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Marta Sánchez-Soto, Verònica Casadó-Anguera, Hideaki Yano, Brian Joseph Bender, Ning-Sheng Cai, Estefanía Moreno, Enric I Canela, Antoni Cortés, Jens Meiler, Vicent Casadó, Sergi Ferré
The poor norepinephrine innervation and high density of Gi/o-coupled α2A - and α2C -adrenoceptors in the striatum and the dense striatal dopamine innervation have prompted the possibility that dopamine could be an effective adrenoceptor ligand. Nevertheless, the reported adrenoceptor agonistic properties of dopamine are still inconclusive. In this study, we analyzed the binding of norepinephrine, dopamine, and several compounds reported as selective dopamine D2 -like receptor ligands, such as the D3 receptor agonist 7-OH-PIPAT and the D4 receptor agonist RO-105824, to α2 -adrenoceptors in cortical and striatal tissue, which express α2A -adrenoceptors and both α2A - and α2C -adrenoceptors, respectively...
March 18, 2018: Molecular Neurobiology
Sanna Rauhamäki, Pekka A Postila, Sanna Niinivehmas, Sami Kortet, Emmi Schildt, Mira Pasanen, Elangovan Manivannan, Mira Ahinko, Pasi Koskimies, Niina Nyberg, Pasi Huuskonen, Elina Multamäki, Markku Pasanen, Risto O Juvonen, Hannu Raunio, Juhani Huuskonen, Olli T Pentikäinen
Monoamine oxidase B (MAO-B) catalyzes deamination of monoamines such as neurotransmitters dopamine and norepinephrine. Accordingly, small-molecule MAO-B inhibitors potentially alleviate the symptoms of dopamine-linked neuropathologies such as depression or Parkinson's disease. Coumarin with a functionalized 3-phenyl ring system is a promising scaffold for building potent MAO-B inhibitors. Here, a vast set of 3-phenylcoumarin derivatives was designed using virtual combinatorial chemistry or rationally de novo and synthesized using microwave chemistry...
2018: Frontiers in Chemistry
Ying Han, Yangmin Zheng, Jingpu Zhang, Changqin Hu
Most third- and fourth-generation cephalosporins, such as cefotaxime, cefmenoxime, cefepime, and cefpirome, contain an aminothiazoyl ring at the C-7 position. Drug impurity, which may be produced either during synthesis or upon degradation, can induce adverse effects. Various reports have indicated that neurotoxicity is a side effect of cephalosporin. In this study, we developed methods for assessing the free-swimming activities and behaviors in zebrafish larvae in response to continuous darkness and stimulation of light-to-dark photoperiod transition by chemical treatments...
2018: Frontiers in Pharmacology
Budimir S Ilić, Ana Kolarević, Gordana Kocić, Andrija Šmelcerović
Apoptotic and/or ROS-induced DNA fragmentation in sperm cells may contribute to the development of male infertility. As the known dietary antioxidant, ascorbic acid prevents ROS production and protects sperm cells from DNA damage. Here, we found that ascorbic acid has the ability to inhibit DNase I, one of the main endonucleases involved in DNA fragmentation during apoptosis. Site Finder and Molecular docking defined the ascorbic acid interactions with the most important residues of DNase I, including H-donor interactions with Asp 168 and Asn 170, and H-acceptor interaction with Asn 170...
March 15, 2018: Biochemical and Biophysical Research Communications
Travis R Helgren, Elif S Seven, Congling Chen, Thomas E Edwards, Bart L Staker, Jan Abendroth, Peter J Myler, James R Horn, Timothy J Hagen
Methionine aminopeptidase (MetAP) is a dinuclear metalloprotease responsible for the cleavage of methionine initiator residues from nascent proteins. MetAP activity is necessary for bacterial proliferation and is therefore a projected novel antibacterial target. A compound library consisting of 294 members containing metal-binding functional groups was screened against Rickettsia prowazekii MetAP to determine potential inhibitory motifs. The compounds were first screened against the target at a concentration of 10 µM and potential hits were determined to be those exhibiting greater than 50% inhibition of enzymatic activity...
March 15, 2018: Bioorganic & Medicinal Chemistry Letters
Keppanan Ravindran, Sivaperumal Sivaramakrishnan, Mubasher Hussain, Chandra Kanta Dash, Bamisope Steve Bamisile, Muhammad Qasim, Wang Liande
Entomopathogenic fungi are rich sources of bioactive secondary metabolites that possess insecticidal properties. The present study reported a novel approach for the identification of insecticidal compounds produced by Lecanicillium lecanii 09 and to assess their toxicity against the diamondback moth Plutella xylostella L. The cyclic peptides groups of toxic substances were separated from L. lecanii 09 through submerged liquid state fermentation. The most abundant toxic metabolite, Bassianolide was purified by high-performance liquid chromatography (HPLC) and its molecular weight and purity were determined by Liquid chromatography - mass spectroscopy (LC-MS), Fourier transformed infrared spectroscopy (FT-IR), and H1 nuclear magnetic resonance (NMR) respectively...
March 15, 2018: Comparative Biochemistry and Physiology. Toxicology & Pharmacology: CBP
Michelle de Paula Reis, Daniely Alves de Lima, Karoline Bach Pauli, Carlos Eduardo Linhares Andreotti, André Luiz Soares de Moraes, Daniela Dib Gonçalves, Italmar Teodorico Navarro, Paulo Sérgio Alves Bueno, Flavio Augusto Vicente Seixas, Arquimedes Gasparotto Junior, Emerson Luiz Botelho Lourenço
Toxoplasmosis is a zoonosis of worldwide distribution. Currently, two drugs, pyrimethamine and sulfadiazine, are used as a reference in the treatment of toxoplasmosis, but the resistance of Toxoplasma gondii appears as a relevant public health problem. In order to identify new drugs to toxoplasmosis treatment, we performed a molecular docking of raltitrexed to T. gondii thymidylate synthase-dihydrofolate reductase (TS-DHFR) and also evaluated its efficacy in infected mice. Initially, raltitrexed was docked on the crystallographic structures of TS-DHFR from T...
March 17, 2018: Parasitology Research
Roberta Gualdani, Maria Maddalena Cavalluzzi, Francesco Tadini-Buoninsegni, Marino Convertino, Philippe Gailly, Anna Stary-Weinzinger, Giovanni Lentini
BACKGROUND/AIMS: Lubeluzole is a benzothiazole derivative that has shown neuroprotective properties in preclinical models of ischemic stroke. However, clinical research on lubeluzole is now at a standstill, since lubeluzole seems to be associated with the acquired long QT syndrome and ventricular arrhythmias. Since the cardiac cellular effects of lubeluzole have not been described thus far, an explanation for the lubeluzole-induced QT interval prolongation is lacking. METHODS: We tested the affinity of lubeluzole, its enantiomer, and the racemate for hERG channel using the patch-clamp technique...
March 10, 2018: Cellular Physiology and Biochemistry
Katarina Ulicna, Zuzana Bednarikova, Wei-Tse Hsu, Martina Holztragerova, Josephine W Wu, Slavka Hamulakova, Steven S-S Wang, Zuzana Gazova
Amyloid aggregates of proteins are one of the most abundant and important naturally occurring self-associated assemblies. Formation of poly/peptide amyloid aggregates is also associated with the widely spread diseases, so called amyloidosis, which include Alzheimer's disease, diabetes mellitus and lysozyme amyloidosis. These disorders are still incurable and novel therapeutical approaches are focused on using small molecules for inhibition of amyloid aggregation. We have observed effect of three structurally distinct groups of tacrine/acridone - coumarin heterodimers on hen egg white (HEW) lysozyme fibrillization in vitro...
March 9, 2018: Colloids and Surfaces. B, Biointerfaces
Mohamed K S El-Nagar, Hajjaj H M Abdu-Allah, Ola I A Salem, Abdel-Hamid N Kafafy, Hanan S M Farghaly
Three new series of 5-aminosalicylic acid derivatives; series I (14, 16-18), series II (19-30) and series III (31-41) were synthesized as potential dual COX-2/5-LOX inhibitors. Their chemical structures were confirmed using spectroscopic tools including IR,1 H NMR,13 C NMR, mass spectroscopy and elemental analyses. The anti-inflammatory activity for all target compounds was evaluated in vivo using carrageenan-induced paw edema. Compound 36 showed the highest anti-inflammatory activity (114.12%) relative to reference drug indomethacin at 4 h interval...
March 6, 2018: Bioorganic Chemistry
Leila Dehestani, Nematollah Ahangar, Seyedeh Mahdieh Hashemi, Hamid Irannejad, Patrick Honarchian Masihi, Aidin Shakiba, Saeed Emami
A series of phenacyl triazole hydrazones 3 have been designed based on the hybridization of (arylalkly)triazole and aroyl hydrazone scaffolds as new anticonvulsant agents. The target compounds 3 were easily synthesized from appropriate phenacyl triazoles and aryl acid hydrazides and characterized by IR, NMR and Mass spectroscopy. The in vivo anticonvulsant evaluation of synthesized compounds by using MES and PTZ tests revealed that they are more effective in MES model respect to PTZ test. All compounds showed 33-100% protection against MES-induced seizures at the dose of 100 mg/kg...
March 7, 2018: Bioorganic Chemistry
Mohamed A Abdelgawad, Madlen B Labib, Waleed A M Ali, Gehan Kamel, Amany A Azouz, El-Shaymaa El-Nahass
A series of newly synthesized 4-aryl-hydrazonopyrazolones were designed and their structures were confirmed by spectral and elemental analyses. All synthesized compounds were evaluated for their in vitro COXs, 5-LOX inhibition, in vivo analgesic and anti-inflammatory activities. Compounds 5d, 5f and 5i were found to be the most potent COX-2/5-LOX inhibitors with superior COX-2 selectivity index values (SI = 5.29-5.69) to reference standard celecoxib (SI = 3.52). Four compounds; 5b, 5c, 5d and 5f showed excellent anti-inflammatory activity (% edema inhibition = 72...
March 8, 2018: Bioorganic Chemistry
Reza Yekta, Gholamreza Dehghan, Samaneh Rashtbari, Rahim Ghadari, Ali Akbar Moosavi-Movahedi
Farnesiferol C (FC) is a natural sesquiterpene coumarin, which includes a widely range of biological activities. In this work, effects of FC on the structure and catalytic function of bovine liver catalase (BLC) was assessed by various spectroscopic and theoretical methods. Kinetic studies showed that FC has a remarkable inhibitory activity on BLC via mixed-type inhibition. The IC50 value as the inhibitory strength of FC was evaluated 1.5 μM. Fluorescence spectroscopy, synchronous fluorescence, CD spectroscopy and UV-vis absorption studies revealed conformational changes in the tertiary and secondary structure of BLC as well as the position of the heme group in the presence of different concentrations of FC...
March 14, 2018: International Journal of Biological Macromolecules
Dipanwita Batabyal, Thomas L Poulos
We have compared the thermodynamics of substrate and redox partner binding of P450cam to its close homologue, CYP101D1, using isothermal titration calorimetry (ITC). CYP101D1 binds camphor about 10-fold more weakly than P450cam which is consistent with the inability of camphor to cause a complete low- to high-spin shift in CYP101D1. Even so molecular dynamics simulations show that camphor is very stable in the CYP101D1 active site similar to P450cam. ITC data on the binding of the CYP101D1 ferredoxin redox partner (abbreviated Arx) shows that the substrate-bound closed state of CYP101D1 binds Arx more tightly than the substrate-free open form...
March 1, 2018: Journal of Inorganic Biochemistry
Liandong Jing, Yanbo Tang, Zhiyan Xiao
Cyclin-dependent kinases (CDKs) are promising drug targets for various human diseases, especially for cancers. Scaffold hopping strategy was applied on CAN508, a known selective CDK9 inhibitor, and a series of pyrazolo[3,4-b]pyridine compounds were synthesized and evaluated in vitro as CDK2 and CDK9 inhibitors. Most compounds exhibited moderate to potent inhibitory activities against both CDK2/cyclin A and CDK9/cyclin T1 systems. Among them, compound 2e showed IC50 values of 0.36 μM for CDK2 and 1.8 μM for CDK9, respectively...
March 8, 2018: Bioorganic & Medicinal Chemistry Letters
Xia Sheng, Xiaotong Jiang, Hailiang Zhao, Dongjin Wan, Yongde Liu, Cleopatra Ashley Ngwenya, Lin Du
The 1:1 complexes of two unsaturated esters with 2,2,2-trifluoroethanol (TFE) were investigated experimentally and computationally. The experimental observations of the spectral shifts of the OH-stretching vibrational transitions were obtained at 113cm-1 for TFE-methyl acrylate (MA) and 92cm-1 for TFE-vinyl acetate (VA). There are three docking sites in the two unsaturated esters for the incoming TFE. The predicted red shifts of the OH-stretching vibrational transitions were found to be larger for the OH⋯OC hydrogen bonded conformer than those for the OH⋯π and OH⋯O ones...
March 10, 2018: Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy
Shaimaa A Abdelatef, Mohammed T El-Saadi, Noha H Amin, Ahmed H Abdelazeem, Hany A Omar, Khaled R A Abdellatif
A novel series of spirobenzo[h]chromene and spirochromane derivatives was designed, synthesized and evaluated as potential anticancer agents against MCF-7 (human breast carcinoma), HT-29 (human colorectal adenocarcinoma) and A549 (human lung carcinoma) cell lines using MTT assay. Eight compounds 7, 8e, 13a-e and 16 showed a better anticancer activity than that of sorafenib, the multi-kinase inhibitor with IC50 values between 1.78 and 5.47 μM or erlotinib with IC50 values over 20 μM. Representative compounds 8e, 13c and 16 were selected for further mechanistic investigation via EGFR, B-RAF and tubulin polymerization assays...
March 5, 2018: European Journal of Medicinal Chemistry
Catalina Soriano-Correa, Carolina Barrientos-Salcedo, Misaela Francisco-Márquez, C Ignacio Sainz-Díaz
Relationships among physicochemical properties, the chemical structure and antibacterial activity of sulfonamides have not been completely explicated yet. Nevertheless, from a therapeutics and prodrugs design point of view, a substituent group can modify the electronic structure, the physicochemical features and chemical reactivity which are critical for the biological activity. In this work, we analyze the substituent effects on the physicochemical properties, toxicity, chemical reactivity and its relation with the bacteriostatic activity of selected sulfonamides by means of DFT-M06-2X calculations in aqueous solution, using quantum chemical and docking descriptors...
February 16, 2018: Journal of Molecular Graphics & Modelling
Shivani Patel, Palmi Modi, Mahesh Chhabria
Caspase-1 is a key endoprotease responsible for the post-translational processing of pro-inflammatory cytokines IL-1β, 18 & 33. Excessive secretion of IL-1β leads to numerous inflammatory and autoimmune diseases. Thus caspase-1 inhibition would be considered as an important therapeutic strategy for development of newer anti-inflammatory agents. Here we have employed an integrated virtual screening by combining pharmacophore mapping and docking to identify small molecules as caspase-1 inhibitors. The ligand based 3D pharmacophore model was generated having the essential structural features of (HBA, HY & RA) using a data set of 27 compounds...
March 8, 2018: Journal of Molecular Graphics & Modelling
Julia B Jasper, Lina Humbeck, Tobias Brinkjost, Oliver Koch
Protein ligand interaction fingerprints are a powerful approach for the analysis and assessment of docking poses to improve docking performance in virtual screening. In this study, a novel interaction fingerprint approach (PADIF, protein per atom score contributions derived interaction fingerprint) is presented which was specifically designed for utilising the GOLD scoring functions' atom contributions together with a specific scoring scheme. This allows the incorporation of known protein-ligand complex structures for a target-specific scoring...
March 16, 2018: Journal of Cheminformatics
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