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Journal of Enzyme Inhibition and Medicinal Chemistry

Ramakrishna V S Nirogi, Thrinath Reddy Bandyala, Pamuletinarasimha Reddy Gangadasari, Mukkanti Khagga
A series of 1-[3-(4-methyl piperazin-1-ylmethyl) phenylsulfonyl]-1H-indole and 1-[3-(4-ethyl piperazin-1-ylmethyl) phenylsulfonyl]-1H-indole derivatives were designed and synthesized as 5-HT6 receptor (5-HT6R) ligands. The lead compound 1-[4-methyl-3-(4-methyl piperazin-1-yl methyl) phenylsulfonyl]-1H-indole dihydrochloride (6b), in this series, has shown potent in vitro binding affinity, selectivity, good pharmacokinetics (PK) profile and activity in the animal models of cognition.
November 3, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Xiao-Hui Gao, Chao Zhou, Hao-Ran Liu, Lin-Bo Liu, Jing-Jing Tang, Xin-Hua Xia
A new series of tertiary amine derivatives of chlorochalcone (4a∼4l) were designed, synthesized and evaluated for the effect on acetylcholinesterase (AChE) and buthylcholinesterase (BuChE). The results indicated that all compounds revealed moderate or potent inhibitory activity against AChE, and some possessed high selectivity for AChE over BuChE. The structure-activity investigation showed that the substituted position of chlorine significantly influenced the activity and selectivity. The alteration of tertiary amine group also leads to obvious change in bioactivity...
November 1, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Erol Licsandru, Muhammet Tanc, Istvan Kocsis, Mihail Barboiu, Claudiu T Supuran
A series of ureido and bis-ureido derivatives were prepared by reacting histamine with alkyl/aryl-isocyanates or di-isocyanates. The obtained derivatives were assayed as activators of the enzyme carbonic anhydrase (CA, EC, due to the fact that histamine itself has this biological activity. Although inhibition of CAs has pharmacological applications in the field of antiglaucoma, anticonvulsant, anticancer, and anti-infective agents, activation of these enzymes is not yet properly exploited pharmacologically for cognitive enhancement or Alzheimer's disease treatment, conditions in which a diminished CA activity was reported...
November 1, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Melissa D'Ascenzio, Paolo Guglielmi, Simone Carradori, Daniela Secci, Rosalba Florio, Adriano Mollica, Mariangela Ceruso, Atilla Akdemir, Anatoly P Sobolev, Claudiu T Supuran
A large number of novel secondary sulfonamides based on the open saccharin scaffold were synthesized and evaluated as selective inhibitors of four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC They were obtained by reductive ring opening of the newly synthesized N-alkylated saccharin derivatives and were shown to be inactive against the two cytosolic off-target hCA I and II (Kis > 10 µM). Interestingly, these compounds inhibited hCA IX in the low nanomolar range with Kis ranging between 20 and 298 nM and were extremely potent inhibitors of hCA XII isoenzyme (Kis ranging between 4...
October 26, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Stanislav Kalinin, Claudiu T Supuran, Mikhail Krasavin
Carbonic anhydrase inhibitors (CAIs) are of growing interest since various isoforms of the enzyme are identified as promising drug targets for treatment of disease. The principal drawback of the clinically used CAIs is the lack of isoform selectivity, which may lead to observable side effects. Studies aiming at the design of isoform-selective CAIs entail generation and biological testing of arrays of compounds, which is a resource- and time-consuming process. Employment of multicomponent reactions is an efficient synthetic strategy in terms of gaining convenient and speedy access to a range of scaffolds with a high degree of molecular diversity...
October 26, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Mikhail Krasavin, Alexey Lukin, Daria Bagnyukova, Nikolay Zhurilo, Ihor Zahanich, Sergey Zozulya
A series of nine compounds based on 3-[4-(benzyloxy)phenyl]propanoic acid core containing a 1-oxa-9-azaspiro[5.5]undecane periphery was designed, synthesized and evaluated as free fatty acid 1 (FFA1 or GPR40) agonists. The spirocyclic appendages included in these compounds were inspired by LY2881835, Eli Lilly's advanced drug candidate for type II diabetes mellitus that was in phase I clinical trials. These polar spirocyclic, fully saturated appendages (that are themselves uncharacteristic of the known FFA1 ligand space) were further decorated with diverse polar groups (such as basic heterocycles or secondary amides)...
October 26, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Mariusz Mojzych, Paweł Tarasiuk, Katarzyna Kotwica-Mojzych, Muhammad Rafiq, Sung-Yum Seo, Michał Nicewicz, Emilia Fornal
A new series of sulfonamide derivatives of pyrazolo[4,3-e][1,2,4]triazine with chiral amino group has been synthesized and characterized. The compounds were tested for their tyrosinase and urease inhibitory activity. Evaluation of prepared derivatives demonstrated that compounds (8b) and (8j) are most potent mushroom tyrosinase inhibitors whereas all of the obtained compounds showed higher urease inhibitory activity than the standard thiourea. The compounds (8a), (8f) and (8i) exhibited excellent enzyme inhibitory activity with IC50 0...
October 25, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Jang Hoon Kim, Ju-Yeon Yoon, Seo Young Yang, Seung-Kook Choi, Sun Jung Kwon, In Sook Cho, Min Hee Jeong, Young Ho Kim, Gug Seoun Choi
A new compound, 9-dihydroxyl-2'-O-(Z)-cinnamoyl-7-methoxy-aloesin (1), and eight known compounds (2-9) were isolated from Aloe vera. Their structures were elucidated using 1D/2D nuclear magnetic resonance and mass spectra. Compound 9 exhibited reversible competitive inhibitory activity against the enzyme tyrosinase, with an IC50 value of 9.8 ± 0.9 µM. A molecular simulation revealed that compound 9 interacts via hydrogen bonding with residues His244, Thr261, and Val283 of tyrosinase. Additionally, compounds 3 and 7 were shown by half-leaf assays to exhibit inhibitory activity towards Pepper mild mottle virus...
October 25, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
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October 25, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Claudia Melis, Rita Meleddu, Andrea Angeli, Simona Distinto, Giulia Bianco, Clemente Capasso, Filippo Cottiglia, Rossella Angius, Claudiu T Supuran, Elias Maccioni
The isatin scaffold is the constitutive fragment of several natural and synthetic bioactive molecules. Albeit several benzene sulphonamide-based carbonic anhydrase inhibitors (CAIs) have been reported, only recently isatin benzene sulphonamides have been studied and proposed as CAIs. In this study we have designed, synthesised, and evaluated the biological activity of a series of differently substituted isatin-based benzene sulphonamides which have been designed for the inhibition of carbonic anhydrase isoforms...
October 24, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Marcello Locatelli, Gokhan Zengin, Ahmet Uysal, Simone Carradori, Elisa De Luca, Giuseppe Bellagamba, Abdurrahman Aktumsek, Irina Lazarova
The current study was carried out to evaluate multicomponent pattern, biological and enzymatic activities of seven Asphodeline taxa root extracts as useful ingredients, due to the fact that these plants are commonly used as traditional food supplements in Turkish regions. The extracts were characterized for free anthraquinones and phenolics to obtain a specific chemical fingerprint useful for quality control. These analyzes were coupled to biological and enzymatic activities in order to obtain comprehensive information of the natural product...
October 24, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Halise Inci Gul, Ebru Mete, Parham Taslimi, Ilhami Gulcin, Claudiu T Supuran
4-(3-(4-Substituted-phenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl) benzenesulfonamides (9-16) were successfully synthesized and their chemical structures were confirmed by (1)H NMR, (13)C NMR, and HRMS spectra. Carbonic anhydrase I and II inhibitory effects of the compounds were investigated. Ki values of the compounds were in the range of 316.7 ± 9.6-533.1 ± 187.8 nM towards hCA I and 412.5 ± 115.4-624.6 ± 168.2 nM towards hCA II isoenzymes. While Ki values of the reference compound Acetazolamide were 278...
October 24, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Riham I Ahmed, Essam Eldin A Osman, Fadi M Awadallah, Samir M El-Moghazy
New target compounds were designed as inhibitors of tubulin polymerization relying on using two types of ring B models (cyclohexenone and indazole) to replace the central ring in colchicine. Different functional groups (R(1)) were attached to manipulate their physicochemical properties and/or their biological activity. The designed compounds were assessed for their antitumor activity on HCT-116 and MCF-7 cancer cell lines. Compounds 4b, 5e and 5f exhibited comparable or higher potency than colchicine against colon HCT-116 and MCF-7 tumor cells...
October 24, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Halise Inci Gul, Ebru Mete, Sakip Emre Eren, Hiroshi Sakagami, Cem Yamali, Claudiu T Supuran
In this study, 4-[3-(4-hydroxyphenyl)-5-aryl-4,5-dihydro-pyrazol-1-yl]benzenesulfonamide (1-9) types compounds were synthesized and their chemical structures were confirmed by (1)H NMR, (13)C NMR and HRMS spectra. Cytotoxic and carbonic anhydrase (CA) inhibitory effects of the compounds were investigated. Cytotoxicity experiments pointed out that compound 4, (4-[5-(4-chlorophenyl)-3-(4-hydroxyphenyl)-4,5-dihydro-pyrazol-1-yl]benzenesulfonamide), exerting the highest tumor selectivity (TS) and potency selectivity expression (PSE) values, can be considered as a lead compound of this study in terms of development of novel anticancer agents...
October 23, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Emilie Evain-Bana, Lucie Schiavo, Christophe Bour, Don Antoine Lanfranchi, Simone Berardozzi, Francesca Ghirga, Denyse Bagrel, Bruno Botta, Gilles Hanquet, Mattia Mori
The cell division cycle 25 phosphatases (CDC25A, B, and C; E.C. are key regulator of the cell cycle in human cells. Their aberrant expression has been associated with the insurgence and development of various types of cancer, and with a poor clinical prognosis. Therefore, CDC25 phosphatases are a valuable target for the development of small molecule inhibitors of therapeutic relevance. Here, we used an integrated strategy mixing organic chemistry with biological investigation and molecular modeling to study novel quinonoid derivatives as CDC25 inhibitors...
October 23, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Zeynep Soyer, Sirin Uysal, Sulunay Parlar, Ayse Hande Tarikogullari Dogan, Vildan Alptuzun
A series of 4-phthalimidobenzenesulfonamide derivatives were designed, synthesized and evaluated for the inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Structures of the title compounds were confirmed by spectral and elemental analyses. The cholinesterase (ChE) inhibitory activity studies were carried out using Ellman's colorimetric method. The biological activity results revealed that all of the title compounds (except for compound 8) displayed high selectivity against AChE...
October 21, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Nadia G Kandile, Mansoura I Mohamed, Hind M Ismaeel
New compounds based on oxindole moiety were synthesized via the reaction of 5-substitued isatins 1a-e with different nucleophiles such as benzidine, 3,3'-dimethoxybenzidine 2a,b and 2,6-diaminopyridine 3 to afford three different classes of bis-Schiff bases 4a-e, 5a-e and 6a-e, respectively. The structures of the new compounds were elucidated on the basis of their FTIR, (1)H NMR, (13)C NMR, GC/MS spectral data and elemental analysis. The in vitro antimicrobial activity of the new compounds was evaluated using a broth dilution technique in terms of minimal inhibitory concentration (MIC) against four bacterial and two fungal pathogens and anticancer activities against HELA cervix...
October 21, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Alessandro Rubini, Vincenzo Catena, Daniele Del Monte, Gerardo Bosco
CONTEXT: Calcium channel blockers may theoretically exhibit relaxing effects not only on vascular smooth muscle but also on airway smooth muscle. OBJECTIVE: To investigate possible effects of nifedipine on respiratory mechanics in the rat. METHODS: Respiratory system mechanical parameters were measured by the end-inflation occlusion method in the rat in vivo before and after the intraperitoneal administration of nifedipine. RESULTS: We found that nifedipine affects respiratory mechanics, inducing a reduction of airway resistance and of respiratory system elastance, probably because of a relaxing action on airway and parenchimal smooth muscle cells...
October 21, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Nahid Alimoradi, Mohammad Reza Ashrafi-Kooshk, Mohsen Shahlaei, Shabnam Maghsoudi, Hadi Adibi, Ross P McGeary, Reza Khodarahmi
Purple acid phosphatases (PAPs) are binuclear metallo-hydrolases that have been isolated from various mammals, plants, fungi and bacteria. In mammals, PAP activity is associated with bone resorption and can lead to bone metabolic disorders such as osteoporosis; thus human PAP is an attractive target to develop anti-osteoporotic drugs. The aim of the present study was to investigate inhibitory effect of synthesized diethylalkylsulfonamido(4-methoxyphenyl)methyl)phosphonate/phosphonic acid derivatives as potential red kidney bean PAP (rkbPAP) inhibitors accompanied by experimental and molecular modeling assessments...
October 21, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Daria M Monti, Giuseppina De Simone, Emma Langella, Claudiu T Supuran, Anna Di Fiore, Simona M Monti
Carbonic anhydrases (CAs) III and VII are two cytosolic isoforms of the α-CA family which catalyze the physiological reaction of carbon dioxide hydration to bicarbonate and proton. Despite these two enzymes share a 49% sequence identity and present a very similar three-dimensional structure, they show profound differences when comparing the specific activity for CO2 hydration reaction, with CA VII being much more active than CA III. Recently, CA III and CA VII have been proposed to play a new role as scavenger enzymes in cells where oxidative damage occurs...
October 21, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
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