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Journal of Enzyme Inhibition and Medicinal Chemistry

Murat Bozdag, Silvia Bua, Sameh M Osman, Zeid AlOthman, Claudiu T Supuran
A series of new derivatives was prepared by derivatisation of the 7-amino moiety present in 7-amino-3,4-dihydroquinolin-2(1H)-one, a compound investigated earlier as CAI. The derivatisation was achieved by: i) reaction with arylsulfonyl isocyanates/aryl isocyanates; (ii) reaction with fluorescein isothiocyanate; (iii) condensation with substituted benzoic acids in the presence of carbodiimides; (iv) reaction with 2,4,6-trimethyl-pyrylium tetrafluoroborate; (v) reaction with methylsulfonyl chloride and (vi) reaction with maleic anhydride...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Ashok Aspatwar, Milka Hammarén, Sanni Koskinen, Bruno Luukinen, Harlan Barker, Fabrizio Carta, Claudiu T Supuran, Mataleena Parikka, Seppo Parkkila
Inhibition of novel biological pathways in Mycobacterium tuberculosis (Mtb) creates the potential for alternative approaches for treating drug-resistant tuberculosis. In vitro studies have shown that dithiocarbamate-derived β-carbonic anhydrase (β-CA) inhibitors Fc14-594 A and Fc14-584B effectively inhibit the activity of Mtb β-CA enzymes. We screened the dithiocarbamates for toxicity, and studied the in vivo inhibitory effect of the least toxic inhibitor on M. marinum in a zebrafish model. In our toxicity screening, Fc14-584B emerged as the least toxic and showed minimal toxicity in 5-day-old larvae at 300 µM concentration...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Elisabetta Bertol, Fabio Vaiano, Francesco Mari, Maria Grazia Di Milia, Silvia Bua, Claudiu T Supuran, Fabrizio Carta
Identification of new psychoactive substances (NPS) in biological and non-biological samples represents a hard challenge for forensic toxicologists. Their great chemical variety and the speed with which new NPS are synthesised and spread make stringent the need of advanced tools for their detection based on multidisciplinary approaches. For this reason, in August 2016, the "Unit of Research and Innovation in Forensic Toxicology and Neuroscience of Addiction" (U.R.I.To.N.) was founded by the Forensic Toxicology Division of the University of Florence...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Claudia Vergelli, Igor A Schepetkin, Letizia Crocetti, Antonella Iacovone, Maria Paola Giovannoni, Gabriella Guerrini, Andrei I Khlebnikov, Samuele Ciattini, Giovanna Ciciani, Mark T Quinn
Human neutrophil elastase (HNE) is an important target for the development of novel and selective inhibitors to treat inflammatory diseases, especially pulmonary pathologies. Here, we report the synthesis, structure-activity relationship analysis, and biological evaluation of a new series of HNE inhibitors with an isoxazol-5(2H)-one scaffold. The most potent compound (2o) had a good balance between HNE inhibitory activity (IC50 value =20 nM) and chemical stability in aqueous buffer (t1/2=8.9 h). Analysis of reaction kinetics revealed that the most potent isoxazolone derivatives were reversible competitive inhibitors of HNE...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Phoebe F Lamie, John N Philoppes, Amany A Azouz, Nesreen M Safwat
Nineteen new compounds containing tetrazole and/or cyanamide moiety have been designed and synthesised. Their structures were confirmed using spectroscopic methods and elemental analyses. Anti-inflammatory activity for all the synthesised compounds was evaluated in vivo. The most active compounds 4c, 5a, 5d-f, 8a and b and 9a and b were further investigated for their ulcerogenic liability and analgesic activity. Pyrazoline derivatives 9b and 8b bearing trimethoxyphenyl part and SO2NH2 or SO2Me pharmacophore showed equal or nearly the same ulcerogenic liability (UI: 0...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Jin-Shuai Lan, Jian-Wei Hou, Yun Liu, Yue Ding, Yong Zhang, Ling Li, Tong Zhang
A novel family of cinnamic acid derivatives has been developed to be multifunctional cholinesterase inhibitors against AD by fusing N-benzyl pyridinium moiety and different substituted cinnamic acids. In vitro studies showed that most compounds were endowed with a noteworthy ability to inhibit cholinesterase, self-induced Aβ (1-42) aggregation, and to chelate metal ions. Especially, compound 5l showed potent cholinesterase inhibitory activity (IC50, 12.1 nM for eeAChE, 8.6 nM for hAChE, 2.6 μM for eqBuChE and 4...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Anita Bosak, Anamarija Knežević, Ivana Gazić Smilović, Goran Šinko, Zrinka Kovarik
We investigated the influence of bronchodilating β2-agonists on the activity of human acetylcholinesterase (AChE) and usual, atypical and fluoride-resistant butyrylcholinesterase (BChE). We determined the inhibition potency of racemate and enantiomers of fenoterol as a resorcinol derivative, isoetharine and epinephrine as catechol derivatives and salbutamol and salmeterol as saligenin derivatives. All of the tested compounds reversibly inhibited cholinesterases with Ki constants ranging from 9.4 μM to 6...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Daniela De Vita, Andrea Angeli, Fabiana Pandolfi, Martina Bortolami, Roberta Costi, Roberto Di Santo, Elisabetta Suffredini, Mariangela Ceruso, Sonia Del Prete, Clemente Capasso, Luigi Scipione, Claudiu T Supuran
We discovered novel and selective sulfonamides/amides acting as inhibitors of the α-carbonic anhydrase (CA, EC from the pathogenic bacterium Vibrio cholerae (VchCA). This Gram-negative bacterium is the causative agent of cholera and colonises the upper small intestine where sodium bicarbonate is present at a high concentration. The secondary sulfonamides and amides investigated here were potent, low nanomolar VchCA inhibitors whereas their inhibition of the human cytosolic isoforms CA I and II was in the micromolar range or higher...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Simone Carradori, Daniela Secci, Bruna Bizzarri, Paola Chimenti, Celeste De Monte, Paolo Guglielmi, Cristina Campestre, Daniela Rivanera, Claudia Bordón, Lorraine Jones-Brando
We designed and synthesised novel N-substituted 1,3-thiazolidin-4-one derivatives for the evaluation of their anti-Toxoplasma gondii efficacy. This scaffold was functionalised both at the N1-hydrazine portion with three structurally different moieties and at the lactam nitrogen with substituted benzyl groups selected on the basis of our previous structure-activity relationships studies. Using three different assay methods, the compounds were assessed in vitro to determine both the levels of efficacy against the tachyzoites of T...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Aleksandrs Pustenko, Dmitrijs Stepanovs, Raivis Žalubovskis, Daniela Vullo, Andris Kazaks, Janis Leitans, Kaspars Tars, Claudiu T Supuran
A new chemotype with carbonic anhydrase (CA, EC inhibitory action has been discovered, the homo-sulfocoumarins (3H-1,2-benzoxathiepine 2,2-dioxides) which have been designed considering the (sulfo)coumarins as lead molecules. An original synthetic strategy of a panel of such derivatives led to compounds with a unique inhibitory profile and very high selectivity for the inhibition of the tumour associated (CA IX/XII) over the cytosolic (CA I/II) isoforms. Although the CA inhibition mechanism with these new compounds is unknown for the moment, we hypothesize that it may be similar to that of the sulfocoumarins, i...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Rosa Perfetto, Sonia Del Prete, Daniela Vullo, Giovanni Sansone, Carmela M A Barone, Mosè Rossi, Claudiu T Supuran, Clemente Capasso
Carbonic anhydrases (CAs; EC are metalloenzymes with a pivotal potential role in the biomimetic CO2 capture process (CCP) because these biocatalysts catalyse the simple but physiologically crucial reaction of carbon dioxide hydration to bicarbonate and protons in all life kingdoms. The CAs are among the fastest known enzymes, with kcat values of up to 10(6) s(-1) for some members of the superfamily, providing thus advantages when compared with other CCP methods, as they are specific for CO2. Thermostable CAs might be used in CCP technology because of their ability to perform catalysis in operatively hard conditions, typical of the industrial processes...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
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December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Hülya Karaca Gençer, Ulviye Acar Çevik, Betül Kaya Çavuşoğlu, Begüm Nurpelin Sağlık, Serkan Levent, Özlem Atlı, Sinem Ilgın, Yusuf Özkay, Zafer Asım Kaplancıklı
No abstract text is available yet for this article.
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Jenny Kouretova, M Zouhir Hammamy, Anton Epp, Kornelia Hardes, Stephanie Kallis, Linlin Zhang, Rolf Hilgenfeld, Ralf Bartenschlager, Torsten Steinmetzer
West Nile virus (WNV) and Dengue virus (DENV) replication depends on the viral NS2B-NS3 protease and the host enzyme furin, which emerged as potential drug targets. Modification of our previously described WNV protease inhibitors by basic phenylalanine analogs provided compounds with reduced potency against the WNV and DENV protease. In a second series, their decarboxylated P1-trans-(4-guanidino)cyclohexylamide was replaced by an arginyl-amide moiety. Compound 4-(guanidinomethyl)-phenylacetyl-Lys-Lys-Arg-NH2 inhibits the NS2B-NS3 protease of WNV with an inhibition constant of 0...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Zhengxing Zhang, Joseph Lau, Chengcheng Zhang, Nadine Colpo, Alessio Nocentini, Claudiu T Supuran, François Bénard, Kuo-Shyan Lin
Carbonic anhydrase IX (CA-IX) is a marker for tumor hypoxia, and its expression is negatively correlated with patient survival. CA-IX represents a potential target for eliminating hypoxic cancers. We synthesized fluorinated cationic sulfonamide inhibitors 1-3 designed to target CA-IX. The binding affinity for CA-IX ranged from 0.22 to 0.96 μM. We evaluated compound 2 as a diagnostic PET imaging agent. Compound 2 was radiolabeled with (18)F in 10 ± 4% decay-corrected radiochemical yield with 85.1 ± 70...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Giuliano Vezzani, Silvia Quartesan, Pasqua Cancellara, Enrico Camporesi, Devanand Mangar, Thomas Bernasek, Prachiti Dalvi, Zhongjin Yang, Antonio Paoli, Alex Rizzato, Gerardo Bosco
Hyperbaric oxygen therapy (HBOT) has beneficial effects on avascular necrosis of femoral head (ANFH), but its mechanism of action is still unclear. We investigated if HBOT upregulates serum osteoprotegerin (OPG) and/or inhibits osteoclast activation. 23 patients with unilateral ANFH at stage I, II and III consented to the study: the patients received standard HBOT. Serum OPG levels were obtained at the beginning of HBOT (T0), after 15 sessions (T1), 30 sessions (T2), after a 30-day break (T3), and after 60 sessions (T4)...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Marco Bragagni, Fabrizio Carta, Sameh M Osman, Zeid AlOthman, Claudiu T Supuran
Acridine orange (AO) a fluorescent cationic dye used for the management of human musculoskeletal sarcomas, due to its strong tumoricidal action and accumulation in the acidic environment typical of hypoxic tumors, was used for the preparation of a primary sulfonamide derivative. The rationale behind the drug design is the fact that hypoxic, acidic tumors overexpress carbonic anhydrase (CA, EC isoforms, such as CA IX, which is involved in pH regulation, proliferation, cell migration and invasion, and this enzyme is strongly inhibited by primary sulfonamides...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Yeganeh Entezari Heravi, Hassan Sereshti, Ali Akbar Saboury, Jahan Ghasemi, Marzieh Amirmostofian, Claudiu T Supuran
A 3D-QSAR modeling was performed on a series of diarylpyrazole-benzenesulfonamide derivatives acting as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC The compounds were collected from two datasets with the same scaffold, and utilized as a template for a new pharmacophore model to screen the ZINC database of commercially available derivatives. The datasets were divided into training, test, and validation sets. As the first step, comparative molecular field analysis (CoMFA), CoMFA region focusing and comparative molecular similarity indices analysis (CoMSIA) in parallel with docking studies were applied to a set of 41 human (h) CA II inhibitors...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Elena Cichero, Michele Tonelli, Federica Novelli, Bruno Tasso, Ilenia Delogu, Roberta Loddo, Olga Bruno, Paola Fossa
Respiratory syncytial virus (RSV) has been identified as a main cause of hospitalisation in infants and children. To date, the current therapeutic arsenal is limited to ribavirin and palivizumab with variable efficacy. In this work, starting from a number of in-house series of previously described anti-RSV agents based on the benzimidazole scaffold, with the aim at gaining a better understanding of the related chemical features involved in potency and safety profiles, we applied a computational study including two focussed comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA)...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Simonetta Caira, Antonio Iannelli, Rosaria Sciarrillo, Gianluca Picariello, Giovanni Renzone, Andrea Scaloni, Pietro Addeo
The proteome of liver biopsies from human obese (O) subjects has been compared to those of nonobese (NO) subjects using two-dimensional gel electrophoresis (2-DE). Differentially represented proteins were identified by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS)-based peptide mass fingerprinting (PMF) and nanoflow-liquid chromatography coupled to electrospray-tandem mass spectrometry (nLC-ESI-MS/MS). Overall, 61 gene products common to all of the liver biopsies were identified within 65 spots, among which 25 ones were differently represented between O and NO subjects...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
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