新型手性单胺氧化酶选择性抑制剂的设计、合成与生物活性研究

本文以取代的手性苯乙胺为原料,设计合成了4种新型叔胺盐酸盐化合物.通过NMR,IR和MS等表征方法对所合成目标产物的结构进行确定.在生物活性方面,首先通过CCK-8法测定4种化合物对正常细胞增殖的影响,实验结果表明:部分化合物对小鼠成纤维细胞L929表现出一定的细胞毒性.酶的选择性实验说明R构型影响小分子对单胺氧化酶(MAO)的选择性抑制活性,另一方面取代基的给电子能力也会对酶的活性有影响.     

Design,synthesis, and biological evaluation of novel histone deacetylase 6 selective inhibitors

Histone deacetylase 6 (HDAC6) is distinguished from other HDACs by its ability to deacetylate α-tubulin and HSP90, and was reported to be related to a variety of human diseases, such as cancers, neurodegenerative diseases, and immunological disorders. The discovery of novel HDAC6 selective inhibitors is important directions of this research field. In this paper, on the basis of a Bcl-2/HDAC6 dual target inhibitor 7g reported by us previously, a novel type of HDAC6 inhibitors was obtained by removing the binding capability to Bcl-2 protein and the subsequent systematical optimization. Among them, compounds Ⅵ-9, Ⅵ-10 and Ⅵ-11 (IC₅₀ = 3.2 ～ 3.9 nM, SI = 20.6 ～ 38.7) showed the best inhibitory activities against and excellent selectivity to HDAC6. These compounds displayed growth inhibitory selectivity to human multiple myeloma cell line over normal cell line, which indicated potential lower toxicity to normal cells and tissues.     

Design,synthesis and biological evaluation of LpxC inhibitors with novel hydrophilic terminus

In order to develop novel LpxC inhibitors with good activities and metabolic stability, two series of compounds with hydrophilic terminus have been synthesized and their in vitro antibacterial activities against Escherichial coli and Pseudomonas aeruginosa were evaluated. Especially, compounds 22b and c exhibited comparable antibacterial activities to CHIR-090 and better metabolic stability than CHIR-090 and LPC-011 in liver microsomes (rat andmouse), which indicated the terminal methylsulfone may be a preferred structure in the design of LpxC inhibitors and worthy of further investigations.     

Design,synthesis and biological evaluation of indole derivatives as novel inhibitors targeting B-Raf kinase

A series of novel indole derivatives were designed and synthesized and their inhibitory activity against B-Raf and HepG2 cell were also described. Among them, compounds 7a and 7b exhibited excellent potency, which showed the potential for further research as lead compounds.     

Microwave-assisted synthesis,characterization and biological activity of novel pyrazole derivatives

A series of 1-(4-substitutedphenyl)-3-phenyl-1H-pyrazole-4-carbaldehydes 4a–l have been synthesized and tested for their biological activities. Formation of the pyrazole derivatives was achieved by treating with Vilsmeier-Haack reagent. The newly synthesized compounds were evaluated for their anti-inflammatory and analgesic activities compared to Diclofenac sodium as standard drug. Compounds 4g, 4i and 4k exhibited the maximum anti-inflammatory and analgesic activities. The detailed synthesis, spectroscopic and toxicity data are reported.     

Design, synthesis, and biological evaluation of estrone-derived hedgehog signaling inhibitors

The design, synthesis, and biological evaluation of new analogs of the naturally occurring compound cyclopamine, a hedgehog signaling inhibitor, are described. Structure-activity relationship studies lead to an evolving model for the pharmacophore of this medically promising compound class of anti-cancer chemotherapeutic agents.     

Design,synthesis, biological evaluation and molecular dynamics of LAR inhibitors

In this study, firstly, the pharmacophore model was established based on LAR inhibitors. ZINC database and drug-like database were screened by Hypo-1-LAR model, and the embryonic compound ZINC71414996 was obtained. Based on this compound, we designed 9 compounds. Secondly, the synthetic route of the compound was determined by consulting Reaxys and Scifinder databases, and 9 compounds (1a-1i) were synthesized by nucleophilic substitution, Suzuki reaction and so on. Meanwhile, their structures were confirmed by ¹H NMR and ¹³C NMR. Thirdly, the Enzymatic assays was carried out, the biological evaluation of compounds 1a-1i led to the identification of a novel PTP-LAR inhibitor 1c, which displayed an IC₅₀ value of 4.8 μM. At last, molecular dynamics simulation showed that compounds could interact strongly with the key amino acids LYS1350, LYS1352, ARG1354, TYR1355, LYS1433, ASP1435, TRP1488, ASP1490, VAL1493, SER1523, ARG1528, ARG1561, GLN1570, LYS1681, thereby inhibiting the protein activity. This study constructed the pharmacophore model of LAR protein, designed small-molecule inhibitors, conducted compound synthesis and enzyme activity screening, so as to provide a basis for searching for drug-capable lead compounds.     

Design, synthesis and biological evaluation of novel glucokinase activators

A new series of benzamide derivatives as glucokinase activators(GKAs) were designed and synthesized,and their activation for glucokinase were evaluated by the preliminary glucokinase activity assay.The structure-activity relationship(SAR) is discussed. The result shows that compound 12d and 12h have potent activity reference drug RO-28-1675.     

Design, synthesis, and biological evaluation of novel fluorinated ethanolamines

The preparation of novel fluorinated allylamines and their use as key fragments for the stereoselective synthesis of hydroxyethyl secondary amine (HEA)-type peptidomimetics is described. Our strategy employs chiral sulfinyl imines as synthesis intermediates, by treatment of hemiaminal precursors with two equivalents of vinylmagnesium bromide. The subsequent oxidation of the allylic amines to the corresponding epoxides was achieved by treatment with methyl(trifluoromethyl)dioxirane. Finally, epoxide ring opening with a range of nitrogen nucleophiles provided a library of HEA-derived peptidomimetics with a phenyldifluoromethylene moiety. The biological evaluation of these derivatives revealed compounds with remarkable BACE1 inhibitory activity. Docking studies revealed the influence of the fluorine atoms in the binding mode of the synthesized ligands. Furthermore, the biological evaluation of our final products and synthesis intermediates led to the discovery of compounds with antimicrobial activity against Mycobacterium and Nocardia species.     

Design,synthesis and biological evaluation of novel isoniazid hybrids

We herein report the design and synthesis of novel isoniazid derivatives. Isoniazid derived Schiff bases (3 a-d) were subjected to cyclization with acetic anhydride and sulphuric acid to yield the 5′-substituted-3′-acetyl-5-(pyridin-4-yl)-3H-spiro[indole-3, 2-[1′, 3′, 4’]oxadiazol]-2′-yl acetates (4 a-d) and 8′-substituted-3’-(pyridin-4-yl)[1′,3′,4’]oxadiazino [6,5-b]indoles (5 a-d) respectively. The advantages of spectral methods were used for the confirmation of the structure of all the newly synthesized hybrid molecules. Further, these compounds were evaluated for their antibacterial activity against B. Subtilis, S. aureus, E. coli & S. typhi, antifungal activity against C. albicans, C. oxysporum, A. Flavus & A. niger, and antimycobacterial activity against M. tuberculosis. Amongst, the compounds 4b, 4c and 5c showed excellent inhibitory activity against tested microorganisms. Also, the DNA cleavage activity of selected compounds was carried out by the AGE method.     

Design, synthesis and characterization of a novel pH-sensitive hydrogel

A novel degradable pH-sensitive hydrogel with pendent carboxyl groups was designed and synthesized from ethylenediaminetetraacetic dianhydride （EDTAh） and butanediamine （BDA） with dicyclohexylcarbodiimide （DCC） as a condensating agent and BDA as a crosslinking agent. The obtained polymers were characterized by ^13C NMR, ^1H NMR and FTIR. The swelling experiments of the hydrogel in pH 3, 7, and 12 media indicated much higher swelling ratio in pH 12 media than in pH 3 and pH 7 media, exhibiting sound pH sensitivity. The pH sensitivity of this type of hydrogel may be regulated through controlling the type and the dose of the crosslinking agent.     

Design and novel synthesis of aryl-heteroaryl-imidazole MAP kinase inhibitors

Inhibitors of the MAP kinase p38, potentially useful for the treatment of rheumatoid arthritis and inflammatory diseases, were found to exhibit antifungal activity. We have developed a new diversity-oriented strategy leading to concise and efficient syntheses of known and new members of this compound class. The strategy is based on carboncarbon cross-coupling reactions using N-protected 4,5-diiodo-imidazoles as the starting templates.     

Design, synthesis and bioactivity of novel ALS inhibitors (V)

By means of the X-ray diffraction method, quantum pharmacology analysis and quantitative structure-activity relationships (QSAR) analysis, the structure-activity relationships of the herbicidal sulfonylureas and fused heterocyclic sulfonamides were systematically studied. The results showed that the structure-activity relationships of these two kinds of herbicides were identical and that the heterocyclic ring and sulfonyl moiety in the molecules were their pharmacophores which likely bind in the same receptor sites of acetolactate synthase (ALS). According to these results, the initial model of these two kinds of herbicides binding with the receptor was put forward. Project supported by the National Natural Science Foundation of China (Grant No.29472056).     

Design, syntheses and biological activity of novel ALS inhibitors (IX)

Quantitative structure-activity relationships for herbicidal activity against rape of sulfonylurea and triazolopyrimidine-2-sulfonamide derivatives were examined three-dimensionally using comparative molecular field analysis (CoMFA). The CoMFA results show that the slopes in steric and electrostatic fields around the molecule were significant for both series in governing the potency variations in herbicidal activity. Based upon the successful superposition between the two series, the herbicidal activity was analyzable with a single equation for the combined set of compounds, which suggested that the two different series of compounds have a common region of the receptor site. Project supported by the National Natural Science Foundation of China (Grant No. 29832050), the Special Key Fund of Natural Science of Tianjin (Grant No. 983801011) and the Doctoral Fund of the Education Ministry of China.     

Design,synthesis, molecular docking,and biological studies of novel phytoestrogen-tanaproget hybrids

A diverse range of novel and highly functionalized flavonoid-based tanaproget hybrids were synthesized and evaluated in vitro for their antimicrobial and antiproliferative activities. Novel products were synthesized in good yields (81–95%) under Pd-catalyzed reaction from bromo flavones and tanaproget boronic acids within 18–20 min at 60 °C. Bioassay results exhibited excellent activities against both hormone-dependent and hormone-independent human breast cancer cells (MCF-7, MDA-MB-231, DU-145, PC-3, and HeLa). Among them, compounds 4e, 9a, 9c, 9e, 9 g, 9 h, 9 m, and 9n displayed excellent activity. Compounds 4d, 4o, and 9o were found equally potent against C. albicans compared to fluconazole. Compound 5c showed better antibacterial activity against S. aureus. Compounds 5a, 9i, 9o, and 10c have shown admirable antibacterial activity against E. coli.     

Identification of novel S-adenosyl-L-homocysteine hydrolase inhibitors through homology-model-based virtual screening, synthesis, and biological evaluation

The present study describes a successful application of computational approaches to identify novel Leishmania donovani (Ld) AdoHcyase inhibitors utilizing the differences for Ld AdoHcyase NAD(+) binding between human and Ld parasite. The development and validation of the three-dimensional (3D) structures of Ld AdoHcyase using the L. major AdoHcyase as template has been carried out. At the same time, cloning of the Ld AdoHcyase gene from clinical strains, its overexpression and purification have been performed. Further, the model was used in combined docking and molecular dynamics studies to validate the binding site of NAD in Ld. The hierarchical structure based virtual screening followed by the synthesis of five active hits and enzyme inhibition assay has resulted in the identification of novel Ld AdoHcyase inhibitors. The most potent inhibitor, compound 5, may serve as a "lead" for developing more potent Ld AdoHcy hydrolase inhibitors as potential antileishmanial agents.     

Design,synthesis, and characterization of some new benzimidazole derivatives and biological evaluation

A new series of benzimidazole derivatives ( 1-15 ) containing 1,2,4-triazole, 1,3,4-thiadiazole, 1,3,4-oxadiazole, and thiazolidinon rings have been synthesized. All new synthesized benzimidazole compounds were confirmed by ¹H NMR, ¹³C NMR spectra, and LC-MS, and they were examined for their antioxidant and antimicrobial activities. Compounds 7 and 1 showed the highest and the lowest antioxidant activities, respectively. The lowest minimum inhibition concentration value found in compound 5 against Enterobacter aerogenes.     

Design, synthesis, and biological evaluation of beta-ketosulfonamide adenylation inhibitors as potential antitubercular agents

[reaction: see text] The antitubercular nucleoside antibiotics 1 and 2 were recently described that inhibit the adenylate-forming enzyme MbtA and disrupt biosynthesis of the virulence-conferring siderophore known as mycobactin in Mycobacterium tuberculosis. Herein, we report efforts to refine this inhibitor scaffold by replacing the labile acylsulfamate linkage (highlighted) with the more chemically robust beta-ketosulfonamide linkage of 3 and 4.     

Design, synthesis and biological activity of a targeted library of potential tryptase inhibitors

We have designed, synthesized, and tested two small collections of potential tryptase inhibitors. The first library consists of diversely N-substituted 3-aminopiperidin-2-ones 6, and the second (compounds 7) was prepared by dimerising compounds 6 through the 3-amino function using diverse carbon chains. We have established efficient routes for obtaining 6 both in solution and on solid supports. We have also compared the dimerisation on-resin and in solution. Four of the compounds showed a high degree of tryptase inhibition at 1 microM, but none surpassed the tryptase inhibition activity of BABIM.     

Design,synthesis and biological evaluation of novel phthalazinone acridine derivatives as dual PARP and Topo inhibitors for potential anticancer agents

In this study,we designed and synthesized a series of phthalazinone acridine derivatives as dual PARP and Topo inhibitors.MTT assays indicated that most of the compounds significantly inhibited multiple cancer cells proliferation.In addition,all the compounds displayed Topo Ⅱ inhibition activity at 10 mol/L,and also possessed good PARP-1 inhibitory activities.Subsequent mechanistic studies showed that compound 9 a induced remarkable apoptosis and caused prominent S cell cycle arrest in HCT116 cells.Our study suggested that 9 a inhibiting Topo and PARP concurrently can be a potential lead compound for cancer therapy.