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Journal of Enzyme Inhibition and Medicinal Chemistry

Thierry Naas, Saoussen Oueslati, Rémy A Bonnin, Maria Laura Dabos, Agustin Zavala, Laurent Dortet, Pascal Retailleau, Bogdan I Iorga
Beta-Lactamase Database (BLDB) is a comprehensive, manually curated public resource providing up-to-date structural and functional information focused on this superfamily of enzymes with a great impact on antibiotic resistance. All the enzymes reported and characterised in the literature are presented according to the class (A, B, C and D), family and subfamily to which they belong. All three-dimensional structures of β-lactamases present in the Protein Data Bank are also shown. The characterisation of representative mutants and hydrolytic profiles (kinetics) completes the picture and altogether these four elements constitute the essential foundation for a better understanding of the structure-function relationship within this enzymes family...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Maria Elisa Melo Branco de Araújo, Yollanda Edwirges Moreira Franco, Thiago Grando Alberto, Marcia Cristina Fernandes Messias, Camila Wielewski Leme, Alexandra Christine Helena Frankland Sawaya, Patricia de Oliveira Carvalho
Studies have reported that flavonoids inhibit xanthine oxidase (XO) activity; however, poor solubility and stability in lipophilic media limit their bioavailability and applications. This study evaluated the kinetic parameters of XO inhibition and partition coefficients of flavonoid esters biosynthesised from hesperidin, naringin, and rutin via enzymatic acylation with hexanoic, octanoic, decanoic, lauric, and oleic acids catalysed by Candida antarctica lipase B (CALB). Quantitative determination by ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) showed higher conversion yields (%) for naringin and rutin esters using acyl donors with 8C and 10C...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Bo Feng, Xinpeng Li, Jie Xia, Song Wu
AChE and BuChE are druggable targets for the discovery of anti-Alzheimer's disease drugs, while dual-inhibition of these two targets seems to be more effective. In this study, we synthesised a series of novel isoflavone derivatives based on our hit compound G from in silico high-throughput screening and then tested their activities by in vitro AChE and BuChE bioassays. Most of the isoflavone derivatives displayed moderate inhibition against both AChE and BuChE. Among them, compound 16 was identified as a potent AChE/BuChE dual-targeted inhibitor (IC50: 4...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
You-Guang Zheng, Xiao-Qing Wu, Jun Su, Ping Jiang, Liang Xu, Jian Gao, Bin Cai, Min Ji
The epidermal growth factor receptor (EGFR) and HER2 are two important tyrosine kinases that play crucial roles in signal transduction pathways that regulate numerous cellular functions including proliferation, differentiation, migration, and angiogenesis. In the past 20 years, many proteomic methods have emerged as powerful methods to evaluate proteins in biological processes and human disease states. Among them, activity-based protein profiling (ABPP) is one useful approach for the functional analysis of proteins...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Adel S El-Azab, Abdullah Al-Dhfyan, Alaa A-M Abdel-Aziz, Laila A Abou-Zeid, Hamad M Alkahtani, Abdulrahman M Al-Obaid, Manal A Al-Gendy
A new series of quinazolinone compounds 16-34 incorporating isatin moieties was synthesized. The antitumor efficacy of the compounds against MDA-MB-231, a breast cancer cell line, and LOVO, a colon cancer cell line, was assessed. Compounds 20, 21, 22, 23, 25, 27, 28, 29, 30, 31, 32, 33, and 34 displayed potent antitumor activity against MDA-MB-231 and LOVO cells (IC50: 10.38-38.67 μM and 9.91-15.77 μM, respectively); the comparative IC50 values for 5-fluorouracil and erlotinib in these cells lines were 70...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Mikhail Krasavin, Mikhail Korsakov, Oksana Ronzhina, Tiziano Tuccinardi, Stanislav Kalinin, Muhammet Tanç, Claudiu T Supuran
No abstract text is available yet for this article.
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Katsuyuki Kusuzaki, Takao Matsubara, Hiroaki Murata, Mariantonia Logozzi, Elisabetta Iessi, Rossella Di Raimo, Fabrizio Carta, Claudiu T Supuran, Stefano Fais
Photodynamic molecules represent an alternative approach for cancer therapy for their property (i) to be photo-reactive; (ii) to be not-toxic for target cells in absence of light; (iii) to accumulate specifically into tumour tissues; (iv) to be activable by a light beam only at the tumour site and (v) to exert cytotoxic activity against tumour cells. However, to date their clinical use is limited by the side effects elicited by systemic administration. Extracellular vesicles are endogenous nanosized-carriers that have been recently introduced as a natural delivery system for therapeutic molecules...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Alberto Cornejo, Felipe Aguilar Sandoval, Leonardo Caballero, Luis Machuca, Patricio Muñoz, Julio Caballero, George Perry, Alejandro Ardiles, Carlos Areche, Francisco Melo
Alzheimer's disease is a common tauopathy where fibril formation and aggregates are the hallmark of the disease. Efforts targeting amyloid-β plaques have succeeded to remove plaques but failed in clinical trials to improve cognition; thus, the current therapeutic strategy is at preventing tau aggregation. Here, we demonstrated that four phenolic diterpenoids and rosmarinic acid inhibit fibrillization. Since, rosmarinic acid was the most active compound, we observe morphological changes in atomic force microscopy images after treatment...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Mostafa M Ghorab, Mansour S Alsaid, Aiten M Soliman, Fatma A Ragab
No abstract text is available yet for this article.
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Romain Duroux, Nicolas Renault, Joana Esteves Cuelho, Laurence Agouridas, David Blum, Luisa V Lopes, Patricia Melnyk, Saïd Yous
The development of adenosine A2A receptor antagonists has received much interest in recent years for the treatment of neurodegenerative diseases. Based on docking studies, a new series of 2-arylbenzoxazoles has been identified as potential A2AR antagonists. Structure-affinity relationship was investigated in position 2, 5 and 6 of the benzoxazole heterocycle leading to compounds with a micromolar affinity towards the A2A receptor. Compound F1, with an affinity of 1 μm, presented good absorption, distribution, metabolism and excretion properties with an excellent aqueous solubility (184 μm) without being cytotoxic at 100 μm...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Serdar Burmaoğlu, Hatice Seçinti, Erkan Mozioğlu, Ahmet C Gören, Ramazan Altundaş, Hasan Seçen
Four multicaulin and miltirone-like phenanthrene derivatives were synthesised and evaluated as antituberculosis agents. The crucial step of the synthesis was Pschorr coupling of 4-(3-isopropyl-4-methoxyphenyl)-2-(2-aminophenyl)ethane (13) to give 2-isopropyl-3-methoxy-9,10-dihydrophenanthrene (9) and 4-isopropyl-3-methoxy-9,10-dihydrophenanthrene (9a). Compound 9 was converted to multicaulin and miltirone-like phenanthrene derivatives by further reactions. The best antituberculosis activity was exhibited by 2-isopropylphenanthrene-3-ol (11)...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
Mauro Marastoni, Claudio Trapella, Alessandra Scotti, Anna Fantinati, Valeria Ferretti, Erika Marzola, Gallerani Eleonora, Riccardo Gavioli, Delia Preti
The ubiquitin-proteasome system has been largely investigated for its key role in protein degradation mechanisms that regulate both apoptosis and cell division. Because of their antitumour activity, different classes of proteasome inhibitors have been identified to date. Some of these compounds are currently employed in the clinical treatment of several types of cancer among which multiple myeloma. Here, we describe the design, chemistry, biological activity and modelling studies of a large series of amino acid derivatives linked to a naphthoquinone pharmacophoric group through variable spacers...
December 2017: 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
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