含噻唑环的二肽基肽酶Ⅳ抑制剂的设计、合成和降血糖活性研究

设计并合成了16个含噻唑环的二肽基肽酶Ⅳ(DPP-Ⅳ)抑制剂,利用IR,1H NMR,13C NMR和HR-MS表征了它们的结构.通过小鼠口服糖耐量实验测试了它们的降血糖作用,结果显示其中两个化合物具有很强的降血糖作用,一个与格列齐特相当,另一个强于格列齐特,显示了在治疗Ⅱ型糖尿病方面的前景.构效关系研究发现,这16个化合物的构效关系呈现出明显的规律.     

苯萘基糖苷类化合物的合成及其治疗糖尿病的活性

以1,2-二甲氧基苯,丁二酸酐以及α-溴代四乙酰基吡喃糖为原料,设计并合成了作为SGLT2抑制剂的两个结构新颖的苯萘基糖苷化合物(6a和6b),其结构经1H NMR, 13C NMR, IR和ESI-MS确认.利用小鼠体内葡萄糖耐受量法测定了6治疗糖尿病的活性,结果发现6a具有明显的降血糖作用,其活性与阳性对照药格列齐特相当.     

单螺环哌嗪季铵盐类化合物的合成及镇痛活性研究

为寻找镇痛活性更好的化合物,以前期发现的螺环哌嗪季铵盐类化合物1为先导物,设计合成了8个未见文献报道的衍生物.通过1H NMR,13C NMR和元素分析或高分辨质谱确定了化合物的结构.利用小鼠醋酸扭体模型初步评价了它们的镇痛活性,构效关系研究表明,苯环上的羟基是关键的药效团,与开链季铵盐相比,螺环季铵盐结构对活性更有利；扩大螺环和引入取代基对活性不利.     

4,4-二甲基-3-异噁唑酮衍生物的合成与表征

以4,4-二甲基-3-异噁唑酮为母体化合物, 通过异氰酸酯法合成了9个磺酰脲类异噁唑酮衍生物, 经IR, MS, NMR及元素分析证实了化合物的结构, 测定了这些化合物的除草活性, 并对构效关系进行了初步探讨.     

具有双光子吸收的咔唑类分子的设计、合成及光谱特性

设计、合成了四个新的咔唑类具有较大双光子吸收截面的化合物,研究它们的光谱特性,对双光子吸收的构效关系进行初步探索.     

二氢噁唑并[5,4-d]吡咯并[1,2-a]嘧啶酮的合成及生物活性研究

以天然产物脱氧鸭嘴花酮生物碱为基础,通过生物电子等排手段,设计并合成了 40个二氢噁唑并[5,4-d]吡咯并[1,2-a]嘧啶酮类化合物,其结构经1H NMR、13C NMR和HRMS进行了确证,并对该类化合物合成方法的关键步骤影响因素和构效关系进行了探讨.使用噻唑蓝(MTT)法对该系列化合物的3种肿瘤细胞(MCF-7...     

含反式环己烷结构的C-葡萄糖苷类SGLT2抑制剂的合成及其降血糖活性Ⅱ

设计并合成了一系列新型含反式-4-烷基环己烷结构的C-葡萄糖苷类SGLT2抑制剂——反式-1-{4-甲氧基-3-[(4-取代环己基)甲基]苯基}-1-脱氧-β-D-吡喃葡萄糖(12a～12d),其结构经1H NMR和MS表征.小鼠口服糖耐量实验表明,12a～12d均显示较强的降血糖活性.对12a～12d进行了较为完整的构效关系分析,得到了良好的构效关系.     

含氟新农药的构效关系研究Ⅱ.三维定量构效关系分析

为了能更深入地认识含氟新化合物作为农药的生物活性和其结构间的关系,建立有意义的药物-受体作用模型,寻找同类化合物的药效团,对合成的含氟化合物在经典QSAR方法研究的基础上,又进一步运用DISCO,CoMFA和Leapfrog方法研究了它们的三维构效关系.首先根据化学结构,将分子进行了分类,然后再分别进行CoMFA计算,根据第I类分子的CoMFA结果,我们进行了含氯化合物的全新设计.根据各类中较好的构效关系模型,我们进行了分子的改造,预测了它们的活性.     

系列C3α-位芳基取代的四氢吡咯并吲哚骨架衍生物的合成

通过银促进的傅-克反应可以合成系列C3α-位为不同类型芳基取代的四氢吡咯并吲哚骨架的类天然产物.在该合成方法的基础上,发现C3α-位分别为对乙酰氨基苯基取代和甲基吲哚取代的四氢吡咯并吲哚类衍生物3a和3b对多种肿瘤细胞均表现出微摩尔级的活性,是具有重要临床应用前景的药物候选化合物.为了进一步研究该类化合物的成药性及其构效关系,以化合物3a为前体化合物合成了一系列类天然产物(化合物4～17),对其抗肿瘤活性进行了研究,并初步探讨了其构效关系.所合成化合物的结构经1H NMR、13C NMR和HRMS分析确证.本研究为该类化合物的临床前研究奠定了基础.     

新型含三氟甲基取代的邻苯二酰胺衍生物的设计、合成及生物活性研究

为了寻找高效、对环境友好的先导生物活性结构,设计合成了10个具有双三氟甲基苯胺取代的邻苯二甲酰胺新型衍生物,其结构通过1H NMR,13C NMR,HRMS以及元素分析确认.初步的生物活性测试结果表明,大部分化合物对小菜蛾和东方粘虫具有一定的杀虫活性.此结果为邻苯二酰胺类化合物构效关系的研究提供了基础.     

Synthesis of New Flavanone Derivatives of Farrerol and Preliminary SAR Studies on Anti-VSMCs Vegetation Activity

A series of new flavanone derivatives of farrerol was designed and synthesized as a potent inhibitor of vascular smooth muscle cells(VSMCs) vegetation according to a convenient method. The structures of all the synthesized compounds were confirmed by 1H NMR, 13C NMR and EIHR-MS. The biological activities of these compounds against VSMCs in vitro were evaluated. The assay results indicate that two compounds, 5,7-dihydroxy-6,8-dimethyl- 2-(2-nitrophenyl)chroman-4-one(7f) and 2,3-dibromo-4,5-dihydroxydiphenylm...     

Targeting norovirus infection-multivalent entry inhibitor design based on NMR experiments

Noroviruses attach to their host cells through histo blood group antigens (HBGAs), and compounds that interfere with this interaction are likely to be of therapeutic or diagnostic interest. It is shown that NMR binding studies can simultaneously identify and differentiate the site for binding HBGA ligands and complementary ligands from a large compound library, thereby facilitating the design of potent heterobifunctional ligands. Saturation transfer difference (STD) NMR experiments, spin-lock filtered NMR experiments, and interligand NOE (ILOE) experiments in the presence of virus-like particles (VLPs), identified compounds that bind to the HBGA binding site of human norovirus. Based on these data two multivalent prototype entry-inhibitors against norovirus infection were synthesized. A surface plasmon resonance based inhibition assay showed avidity gains of 1000 and one million fold over a millimolar univalent ligand. This suggests that further rational design of multivalent inhibitors based on our strategy will identify potent entry-inhibitors against norovirus infections.     

Novel 5-substituted-1H-tetrazole derivatives as potent glucose and lipid lowering agents

A series of 5-(4-alkoxyphenylalkyl)-1H-tetrazole derivatives, containing an oxazole-based group at the alkoxy moiety, was prepared and their antidiabetic effects were evaluated in two genetically obese and diabetic animal models, KKAy mice and Wistar fatty rats. Syntheses were performed by cyclization of the corresponding nitrites reacting with azide compounds. A large number of the 5-(4-alkoxyphenylalkyl)-1H-tetrazoles showed potent glucose and lipid lowering activities in KKAy mice. In particular, 5-[3-[6-(5-methyl-2-phenyl-4-oxazolyl-methoxy)-3-pyridyl]propyl]-1H-tetrazole had potent glucose lowering activity (ED25=0.0839 mg x kg(-1) x d(-1)), being 72 times more active than pioglitazone hydrochloride (ED25=6.0 mg x kg(-1) x d(-1)). This compound also showed strong glucose lowering (ED25=0.0873 mg x kg(-1) x d(-1)) and lipid lowering effects (ED25=0.0277 mg x kg(-1) x d(-1)) in Wistar fatty rats. The antidiabetic effects of this compound are considered to be due to its potent agonistic activity for peroxisome proliferator-activated receptor gamma (PPARgamma) (EC50 = 6.75 nM).     

1—[2—（N—甲基—N—取代苄基）氨基—2—（4—叔丁基苯基）乙？…

根据氮唑类和苄胺类抗真菌药物的构效关系和作用机理,设计合成了２３种１－「２－（Ｎ－甲基－Ｎ－取代苄基）氨基－２－（４－叔丁基苯基）乙基」－１Ｈ－１,２,４－三唑类化合物,其结构经元素分析、红外光谱及核磁共振谱分析 证实。体外抑菌实验结果表明：目标化合物对常见的９种致病真菌均有一定活性,对浅表真菌活性优于深部真菌,其中化合物３,４,６,１０,１２,１４和１５对羊毛样小孢菌具有较强的活性。     

6-(4-取代苯基)-5-甲基-4,5二氢-3(2H)哒嗪酮化合物的合成及其抑制血小板聚集作用

血小板聚集在血栓形成中起着先导而关键的作用,而严重威胁人类生命健康的心脑血管疾病多数与血栓形成和血栓栓塞有着密切的联系[1]。二氢哒嗪酮类化合物对抑制血小板聚集有较强的药理活性,对二磷酸腺苷(ADP)、花生四烯酸(AA)、血小板活化因子(PAF)和胶原(Collagen)引起的血小板聚集均有抑制作用。深入研究二氢哒嗪酮类化合物的构效关系,以期寻找活性更强的抗血小板聚集药物,是开发新型心脑血管系统疾病药物的重要研究方向之一。本文设计合成了6-(4-取代苯基)-5-甲基-4,5二氢-3(2H)哒嗪酮类化合物[2,3,4],并进行了体外药理实验。1实验部…     

Virtual Screening,Synthesis, and Biological Evaluation of Some Carbohydrazide Derivatives as Potential DPP-IV Inhibitors

Dipeptidyl peptidase-4 (DPP-IV) inhibitors are known as safe and well-tolerated antidiabetic medicine. Therefore, the aim of the present work was to synthesize some carbohydrazide derivatives (1a–5d) as DPP-IV inhibitors. In addition, this work involves simulations using molecular docking, ADMET analysis, and Lipinski and Veber’s guidelines. Wet-lab synthesis was used to make derivatives that met all requirements, and then FTIR, NMR, and mass spectrometry were used to confirm the structures and perform biological assays. In this context, in vitro enzymatic and in vivo antidiabetic activity evaluations were carried out. None of the molecules had broken the majority of the drug-likeness rules. Furthermore, these molecules were put through additional screening using molecular docking. In molecular docking experiments (PDB ID: 2P8S), many molecules displayed more potent interactions than native ligands, exhibiting more hydrogen bonds, especially those with chloro- or fluoro substitutions. Our findings indicated that compounds 5b and 4c have IC₅₀ values of 28.13 and 34.94 µM, respectively, under in vitro enzymatic assays. On the 21st day of administration to animals, compound 5b exhibited a significant reduction in serum blood glucose level (157.33 ± 5.75 mg/dL) compared with the diabetic control (Sitagliptin), which showed 280.00 ± 13.29 mg/dL. The antihyperglycemic activity showed that the synthesized compounds have good hypoglycemic potential in fasting blood glucose in the type 2 diabetes animal model (T2DM). Taken all together, our findings indicate that the synthesized compounds exhibit excellent hypoglycemic potential and could be used as leads in developing novel antidiabetic agents.     

Syzygium samarangense leaf extract exhibits distinct antidiabetic activities: Evidences from in silico and in vivo studies

The wax apple, Syzygium samarangense, is widely used in traditional medicine. We have previously described a plethora of biological activities from its leaf extract. These include antioxidant, anti-inflammatory, antiulcer, antitrypanosomal and hepatoprotective effects. Here, we explored the antidiabetic activities from the bioactive leaf extract in silico on two crucial receptors involved in the management of diabetes disease namely peroxisome proliferator activated receptor gamma (PPAR?) and glucagon like peptide-1 (GLP-1) and in vivo against streptozotocin-induced diabetic rats. Altogether, 457 secondary metabolites belonging to 10 classes (phenolic acids (86 compounds), flavonoids (139 compounds), anthocyanins (61 compounds), alkylphenols (17 compounds), chalcone (15 compounds), stilbenes (9 compounds), lignans (29 compounds), tannins (29 compounds), tyrosols (13 compounds), and terpenes and others (59 compounds), were docked into the active site of PPAR? and GLP-1 receptors. From the PDB codes used for each receptor, the co-crystallized ligand was extracted and docked together with a known reference ligand. This was done simultaneously with docking the extract’s compounds to serve as references for comparative purposes. Out of the docked candidates, the top 30 compounds affording the best docking scores were compiled for further inspection and they appeared to exhibit better scores than the respective co-crystallized and reference ligands, highlighting the antidiabetic potential of the tested extract. Nine compounds exhibited highly negative scores on both receptors, demonstrating their high probability of being potent antidiabetic agents through forming stable ligand-receptor complexes. These activities were also confirmed in STZ diabetic rats where the extract reduced the elevated levels of serum glucose and lipid peroxides and increased the declined serum insulin hormone level. Taking all together, S. samarangense can be a potential candidate for further investigations for the treatment of numerous health disorders including diabetes.     

Uncinoside A and B, two new antiviral chromone glycosides from Selaginella uncinata

Five compounds have been isolated from the dried whole plants of Selaginella uncinata, two of them were new chromone glycosides, 5-hydroxy-2,6,8-trimethylchromone 7-O-beta-D-glucopyranoside (uncinoside A) and 5-acetoxyl-2,6,8-trimethylchromone 7-O-beta-D-glucopyranoside (uncinoside B). Their structures were elucidated by spectroscopic methods including one- and two-dimensional NMR techniques. The other three compounds were identified as 8-methyl eugenitol, amentoflavone and hinokiflavone. Uncinoside A and B showed potent antiviral activities against respiratory syncytial virus (RSV) with IC(50) value of 6.9 and 1.3 microg/ml, moderate antiviral activities against parainfluenza type 3 virus (PIV 3) with IC(50) value of 13.8 and 20.8 microg/ml, respectively.     

Improved Antiproliferative Activities of a New Series of 1,3,4-Thiadiazole Derivatives Against Human Leukemia and Breast Cancer Cell Lines

Twenty-two novel 1,3,4-thiadiazole derivatives were synthesized using different aromatic acids as starting materials, followed by cyclization, coupling and deprotection reaction. The structures of all the target compounds were identified by means of ¹H nuclear magnetic resonance(NMR), ¹³C NMR and high resolution mass spectrometer(HRMS). Further biological evaluations were performed for chronic myelogenous leukemia cell and breast cancer cell. The results suggest that most of the target compounds exhibit potent anti-proliferative activities. Especially, compound 5b shows better antiproliferative activities against MDA-MB-231 and K562 cell lines compared with gossypol.