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Journal of Enzyme Inhibition and Medicinal Chemistry

Mehdi Bouchouit, Sofiane Bouacida, Bachir Zouchoune, Hocine Merazig, Silvia Bua, Zouhair Bouaziz, Marc Le Borgne, Claudiu T Supuran, Abdelmalek Bouraiou
Three coordination compounds of formula {M(bmim)2 Cl2 } were synthetised (M = Co, Zn, and Hg) and fully characterised. Each complex incorporates 1-benzyl-2-methylimidazole (bmim) as ligand. The coordination polyhedron around the metal center for all complexes has a quasi-regular tetragonal geometry. Density functional theory calculations were carried out on the title compounds and as well on hypothetical complexes (Cu, Ni), in order to elucidate their electronic and molecular structure. The calculations reproduced the Co, Zn, and Hg experimental structures and could predict stable complexes in the case of Ni(II) and Cu(II) ions...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Ismail Koyuncu, Ataman Gonel, Abdurrahim Kocyigit, Ebru Temiz, Mustafa Durgun, Claudiu T Supuran
Selective inhibition with sulphonamides of carbonic anhydrase (CA) IX reduces cell proliferation and induces apoptosis in human cancer cells. The effect on CA IX expression of seven previously synthesised sulphonamide inhibitors, with high affinity for CA IX, as well as their effect on the proliferation/apoptosis of cancer/normal cell lines was investigated. Two normal and three human cancer cell lines were used. Treatment resulted in dose- and time-dependent inhibition of the growth of various cancer cell lines...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Silvia Bua, Emanuela Berrino, Sonia Del Prete, Vallabhaneni S Murthy, Vijayaparthasarathi Vijayakumar, Yasinalli Tamboli, Clemente Capasso, Elisabetta Cerbai, Alessandro Mugelli, Fabrizio Carta, Claudiu T Supuran
The synthesis of a new series of sulfamides incorporating ortho-, meta, and para-benzenesulfamide moieties is reported, which were investigated for the inhibition of two human (h) isoforms of the zinc enzyme carbonic anhydrase (CA, EC, hCA I and II, and two Vibrio cholerae enzymes, belonging to the α- and β-CA classes (VchCAα, VchCAβ). The compounds were prepared by using the "tail approach", aiming to overcome the scarcity of selective inhibition profiles associated to CA inhibitors belonging to the zinc binders...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Maria Paola Giovannoni, Igor A Schepetkin, Mark T Quinn, Niccolò Cantini, Letizia Crocetti, Gabriella Guerrini, Antonella Iacovone, Paola Paoli, Patrizia Rossi, Gianluca Bartolucci, Marta Menicatti, Claudia Vergelli
We report the synthesis and biological evaluation of a new series of 3- or 4-(substituted)phenylisoxazolones as HNE inhibitors. Due to tautomerism of the isoxazolone nucleus, two isomers were obtained as final compounds (2-NCO and 5-OCO) and the 2-NCO derivatives were the most potent with IC50 values in the nanomolar range (20-70 nM). Kinetic experiments indicated that 2-NCO 7d and 5-OCO 8d are both competitive HNE inhibitors. Molecular modelling on 7d and 8d suggests for the latter a more crowded region about the site of the nucleophilic attack, which could explain its lowered activity...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Ahmed Sabt, Omaima M Abdelhafez, Radwan S El-Haggar, Hassan M F Madkour, Wagdy M Eldehna, Ezz El-Din A M El-Khrisy, Mohamed A Abdel-Rahman, Laila A Rashed
Herein, we report the synthesis of different novel sets of coumarin-6-sulfonamide derivatives bearing different functionalities (4a, b, 8a-d, 11a-d, 13a, b, and 15a-c), and in vitro evaluation of their growth inhibitory activity towards the proliferation of three cancer cell lines; HepG2 (hepatocellular carcinoma), MCF-7 (breast cancer), and Caco-2 (colon cancer). HepG2 cells were the most sensitive cells to the influence of the target coumarins. Compounds 13a and 15a emerged as the most active members against HepG2 cells (IC50  = 3...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Guangwei Xu, Tianqi Wang, Yongtao Li, Zhi Huang, Xin Wang, Jianyu Zheng, Shengyong Yang, Yan Fan, Rong Xiang
Indoleamine 2,3-dioxygenase 1 (IDO1) activity links to immune escape of cancers. Inhibition of IDO1 provides a new approach for cancer treatment. Most clinical IDO1 drugs show marginal efficacy as single agents. On basis of molecular docking and pharmacophore modelling, a novel inhibitor Roxyl-WL was discovered with a half maximal inhibitory concentration (IC50) value of 1 nM against IDO1 and 10-100-fold increased potent activity compared with IDO1 drugs in clinical trials. Roxyl-WL displayed excellent kinase spectrum selectivity with no activity out of the 337 protein kinases...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Hany E A Ahmed, Mohammed A A El-Nassag, Ahmed H Hassan, Rawda M Okasha, Saleh Ihmaid, Ahmed M Fouda, Tarek H Afifi, Ateyatallah Aljuhani, Ahmed M El-Agrody
In our effort to develop novel and powerful agents with anti-proliferative activity, two new series of 1H-benzo[f]chromene derivatives, 4a-h and 6a-h, were synthesised using heterocyclocondensation methodologies under microwave irradiation condition. The structures of the target compounds were established on the basis of their spectral data, IR, 1 H NMR, 13  C NMR, 13  C NMR-DEPT/APT, and MS data. The new compounds have been examined for their anti-proliferative activity against three cancer cell lines, MCF-7, HCT-116, and HepG-2...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Ashok Aspatwar, Holger M Becker, Nanda Kumar Parvathaneni, Milka Hammaren, Aleksandra Svorjova, Harlan Barker, Claudiu T Supuran, Ludwig Dubois, Philippe Lambin, Mataleena Parikka, Seppo Parkkila, Jean-Yves Winum
Carbonic anhydrase (CA) IX is a hypoxia inducible enzyme that is highly expressed in solid tumours. Therefore, it has been considered as an anticancer target using specific chemical inhibitors. The nitroimidazoles DTP338 and DTP348 have been shown to inhibit CA IX in nanomolar range in vitro and reduce extracellular acidification in hypoxia, and impair tumour growth. We screened these compounds for toxicity using zebrafish embryos and measured their in vivo effects on human CA IX in Xenopus oocytes. In the toxicity screening, the LD50 for both compounds was 3...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Jelena Krasilnikova, Liga Lauberte, Elena Stoyanova, Desislava Abadjieva, Mihail Chervenkov, Mattia Mori, Elisa De Paolis, Vanya Mladenova, Galina Telysheva, Bruno Botta, Elena Kistanova
Oregonin is an open-chain diarylheptanoid isolated from Alnus incana bark that possesses remarkable antioxidant and anti-inflammatory properties, inhibits adipogenesis, and can be used in the prevention of obesity and related metabolic disorders. Here, we aimed to investigate the effects of oregonin on the epigenetic regulation in cells as well as its ability to modulate DNA methylating enzymes expression and mitochondrial DNA (mtDNA) copies. Our results show that oregonin altered the expression of DNA methyltransferases and mtDNA copy numbers in dependency on concentration and specificity of cells genotype...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Jang Hoon Kim, In Sook Cho, Yang Kang So, Hyeong-Hwan Kim, Young Ho Kim
Tyrosinase is known for an enzyme that plays a key role in producing the initial precursor of melanin biosynthesis. Inhibition of the catalytic reaction of this enzyme led to some advantage such as skin-whitening and anti-insect agents. To find a natural compound with inhibitory activity towards tyrosinase, the five flavonoids of kushenol A (1), 8-prenylkaempferol (2), kushenol C (3), formononetin (4) and 8-prenylnaringenin (5) were isolated by column chromatography from a 95% methanol extract of Sophora flavescens...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Carlos Roca, Carlos Requena, Víctor Sebastián-Pérez, Sony Malhotra, Chris Radoux, Concepción Pérez, Ana Martinez, Juan Antonio Páez, Tom L Blundell, Nuria E Campillo
Allosteric sites on proteins are targeted for designing more selective inhibitors of enzyme activity and to discover new functions. Acetylcholinesterase (AChE), which is most widely known for the hydrolysis of the neurotransmitter acetylcholine, has a peripheral allosteric subsite responsible for amyloidosis in Alzheimer's disease through interaction with amyloid β-peptide. However, AChE plays other non-hydrolytic functions. Here, we identify and characterise using computational tools two new allosteric sites in AChE, which have allowed us to identify allosteric inhibitors by virtual screening guided by structure-based and fragment hotspot strategies...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Astrid Drenckhan, Morton Freytag, Claudiu T Supuran, Guido Sauter, Jakob R Izbicki, Stephanie J Gros
The hypoxic tumour microenvironment of solid tumours represents an important starting point for modulating progression and metastatic spread. Carbonic anhydrase IX (CAIX) is a known HIF-1α-dependent key player in maintaining cell pH conditions under hypoxia. We show that CAIX is strongly expressed in esophageal carcinoma tissues. We hypothesize that a moderate CAIX expression facilitates metastases and thereby worsens prognosis. Selective inhibition of CAIX by specific CAIX inhibitors and a CAIX knockdown effectively inhibit proliferation and migration in vitro...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Robert Czarnomysy, Arkadiusz Surażyński, Anna Muszynska, Agnieszka Gornowicz, Anna Bielawska, Krzysztof Bielawski
Six novel compounds of platinum(II) with pyrazole derivatives PtPz1-PtPz6 were synthesised and characterised (PtPz1 - [Pt2 N-hydroksymethyl-3,5-dimethylpyrazole4 (berenil)2 ]Cl4 ; PtPz2 - [Pt2 3,5-dimethylpyrazole4 (berenil)2 ]Cl4 ; PtPz3 - [Pt2 3,4-dimethylpyrazole4 (berenil)2 ]Cl4 ; PtPz4 - [Pt2 pyrazole4 (berenil)2 ]Cl4 ; PtPz5- [Pt2 5-methylpyrazole4 (berenil)2 ]Cl4 ; PtPz6 - [Pt2 N-ethylpyrazole4 (berenil)2 ]Cl4 ). The cytotoxic activity of these complexes against MCF-7 and MDA-MB-231 breast cancer cell lines was determined using the MTT assay...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Adel S El-Azab, Alaa A-M Abdel-Aziz, Laila A Abou-Zeid, Walaa M El-Husseiny, Ahmad M El Morsy, Manal A El-Gendy, Magda A-A El-Sayed
A new series of NSAID thioesters were synthesized and evaluated for their in vitro antitumor effects against a panel of four human tumor cell lines, namely: HepG2, MCF-7, HCT-116 and Caco-2, using the MTT assay. Compared to the reference drugs 5-FU, afatinib and celecoxib, compounds 2b, 3b, 6a, 7a, 7b and 8a showed potent broad-spectrum antitumor activity against the selected tumour cell lines. Accordingly, these compounds were selected for mechanistic studies about COX inhibition and kinase assays. In vitro COX-1/COX-2 enzyme inhibition assay results indicated that compounds 2b, 3b, 6a, 7a, 7b, 8a and 8 b selectively inhibited the COX-2 enzyme (IC50  = ∼0...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Marta Ferraroni, Roberto Gaspari, Andrea Scozzafava, Andrea Cavalli, Claudiu T Supuran
Carbonic anhydrases (CAs, EC are ubiquitous metalloenzymes, grouped into seven different classes, which catalyze the reaction of CO2 hydration to bicarbonate and protons. All of the fifteen human isoforms reported to date belong to the α-class and contain zinc as a cofactor. The structure of human Zn,Cu-CA II has been solved which contains a copper ion bound at its N-terminal, coordinated to His4 and His64. In the active site a dioxygen molecule is coordinated to the zinc ion. Since dioxygen is a rather unexpected CA ligand, molecular dynamics (MD) simulations were performed which suggested a superoxide character of the zinc bound O2 ...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Chetan P Shah, Prashant S Kharkar
Human inosine 5'-monophosphate dehydrogenase 2 (hIMPDH2), being an age-old target, has attracted attention recently for anticancer drug development. Mycophenolic acid (MPA), a well-known immunosuppressant drug, was used a lead structure to design and develop modestly potent and selective analogues. The steep structure-activity relationship (SAR) requirements of the lead molecule left little scope to synthesise newer analogues. Here, newer MPA amides were designed, synthesised and evaluated for hIMPDH2 inhibition and cellular efficacy in breast, prostate and glioblastoma cell lines...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Mashooq Ahmad Bhat, Mohamed A Al-Omar, Ahmed M Naglah
Dihydropyrimidinone derivatives containing piperidine moiety were synthesised in a good yield. All the compounds were confirmed by elemental analysis and spectral data. Anti-ulcer activity of novel dihydropyrimidinone-piperidine hybrids (1-18) was evaluated. Among them, four compounds (3, 8, 11 and 15) were found to be most active in 80% ethanol-induced ulcer experimental animal model. All the potent compounds were further evaluated for anti-ulcer activity by different in vivo anti-ulcer models to study the effect of compounds on anti-secretory and cytoprotective activities...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Tanvi V Wani, Silvia Bua, Pravin S Khude, Abdul H Chowdhary, Claudiu T Supuran, Mrunmayee P Toraskar
A series of novel sulphonamide derivatives was obtained from sulphanilamide which was N4-alkylated with ethyl bromoacetate followed by reaction with hydrazine hydrate. The hydrazide obtained was further reacted with various aromatic aldehydes. The novel sulphonamides were characterised by infrared, mass spectrometry, 1 H- and 13 C-NMR and purity was determined by high-performance liquid chromatography (HPLC). Human (h) carbonic anhydrase (CA, EC isoforms hCA I and II and Mycobacterium tuberculosis β-CA encoded by the gene Rv3273 (mtCA 3) inhibition activity was investigated with the synthesised compounds which showed promising inhibition...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Bassam M Ayoub, Yasmeen M Attia, Mahmoud S Ahmed
Chemical entities with structural diversity were introduced as candidates targeting adenosine receptor with different clinical activities, containing 3,7-dihydro-1H-purine-2,6-dione, especially adenosine 3 receptors (ADORA3). Our initial approach started with pharmacophore screening of ADORA3 modulators; to choose linagliptin (LIN), approved anti-diabetic drug as Dipeptidyl peptidase-4 inhibitors, to be studied for its modulating effect towards ADORA3. This was followed by generation, purification, analytical method development, and structural elucidation of oxidative degraded product (DEG)...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Wang Shih-Wei, Chung Chih-Ling, Yu-Chen Kao, René Martin, Hans-Joachim Knölker, Meng-Shin Shiao, Chun-Lin Chen
Pentabromopseudilin (PBrP) is a marine antibiotic isolated from the marine bacteria Pseudomonas bromoutilis and Alteromonas luteoviolaceus. PBrP exhibits antimicrobial, anti-tumour, and phytotoxic activities. In mammalian cells, PBrP is known to act as a reversible and allosteric inhibitor of myosin Va (MyoVa). In this study, we report that PBrP is a potent inhibitor of transforming growth factor-β (TGF-β) activity. PBrP inhibits TGF-β-stimulated Smad2/3 phosphorylation, plasminogen activator inhibitor-1 (PAI-1) protein production and blocks TGF-β-induced epithelial-mesenchymal transition in epithelial cells...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
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