vitro

This study was designed to compare the in vitro inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) of donepezil and some other cholinesterase (ChE) inhibitors which have been developed for the treatment of Alzheimer's disease. The carbamate derivatives physostigmine and rivastigmine needed preincubation to exhibit appropriate anti-ChE activity. The maximum ChE inhibition by physostigmine developed within 30-60 min, while the inhibitory effect of rivastigmine on AChE and BuChE activities reached its peak after 48 and 6 h, respectively. The order of inhibitory potency (IC50) towards AChE activity under optimal assay conditions for each ChE inhibitor was: physostigmine (0.67 nM) > rivastigmine (4.3 nM) > donepezil (6.7 nM) > TAK-147 (12 nM) > tacrine (77 nM) > ipidacrine (270 nM). The benzylpiperidine derivatives donepezil and TAK-147 showed high selectivity for AChE over BuChE. The carbamate derivatives showed moderate selectivity, while the 4-aminopyridine derivatives tacrine and ipidacrine showed no selectivity. The inhibitory potency of these ChE inhibitors towards AChE activity may illustrate their potential in vivo activity.     

Azaepothilone B and its derivatives: a patent review

Introduction: Azaepothilone B, also known as ixabepilone, is a semi synthetic second generation epothilone B analogue. Azaepothilone B, its derivatives, and analogues, are used for treating advance metastatic breast cancer. It has been used as a chemotherapeutic medication for cancer.

Areas covered: This review highlights the patents on different routes for synthesis of azaepothilone B, its derivatives and analogues. The review will also provide the reported pharmacological activity and its polymorphs in the treatment of several cancers, such as breast cancer (metastatic or locally advanced), non-Hodgkin’s lymphoma, and pancreatic cancer. In addition, it considers other proliferative diseases such as viral infections, degenerative diseases of the musculoskeletal system, kidney disease, and immune response related diseases. Different databases such as Espacenet, ISI Web of Knowledge, Patbase, and Thomson Innovation have been searched extensively to review the patents. The analysis has been done to indicate the patenting trend across years and the comparison of active assignees.

Expert opinion: Azaepothilone B, along with its derivatives and analogues, can damage cancer cells in very low concentrations and retain its activity when tumor cells are insensitive to paclitaxel. Hence, it is highly potent agent. Azaepothilone B alone, in combination with other chemotherapeutics, or in the form of formulations, led to applications in various types of cancer. Also, antiproliferative activity of azaepothilone B has great potential for the treatment of proliferative diseases, such as skin diseases and infections. Recent progress in synthesizing azaepothilone B has encouraged researchers to develop new methods for the synthesis of azaepothilone B, its derivatives, and analogues, to obtain maximum yield in minimum steps.