N-[4-氯-2-取代氨基甲酰基-6-甲基苯基]-1-芳基-5-氯-3-三氟甲基-1H-吡唑-4-甲酰胺的合成及生物活性

通过改变传统氯虫酰胺中吡唑环上氨基甲酰基与吡啶环之间的相对位置, 或以其它芳环取代原分子中的吡啶环, 设计合成了24个结构新颖的N-[4-氯-2-取代氨基甲酰基-6-甲基苯基]-1-芳基-5-氯-3-三氟甲基-1H-吡唑-4-甲酰胺类化合物. 所有目标化合物的结构均通过¹H NMR谱、 元素分析或高分辨质谱表征确定. 初步的生物活性测试结果表明, 部分化合物对东方粘虫具有较好的杀虫活性, 其中化合物6m在浓度为50 mg/L时具有80%的杀虫活性. 同时, 在浓度为50 mg/L时目标化合物对5种常见病菌具有明显的抑制作用, 其中化合物6n和6x对苹果轮纹菌的抑菌率达62.1%.     

新型含取代哌嗪的5-(吡啶-3-基)-1,2,4-三唑Mannich碱和双Mannich碱的合成及生物活性

根据药物分子设计的活性基团组合原理,通过在1,2,4-三唑环的5位引入吡啶基,同时在4位芳基亚甲氨基的苯环上引入氟或三氟甲基,设计合成了一系列含氟、吡啶和哌嗪基团的1,2,4-三唑Mannich碱和双Mannich碱类化合物.通过核磁共振氢谱(~1H NMR)、碳谱(~(13)C NMR)和元素分析确证了目标化合物的结构.生物活性测试结果表明,部分化合物对油菜具有一定的除草活性;化合物2a,2d和2f(50 mg/L)对苹果轮纹病菌表现出较好的抑制活性,与对照药三唑酮活性相当;化合物2a,2b,2d和2i(180 mg/L)对酮醇酸还原异构酶(KARI酶)表现出了显著的离体抑制活性(抑制率51.7%~88.7%).     

基于天然产物Aphadilactone C结构关键片段的二酰基甘油酰基转移酶1抑制剂的设计与合成

二酰基甘油酰基转移酶(DGAT)作为甘油三酯合成的唯一限速酶,成为治疗肥胖以及其他代谢综合征的重要靶标.利用从具有DGAT1抑制活性的天然产物aphadilactone C分子中重要内酯环与进入临床研究的2-((1R,4R)-4-(4-(4-氨基-5-氧亚基-7,8-二氢嘧啶[5,4-f][1,4]氧氮杂-6(5H)-基)苯基)环己基)乙酸(PF-04620110),2-((1R,4R)-4-(4-(6-氨甲酰基-3,5-二甲基对二氮杂苯-2-基)苯基)环己基)乙酸(AZD-7687)分子中杂环单元的重新组合,设计合成了化合物5~8,以此来验证aphadilactone C中内酯环单元是否与已知DGAT1抑制剂中的环己基乙酸部分相等同.最终的活性测试结果显示,化合物5~8并不具有DGAT1的抑制作用.天然产物aphadilactone C的DGAT抑制机制值得深入研究.     

前胡内酯肟酯衍生物的合成及其抑制乙酰胆碱酯酶活性评价

本文以香豆素类化合物前胡内酯为先导化合物,设计合成了12个前胡内酯肟酯衍生物,所有目标化合物经熔点、~1H NMR和MS进行结构确证。体外抑制乙酰胆碱酯酶(AChE)活性评价结果表明,在1μmol/mL浓度下,目标化合物4a和4k对AChE具有较强的抑制活性,其抑制率分别达到58.05%和66.27%。初步构效关系研究表明,引入吲哚环能提高前胡内酯对AChE的抑制活性。通过分子对接方法考察了化合物4k与AChE结合的模式,发现目标化合物可以和AChE的催化活性中心部位结合。     

卤代查尔酮氨基硫脲席夫碱的合成及生物活性研究

本文合成了一系列卤代查尔酮及其氨基硫脲席夫碱,并考察了所合成化合物的酪氨酸酶抑制活性及抗氧化活性。结果表明,部分化合物具有较好的酪氨酸酶抑制活性,其中3个化合物的抑制活性强于阳性对照曲酸,4-溴代查尔酮氨基硫脲席夫碱(化合物9)表现出最好的抑制活性,其IC50值为2.02μmol/L;部分化合物还具有一定的抗氧化活性。抑制机理研究表明,化合物9属于不可逆抑制剂。优选化合物9进行了分子对接探讨,初步构效关系分析为进一步研究具有酪氨酸酶抑制活性的类似化合物提供了参考。     

甾体不对称合成的研究 Ⅻ.光学活性7α(β),18-双甲基-19-失碳睾丸酮的合成

甾体分子中引入7位甲基往往可以增强或改变其生理活性,例如7α,17α-甲基-19-失碳睾丸酮1具有比母体更强的抗生育活性而无雌激素活性。有关光学活性的7-甲基甾体化合物的合成,至今似只见到以光学活性的化合物2合成了7α(β)-甲基雌酮-3-甲醚的衍生物3a,b。本文报道利用我们新近合成的光学活性合成原4来合成标题化合物。     

含咔唑/苯并咪唑环的2,5-二取代-1,3,4-噻二唑酰胺衍生物的合成及对PTP1B/TCPTP抑制活性的评价

合成了一系列新型含咔唑/苯并咪唑环的2,5-二取代-1,3,4-噻二唑酰胺衍生物.利用IR, ~1HNMR, ~(13)CNMR和元素分析对其进行了结构表征.评价了目标化合物对蛋白酪氨酸磷酸酶1B(PTP1B)和T细胞蛋白酪氨酸磷酸酶(TCPTP)的抑制活性,讨论了结构与活性的关系.实验结果显示,绝大多数化合物对PTP1B的抑制活性超过高度同源的TCPTP的抑制活性,其中2-(9-咔唑基亚甲基)-5-(3-氯苯甲酰氨基)-1,3,4-噻二唑(5c)对PTP1B的抑制活性最高[IC_(50)=(2.43±0.43)mg/mL], 2-(9-咔唑基亚甲基)-5-(4-甲基苯甲酰氨基)-1,3,4-噻二唑(5b)和化合物5c对PTP1B的抑制活性均高于阳性对照药物齐墩果酸.对目标化合物5c进行分子对接研究和密度泛函理论(DFT)计算.分子对接结果表明,5c与PTP1B酶通过形成氢键、疏水和p-p等相互作用形成稳定的复合物.     

5-氟尿嘧啶的三元环类化合物的缀合物的合成及其抗肿瘤活性

基于具有三元环状结构的化合物的广泛生理活性和氟尿嘧啶的抗癌作用机制,本文设计、合成并表征了一系列新型5-氟尿嘧啶（5-FU）的三元碳环缀合物及三元氧杂环缀合物。并对5-FU 的N-1和N-3位的选择性烷基化方法进行了系统研究,发现苄氧甲酰氧甲基保护基具有稳定性高、有效保护性好、制备方便、易于脱除等特点,适宜于在本类反应中应用。测试了所合成的新型5-FU三元环缀合物的体外抗肿瘤活性,化合物7、8、12、13显示了对人食管癌细胞Ec9706不同程度的抑制活性。     

1-苯基-3-甲基-5-芳氧基-1H-吡唑-4-甲醛-O-[(2-氯吡啶-5-基)甲基]肟的合成与生物活性

利用1-苯基-3-甲基-5-芳氧基吡唑4-甲醛肟与2-氯-5-氯甲基吡啶发生缩合反应,合成了14个新型含吡啶环的吡唑肟醚衍生物.通过1H NMR,13C NMR和元素分析对所合成的化合物进行了结构表征.初步生物活性测试结果表明,在试验浓度下部分化合物具有一定的杀菌和植物生长调节活性.     

1-[(乙氧基)甲基]-6-(1-萘甲基)胸腺嘧啶的合成

HEPT是抑制HIV-1逆转录酶的潜在活性化合物。1-[(乙氧基)甲基]-6-(1-萘甲基)胸腺嘧啶是HEPT的类似物,通过增加6位取代基的位阻可提高药效。文献设计并合成了该化合物,并对关键中间体(d)的合成及脱羟基反应作了初步讨论。     

Synthesis and Biological Evaluation of Analogs of Methyl Ursolate 3-O-β-Chacotrioside as H5N1 Viral Entry Inhibitors

The earliest stage of influenza virus infection is the viral entry to the host cell. In our previous work, we discovered the first three small molecule H5N1 viral entry inhibitors 1–3. Here, based on saponin 3, methyl ursolate 3-O-β-chacotrioside, several analogs were synthesized and evaluated to understand the structure-activity relationships of this type of compound on the H5N1 viral entry inhibitory activity. The preliminary studies demonstrated that unlike saponins 1 and 2, it is possible to reduce the 3-O-chacotriosyl residue of compound 3 to a disaccharide without affecting the viral entry activities significantly. The results obtained will render new clues to the understanding of the antiviral profile for these types of compounds.     

Topology-Matching Design of an Influenza-Neutralizing Spiky Nanoparticle-Based Inhibitor with a Dual Mode of Action

In this study, we demonstrate the concept of “topology-matching design” for virus inhibitors. With the current knowledge of influenza A virus (IAV), we designed a nanoparticle-based inhibitor (nano-inhibitor) that has a matched nanotopology to IAV virions and shows heteromultivalent inhibitory effects on hemagglutinin and neuraminidase. The synthesized nano-inhibitor can neutralize the viral particle extracellularly and block its attachment and entry to the host cells. The virus replication was significantly reduced by 6 orders of magnitude in the presence of the reverse designed nano-inhibitors. Even when used 24 hours after the infection, more than 99.999 % inhibition is still achieved, which indicates such a nano-inhibitor might be a potent antiviral for the treatment of influenza infection.     

Effects of structural modification of calcium spirulan, a sulfated polysaccharide from Spirulina platensis, on antiviral activity

Calcium ion binding with the anionic part of a molecule was replaced with various metal cations and their inhibitory effects on the replication of herpes simplex virus type 1 were evaluated. Replacement of calcium ion with sodium and potassium ions maintained the antiviral activity while divalent and trivalent metal cations reduced the activity. Depolymerization of sodium spirulan with hydrogen peroxide decreased in antiviral activity as its molecular weight decreased.     

Topology‐Matching Design of an Influenza‐Neutralizing Spiky Nanoparticle‐Based Inhibitor with a Dual Mode of Action

In this study, we demonstrate the concept of “topology‐matching design” for virus inhibitors. With the current knowledge of influenza A virus (IAV), we designed a nanoparticle‐based inhibitor (nano‐inhibitor) that has a matched nanotopology to IAV virions and shows heteromultivalent inhibitory effects on hemagglutinin and neuraminidase. The synthesized nano‐inhibitor can neutralize the viral particle extracellularly and block its attachment and entry to the host cells. The virus replication was significantly reduced by 6 orders of magnitude in the presence of the reverse designed nano‐inhibitors. Even when used 24 hours after the infection, more than 99.999 % inhibition is still achieved, which indicates such a nano‐inhibitor might be a potent antiviral for the treatment of influenza infection.     

Inhibition of influenza virus sialidase and anti-influenza virus activity by plant flavonoids

Flavonoids (103 species) were tested for inhibitory activity against influenza virus sialidase using sodium p-nitrophenyl-N-acetyl-alpha-D-neuraminate as substrate. 5,7,4'-Trihydroxy-8-methoxyflavone from the root of Scutellaria baicalensis showed the most potent activity (IC50, 55 microM), and this flavone appeared to be a non-competitive inhibitor of the enzyme. Whereas, negligible or weak inhibitory activities were observed for mouse liver sialidase, beta-galactosidase and alpha-mannosidase as tested. This flavone also inhibited the infection by influenza virus A/PR/8/34 of Madin-Darby canine kidney cells, and replication of the virus in the allantoic sack of embryonated egg. These results suggest that flavone, which has potent influenza virus sialidase inhibitory activity, may have anti-influenza virus activity.     

一枝蒿酮酸苄酯类衍生物的合成、体外抗流感病毒和单纯I, II型疱疹病毒活性研究

为了提高一枝蒿酮酸的生物活性, 以一枝蒿酮酸和取代苄醇为原料. 在偶联剂DCC/DMAP的作用下, 合成了10种一枝蒿酮酸苄酯衍生物2a～2j, 所合成的化合物均经过IR, 1H NMR, ESI-MS等分析方法进行了表征, 并对所合成的化合物2a～2j进行了初步的体外抗A, B型流感病毒和单纯I, II型疱疹病毒活性研究, 结果表明: 大部分化合物对A, B型流感病毒具有较强的抑制活性, 其中化合物2e抑制A3, B型流感病毒的IC50值分别为5.5, 5.5 μmol/L, 化合物2i抑制A型流感病毒IC50值为: 7.8 μmol/L, 化合物2e和2i可作为抗流感病毒的先导化合物; 大部分化合物在0.1 μg/mL浓度下对I, II型疱疹病毒具有显著的抑制活性．     

Synthesis and anti-influenza evaluation of polyvalent sialidase inhibitors bearing 4-guanidino-Neu5Ac2en derivatives

Polyvalent sialidase inhibitors bearing 4-guanidino-Neu5Ac2en derivatives on a poly-L-glutamine backbone are described. Aiming for a longer retention time of 4-guanidino-Neu5Ac2en (zanamivir) in bronchi and lungs, we focused on supermolecules bearing 4-guanidino-Neu5Ac2en derivatives bound at their C-7 position through noncleavable alkyl ether linkages. We first found that alkylation of the 7-hydroxyl group of sialic acid derivative 8 proceeded smoothly, and produced 7-O-alkyl-4-guanidino-Neu5Ac2en derivatives 13, which exhibited equipotent inhibitory activity against not only influenza A virus sialidase but also influenza A virus in the cell culture. Next, we synthesized poly-L-glutamine bearing 7-O-alkyl-4-guanidino-Neu5Ac2en derivatives linked by amide bonds, 26, which showed enhanced antiviral activity against influenza A virus and more potent efficacy in vivo relative to a monomeric sialidase inhibitor.     

Screening of inhibitors for influenza A virus using high-performance affinity chromatography and combinatorial peptide libraries

The affinity inhibitor of fusion peptide of influenza A virus has been studied using a combination of high-performance affinity chromatography (HPAC) and combinatorial peptide libraries. Fusion peptide (FP) (1-11) of influenza A virus was used as the affinity ligand and immobilized onto the poly(glycidyl methacrylate) (PGMA) beads. Positional scanning peptide libraries based on antisense peptide strategy and extended peptide libraries were designed and synthesized. The screening was carried out at acidic pH (5.5) in order to imitate the environment of virus fusion. A hendecapeptide FHRKKGRGKHK was identified to have a strong affinity to the FP (1-11). The dissociation constant of the complex of the hendecapeptide and the FP (1-11) is 3.10 x 10(-6) mol l(-1) in a physiological buffer condition. The polypeptide has a fairly inhibitory effect on three different strains of influenza A virus H1N1 subtype.     

Design,Synthesis, and Evaluation of 3‐((4‐(t‐Butyl)‐2‐(2‐benzylidenehydrazinyl)thiazol‐5‐yl)methyl)quinolin‐2(1H)‐ones as Neuraminidase Inhibitors

A series of novel 3‐((4‐(t‐butyl)‐2‐(2‐benzylidenehydrazinyl)thiazol‐5‐yl)methyl)quinolin‐2(1H)‐ones ( 7a – 7z ) were designed, synthesized and evaluated for their ability of inhibiting neuraminidase (NA) of in?uenza H1N1 virus. Some compounds displayed moderate influenza NA inhibitory activity. Compound 7l with the scaffold of 2‐(2‐(2‐methoxybenzylidene)hydrazinyl)thiazole was the best one, exhibiting moderate NA inhibitory activity with IC₅₀ of 44.66 µmol/L. Structure‐activity relationship showed that compounds with methoxy or hydroxy groups at the ortho position, fluorine and nitro groups at the meta position and chlorine and bromine groups at the para position of phenyl ring were more active. Docking study indicated that compound 7l has important interactions with some key residues (including Asp151, Glu119, Arg292, Tyr406, and Asn347) and binds to 430‐cavity adjacent to NA active site.