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Journal of Enzyme Inhibition and Medicinal Chemistry

Wagdy M Eldehna, Hadia Almahli, Ghada H Al-Ansary, Hazem A Ghabbour, Mohamed H Aly, Omnia E Ismael, Abdullah Al-Dhfyan, Hatem A Abdel-Aziz
Treatment of patients with triple-negative breast cancer (TNBC) is challenging due to the absence of well- defined molecular targets and the heterogeneity of such disease. In our endeavor to develop potent isatin-based anti-proliferative agents, we utilized the hybrid-pharmacophore approach to synthesize three series of novel isatin-based hybrids 5a-h, 10a-h and 13a-c, with the prime goal of developing potent anti-proliferative agents toward TNBC MDA-MB-231 cell line. In particular, compounds 5e and 10g were the most active hybrids against MDA-MB-231 cells (IC50 = 12...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Gülru Kayık, Nurcan Ş Tüzün, Serdar Durdagi
The essential biological function of phosphodiesterase (PDE) type enzymes is to regulate the cytoplasmic levels of intracellular second messengers, 3',5'-cyclic guanosine monophosphate (cGMP) and/or 3',5'-cyclic adenosine monophosphate (cAMP). PDE targets have 11 isoenzymes. Of these enzymes, PDE5 has attracted a special attention over the years after its recognition as being the target enzyme in treating erectile dysfunction. Due to the amino acid sequence and the secondary structural similarity of PDE6 and PDE11 with the catalytic domain of PDE5, first-generation PDE5 inhibitors (i...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Vito Boido, Marcella Ercoli, Michele Tonelli, Federica Novelli, Bruno Tasso, Fabio Sparatore, Elena Cichero, Paola Fossa, Paola Dorigo, Guglielmina Froldi
Positive inotropic agents are fundamental in the treatment of heart failure; however, their arrhythmogenic liability and the increased myocardial oxygen demand strongly limit their therapeutic utility. Pursuing our study on cardiovascular activities of lupin alkaloid derivatives, several 2-(4-substituted-phenyl)-2-dehydrosparteines and 2-(4-substituted-phenyl)sparteines were prepared and tested for inotropic and chronotropic activities on isolated guinea pig atria. Four compounds (6b, 6e, 7b, and 7f) exhibited significant inotropism that, at the higher concentrations, was followed by negative inotropism or toxicity...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Wen-Yu Wu, Yu-Chen Dai, Nian-Guang Li, Ze-Xi Dong, Ting Gu, Zhi-Hao Shi, Xin Xue, Yu-Ping Tang, Jin-Ao Duan
Alzheimer's disease (AD) is a neurodegenerative disorder, which is complex and progressive; it has not only threatened the health of elderly people, but also burdened the whole social medical and health system. The available therapy for AD is limited and the efficacy remains unsatisfactory. In view of the prevalence and expected increase in the incidence of AD, the design and development of efficacious and safe anti-AD agents has become a hotspot in the field of pharmaceutical research. Due to the multifactorial etiology of AD, the multitarget-directed ligands (MTDLs) approach is promising in search for new drugs for AD...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Abhishek Albert, Vidhi Tiwari, Eldho Paul, Divya Ganesan, Mahesh Ayyavu, Ritu Kujur, Sasikumar Ponnusamy, Kathiresan Shanmugam, Luciano Saso, Selvam Govindan Sadasivam
Oxalates stimulate alterations in renal epithelial cells and thereby induce calcium oxalate (CaOx) stone formation. Bacillus subtilis YvrK gene encodes for oxalate decarboxylase (OxdC) which degrades oxalate to formate and CO2. The present work is aimed to clone the oxdC gene in a mammalian expression vector pcDNA and transfect into Human Embryonic Kidney 293 (HEK293) cells and evaluate the oxdC expression, cell survival rate and oxalate degrading efficiency. The results indicate cell survival rate of HEK293/pcDNAOXDC cells pre-incubated with oxalate was enhanced by 28%...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Serdar Burmaoglu, Oztekin Algul, Arzu Gobek, Derya Aktas Anil, Mahmut Ulger, Busra Gul Erturk, Engin Kaplan, Aylin Dogen, Gönül Aslan
Owing to ever-increasing bacterial and fungal drug resistance, we attempted to develop novel antitubercular and antimicrobial agents. For this purpose, we developed some new fluorine-substituted chalcone analogs (3, 4, 9-15, and 20-23) using a structure-activity relationship approach. Target compounds were evaluated for their antitubercular efficacy against Mycobacterium tuberculosis H37Rv and antimicrobial activity against five common pathogenic bacterial and three common fungal strains. Three derivatives (3, 9, and 10) displayed significant antitubercular activity with IC50 values of ≤16,760...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Miguel Marchena, Beatriz Villarejo-Zori, Josefa Zaldivar-Diez, Valle Palomo, Carmen Gil, Catalina Hernández-Sánchez, Ana Martínez, Enrique J de la Rosa
Retinitis pigmentosa (RP) is an inherited retinal dystrophy that courses with progressive degeneration of retinal tissue and loss of vision. Currently, RP is an unpreventable, incurable condition. We propose glycogen synthase kinase 3 (GSK-3) inhibitors as potential leads for retinal cell neuroprotection, since the retina is also a part of the central nervous system and GSK-3 inhibitors are potent neuroprotectant agents. Using a chemical genetic approach, diverse small molecules with different potency and binding mode to GSK-3 have been used to validate and confirm GSK-3 as a pharmacological target for RP...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Peifeng Tang, Jianlin Xu, Christopher L Oliveira, Zheng Jian Li, Shijie Liu
As a key enzyme for glycolysis, lactate dehydrogenase (LDH) remains as a topic of great interest in cancer study. Though a number of kinetic models have been applied to describe the dynamic behavior of LDH, few can reflect its actual mechanism, making it difficult to explain the observed substrate and competitor inhibitions at wide concentration ranges. A novel mechanistic kinetic model is developed based on the enzymatic processes and the interactive properties of LDH. Better kinetic simulation as well as new enzyme interactivity information and kinetic properties extracted from published articles via the novel model was presented...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Sara Guariento, Silvia Franchini, Michele Tonelli, Paola Fossa, Claudia Sorbi, Elena Cichero, Livio Brasili
The 5-hydroxytryptamine (5-HT1A) receptors represent an attractive target in drug discovery. In particular, 5-HT1A agonists and partial agonists are deeply investigated for their potential role in the treatment of anxiety, depression, ischaemic brain disorder and more recently, of pain. On the other hand, 5-HT1A antagonists have been revealed promising compounds in cognition disorders and, lately, in cancer. Thus, the discovery of 5HT1A ligands is nowadays an appealing research activity in medicinal chemistry...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Agustín Zavala, Verónica Kovacec, Gustavo Levín, Albertina Moglioni, María Victoria Miranda, Ernesto García, Laura Bonofiglio, Marta Mollerach
The UDP-glucose pyrophosphorylase of Streptococcus pneumoniae (GalUSpn) is absolutely required for the biosynthesis of capsular polysaccharide, the sine qua non virulence factor of pneumococcus. Since the eukaryotic enzymes are completely unrelated to their prokaryotic counterparts, we propose that the GalU enzyme is a critical target to fight the pneumococcal disease. A recombinant GalUSpn was overexpressed and purified. An enzymatic assay that is rapid, sensitive and easy to perform was developed. This assay was appropriate for screening chemical libraries for searching GalU inhibitors...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Nurgün Büyükkıdan, Bülent Büyükkıdan, Metin Bülbül, Rahmi Kasımoğulları, Samet Mert
Sulfonamides represent an important class of biologically active compounds. A sulfonamide possessing carbonic anhydrase (CA) inhibitory properties obtained from a pyrazole based sulfonamide, ethyl 1-(3-nitrophenyl)-5-phenyl-3-((5-sulfamoyl-1,3,4-thiadiazol-2-yl)carbamoyl)-1H-pyrazole-4-carboxylate (1), and its metal complexes with the Ni(II) for (2), Cu(II) for (3) and Zn(II) for (4) have been synthesized. The structures of metal complexes (2-4) were established on the basis of their elemental analysis, (1)H NMR, IR, UV-Vis and MS spectral data...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Lucia Squarcialupi, Marco Betti, Daniela Catarzi, Flavia Varano, Matteo Falsini, Annalisa Ravani, Silvia Pasquini, Fabrizio Vincenzi, Veronica Salmaso, Mattia Sturlese, Katia Varani, Stefano Moro, Vittoria Colotta
New 7-amino-2-phenylpyrazolo[4,3-d]pyrimidine derivatives, substituted at the 5-position with aryl(alkyl)amino- and 4-substituted-piperazin-1-yl- moieties, were synthesized with the aim of targeting human (h) adenosine A1 and/or A2A receptor subtypes. On the whole, the novel derivatives 1-24 shared scarce or no affinities for the off-target hA2B and hA3 ARs. The 5-(4-hydroxyphenethylamino)- derivative 12 showed both good affinity (Ki = 150 nM) and the best selectivity for the hA2A AR while the 5-benzylamino-substituted 5 displayed the best combined hA2A (Ki = 123 nM) and A1 AR affinity (Ki = 25 nM)...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Alessia Bino, Anna Baldisserotto, Emanuela Scalambra, Valeria Dissette, Daniela Ester Vedaldi, Alessia Salvador, Elisa Durini, Stefano Manfredini, Silvia Vertuani
An ever-increasing incidence of skin neoplastic diseases is registered. Therefore, it is important to protect the skin from the UV radiation that reaches the epidermis and dermis but also to block ROS generated by them. Our attention was attracted in developing new compounds provided with both UV filtering and antioxidant capacities. To this end, 2-phenyl-1H-benzimidazole-5-sulfonic acid (PBSA), a known UV filter, was selected as lead compound for its lack of antioxidant activity, high water solubility and good safety profile...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Federica Rinaldi, Elena Del Favero, Valeria Rondelli, Stefano Pieretti, Alessia Bogni, Jessica Ponti, François Rossi, Luisa Di Marzio, Donatella Paolino, Carlotta Marianecci, Maria Carafa
pH-sensitive nonionic surfactant vesicles (niosomes) by polysorbate-20 (Tween-20) or polysorbate-20 derivatized by glycine (added as pH sensitive agent), were developed to deliver Ibuprofen (IBU) and Lidocaine (LID). For the physical-chemical characterization of vesicles (mean size, size distribution, zeta potential, vesicle morphology, bilayer properties and stability) dynamic light scattering (DLS), small angle X-ray scattering and fluorescence studies were performed. Potential cytotoxicity was evaluated on immortalized human keratinocyte cells (HaCaT) and on immortalized mouse fibroblasts Balb/3T3...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Jean Guillon, Anita Cohen, Nassima Meriem Gueddouda, Rabindra Nath Das, Stéphane Moreau, Luisa Ronga, Solène Savrimoutou, Louise Basmaciyan, Alix Monnier, Myriam Monget, Sandra Rubio, Timothée Garnerin, Nadine Azas, Jean-Louis Mergny, Catherine Mullié, Pascal Sonnet
Novel series of bis- and tris-pyrrolo[1,2-a]quinoxaline derivatives 1 were synthesized and tested for in vitro activity upon the intraerythrocytic stage of W2 and 3D7 Plasmodium falciparum strains. Biological results showed good antimalarial activity with IC50 in the μM range. In attempting to investigate the large broad-spectrum antiprotozoal activities of these new derivatives, their properties toward Leishmania donovani were also investigated and revealed their selective antiplasmodial profile. In parallel, the in vitro cytotoxicity of these molecules was assessed on the human HepG2 cell line...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Naresh Sunduru, Mona Svensson, Mariateresa Cipriano, Sania Marwaha, C David Andersson, Richard Svensson, Christopher J Fowler, Mikael Elofsson
Fatty acid amide hydrolase (FAAH) is a promising target for the development of drugs to treat neurological diseases. In search of new FAAH inhibitors, we identified 2-(4-cyclohexylphenoxy)-N-(3-(oxazolo[4,5-b]pyridin-2-yl)phenyl)acetamide, 4g, with an IC50 of 2.6 µM as a chemical starting point for the development of potent FAAH inhibitors. Preliminary hit-to-lead optimisation resulted in 2-(4-phenylphenoxy)-N-(3-(oxazolo[4,5-b]pyridin-2-yl)phenyl)acetamide, 4i, with an IC50 of 0.35 µM.
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Ji-Young Park, Heung Joo Yuk, Hyung Won Ryu, Su Hwan Lim, Kyung Su Kim, Ki Hun Park, Young Bae Ryu, Woo Song Lee
The current study was designed to assess the inhibitory activity of Broussonetia papyrifera-derived polyphenols against 3-chymotrypsin-like and papain-like coronavirus cysteine proteases. The isolated compounds were broussochalcone B (1), broussochalcone A (2), 4-hydroxyisolonchocarpin (3), papyriflavonol A (4), 3'-(3-methylbut-2-enyl)-3',4,7-trihydroxyflavane (5), kazinol A (6), kazinol B (7), broussoflavan A (8), kazinol F (9), and kazinol J (10). All polyphenols were more potent against papain-like protease (PL(pro)) than against 3-chymotripsin-like protease (3CL(pro)); therefore, we investigated their structural features that were responsible for this selectivity...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Zuhal Alim, Namik Kilinç, Bülent Şengül, Şükrü Beydemir
Aldose reductase (AR) inhibitors have vital importance in the treatment and prevention of diabetic complications. In this study, rat kidney AR was purified 19.34-fold with a yield of 3.49% and a specific activity of 0.88 U/mg using DE-52 Cellulose anion exchange chromatography, gel filtration chromatography and 2'5' ADP Sepharose-4B affinity chromatography, respectively. After purification, the in vitro inhibition effects of some phenolic acids (tannic acid, chlorogenic acid, sinapic acid, protocatechuic acid, 4-hydroxybenzoic acid, p-coumaric acid, ferulic acid, vanillic acid, syringic acid, α-resorcylic acid, 3-hydroxybenzoic acid and gallic acid) were investigated on purified enzyme...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Ashley A Burke, Elizabeth S Severson, Shreya Mool, Maria J Solares Bucaro, Frederick T Greenaway, Charles E Jakobsche
Lysyl oxidase has emerged as an important enzyme in cancer metastasis. Its activity has been reported to become upregulated in several types of cancer, and blocking its activity has been shown to limit the metastatic potential of various cancers. The small-molecules phenylhydrazine and β-aminopropionitrile are known to inhibit lysyl oxidase; however, issues of stability, toxicity, and poorly defined mechanisms limit their potential use in medical applications. The experiments presented herein evaluate three other families of hydrazine-derived compounds - hydrazides, alkyl hydrazines, and semicarbazides - as irreversible inhibitors of lysyl oxidase including determining the kinetic parameters and comparing the inhibition selectivities for lysyl oxidase against the topaquinone-containing diamine oxidase from lentil seedlings...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Aida Begic, Ana Djuric, Milica Ninkovic, Ivana Stevanovic, Dragan Djurdjevic, Milos Pavlovic, Katarina Jelic, Ana Pantelic, Goran Zebic, Bratislav Dejanovic, Ivan Stanojevic, Danilo Vojvodic, Petar Milosavljevic, Mirjana Djukic, Luciano Saso
Examination of cadmium (Cd) toxicity and disulfiram (DSF) effect on liver was focused on oxidative stress (OS), bioelements status, morphological and functional changes. Male Wistar rats were intraperitoneally treated with 1 mg CdCl2/kg BW/day; orally with 178.5 mg DSF/kg BW/day for 1, 3, 10 and 21 days; and co-exposed from 22nd to 42nd day. The co-exposure nearly restored previously suppressed total superoxide dismutase (SOD), catalase (CAT) and increased glutathione peroxidase (GPx) activities; increased previously reduced glutathione reductase (GR) and total glutathione-S-transferase (GST) activities; reduced previously increased superoxide anion radical (O2(·-)) and malondialdehyde (MDA) levels; increased zinc (Zn) and iron (Fe), and decreased copper (Cu) (yet above control value), while magnesium (Mg) was not affected; and decreased serum alanine aminotransferases (ALT) levels...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
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