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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
Azzurra Stefanucci, Andrea Angeli, Marilisa Pia Dimmito, Grazia Luisi, Sonia Del Prete, Clemente Capasso, William A Donald, Adriano Mollica, Claudiu T Supuran
Six tripeptides incorporating acidic amino acid residues were prepared for investigation as activators of β- and γ-carbonic anhydrases (CAs, EC from the pathogenic bacteria Vibrio cholerae, Mycobacterium tuberculosis, and Burkholderia pseudomallei. The primary amino acid residues that are involved in the catalytic mechanisms of these CA classes are poorly understood, although glutamic acid residues near the active site appear to be involved. The tripeptides that contain Glu or Asp residues can effectively activate VchCAβ and VchCAγ (enzymes from V...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Giulio Poli, Margherita Lapillo, Carlotta Granchi, Jessica Caciolla, Nayla Mouawad, Isabella Caligiuri, Flavio Rizzolio, Thierry Langer, Filippo Minutolo, Tiziano Tuccinardi
Fyn tyrosine kinase inhibitors are considered potential therapeutic agents for a variety of human cancers. Furthermore, the involvement of Fyn kinase in signalling pathways that lead to severe pathologies, such as Alzheimer's and Parkinson's diseases, has also been demonstrated. In this study, starting from 3-(benzo[d][1,3]dioxol-5-ylamino)-6-methyl-1,2,4-triazin-5(2H)-one (VS6), a hit compound that showed a micromolar inhibition of Fyn (IC50  = 4.8 μM), we computationally investigated the binding interactions of the 3-amino-1,2,4-triazin-5(2H)-one scaffold and started a preliminary hit to lead optimisation...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Manuel Torres López, Mario Pérez Sayáns, Cintia Chamorro Petronacci, Francisco Barros Angueira, Pilar Gándara Vila, Alejandro Lorenzo Pouso, Abel García García
BACKGROUND: Oral leukoplakia is one of the most common oral premalignant disorder. The classical evaluation through tissue biopsy is not always valid to evaluate the risk of malignization. MATERIAL AND METHODS: RT-qPCR was performed on 47 blood samples (21 patients with leukoplakia, 2 with oral squamous cell carcinoma (OSCC), and 24 healthy patients) and on 11 tissue samples (3 leukoplakia, 4 OSCC, and 4 samples of healthy tissue). RESULTS: There are significant differences in expression between the different groups (F = 4...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Andrea Jiménez-González, Cristina Quispe, Jorge Bórquez, Beatriz Sepúlveda, Felipe Riveros, Carlos Areche, Edgar Nagles, Olimpo García-Beltrán, Mario J Simirgiotis
UHPLC/ESI/MS identification of organic compounds is the first step in the majority of screening techniques for the characterization of biologically active metabolites in natural sources. This paper describes a method for the fast identification and characterisation of secondary metabolites in Leptocarpha rivularis DC. (Palo negro) extracts by HPLC/UV (DAD)-Mass Spectrometry (HPLC/MS). The plant is used for the treatment of several diseases since pre-hispanic Mapuche times. Thirty-seven compounds were detected in the aqueous edible extract for the first time including 4 sesquiterpenes, 10 flavonoids, 9 oxylipins, 2 organic acids, and 11 phenolic acids...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Zixin Xie, Donghua Cheng, Lu Luo, Guoliang Shen, Suwei Pan, Yaqian Pan, Bo Chen, Xuebao Wang, Zhiguo Liu, Yuan Zhang, Faqing Ye
A series of 4-bromo-N-(3,5-dimethoxyphenyl)benzamide derivatives were designed and synthesised as novel fibroblast growth factor receptor-1 (FGFR1) inhibitors. We found that one of the most promising compounds, C9, inhibited five non-small cell lung cancer (NSCLC) cell lines with FGFR1 amplification, including NCI-H520, NCI-H1581, NCI-H226, NCI-H460 and NCI-H1703. Moreover, the IC50 values for the compound C9 were 1.36 ± 0.27 µM, 1.25 ± 0. 23 µM, 2.31 ± 0.41 µM, 2.14 ± 0.36 µM and 1...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Jun Lu, Maolin Wang, Ziyue Wang, Zhongqi Fu, Aiping Lu, Ge Zhang
Cathepsin K (Cat K), highly expressed in osteoclasts, is a cysteine protease member of the cathepsin lysosomal protease family and has been of increasing interest as a target of medicinal chemistry efforts for its role in bone matrix degradation. Inhibition of the Cat K enzyme reduces bone resorption and thus, has rendered the enzyme as an attractive target for anti-resorptive osteoporosis therapy. Over the past decades, considerable efforts have been made to design and develop highly potent, excellently selective and orally applicable Cat K inhibitors...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Shahenda M El-Messery, El-Sayed E Habib, Sarah T A Al-Rashood, Ghada S Hassan
A series of amide chalcones conjugated with different secondary amines were synthesised and characterised by different spectroscopic techniques 1 H NMR, 13 C NMR, and ESI-MS. They were screened for in vitro antibacterial activity. Compounds 36, 37, 38, 42, and 44 are the most active among the synthesised series exhibiting MIC value of 2.0-10.0 µg/ml against different bacterial strains. Compound 36 was equipotent to the standard drug Ampicillin displaying MBC value of 2.0 µg/ml against the bacterial strain Staphylococcus aureus...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Ning Sun, Ruo-Lan Du, Yuan-Yuan Zheng, Qi Guo, Sen-Yuan Cai, Zhi-Hua Liu, Zhi-Yuan Fang, Wen-Chang Yuan, Ting Liu, Xiao-Mei Li, Yu-Jing Lu, Kwok-Yin Wong
The increasing incidence of multidrug resistant bacterial infection renders an urgent need for the development of new antibiotics. To develop small molecules disturbing FtsZ activity has been recognized as promising approach to search for antibacterial of high potency systematically. Herein, a series of novel quinolinium derivatives were synthesized and their antibacterial activities were investigated. The compounds show strong antibacterial activities against different bacteria strains including MRSA, VRE and NDM-1 Escherichia coli...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Verônica da Silva Cardoso, Alane Beatriz Vermelho, Eduardo Ricci Junior, Igor Almeida Rodrigues, Ana Maria Mazotto, Claudiu T Supuran
The β-carbonic anhydrase (CA, EC from Leishmania spp. (LdcCA) is effectively inhibited by aromatic/heterocyclic sulphonamides, in the low nanomolar range, but no in vitro antileishmanial activity was detected for such compounds. We formulated some of these sulphonamides as nanoemulsions (NEs) in clove oil, and tested them in vitro against Leishmania infantum MHOM/BR/1974/PP75 and Leishmania amazonensis IFLA/BR/1967/PH8 strains. Interesting inhibitory concentrations IC50 were observed for some of the sulphonamides NEs, with IC50 as low as 3...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Samar Said Fatahala, Shahenda Mahgub, Heba Taha, Rania Helmy Abd-El Hameed
No abstract text is available yet for this article.
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Wagdy M Eldehna, Reem I Al-Wabli, Maha S Almutairi, Adam B Keeton, Gary A Piazza, Hatem A Abdel-Aziz, Mohamed I Attia
In connection with our research program on the development of novel indolin-2-one-based anticancer candidates, herein we report the design and synthesis of different series of hydrazonoindolin-2-ones 3a-e, 5a-e, 7a-c, and 10a-l. The synthesised derivatives were in vitro evaluated for their anti-proliferative activity towards lung A-549, colon HT-29, and breast ZR-75 human cancer cell lines. Compounds 5b, 5c, 7b, and 10e emerged as the most potent derivatives with average IC50 values of 4.37, 2.53, 2.14, and 4...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Benoit Métayer, Andrea Angeli, Agnès Mingot, Kévin Jouvin, Gwilherm Evano, Claudiu T Supuran, Sébastien Thibaudeau
After hydrofluorination of ynesulphonamides in superacid or in the presence of hydrofluoric acid/base reagents, a series of α-fluoroenamides has been synthesised and tested for the inhibition of carbonic anhydrase (CA, EC isoforms. This study reveals a new, highly selective family of cancer-related transmembrane human (h) CA IX/XII inhibitors. These original fluorinated ureido isosters do not inhibit the widespread cytosolic isoforms hCA I and II and selectively inhibit the transmembrane cancer-related hCA IX and XII, offering interesting new leads for future studies...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
María Sebastián, Adrián Velázquez-Campoy, Milagros Medina
Emergence of multidrug-resistant bacteria forces us to explore new therapeutic strategies, and proteins involved in key metabolic pathways are promising anti-bacterial targets. Bifunctional flavin-adenine dinucleotide (FAD) synthetases (FADS) are prokaryotic enzymes that synthesise the flavin mononucleotide (FMN) and FAD cofactors. The FADS from the human pathogen Streptococcus pneumoniae (SpnFADS)-causative agent of pneumonia in humans - shows relevant catalytic dissimilarities compared to other FADSs...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Cheng-Shi Jiang, Chun-Lin Zhuang, Kongkai Zhu, Juan Zhang, Luis Alexandre Muehlmann, João Paulo Figueiró Longo, Ricardo Bentes Azevedo, Wen Zhang, Ning Meng, Hua Zhang
A new Keap1-Nrf2 protein-protein interaction (PPI) inhibitor ZJ01 was identified from our compound library by fluorescence polarization assay, surface plasmon resonance, molecular docking and molecular dynamics simulation. ZJ01 could in vitro trigger Nrf2 nuclear translocation, subsequently resulting in increased mRNA levels of Nrf2 target genes HO-1 and NQO1. Meanwhile, ZJ01 suppressed LPS-induced production of ROS and the mRNA levels of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 in H9c2 cardiac cells...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Rosanna Caliandro, Alessandro Pesaresi, Luca Cariati, Antonio Procopio, Manuela Oliverio, Doriano Lamba
Acetylcholinesterase inhibitors were introduced for the symptomatic treatment of Alzheimer's disease (AD). Among the currently approved inhibitors, donepezil (DNP) is one of the most preferred choices in AD therapy. The X-ray crystal structures of Torpedo californica AChE in complex with two novel rigid DNP-like analogs, compounds 1 and 2, have been determined. Kinetic studies indicated that compounds 1 and 2 show a mixed-type inhibition against TcAChE, with Ki values of 11.12 ± 2.88 and 29.86 ± 1...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Hongzhi Lin, Qihang Li, Qi Li, Jie Zhu, Kai Gu, Xueyang Jiang, Qianqian Hu, Feng Feng, Wei Qu, Yao Chen, Haopeng Sun
Histone demethylation is a vital process in epigenetic regulation of gene expression. A number of histone demethylases are present to control the methylated states of histone. Among these enzymes, KDM4s are one subfamily of JmjC KDMs and play important roles in both normal and cancer cells. The discovery of KDM4s inhibitors is a potential therapeutic strategy against different diseases including cancer. Here, we summarize the development of KDM4s inhibitors and some related pharmaceutical information to provide an update of recent progress in KDM4s inhibitors...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Irini Doytchinova, Mariyana Atanasova, Iva Valkova, Georgi Stavrakov, Irena Philipova, Zvetanka Zhivkova, Dimitrina Zheleva-Dimitrova, Spiro Konstantinov, Ivan Dimitrov
The inhibition of the enzyme acetylcholinesterase (AChE) increases the levels of the neurotransmitter acetylcholine and symptomatically improves the affected cognitive function. In the present study, we searched for novel AChE inhibitors by docking-based virtual screening of the standard lead-like set of ZINC database containing more than 6 million small molecules using GOLD software. The top 10 best-scored hits were tested in vitro for AChE affinity, neurotoxicity, GIT and BBB permeability. The main pharmacokinetic parameters like volume of distribution, free fraction in plasma, total clearance, and half-life were predicted by previously derived models...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
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