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European Journal of Medicinal Chemistry

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https://www.readbyqxmd.com/read/28646657/-half-sandwich-schiff-base-ir-iii-complexes-as-anticancer-agents
#1
Ze-Dong Mou, Ning Deng, Feng Zhang, Jiaying Zhang, Juan Cen, Xia Zhang
A series of "half-sandwich" Schiff-base Ir(III) complexes were synthesized and investigated for their in vitro activities against the leukemia K562 cell line. These compounds demonstrated antiproliferative activities against K562 cells with IC50 values of 0.26-4.77 μM. In particular, compound 10c showed cytotoxicity against five cancer cell lines/sublines and stronger activities than cisplatin in K562, K562/A02, MCF-7, MCF-7/ADM, and A549 cells. Mechanism studies illustrated that compound 10c increased the level of reactive oxygen species and induced apoptosis of K562 cells...
June 15, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28641156/mild-c-sp-3-h-functionalization-of-dihydrosanguinarine-and-dihydrochelerythrine-for-development-of-highly-cytotoxic-derivatives
#2
Adriana Romo-Pérez, Luis Demetrio Miranda, Alma D Chávez-Blanco, Alfonso Dueñas-González, María Del Rayo Camacho-Corona, Alejandrina Acosta-Huerta, Abraham García
A series of C(6)-substituted dihydrobenzo[c]phenanthridines were synthesized by mild copper-catalyzed C(sp(3))-H functionalization of dihydrosanguinarine (2) and dihydrochelerythrine (3) with certain nucleophiles selected to enhance cytotoxicity against human breast, colorectal, and prostate cancer cell lines. We also investigated the cytotoxicity of our previously reported C(6)-functionalized N-methyl-5,6-dihydrobenzo[c]phenanthridines 1a-1e to perform structure-activity relationship (SAR) studies. Among the target compounds, five β-aminomalonates (1a, 1b, 2a, 2b, and 3b), one α-aminophosphonate (2c), and one nitroalkyl derivative (2h) exhibited half maximal inhibitory concentration (IC50) values in the range of 0...
June 13, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28641157/design-synthesis-and-structure-activity-relationship-studies-of-a-novel-focused-library-of-2-3-4-substituted-oxazolidines-with-antiproliferative-activity-against-cancer-cell-lines
#3
Saulo F Andrade, Bárbara G Oliveira, Larissa C Pereira, Jonas P Ramos, Angélica R Joaquim, Martin Steppe, Elaine M Souza-Fagundes, Ricardo J Alves
In the present work we describe the synthesis and antiproliferative evaluation of a focused library of 30 novel oxazolidines designed by modification of N-substituent, by ring variation, by alkyl variation or by extension of the structure. It was noted that carbamate and N,O-aminal groups were essential for activity. In general, replacement of the phenyl ring with pyridinyl was not tolerated. However, the introduction of a second phenyl ring with an appropriate spacer at the 3- or 4-position of the first phenyl ring generally enhanced the cytotoxic profile...
June 12, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28615111/synthesis-and-antitumor-activities-of-1-2-3-triazines-and-their-benzo-and-heterofused-derivatives
#4
Stella Cascioferro, Barbara Parrino, Virginia Spanò, Anna Carbone, Alessandra Montalbano, Paola Barraja, Patrizia Diana, Girolamo Cirrincione
1,2,3-Triazines are a class of biologically active compounds that exhibit a broad spectrum of activities, including antibacterial, antifungal, antiviral, antiproliferative, analgesic and anti-inflammatory properties. This review, which covers the literature from the end of last century to 2016, treats, through a comprehensive, systematic approach, the 1,2,3-triazine and related benzo- and hetero-fused derivatives possessing antitumor activity. Their efficacy, combined with a simple synthesis confers to these molecules a great potential as scaffold for the development of antitumor compounds...
June 11, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28646757/discovery-and-structure-activity-relationship-studies-of-2-benzylidene-2-3-dihydro-1h-inden-1-one-and-benzofuran-3-2h-one-derivatives-as-a-novel-class-of-potential-therapeutics-for-inflammatory-bowel-disease
#5
Tara Man Kadayat, Suhrid Banskota, Pallavi Gurung, Ganesh Bist, Til Bahadur Thapa Magar, Aarajana Shrestha, Jung-Ae Kim, Eung-Seok Lee
To develop effective therapeutics for inflammatory bowel disease (IBD), 2-benzylidene-2,3-dihydro-1H-inden-1-one and benzofuran-3(2H)-one derivatives, were designed and synthesized and their structure-activity relationships (SAR) were investigated. Compounds 7, 25, 26, 32, 39, 41, 52, 54, and 55 showed potent inhibitory effect (>70%) on the TNF-α-induced adhesion of monocytes to colon epithelial cells, which is one of the hallmark events leading to IBD. Such inhibitory activity of the compounds correlated with their suppressive activities against the TNF-α-induced production of ROS; ICAM-1 and MCP-1 expression, critical molecules involved in monocyte-epithelial adhesion; and NF-κB transcriptional activity...
June 10, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28644986/designing-novel-inhibitors-against-histone-acetyltransferase-hat-%C3%A2-gcn5-of-plasmodium-falciparum
#6
Amarjeet Kumar, Krishanu Bhowmick, Kunwar Somesh Vikramdeo, Neelima Mondal, Naidu Subbarao, Suman Kumar Dhar
During active proliferation phase of intra-erythrocytic cycle, the genome of P. falciparum is regulated epigenetically and evolutionary conserved parasite-specific histone proteins are extensively acetylated. The reversible process of lysine acetylation, causing transcriptional activation and its deacetylation, causing transcriptional repression is regulated by balanced activities of HATs and HDACs. They are also known to regulate antigenic variations and gametocytic conversion in P. falciparum. These histone modifying enzymes have been identified as potential targets for development of anitmalarials in literature...
June 10, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28624701/2-substituted-thio-n-4-substituted-thiazol-1h-imidazol-2-yl-acetamides-as-bace1-inhibitors-synthesis-biological-evaluation-and%C3%A2-docking-studies
#7
Gang Yan, Lina Hao, Yan Niu, Wenjie Huang, Wei Wang, Fengrong Xu, Lei Liang, Chao Wang, Hongwei Jin, Ping Xu
In this work, a series of 2-substituted-thio-N-(4-substituted-thiazol/1H-imidazol-2-yl)acetamide derivatives were developed as β-secretase (BACE-1) inhibitors. Supported by docking study, a small library of derivatives were designed, synthesized and biologically evaluated in vitro. In addition, the selected compounds were tested with affinity (KD) towards BACE-1, blood brain barrier (BBB) permeability and cytotoxicity. The studies revealed that the most potent analog 41 (IC50 = 4.6 μM) with high predicted BBB permeability and low cellular cytotoxicity, could serve as a good lead structure for further optimization...
June 10, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28609708/anti-diabetic-activity-of-fused-ppar%C3%AE-sirt1-ligands-with-limited-body-weight-gain-by-mimicking-calorie-restriction-and-decreasing-sgk1-expression
#8
Celine Pirat, Catherine Dacquet, Veronique Leclerc, Nathalie Hennuyer, Monique Beucher-Gaudin, Ghislaine Zanirato, Anne Géant, Bart Staels, Alain Ktorza, Amaury Farce, Daniel-Henri Caignard, Pascal Berthelot, Nicolas Lebegue
A series of benzothiazol-2-one containing α-ethoxyphenylpropionic acid derivatives incorporating resveratrol or butein scaffolds were designed as fused full PPARγ agonist ligands and SIRT1-activating compounds for the treatment of type 2 diabetes (T2D) and its complications. Compound 14d displayed the best in vitro pharmacological profile with full PPARγ agonist activity (Emax = 98%, EC50 = 200 nM), SIRT1 enzymatic activation (+128%) and SGK1 expression inhibition (- 57%) which is known to limit side effects as fluid retention and body-weight gain...
June 10, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28646656/azide-alkyne-cycloaddition-towards-1h-1-2-3-triazole-tethered-gatifloxacin-and-isatin-conjugates-design-synthesis-and-in%C3%A2-vitro-anti-mycobacterial-evaluation
#9
Zhi Xu, Xu-Feng Song, Yuan-Qiang Hu, Min Qiang, Zao-Sheng Lv
Twelve novel 1H-1,2,3-triazole-tethered gatifloxacin (GTFX) isatin conjugates 5a-l with greater lipophilicity compared with GTFX were designed, synthesized and evaluated for their in vitro anti-mycobacterial activities against M. tuberculosis (MTB) H37Rv and MDR-TB as well as cytotoxicity. The preliminary results showed that all the targets (MIC: 0.10-8 μg/mL) exhibited excellent inhibitory activity against MTB H37Rv and MDR-TB, but eight of them (CC50: 7.8-62.5 μg/mL) were much more toxic than the parent GTFX (CC50: 125 μg/mL)...
June 9, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28628824/structure-activity-relationship-investigation-for-benzonaphthyridinone-derivatives-as-novel-potent-bruton-s-tyrosine-kinase-btk-irreversible-inhibitors
#10
Beilei Wang, Yuanxin Deng, Yongfei Chen, Kailin Yu, Aoli Wang, Qianmao Liang, Wei Wang, Cheng Chen, Hong Wu, Chen Hu, Weili Miao, Wooyoung Hur, Wenchao Wang, Zhenquan Hu, Ellen L Weisberg, Jinhua Wang, Tao Ren, Yinsheng Wang, Nathanael S Gray, Qingsong Liu, Jing Liu
Through a structure-based drug design approach, a tricyclic benzonaphthyridinone pharmacophore was used as a starting point for carrying out detailed medicinal structure-activity relationhip (SAR) studies geared toward characterization of a panel of proposed BTK inhibitors, including 6 (QL-X-138), 7 (BMX-IN-1) and 8 (QL47). These studies led to the discovery of the novel potent irreversible BTK inhibitor, compound 18 (CHMFL-BTK-11). Kinetic analysis of compound 18 revealed an irreversible binding efficacy (kinact/Ki) of 0...
June 9, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28624700/discovery-of-unsymmetrical-aromatic-disulfides-as-novel-inhibitors-of-sars-cov-main-protease-chemical-synthesis-biological-evaluation-molecular-docking-and-3d-qsar-study
#11
Li Wang, Bo-Bo Bao, Guo-Qing Song, Cheng Chen, Xu-Meng Zhang, Wei Lu, Zefang Wang, Yan Cai, Shuang Li, Sheng Fu, Fu-Hang Song, Haitao Yang, Jian-Guo Wang
The worldwide outbreak of severe acute respiratory syndrome (SARS) in 2003 had caused a high rate of mortality. Main protease (M(pro)) of SARS-associated coronavirus (SARS-CoV) is an important target to discover pharmaceutical compounds for the therapy of this life-threatening disease. During the course of screening new anti-SARS agents, we have identified that a series of unsymmetrical aromatic disulfides inhibited SARS-CoV M(pro) significantly for the first time. Herein, 40 novel unsymmetrical aromatic disulfides were synthesized chemically and their biological activities were evaluated in vitro against SARS-CoV M(pro)...
June 9, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28605675/isosteroidal-alkaloids-as-potent-dual-binding-site-inhibitors-of-both-acetylcholinesterase-and-butyrylcholinesterase-from-the-bulbs-of-fritillaria-walujewii
#12
Yu-Ming Liu, Ya-Dong Feng, Xi Lu, Jian-Bing Nie, Wei Li, Li-Ning Wang, Li-Jun Tian, Qing-Hua Liu
Five new isosteroidal alkaloids, walujewine A (1), walujewine B (4), walujewine C (5), walujewine D (6), walujewine E (10) were isolated from the bulbs of Fritillaria walujewii together with seven known isosteroidal alkaloids (2, 3, 7-9, 11, 12). Their structures were elucidated on the basis of IR, ESI-MS, HR-ESI-MS, 1D and 2D NMR spectroscopic data analyses and single-crystal X-ray diffraction. All the isolates were tested for ChE inhibiting activity by the Ellman's method. Compounds 3-5 and 8-10 were potent dual AChE-BChE inhibitors, and compound 1 showed highly selective AChE inhibition...
June 9, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28646655/syntheses-toxicities-and-anti-inflammation-of-h2s-donors-based-on-non-steroidal-anti-inflammatory-drugs
#13
Meng Li, Jili Li, Taofeng Zhang, Quanyi Zhao, Jie Cheng, Bin Liu, Zhen Wang, Libo Zhao, Chenwei Wang
Three series of H2S donors based on NSAIDs were synthesized and characterized by (1)H-NMR, IR and ESI-HRMS. The H2S-release abilities of all compounds were evaluated in the presence of TECP or cysteine. The results show all compounds were fast H2S-releasers, and their half-lives were in range of 0-20 min. Under the same condition, H2S released from compound 9 was more than any other compounds. In cytotoxicity aspect, all compounds but 1 and 2 displayed much lower toxicities to both LO2 and HepG2 cell lines, and the IC50 values of most compounds were over 800 μM...
June 7, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28624702/evaluation-of-the-antidepressant-therapeutic-potential-of-isocyanine-and-pseudoisocyanine-analogues-of-the-organic-cation-decynium-22
#14
Anwen M Krause-Heuer, Rheaclare Fraser-Spears, Jeremy C Dobrowolski, Mark E Ashford, Naomi A Wyatt, Maxine P Roberts, Georgianna G Gould, Wai-Ching Cheah, Clarissa K L Ng, Mohan Bhadbhade, Bo Zhang, Ivan Greguric, Nial J Wheate, Naresh Kumar, Wouter Koek, Paul D Callaghan, Lynette C Daws, Benjamin H Fraser
Herein we describe the synthesis and evaluation of antidepressant properties of seven analogues (1-7) of the low affinity/high capacity transporter blocker decynium-22 (D-22). All analogues (1-7) were synthesized via base promoted coupling reactions between N-alkylated-2-methylquinolinium iodides or N-alkylated-4-methylquinolinium iodides and electrophilic N-alkylated-2-iodoquinolinium iodides. All final compounds were purified by re-crystallization or preparative HPLC and initial evaluation studies included; 1) screening for in vitro α1-adrenoceptor activity (a property that can lead to unwanted side-effects), 2) measuring antidepressant-like activity in a mouse tail suspension test (TST), and 3) measuring effects upon mouse locomotion...
June 7, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28614758/synthesis-iron-iii-complexation-properties-molecular-dynamics-simulations-and-p-%C3%A2-aeruginosa-siderophore-like-activity-of-two-pyoverdine-analogs
#15
Viviane Antonietti, Stéphanie Boudesocque, Laurent Dupont, Natacha Farvacques, Christine Cézard, Sophie Da Nascimento, Jean-François Raimbert, Larissa Socrier, Thierry-Johann Robin, Sandrine Morandat, Karim El Kirat, Catherine Mullié, Pascal Sonnet
P. aeruginosa ranks among the top five organisms causing nosocomial infections. Among the many novel strategies for developing new therapeutics against infection, targeting iron uptake mechanism seems promising as P. aeruginosa needs iron for its growth and survival. To scavenge iron, the bacterium produces siderophores possessing a very high affinity towards Fe(III) ions such as pyoverdines. In this work, we decided to study two pyoverdine analogs, aPvd2 and aPvd3, structurally close to the endogen pyoverdine...
June 7, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28644987/thiophene-thiazole-benzene-replacement-on-guanidine-derivatives-targeting-%C3%AE-2-adrenoceptors
#16
Aoife Flood, Cristina Trujillo, Goar Sanchez-Sanz, Brendan Kelly, Carolina Muguruza, Luis F Callado, Isabel Rozas
Searching for improved antagonists of α2-adrenoceptors, a thorough theoretical study comparing the aromaticity of phenyl-, pyridinyl-, thiophenyl- and thiazolylguanidinium derivatives has been carried out [at M06-2X/6-311++G(p,d) computational level] confirming that thiophene and thiazole will be good 'ring equivalents' to benzene in these guanidinium systems. Based on these results, a small but chemically diverse library of guanidine derivatives (15 thiophenes and 2 thiazoles) were synthesised to explore the effect that the bioisosteric change has on affinity and activity at α2-adrenoceptors in comparison with our previously studied phenyl derivatives...
June 6, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28633106/selective-photocytotoxicity-of-anthrols-on-cancer-stem-like-cells-the-effect-of-quinone-methides-or-reactive-oxygen-species
#17
Lidija Uzelac, Đani Škalamera, Kata Mlinarić-Majerski, Nikola Basarić, Marijeta Kralj
Cancer stem cells (CSCs) are a subpopulation of cancer cells that share properties of embryonic stem cells like pluripotency and self-renewal and show increased resistance to chemo- and radiotherapy. Targeting CSC, rather than cancer cells in general, is a novel and promising strategy for cancer treatment. Novel therapeutic approaches, such as photodynamic therapy (PDT) have been investigated. A promising group of phototherapeutic agents are reactive intermediates - quinone methides (QMs). This study describes preparation of QM precursor, 2-hydroxy-3-hydroxymethylanthracene (2) and a detailed photochemical and photobiological investigation on similar anthracene derivatives 3 and 4...
June 3, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28628823/drug-development-against-tuberculosis-impact-of-alkaloids
#18
REVIEW
Shardendu K Mishra, Garima Tripathi, Navneet Kishore, Rakesh K Singh, Archana Singh, Vinod K Tiwari
Despite of the advances made in the treatment and management, tuberculosis (TB) still remains one of main public health problem. The contrary effects of first and second-line anti-tuberculosis drugs have generated extended research interest in natural products in the hope of devising new antitubercular leads. Interestingly, plethoras of natural products have been discovered to exhibit activity towards various resistant strains of M. tuberculosis. Extensive applications of alkaloids in the field of therapeutics is well-established and nowday's researches being pursued to develop new potent drugs from natural sources for tuberculosis...
June 3, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28624703/modification-of-c-seco-taxoids-through-ring-tethering-and-substituent-replacement-leading-to-effective-agents-against-tumor-drug-resistance-mediated-by-%C3%AE-iii-tubulin-and-p-glycoprotein-p-gp-overexpressions
#19
Yong Tang, Javier Rodríguez-Salarichs, Yu Zhao, Pei Cai, Juan Estévez-Gallego, Francisco Balaguer-Pérez, Mariano Redondo Horcajo, Daniel Lucena-Agell, Isabel Barasoain, J Fernando Díaz, Wei-Shuo Fang
In our efforts to improve the efficacy of taxane-based microtubule (MT) stabilizing agents against tumor drug resistance mediated by multiple mechanisms, two clinically relevant factors were focused: i.e., P-glycoprotein and βIII-tubulin overexpression. Based on the structure of C-seco taxoid 1 m (IDN5390) which was believed to more selectively interact with βIII-tubulin than paclitaxel, we prepared a series of C-seco taxoids bearing various 7,9-O-linkages and/or different substituents at C2 and C3' positions...
June 3, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28623814/synthesis-antimicrobial-antiquorum-sensing-and-antitumor-activities-of-new-benzimidazole-analogs
#20
N S El-Gohary, M I Shaaban
New benzimidazole analogs were prepared and tested for antimicrobial efficacy toward Escherichia coli ATCC 12435, Bacillus cereus UW 85, Staphylococcus aureus ATCC 29213, Candida albicans and Aspergillus fumigatus 293. Results indicated that compound 10 has potent and broad spectrum antimicrobial activity. In addition, 4b and 5c showed eminent antimicrobial efficacy toward B. cereus, S. aureus, C. albicans and A. fumigatus. Furthermore, 12 and 14 demonstrated interesting antifungal activity toward C. albicans...
June 3, 2017: European Journal of Medicinal Chemistry
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