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1.
A series of hydrophobic p-aminosalicylic acid derivatives containing a lipophilic side chain at C-2 and an amino or guanidine at C-5 were synthesized and evaluated for their ability to inhibit neuraminidase (NA) of influenza A virus (H3N2). All compounds were synthesized in good yields starting from commercially available p-aminosalicylic acid (PAS) using a suitable synthetic strategy. These compounds showed potent inhibitory activity against influenza A NA. Within this series, six compounds, 11, 12, 13e, 16e, 17c, and 18e, have the good potency (IC(50)=0.032-0.049 microM), which are compared to Oseltamivir (IC(50)=0.021 microM) and could be used as lead compounds in the future. 相似文献
2.
Design, synthesis, and activity of caffeoyl pyrrolidine derivatives as potential gelatinase inhibitors 总被引:3,自引:0,他引:3
The synthesis and biological evaluation of caffonyl pyrrolidine derivatives as MMPs inhibitors are reported in this paper. Inhibiting activities of synthesized compounds on gelatinase (MMP-2 and -9) were tested by using succinylated gelatin as substrate. Structure-activity relationship results from these tested compounds demonstrated that longer and more flexible side chain linked to the pyrrolidine ring at C(4) produced higher activity at gelatinase. Furthermore, aromatic heterocycle and sulfamide in the same position could enhance the activities. Compounds with free phenol hydroxyl group showed higher activity compared to methylated derivatives (or counterparts), which confirms the importance of phenol hydroxyl functionality in the interaction with gelatinase. The anti-metastasis model of mice bearing H(22) tumor cell was used to evaluate their in vivo inhibiting activities. All tested compounds were orally administered at a dose of 50 or 100mg/kg, 6days/week for two weeks. The test results demonstrated that most of these inhibitors showed significant anti-cancer activities (inhibitory rate>35%) and were devoid of toxic effects. Compound 29 showed the highest inhibitory rate at 69.25%, indicating that it might be a promising lead compound. 相似文献
3.
Liu Y Zhang L Gong J Fang H Liu A Du G Xu W 《Journal of enzyme inhibition and medicinal chemistry》2011,26(4):506-513
A series of novel influenza neuraminidase (NA) inhibitors based on thiazole core were synthesized and evaluated for their ability to inhibit NA of influenza A virus (H(3)N(2)). All compounds were synthesized in good yields starting from commercially available 2-amino-4-thiazole-acetic ester using a suitable synthetic strategy. These compounds showed moderate inhibitory activity against influenza A NA. The most potent compound of this series is compound 4d (IC(50)?=?3.43 μM), which is about 20-fold less potent than oseltamivir, and could be used to design novel influenza NA inhibitors that exhibit increased activity based on thiazole ring. 相似文献
4.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(4):506-513
A series of novel influenza neuraminidase (NA) inhibitors based on thiazole core were synthesized and evaluated for their ability to inhibit NA of influenza A virus (H3N2). All compounds were synthesized in good yields starting from commercially available 2-amino-4-thiazole-acetic ester using a suitable synthetic strategy. These compounds showed moderate inhibitory activity against influenza A NA. The most potent compound of this series is compound 4d (IC50?=?3.43 μM), which is about 20-fold less potent than oseltamivir, and could be used to design novel influenza NA inhibitors that exhibit increased activity based on thiazole ring. 相似文献
5.
Liu Y Jing F Xu Y Xie Y Shi F Fang H Li M Xu W 《Bioorganic & medicinal chemistry》2011,19(7):2342-2348
A series of thiazolidine-4-carboxylic acid derivatives were synthesized and evaluated for their ability to inhibit neuraminidase (NA) of influenza A virus. All the compounds were synthesized in good yields starting from commercially available l-cysteine hydrochloride using a suitable synthetic strategy. These compounds showed moderate inhibitory activity against influenza A neuraminidase. The most potent compound of this series is compound 4f (IC(50)=0.14 μM), which is about sevenfold less potent than oseltamivir and could be used to design novel influenza NA inhibitors that exhibit increased activity based on thiazolidine ring. 相似文献
6.
A series of novel sulfonyl pyrrolidine derivatives were designed, synthesized and assayed for their inhibitory activities on matrix metalloproteinase 2 (MMP-2) and aminopeptidase N (AP-N). The results showed that these pyrrolidine derivatives exhibited highly selective inhibition against MMP-2 as compared with AP-N. Compounds 6a-d were more potent MMP-2 inhibitors than the positive control LY52. The structure-activity relationships were also briefly discussed. 相似文献
7.
Zhen Wang Li Ping Cheng Xing Hua Zhang Wan Pang Liang Li Jin Long Zhao 《Bioorganic & medicinal chemistry letters》2017,27(24):5429-5435
Neuraminidase (NA) is one of the particular potential targets for novel antiviral therapy. In this work, a series of neuraminidase inhibitors with the cyclohexene scaffold were studied based upon the combination of 3D-QSAR, molecular docking, and molecular dynamics techniques. The results indicate that the built 3D-QSAR models yield reliable statistical information: the correlation coefficient (r2) and cross-validation coefficient (q2) of CoMFA (comparative molecular field analysis) are 0.992 and 0.819; the r2 and q2 of CoMSIA (comparative molecular similarity analysis) are 0.992 and 0.863, respectively. Molecular docking and MD simulations were conducted to confirm the detailed binding mode of enzyme-inhibitor system. The new NA inhibitors had been designed, synthesized, and their inhibitory activities against group-1 neuraminidase were determined. One agent displayed excellent neuraminidase inhibition, with IC50 value of 39.6?μM against NA, while IC50 value for oseltamivir is 61.1?μM. This compound may be further investigated for the treatment of infection by the new type influenza virus. 相似文献
8.
Li Ping Cheng Tian Chi Wang Rao Yu Meng Li Jin Wen Huang 《Bioorganic & medicinal chemistry letters》2018,28(23-24):3622-3629
Neuraminidase (NA) is an important antiviral drug target. Zanamivir is one of the most potent NA inhibitors. In this paper, a series of zanamivir derivatives as potential NA inhibitors were studied by combination of molecular modeling techniques including 3D-QSAR, molecular docking, and molecular dynamics (MD) simulation. The results show that the best CoMFA (comparative molecular field analysis) model has q2?=?0.728 and r2?=?0.988, and the best CoMSIA (comparative molecular similarity indices analysis) model has q2?=?0.750 and r2?=?0.981, respectively. The built 3D-QSAR models show significant statistical quality and excellent predictive ability. Seven new NA inhibitors were designed and predicted. 20?ns of MD simulations were carried out and their binding free energies were calculated. Two designed compounds were selected to be synthesized and biologically evaluated by NA inhibition and virus inhibition assays. One compound (IC50?=?0.670?µM, SI?>?149) exhibits excellent antiviral activity against A/WSN/33 H1N1, which is superior to the reference drug zanamivir (IC50?=?0.873?µM, SI?>?115). The theoretical and experimental results may provide reference for development of new anti-influenza drugs. 相似文献
9.
A series of new cinnamoyl pyrrolidine derivatives have been synthesized based on the l-hydroxyproline scaffold and inhibiting activities on gelatinase (MMP-2 and -9) and APN were tested. Structure–activity relationship studies showed that the side chain with aromatic ring at C4in pyrrolidine ring showed better inhibitory activities on gelatinase than aliphatic side chain. Most compounds exhibited poor activities on APN compared with MMP-2. Within this series, three compounds, A8, B9 and C10, have the good potency (IC50 = 5.2–9.7 nM) and could be used as lead compounds in the future. 相似文献
10.
Two series of thiazole derivatives containing amide skeleton were synthesized and developed as potent Escherichia coli β-ketoacyl-(acyl-carrier-protein) synthase III (ecKAS III) inhibitors. All the 24 new synthesized compounds were assayed for antibacterial activity against the respective Gram-negative and Gram-positive bacterial strains, including E. coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus. In which, 10 compounds with broad-spectrum antibacterial activities were further tested for their ecKAS III inhibitory activity. Last, we have successfully found that compound 4e showed both the promising broad antibacterial activity with MIC of 1.56–6.25 μg/mL against the representative bacterial stains, and also processed the most potent ecKAS III inhibitory activity with IC50 of 5.3 μM. In addition, docking simulation also carried out in this study to give a potent prediction binding mode between the small molecule and ecKAS III (PDB code: 1hnj) protein. 相似文献
11.
Boyu Wang Kuanglei Wang Peipei Meng Yaping Hu Fei Yang Kemin Liu Zaiqiang Lei Binfeng Chen Yongshou Tian 《Bioorganic & medicinal chemistry letters》2018,28(21):3477-3482
In this study, a series of carboxyl-modified oseltamivir analogs with improved lipophilicity were designed and synthesized, and their inhibitory activities against neuraminidase from influenza A virus H5N1 subtype were evaluated. The results demonstrated that compound 5m exhibited potent inhibitory activity (IC50?=?1.30?±?0.23?μM), and it targeted the recently discovered 430-cavity. Compound 5m (Log D?=??0.12) is more lipophilic than oseltamivir carboxylate (Log D?=??1.69) at pH 7.4, which is potentially propitious to improved membrane permeability and oral drug absorption. Meanwhile, 5m showed high stability in human liver microsomes. The findings of this study can be valuable in identifying neuraminidase inhibitors with optimal lipophilicity and in the exploration of 430-cavity. 相似文献
12.
T Su Y Wu B Doughan Z J Jia J Woolfrey B Huang P Wong G Park U Sinha R M Scarborough B Y Zhu 《Bioorganic & medicinal chemistry letters》2001,11(22):2947-2950
A series of potent and selective factor Xa inhibitors was synthesized using various readily available amino acids as central templates. The most potent compound displays IC(50) of 3 nM. 相似文献
13.
Yoshikawa K Yoshino T Yokomizo Y Uoto K Naito H Kawakami K Mochizuki A Nagata T Suzuki M Kanno H Takemura M Ohta T 《Bioorganic & medicinal chemistry letters》2011,21(7):2133-2140
We previously reported on a series of cyclohexanediamine derivatives as highly potent factor Xa inhibitors. Herein, we describe the modification of the spacer moiety to discover an alternative scaffold. Ethylenediamine derivatives possessing a substituent at the C1 position in S configuration and phenylenediamine derivatives possessing a substituent at the C5 position demonstrated moderate to strong anti-fXa activity. Further SAR studies led to the identification of compound 30h which showed both good in vitro activity (fXa IC50 = 2.2 nM, PTCT2 = 3.9 μM) and in vivo antithrombotic efficacy. 相似文献
14.
Lu A Luo H Shi M Wu G Yuan Y Liu J Tang F 《Bioorganic & medicinal chemistry letters》2011,21(16):4924-4927
A series of benzamide derivatives including two scaffolds were designed and synthesized as potential histone deacetylase inhibitors. Most of synthesized compounds showed moderate enzymatic potency at the same order of magnitude, and compound 12b possessed better potency to the positive control (3.8 μM vs 13.0 μM). It also showed a 50-fold increase in vitro anticancer activity against DU-145 cell-lines. Molecular docking studies were carried out and used to explain the structure-activity relationships observed in vitro. Then we found that the cavity surrounded by ASP104, HIS33, PRO34 and PHE155 may be crucial for the inhibitors’ activity. The docking results provide some useful information for future design of more potent inhibitors. 相似文献
15.
Seyed Mohammad Seyedi Zeinab Jafari Neda Attaran Hamid Sadeghian Mohammad Reza Saberi Mohammad Mahdi Riazi 《Bioorganic & medicinal chemistry》2009,17(4):1614-1622
A group of 4-allyloxyaniline amides 5a–o were designed, synthesized and evaluated as potential inhibitors of soybean 15-lipoxygenase (SLO) on the basis of eugenol and esteragol structures. Compound 5e showed the best IC50 in SLO inhibition (IC50 = 0.67 ± 0.06 μM). All compounds were docked in SLO active site retrieved from RCSB Protein Data Bank (PDB entry: 1IK3) and showed that allyloxy group of compounds is oriented towards the Fe3+-OH moiety in the active site of enzyme and fixed by hydrogen bonding with two conserved His513 and Gln716. It is resulted that molecular volume of the amide moiety would be a major factor in inhibitory potency variation of the synthetic amides, where the hydrogen bonding of the amide group could also involve in the activity of the inhibitors. 相似文献
16.
A Vontzalidou G Zoidis E Chaita M Makropoulou N Aligiannis G Lambrinidis E Mikros AL Skaltsounis 《Bioorganic & medicinal chemistry letters》2012,22(17):5523-5526
The synthesis, molecular modeling and biological evaluation of substituted deoxybenzoins and optimized dihydrostilbenes are reported. Preliminary structure-activity relationship data were elucidated and lead compounds suitable for further optimization were discovered. Dihydrostilbene 7 is a particularly potent inhibitor (IC(50)=8.44μM, more potent than kojic acid). 相似文献
17.
Krueger AC Xu Y Kati WM Kempf DJ Maring CJ McDaniel KF Molla A Montgomery D Kohlbrenner WE 《Bioorganic & medicinal chemistry letters》2008,18(5):1692-1695
The synthesis of several pyrrolidine inhibitor analogs is described that possess nanomolar in vitro potencies against the neuraminidase enzymes expressed by the B/Memphis/3/89 and A/N1/PR/8/34 influenza strains. 相似文献
18.
Guo T Gu H Hobbs DW Rokosz LL Stauffer TM Jacob B Clader JW 《Bioorganic & medicinal chemistry letters》2007,17(11):3010-3013
Gamma-secretase is a key enzyme involved in the production of beta-amyloid peptides which are believed to play a critical role in the onset and progression of Alzheimer's disease (AD). As such, inhibition of gamma-secretase has been an attractive approach to AD therapy. In this paper, the design, synthesis, and evaluation of tetrahydroquinoline and pyrrolidine sulfonamide carbamates as gamma-secretase inhibitors are described. 相似文献
19.
Masakazu Atobe Naomi Maekawara Masashi Kawanishi Hiroko Suzuki Eiichi Tanaka Shiro Miyoshi 《Bioorganic & medicinal chemistry letters》2013,23(7):2111-2116
A series of 1,1-dioxothieno[2,3-d]isothiazole (thienosultam) derivatives were designed and synthesized as novel ADAMTS-5 inhibitors for an investigation into a side chain of thienosultam for the S1′ pocket. The resulting compounds (19 and 24) show high ADAMTS-5 inhibition and other MMP selectivity, and these compounds show good oral bioavailability. 相似文献
20.
Zhou G Ting PC Aslanian R Cao J Kim DW Kuang R Lee JF Schwerdt J Wu H Herr RJ Zych AJ Yang J Lam S Wainhaus S Black TA McNicholas PM Xu Y Walker SS 《Bioorganic & medicinal chemistry letters》2011,21(10):2890-2893
A novel series of pyridazinone analogs has been developed as potent β-1,3-glucan synthase inhibitors through structure-activity relationship study of the lead 5-[4-(benzylsulfonyl)piperazin-1-yl]-4-morpholino-2-phenyl-pyridazin-3(2H)-one (1). The effect of changes to the core structure is described in detail. Optimization of the sulfonamide moiety led to the identification of important compounds with much improved systematic exposure while retaining good antifungal activity against the fungal strains Candida glabrata and Candida albicans. 相似文献