共查询到20条相似文献,搜索用时 31 毫秒
1.
Elizaveta M. Igumnova Ekaterina Mishchenko Tor Haug Hans-Matti Blencke Johanna U. Ericson Sollid Elizabeth G. Aarag Fredheim Silje Lauksund Klara Stensvåg Morten B. Strøm 《Bioorganic & medicinal chemistry》2018,26(17):4930-4941
There is an urgent need for novel antimicrobial agents to address the threat of bacterial resistance to modern society. We have used a structural motif found in antimicrobial marine hit compounds as a basis for synthesizing a library of antimicrobial sulfonamidobenzamide lead compounds. Potent in vitro antimicrobial activity against clinically relevant bacterial strains was demonstrated for two compounds, G6 and J18, with minimal inhibitory concentrations (MIC) of 4–16?μg/ml against clinical methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE). The two compounds G6 and J18, together with several other compounds of this library, also caused ≥90% eradication of pre-established biofilm of methicillin-resistant S. epidermidis (MRSE) at 40?μg/ml. Using a luciferase assay, the mechanism of action of G6 was shown to resemble the biocide chlorhexidine by targeting the bacterial cell membrane. 相似文献
2.
Viviana Teresa Orlandi Morten Rybtke Enrico Caruso Stefano Banfi Tim Tolker-Nielsen Paola Barbieri 《Biofouling》2014,30(8):883-891
Photodynamic therapy (PDT) combines the use of organic dyes (photosensitizers, PSs) and visible light in order to elicit a photo-oxidative stress which causes bacterial death. GD11, a recently synthesized PS belonging to the boron-dipyrromethene (BODIPY) class, was demonstrated to be efficient against planktonic cultures of Pseudomonas aeruginosa, causing a 7 log unit reduction of viable cells when administered at 2.5?μM. The effectiveness of GD11 against P. aeruginosa biofilms grown in flow-cells and microtiter trays was also demonstrated. Confocal laser scanning microscopy of flow-cell-grown biofilms suggests that the treatment has a biocidal effect against bacterial biofilm cells. 相似文献
3.
Jorge E. Gómez-Galeno Cecilia Hurtado Jiongjia Cheng Ceren Yardimci Mark Mercola John R. Cashman 《Bioorganic & medicinal chemistry letters》2018,28(20):3363-3367
The Notch signaling pathway is involved in cell proliferation and differentiation, and has been recognized as an active pathway in regenerating tissue and cancerous cells. Notch signaling inhibition is considered a viable approach to the treatment of a variety of conditions including colorectal cancer, pancreatic cancer, breast cancer and metastatic melanoma. The discovery that the b-annulated dihydropyridine FLI-06 (1) is an inhibitor of the Notch pathway with an EC50?≈?2.5?μM prompted us to screen a library of related analogs. After structure activity studies were conducted, racemic compound 7 was identified with an EC50?=?0.36?μM. Synthesis of individual enantiomers provided (+)-7 enantiomer with an EC50?=?0.13?μM, or about 20-fold the potency of 1. 相似文献
4.
Prasanthi Malapati Vagolu Siva Krishna Radhika Nallangi Nikhila Meda Rudraraju Reshma Srilakshmi Dharmarajan Sriram 《Bioorganic & medicinal chemistry》2018,26(1):177-190
Mycobacterium tuberculosis glutamate racemase is an essential enzyme involved in peptidoglycan synthesis and conserved in most bacteria. Small molecule inhibitors were reported on other bacterial species whereas in M. tuberculosis it wasn’t explored much. In this study we have screened in house compound library using fluorescence thermal shift assay and enzyme inhibition assay, form this (1-(3-(benzo[d]thiazol-2-yl)phenyl)-3-(p-tolyl)thiourea) was identified as lead compound with IC50 19.47?±?0.81?μM. Further lead optimization by synthesis resulted in twenty-three compounds, of which Compound 25?has shown more efficacy compared to lead 1 showing non-competitive mode of inhibition with IC50 1.32?±?0.43?μM. It also showed significant activity (represented in log reduction) in nutrient starved dormant M. tuberculosis model (2.1), M. tuberculosis biofilm assay (2.0) and in vivo M. marinum infected zebrafish model (3.5). 相似文献
5.
Rui Xu Ganyuan Xiao Yan Li Hongyan Liu Qing Song Xiaoyu Zhang Ziyi Yang Yunxiaozhu Zheng Zhenghuai Tan Yong Deng 《Bioorganic & medicinal chemistry》2018,26(8):1885-1895
A series of 5,6-dimethoxybenzo[d]isothiazol-3(2H)-one-N-alkylbenzylamine derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer’s disease (AD). The in vitro assays indicated that most of these derivatives were selective AChE inhibitors with good multifunctional properties. Among them, compounds 11b and 11d displayed comprehensive advantages, with good AChE (IC50?=?0.29?±?0.01?μM and 0.46?±?0.02?μM, respectively), MAO-A (IC50?=?8.2?±?0.08?μM and 7.9?±?0.07?μM, respectively) and MAO-B (IC50?=?20.1?±?0.16?μM and 43.8?±?2.0% at 10?μM, respectively) inhibitory activities, moderate self-induced Aβ1–42 aggregation inhibitory potency (35.4?±?0.42% and 48.0?±?1.53% at 25?μM, respectively) and potential antioxidant activity. In addition, the two representative compounds displayed high BBB permeability in vitro. Taken together, these multifunctional properties make 11b and 11d as a promising candidate for the development of efficient drugs against AD. 相似文献
6.
Zhijian Li Qingxi Min Haoji Huang Ruixuan Liu Yongyan Zhu Quanhong Zhu 《Bioorganic & medicinal chemistry letters》2018,28(9):1501-1506
A series of seco-A-pentacyclic triterpenoids-3,4-lactone were synthesized and the anti-HBV activities were evaluated in vitro. Several compounds inhibited the secretion of HBV antigen and the replication of HBV DNA in micromolar level. Compounds D7 and D10, seco-A-oleanane-3,4-lactone, suppressed the HBeAg secretion with IC50 values of 0.14?μM and 0.86?μM respectively, and the inhibitory activities were also confirmed by detecting the fluorescence intensity of FITC-labeled monoclonal mouse HBeAg antibody via flow cytometry. Compounds D7 and D10 as well as B4, ring-A cleaved 3,30-dioic acid, also displayed remarkable inhibition on both HBV DNA replication at the concentration of 25?μM and HBV cccDNA (covalently closed circularDNA) replication with IC50 values of 33.5?μM, 32.7?μM and 12.3?μM respectively. 相似文献
7.
Ricardo Gallardo-Macias Pradeep Kumar Mark Jaskowski Todd Richmann Riju Shrestha Riccardo Russo Eric Singleton Matthew D. Zimmerman Hsin Pin Ho Véronique Dartois Nancy Connell David Alland Joel S. Freundlich 《Bioorganic & medicinal chemistry letters》2019,29(4):601-606
The optimization campaign for a nitrofuran antitubercular hit (N-benzyl-5-nitrofuran-2-carboxamide; JSF-3449) led to the design, synthesis, and biological profiling of a family of analogs. These compounds exhibited potent in vitro antitubercular activity (MIC?=?0.019–0.20?μM) against the Mycobacterium tuberculosis H37Rv strain and low in vitro cytotoxicity (CC50?=?40–>120?μM) towards Vero cells. Significant improvements in mouse liver microsomal stability and mouse pharmacokinetic profile were realized by introduction of an α, α-dimethylbenzyl moiety. Among these compounds, JSF-4088 is highlighted due to its in vitro antitubercular potency (MIC?=?0.019?μM) and Vero cell cytotoxicity (CC50?>?120?μM). The findings suggest a rationale for the continued evolution of this promising series of antitubercular small molecules. 相似文献
8.
Yu-Shun Yang Mi-Mi Su Xu-Ping Zhang Qi-Xing Liu Zhen-Xiang He Chen Xu Hai-Liang Zhu 《Bioorganic & medicinal chemistry letters》2018,28(19):3182-3186
By recruiting the important moiety from Shikonin, a series of novel oxoindoline derivatives S1–S20 have been synthesized for inhibiting H. pylori urease. The most potent compound S18 displayed better activity (IC50?=?0.71?μM; MIC?=?0.48?μM) than the positive controls AHA (IC50?=?17.2?μM) and Metronidazole (MIC?=?31.3?μM). With low cytotoxicity, it showed considerable potential for further development. Docking simulation revealed the possible binding pattern of this series. 3D QSAR model was built to discuss SAR and give useful hints for future modification. 相似文献
9.
Fei Li Xi-Xi Guo Guang-Zhi Zeng Wei-Wei Qin Bo Zhang Ning-Hua Tan 《Bioorganic & medicinal chemistry letters》2018,28(14):2523-2527
To further investigate on the structure-activity relationships of immunosuppressive Astin C, seventeen analogues 1–17 were designed and synthetized via amino acid substitution strategy by the solid-phase peptide synthesis method for the first time. In comparison with Astin C (IC50?=?12.6?±?3.3?μM), only compounds 2 (IC50?=?38.4?±?16.2?μM), 4 (IC50?=?51.8?±?12.7?μM), 5 (IC50?=?65.2?±?15.6?μM), and 8 (IC50?=?61.8?±?12.4?μM) exhibited immunosuppressive activity in the Lymph node cells of mice. These results showed that the Astin C analogues containing D-amino acid residues, hydrophobic long-chain alkyl substituents, and aryl substituents performed better than those carrying hydrophilic amino acid residues and short-chain alkyl substituents. Moreover compounds 15, 16, and 17 had no immunosuppressive activity, which suggested that cis-3,4-dichlorinated proline played an important role in the immunosuppressive activity of Astin C. 相似文献
10.
Zhanxiong Liu Zhenfeng Zhang Wanbin Zhang Deyue Yan 《Bioorganic & medicinal chemistry letters》2018,28(14):2454-2458
Thirty-six of novel compounds 2-substituted-1-(2-morpholinoethyl)-1H-naphtho[2,3-d]imidazole-4,9-diones, bearing a N-(2-morpholinoethyl) group and a 2-substituted imidazole segment on a naphthoquinone skeleton, were designed, synthesized and tested as anticancer agents. Cytotoxicity was evaluated in vitro against three human cancer cell lines: human breast carcinoma cell line (MCF-7), human cervical carcinoma cell line (Hela), and human lung carcinoma cell line (A549); and one normal cell line: mouse fibroblast cell line (L929). Among them, the compound 2-(3-chloro-4-methoxyphenyl)-1-(2-morpholinoethyl)-1H-naphtho[2,3-d]imidazole-4,9-dione showed good antiproliferative activity against MCF-7, Hela and A549 (IC50 values are equal to 10.6?μM, 8.3?μM and 4.3?μM respectively) and low cytotoxicity to L929 (IC50 value is equal to 67.3?μM). 相似文献
11.
Allan M. Prior Xufen Yu Eun-Jung Park Tamara P. Kondratyuk Yan Lin John M. Pezzuto Dianqing Sun 《Bioorganic & medicinal chemistry letters》2017,27(24):5393-5399
In our ongoing effort of discovering anticancer and chemopreventive agents, a series of 2-arylindole derivatives were synthesized and evaluated toward aromatase and quinone reductase 1 (QR1). Biological evaluation revealed that several compounds (e.g., 2d, IC50?=?1.61?μM; 21, IC50?=?3.05?μM; and 27, IC50?=?3.34?μM) showed aromatase inhibitory activity with half maximal inhibitory concentration (IC50) values in the low micromolar concentrations. With regard to the QR1 induction activity, 11 exhibited the highest QR1 induction ratio (IR) with a low concentration to double activity (CD) value (IR?=?8.34, CD?=?2.75?μM), while 7 showed the most potent CD value of 1.12?μM. A dual acting compound 24 showed aromatase inhibition (IC50?=?9.00?μM) as well as QR1 induction (CD?=?5.76?μM) activities. Computational docking studies using CDOCKER (Discovery Studio 3.5) provided insight in regard to the potential binding modes of 2-arylindoles within the aromatase active site. Predominantly, the 2-arylindoles preferred binding with the 2-aryl group toward a small hydrophobic pocket within the active site. The C-5 electron withdrawing group on indole was predicted to have an important role and formed a hydrogen bond with Ser478 (OH). Alternatively, meta-pyridyl analogs may orient with the pyridyl 3′-nitrogen coordinating with the heme group. 相似文献
12.
Anilkumar GN Selyutin O Rosenblum SB Zeng Q Jiang Y Chan TY Pu H Wang L Bennett F Chen KX Lesburg CA Duca J Gavalas S Huang Y Pinto P Sannigrahi M Velazquez F Venkatraman S Vibulbhan B Agrawal S Ferrari E Jiang CK Huang HC Shih NY George Njoroge F Kozlowski JA 《Bioorganic & medicinal chemistry letters》2012,22(1):713-717
Development of SAR at the C2 position of indole lead 1, a palm site inhibitor of HCV NS5B polymerase (NS5B IC(50)=0.053μM, replicon EC(50)=4.8μM), is described. Initial screening identified an acyl sulfonamide moiety as an isostere for the C2 carboxylic acid group. Further SAR investigation resulted in identification of acyl sufonamide analog 7q (NS5B IC(50)=0.039μM, replicon EC(50)=0.011μM) with >100-fold improved replicon activity. 相似文献
13.
《Plant science》1986,43(1):37-43
The lichen Evernia prunastri synthesizes urease (EC 3.5.1.5) as a response to urea supplied in the medium. Nickel is required to produce the active protein. In addition, nickel behaves as an activator of the enzyme (Ka = 8.1 μM) at low concentrations whereas it is shown to be a competitive inhibitor of urease when it is supplied at concentrations higher than 40 μM (Ki = 50 μM). 相似文献
14.
Jian-Fei Xu Tian-Tian Wang Qing Yuan Yong-Tao Duan Yun-Jie Xu Peng-Cheng Lv Xiao-Ming Wang Yu-Shun Yang Hai-Liang Zhu 《Bioorganic & medicinal chemistry》2019,27(8):1509-1516
A series of rhodanine derivatives RB1–RB23 were synthesized through a two-round screening. Their Mycobacterial tuberculosis (Mtb) InhA inhibitory activity and Mtb growth blocking capability were evaluated. The most potent hit compound RB23 indicated comparable InhA inhibiton (IC50?=?2.55?μM) with the positive control Triclosan (IC50?=?6.14?μM) and Isoniazid (IC50?=?8.29?μM). Its improved growth-blocking effect on Mtb and low toxicity were attractive for further development. The docking simulation revealed the possible binding pattern of this series and picked the key interacted residues as Ser20, Phe149, Lys165 and Thr196. The 3D-QSAR model visualized the SAR discussion and hinted new information. Modifying the surroundings near rhodanine moiety might be promising attempts in later investigations. 相似文献
15.
Shuang Guo Mingshuo Xu Qi Guo Fuqiang Zhu Xiangrui Jiang Yuanchao Xie Jingshan Shen 《Bioorganic & medicinal chemistry》2019,27(5):748-759
To explore the application potential of dual prodrug strategies in the development of anti-HCV agents, a variety of sofosbuvir derivatives with modifications at the C4 or N3 position of the uracil moiety were designed and synthesized. Some compounds exhibited potent anti-HCV activities, such as 4e and 8a–8c with similar EC50 values (0.20–0.22?μM) comparative to that of sofosbuvir (EC50?=?0.18?μM) in a genotype 1b based replicon Huh-7 cell line. Moreover, 8b displayed a good human plasma stability profile, and was easily metabolized in human liver microsomes expectantly. On the other hand, aiming to discover novel anti-HCV nucleosides, pyrazin-2(1H)-one nucleosides and their phosphoramidate prodrugs were investigated. Several active compounds were discovered, such as 25e (EC50?=?7.3?μM) and S-29b (EC50?=?19.5?μM). This kind of nucleosides were interesting and would open a new avenue for the development of antiviral agents. 相似文献
16.
Muhammad Taha Hayat Ullah Laode Muhammad Ramadhan Al Muqarrabun Muhammad Naseem Khan Fazal Rahim Norizan Ahmat Muhammad Tariq Javid Muhammad Ali Khalid Mohammed Khan 《Bioorganic & medicinal chemistry》2018,26(1):152-160
Bisindolylmethane thiosemicarbazides 1-18 were synthesized, characterized by 1H NMR and ESI MS and evaluated for urease inhibitory potential. All analogs showed outstanding urease inhibitory potentials with IC50 values ranging between 0.14?±?0.01 to 18.50?±?0.90?μM when compared with the standard inhibitor thiourea having IC50 value 21.25?±?0.90?μM. Among the series, analog 9 (0.14?±?0.01?μM) with di-chloro substitution on phenyl ring was identified as the most potent inhibitor of urease. The structure activity relationship has been also established on the basis of binding interactions of the active analogs. These binding interactions were identified by molecular docking studies. 相似文献
17.
Qing Song Yan Li Zhongcheng Cao Hongyan Liu Chaoquan Tian Ziyi Yang Xiaoming Qiang Zhenghuai Tan Yong Deng 《Bioorganic & medicinal chemistry》2018,26(23-24):6115-6127
A series of 2,5-dihydroxyterephthalamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer’s disease. In vitro assays demonstrated that most of the derivatives exhibited good multifunctional activities. Among them, compound 9d showed the best inhibitory activity against both RatAChE and EeAChE (IC50?=?0.56?μM and 5.12?μM, respectively). Moreover, 9d exhibited excellent inhibitory effects on self-induced Aβ1–42 aggregation (IC50?=?3.05?μM) and Cu2+-induced Aβ1–42 aggregation (71.7% at 25.0?μM), and displayed significant disaggregation ability to self- and Cu2+-induced Aβ1–42 aggregation fibrils (75.2% and 77.2% at 25.0?μM, respectively). Furthermore, 9d also showed biometal chelating abilities, antioxidant activity, anti-neuroinflammatory activities and appropriate BBB permeability. These multifunctional properties highlight 9d as promising candidate for further studies directed to the development of novel drugs against AD. 相似文献
18.
19.
Firoz A. Kalam Khan Rashmi N. Kaduskar Rajesh Patil Rajendra H. Patil Siddique Akber Ansari Hamad M. Alkahtani Abdulrahman A. Almehizia Devanand B. Shinde Jaiprakash N. Sangshetti 《Bioorganic & medicinal chemistry letters》2019,29(4):623-630
In the present investigation, new chloroquinoline derivatives bearing vinyl benzylidene aniline substituents at 2nd position were synthesized and screed for biofilm inhibitory, antifungal and antibacterial activity. The result of biofilm inhibition of C. albicans suggested that compounds 5j (IC50 value?=?51.2?μM) and 5a (IC50 value?=?66.2?μM) possess promising antibiofilm inhibition when compared with the standard antifungal drug fluconazole (IC50?=?40.0?μM). Two compounds 5a (MIC?=?94.2?μg/mL) and 5f (MIC?=?98.8?μg/mL) also exhibited good antifungal activity comparable to standard drug fluconazole (MIC?=?50.0?μg/mL). The antibacterial screening against four strains of bacteria viz. E. coli, P. aeruginosa, B. subtilis, and S. aureus suggested their potential antibacterial activity and especially all the compounds except 5g were found more active than the standard drug ciprofloxacin against B. subtilis. To further gain insights into the possible mechanism of these compounds in biofilm inhibition through the agglutinin like protein (Als), molecular docking and molecular dynamics simulation studies were carried out. Molecular modeling studies suggested the clear role in inhibition of this protein and the resulting biofilm inhibitory activity. 相似文献
20.
F. Zehra Küçükbay Hasan Küçükbay Muhammet Tanc 《Journal of enzyme inhibition and medicinal chemistry》2016,31(6):1198-1202
N-Protected amino acids (Gly, Ala and Phe) were reacted with amino substituted coumarin and quinolinone derivatives, leading to the corresponding N-protected amino acid–coumarin/quinolinone conjugates. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the new compounds was assessed against various human (h) isoforms, such as hCA I, hCA II, hCA IV and hCA XII. The quinolinone conjugates were inactive as enzyme inhibitors, whereas the coumarins were ineffective hCA I/II inhibitors (KIs?>?50?μM) but were submicromolar hCA IV and XII inhibitors, with inhibition constants ranging between 92?nM and 1.19?μM for hCA IV, and between 0.11 and 0.79?μM for hCA XII. These coumarin derivatives, as many others reported earlier, thus show an interesting selective inhibitory profile for the membrane-bound over the cytosolic CA isoforms. 相似文献