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Journal of Enzyme Inhibition and Medicinal Chemistry

Songsong Zhang, Beibei Qiu, Jinhua Zhu, Weiping Hu, Fanyi Ma, M Z H Khan, Xiuhua Liu
Present study aimed to immobilise the α-glucosidase on suitable supports to construct enzymatic microreactors and their subsequent applicability in efficient inhibitor screening from the Chinese Yam (Dioscorea opposita Thunb.) peel. A type of lamellar and porous composites (rGO@Fe3 O4 ) were synthesised with a facile one-step solvothermal method and employed as carriers to construct enzymatic microreactors for screening α-glucosidase ligand from the Chinese Yam peel in league with the high performance liquid chromatography and mass spectrometry (HPLC-MS)...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Hak Kyun Yang, Woo Seung Son, Keon Seung Lim, Gun Hee Kim, Eun Jeong Lim, Changdev G Gadhe, Jae Yeol Lee, Kyu-Sung Jeong, Sang Min Lim, Ae Nim Pae
The treatment of neuropathic pain is one of the urgent unmet medical needs and T-type calcium channels are promising therapeutic targets for neuropathic pain. Several potent T-type channel inhibitors showed promising in vivo efficacy in neuropathic pain animal models and are being investigated in clinical trials. Herein we report development of novel pyrrolidine-based T-type calcium channel inhibitors by pharmacophore mapping and structural hybridisation followed by evaluation of their Cav 3.1 and Cav 3.2 channel inhibitory activities...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Ildikó Bacsa, Bianka Edina Herman, Rebeka Jójárt, Kevin Stefán Herman, János Wölfling, Gyula Schneider, Mónika Varga, Csaba Tömböly, Tea Lanišnik Rižner, Mihály Szécsi, Erzsébet Mernyák
Ring A halogenated 13α-, 13β-, and 17-deoxy-13α-estrone derivatives were synthesised with N-halosuccinimides as electrophile triggers. Substitutions occurred at positions C-2 and/or C-4. The potential inhibitory action of the halogenated estrones on human aromatase, steroid sulfatase, or 17β-hydroxysteroid dehydrogenase 1 activity was investigated via in vitro radiosubstrate incubation. Potent submicromolar or low micromolar inhibitors were identified with occasional dual or multiple inhibitory properties...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Joana Magalhães, Nina Franko, Giannamaria Annunziato, Martin Welch, Stephen K Dolan, Agostino Bruno, Andrea Mozzarelli, Stefano Armao, Aigars Jirgensons, Marco Pieroni, Gabriele Costantino, Barbara Campanini
Several bacteria rely on the reductive sulphur assimilation pathway, absent in mammals, to synthesise cysteine. Reduction of virulence and decrease in antibiotic resistance have already been associated with mutations on the genes that codify cysteine biosynthetic enzymes. Therefore, inhibition of cysteine biosynthesis has emerged as a promising strategy to find new potential agents for the treatment of bacterial infection. Following our previous efforts to explore OASS inhibition and to expand and diversify our library, a scaffold hopping approach was carried out, with the aim of identifying a novel fragment for further development...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Alessio Nocentini, Alessandro Bonardi, Paola Gratteri, Bruno Cerra, Antimo Gioiello, Claudiu T Supuran
Bile acids have been shown to inhibit human (h) carbonic anhydrases (CA, EC along the gastrointestinal tract, including hCA II. The elucidation of the hormonal inhibition mechanism of the bile acid cholate to hCA II was provided in 2014 by X-ray crystallography. Herein, we extend the inhibition study to a wealth of steroids against four relevant hCA isoforms. Steroids displaying pendants and functional groups of the carboxylate, phenolic or sulfonate types appended at the tetracyclic ring were shown to inhibit the cytosolic CA II and the tumor-associated, transmembrane CA IX in a medium micromolar range (38...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Petar Žuvela, J Jay Liu, Myunggi Yi, Paweł P Pomastowski, Gulyaim Sagandykova, Mariusz Belka, Jonathan David, Tomasz Bączek, Krzysztof Szafrański, Beata Żołnowska, Jarosław Sławiński, Claudiu T Supuran, Ming Wah Wong, Bogusław Buszewski
In this work, a target-based drug screening method is proposed exploiting the synergy effect of ligand-based and structure-based computer-assisted drug design. The new method provides great flexibility in drug design and drug candidates with considerably lower risk in an efficient manner. As a model system, 45 sulphonamides (33 training, 12 testing ligands) in complex with carbonic anhydrase IX were used for development of quantitative structure-activity-lipophilicity (property)-relationships (QSPRs). For each ligand, nearly 5,000 molecular descriptors were calculated, while lipophilicity (logkw ) and inhibitory activity (logKi ) were used as drug properties...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Yahui Ding, Zhongjin Yang, Weizhi Ge, Beijia Kuang, Junqing Xu, Juan Yang, Yue Chen, Quan Zhang
A series of dithiocarbamate esters of parthenolide (PTL) was designed, synthesised, and evaluated for their anti- acute myelogenous leukaemia (AML) activities. The most promising compound 7l showed greatly improved potency against AML progenitor cell line KG1a with IC50 value of 0.7 μM, and the efficacy was 8.7-folds comparing to that of PTL (IC50  = 6.1 μM). Compound 7l induced apoptosis of total primary human AML cells and leukaemia stem cell (LSCs) of primary AML cells while sparing normal cells...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Mohammed K AbdElhameid, Madlen B Labib, Ahmed T Negmeldin, Muhammad Al-Shorbagy, Manal R Mohammed
In this work, design, synthesis, and screening of thiophene carboxamides 4-13 and 16-23 as dual vascular endothelial growth factor receptors (VEGFRs) and mitotic inhibitors was reported. All compounds were screened against two gastrointestinal solid cancer cells, HepG-2 and HCT-116 cell lines. The most active cytotoxic derivatives 5 and 21 displayed 2.3- and 1.7-fold higher cytotoxicity than Sorafenib against HepG-2 cells. Cell cycle and apoptosis analyses for compounds 5 and 21 showed cells accumulation in the sub-G1 phase, and cell cycle arrest at G2/M phase...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Anastasia O Komarova, Mikhail S Drenichev, Nadezhda S Dyrkheeva, Irina V Kulikova, Vladimir E Oslovsky, Olga D Zakharova, Alexandra L Zakharenko, Sergey N Mikhailov, Olga I Lavrik
A new class of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors based on disaccharide nucleosides was identified. TDP1 plays an essential role in the resistance of cancer cells to currently used antitumour drugs based on Top1 inhibitors such as topotecan and irinotecan. The most effective inhibitors investigated in this study have IC50 values (half-maximal inhibitory concentration) in 0.4-18.5 µM range and demonstrate relatively low own cytotoxicity along with significant synergistic effect in combination with anti-cancer drug topotecan...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Ante Bubić, Natalia Mrnjavac, Igor Stuparević, Marta Łyczek, Beata Wielgus-Kutrowska, Agnieszka Bzowska, Marija Luić, Ivana Leščić Ašler
Adenylosuccinate synthetase (AdSS) is an enzyme at regulatory point of purine metabolism. In pathogenic organisms which utilise only the purine salvage pathway, AdSS asserts itself as a promising drug target. One of these organisms is Helicobacter pylori, a wide-spread human pathogen involved in the development of many diseases. The rate of H. pylori antibiotic resistance is on the increase, making the quest for new drugs against this pathogen more important than ever. In this context, we describe here the properties of H...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Cailan Li, Ping Huang, Kambo Wong, Yifei Xu, Lihua Tan, Hanbin Chen, Qiang Lu, Chaodan Luo, Chunlai Tam, Lixiang Zhu, Ziren Su, Jianhui Xie
In this study, we examined the anti-Helicobactor pylori effects of the main protoberberine-type alkaloids in Rhizoma Coptidis. Coptisine exerted varying antibacterial and bactericidal effects against three standard H. pylori strains and eleven clinical isolates, including four drug-resistant strains, with minimum inhibitory concentrations ranging from 25 to 50 μg/mL and minimal bactericidal concentrations ranging from 37.5 to 125 μg/mL. Coptisine's anti-H. pylori effects derived from specific inhibition of urease in vivo...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Daniela Giustarini, Valerio Tazzari, Ivan Bassanini, Ranieri Rossi, Anna Sparatore
The synthesis of a new dithiolethione-cysteine ethyl ester hybrid, ACS94, its metabolites, and its effect on GSH levels in rat tissues and on the concentration of circulating H2 S is described. ACS94 rapidly enters the cells, where it is metabolised to cysteine and the dithiolethione moiety ACS48. Experiments performed through the oral administration of ACS94 to healthy rats showed that it is capable of increasing the GSH levels in most of the analysed organs and the concentration of circulating H2 S. Although the increase in GSH concentration was similar to that obtained by ACS48 and N-acetylcysteine ethyl ester, the H2 S increase was long-lasting and more evident with respect to the parent molecules...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Andrea Bistrović, Luka Krstulović, Ivana Stolić, Domagoj Drenjančević, Jasminka Talapko, Martin C Taylor, John M Kelly, Miroslav Bajić, Silvana Raić-Malić
Amidinobenzimidazole derivatives connected to 1-aryl-substituted 1,2,3-triazole through phenoxymethylene linkers 7a-7e, 8a-8e, and 9a-9e were designed and synthesised with the aim of evaluating their anti-bacterial and anti-trypanosomal activities and DNA/RNA binding affinity. Results from anti-bacterial evaluations of antibiotic-resistant pathogenic bacteria revealed that both o-chlorophenyl-1,2,3-triazole and N-isopropylamidine moieties in 8c led to strong inhibitory activity against resistant Gram-positive bacteria, particularly the MRSA strain...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Bogdan Ioan Coculescu, Gabi Valeriu Dincă, Constantin Bălăeţ, Gheorghe Manole, Maria Bălăeţ, Cristina Mariana Stocheci
The current study was conducted on a sample of 91 patients diagnosed with diastolic dysfunction (DD) with preserved systolic function caused by a painful chronic ischaemic cardiopathy - angina pectoris stable at the effort. The diagnosis was established following anamnesis, electrocardiogram, and echocardiography. Myeloperoxidase (MPO) serum levels were assessed in all patients and then these values were correlated with some of the echocardiography parameters that proved the mentioned diagnosis. In conclusion, the execution of this investigation triad (electrocardiogram, echocardiography, and MPO) allows: Stratifying the patients depending on the disease risk by early detecting of any possible DD with preserved systolic function...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Ningbo Qin, Tatsunori Sasaki, Wei Li, Jian Wang, Xiangyu Zhang, Dahong Li, Zhanlin Li, Maosheng Cheng, Huiming Hua, Kazuo Koike
Protein tyrosine phosphatase 1B (PTP1B) is an attractive molecular target for anti-diabetes, anti-obesity, and anti-cancer drug development. From the seeds of Silybum marianum, nine flavonolignans, namely, silybins A, B (1, 2), isosilybins A, B (3, 4), silychristins A, B (5, 6), isosilychristin A (7), dehydrosilychristin A (8), and silydianin (11) were identified as a novel class of natural PTP1B inhibitors (IC50 1.3 7-23.87 µM). Analysis of structure-activity relationship suggested that the absolute configurations at C-7" and C-8" greatly affected the PTP1B inhibitory activity...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Luca Piemontese, Daniel Tomás, Asha Hiremathad, Vito Capriati, Emanuel Candeias, Sandra M Cardoso, Sílvia Chaves, M Amélia Santos
A new series of multifunctional hybrids, based on the structure of the donepezil (DNP) drug, have been developed and evaluated as potential anti Alzheimer's disease (AD) agents. The rationale of this study was the conjugation of a benzylpiperidine/benzylpiperazine moiety with derivatives of bioactive heterocyclics (benzimidazole or benzofuran), to mimic the main structure of DNP and to endow the hybrids with additional relevant properties such as inhibition of amyloid beta (Aβ) peptide aggregation, antioxidant activity and metal chelation...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Jure Borišek, Sara Pintar, Mitja Ogrizek, Simona Golič Grdadolnik, Vesna Hodnik, Dušan Turk, Andrej Perdih, Marjana Novič
Autolysin E (AtlE) is a cell wall degrading enzyme that catalyzes the hydrolysis of the β-1,4-glycosidic bond between the N-acetylglucosamine and N-acetylmuramic acid units of the bacterial peptidoglycan. Using our recently determined crystal structure of AtlE from Staphylococcus aureus and a combination of pharmacophore modeling, similarity search, and molecular docking, a series of (Phenylureido)piperidinyl benzamides were identified as potential binders and surface plasmon resonance (SPR) and saturation-transfer difference (STD) NMR experiments revealed that discovered compounds bind to AtlE in a lower micromolar range...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Delia Preti, Romeo Romagnoli, Riccardo Rondanin, Barbara Cacciari, Ernest Hamel, Jan Balzarini, Sandra Liekens, Dominique Schols, Francisco Estévez-Sarmiento, José Quintana, Francisco Estévez
Inhibition of microtubule function using tubulin targeting agents has received growing attention in the last several decades. The indole scaffold has been recognized as an important scaffold in the design of novel compounds acting as antimitotic agents. Indole-based chalcones, in which one of the aryl rings was replaced by an indole, have been explored in the last few years for their anticancer potential in different cancer cell lines. Eighteen novel (3',4',5'-trimethoxyphenyl)-indolyl-propenone derivatives with general structure 9 were synthesized and evaluated for their antiproliferative activity against a panel of four different human cancer cell lines...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Xing Chen, Gao-Feng Zha, Jie Quan Wang, Xin-Hua Liu
Based on our previous docking model, in order to carry out more rational drug design, totally 82 vinyl sulfonyl fluorides, including some 2-(hetero)arylethenesulfonyl fluorides and 1,3-dienylsulfonyl fluorides derivatives as potential human telomerase inhibitors were designed and synthesised. The in vitro anticancer activity assay showed that compound 57 (1E,3E)-4-(4-((E)-2-(fluorosulfonyl)vinyl)phenyl)buta-1,3-diene-1-sulfonyl fluoride exhibited high activity against A375 and MDA-MB-231 cell lines with IC50 1...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Jie Quan Wang, Meng Di Yang, Xing Chen, Yang Wang, Liu Zeng Chen, Xiu Cheng, Xin Hua Liu
A series of new trimethoxyphenyl-4H-chromen derivatives as telomerase inhibitors through regulation dyskerin were designed and synthesised. The anticancer activity assay in vitro showed that compound 5i 3-(4-(4-isonicotinoylpiperazin-1-yl)butoxy)-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromen-4-one exhibited high activity against Hela, SMMC-7721, SGC-7901, U87 and HepG2 cell lines. Compound 5i also showed potent inhibitory activity against telomerase. The further results confirmed this title compound could significantly improve pathological changes induced rat hepatic tumor in vivo...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
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