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  Subjects -> CHEMISTRY (Total: 849 journals)
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    - CHEMISTRY (604 journals)
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CHEMISTRY (604 journals)                  1 2 3 4 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 6)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 25)
ACS Catalysis     Full-text available via subscription   (Followers: 30)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 16)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 24)
ACS Macro Letters     Full-text available via subscription   (Followers: 22)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 36)
ACS Nano     Full-text available via subscription   (Followers: 197)
ACS Photonics     Full-text available via subscription   (Followers: 9)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 20)
Acta Chemica Iasi     Open Access   (Followers: 2)
Acta Chimica Sinica     Full-text available via subscription  
Acta Chimica Slovaca     Open Access   (Followers: 1)
Acta Chromatographica     Full-text available via subscription   (Followers: 8)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 5)
Acta Scientifica Naturalis     Open Access   (Followers: 2)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 5)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 7)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 4)
Advanced Functional Materials     Hybrid Journal   (Followers: 45)
Advanced Science Focus     Free   (Followers: 3)
Advances in Chemical Engineering and Science     Open Access   (Followers: 52)
Advances in Chemical Science     Open Access   (Followers: 11)
Advances in Chemistry     Open Access   (Followers: 11)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 18)
Advances in Drug Research     Full-text available via subscription   (Followers: 22)
Advances in Enzyme Research     Open Access   (Followers: 8)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 14)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 16)
Advances in Nanoparticles     Open Access   (Followers: 12)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15)
Advances in Polymer Science     Hybrid Journal   (Followers: 40)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 17)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Science and Technology     Full-text available via subscription   (Followers: 7)
African Journal of Bacteriology Research     Open Access  
African Journal of Chemical Education     Open Access   (Followers: 2)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 7)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Alchemy : Jurnal Penelitian Kimia     Open Access  
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 65)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 14)
American Journal of Chemistry     Open Access   (Followers: 24)
American Journal of Plant Physiology     Open Access   (Followers: 12)
American Mineralogist     Full-text available via subscription   (Followers: 8)
Anadolu University Journal of Science and Technology     Open Access  
Analyst     Full-text available via subscription   (Followers: 42)
Angewandte Chemie     Hybrid Journal   (Followers: 146)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 194)
Annales UMCS, Chemia     Open Access   (Followers: 1)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 1)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 3)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 3)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 7)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 12)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 14)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antiviral Chemistry and Chemotherapy     Hybrid Journal  
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 6)
Applied Spectroscopy     Full-text available via subscription   (Followers: 23)
Applied Surface Science     Hybrid Journal   (Followers: 23)
Arabian Journal of Chemistry     Open Access   (Followers: 6)
ARKIVOC     Open Access   (Followers: 2)
Asian Journal of Biochemistry     Open Access   (Followers: 1)
Atomization and Sprays     Full-text available via subscription   (Followers: 3)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 6)
Autophagy     Hybrid Journal   (Followers: 2)
Avances en Quimica     Open Access   (Followers: 1)
Biochemical Pharmacology     Hybrid Journal   (Followers: 9)
Biochemistry     Full-text available via subscription   (Followers: 258)
Biochemistry Insights     Open Access   (Followers: 5)
Biochemistry Research International     Open Access   (Followers: 6)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 9)
Bioinspired Materials     Open Access   (Followers: 3)
Biointerface Research in Applied Chemistry     Open Access   (Followers: 2)
Biointerphases     Open Access   (Followers: 1)
Biology, Medicine, & Natural Product Chemistry     Open Access  
Biomacromolecules     Full-text available via subscription   (Followers: 18)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 10)
Biomedical Chromatography     Hybrid Journal   (Followers: 7)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 3)
BioNanoScience     Partially Free   (Followers: 4)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 114)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 100)
Bioorganic Chemistry     Hybrid Journal   (Followers: 10)
Biopolymers     Hybrid Journal   (Followers: 17)
Biosensors     Open Access   (Followers: 1)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 2)
Bitácora Digital     Open Access  
Boletin de la Sociedad Chilena de Quimica     Open Access  
Bulletin of the Chemical Society of Ethiopia     Open Access   (Followers: 3)
Bulletin of the Chemical Society of Japan     Full-text available via subscription   (Followers: 26)
Bulletin of the Korean Chemical Society     Hybrid Journal   (Followers: 1)
C - Journal of Carbon Research     Open Access   (Followers: 2)
Canadian Association of Radiologists Journal     Full-text available via subscription   (Followers: 2)
Canadian Journal of Chemistry     Full-text available via subscription   (Followers: 8)
Canadian Mineralogist     Full-text available via subscription   (Followers: 3)
Carbohydrate Research     Hybrid Journal   (Followers: 26)
Carbon     Hybrid Journal   (Followers: 64)
Catalysis for Sustainable Energy     Open Access   (Followers: 5)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 7)
Catalysis Science and Technology     Free   (Followers: 6)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 7)
Cellulose     Hybrid Journal   (Followers: 5)
Cereal Chemistry     Full-text available via subscription   (Followers: 4)
ChemBioEng Reviews     Full-text available via subscription   (Followers: 1)
ChemCatChem     Hybrid Journal   (Followers: 7)
Chemical and Engineering News     Free   (Followers: 12)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 71)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 21)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 18)
Chemical Reviews     Full-text available via subscription   (Followers: 159)
Chemical Science     Open Access   (Followers: 20)
Chemical Technology     Open Access   (Followers: 14)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 4)
Chemical Week     Full-text available via subscription   (Followers: 7)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 53)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 25)
ChemInform     Hybrid Journal   (Followers: 7)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 5)
Chemistry & Biology     Full-text available via subscription   (Followers: 30)
Chemistry & Industry     Hybrid Journal   (Followers: 4)
Chemistry - A European Journal     Hybrid Journal   (Followers: 128)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 15)
Chemistry and Materials Research     Open Access   (Followers: 15)
Chemistry Central Journal     Open Access   (Followers: 4)
Chemistry Education Research and Practice     Free   (Followers: 4)
Chemistry in Education     Open Access   (Followers: 3)
Chemistry International     Hybrid Journal   (Followers: 1)
Chemistry Letters     Full-text available via subscription   (Followers: 45)
Chemistry of Materials     Full-text available via subscription   (Followers: 168)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
Chemistry-Didactics-Ecology-Metrology     Open Access  
ChemistryOpen     Open Access   (Followers: 2)
Chemkon - Chemie Konkret, Forum Fuer Unterricht Und Didaktik     Hybrid Journal  
Chemoecology     Hybrid Journal   (Followers: 2)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 15)
Chemosensors     Open Access  
ChemPhysChem     Hybrid Journal   (Followers: 8)
ChemPlusChem     Hybrid Journal   (Followers: 1)
ChemTexts     Hybrid Journal  
CHIMIA International Journal for Chemistry     Full-text available via subscription   (Followers: 3)
Chinese Journal of Chemistry     Hybrid Journal   (Followers: 6)
Chinese Journal of Polymer Science     Hybrid Journal   (Followers: 10)
Chromatographia     Hybrid Journal   (Followers: 24)
Chromatography Research International     Open Access   (Followers: 7)
Clay Minerals     Full-text available via subscription   (Followers: 8)
Cogent Chemistry     Open Access  
Colloid and Interface Science Communications     Open Access  
Colloid and Polymer Science     Hybrid Journal   (Followers: 10)
Colloids and Surfaces B: Biointerfaces     Hybrid Journal   (Followers: 8)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 3)
Combustion Science and Technology     Hybrid Journal   (Followers: 18)
Comments on Inorganic Chemistry: A Journal of Critical Discussion of the Current Literature     Hybrid Journal   (Followers: 1)
Composite Interfaces     Hybrid Journal   (Followers: 5)
Comprehensive Chemical Kinetics     Full-text available via subscription   (Followers: 2)
Comptes Rendus Chimie     Full-text available via subscription  
Comptes Rendus Physique     Full-text available via subscription   (Followers: 1)
Computational and Theoretical Chemistry     Hybrid Journal   (Followers: 9)
Computational Biology and Chemistry     Hybrid Journal   (Followers: 11)
Computational Chemistry     Open Access   (Followers: 2)
Computers & Chemical Engineering     Hybrid Journal   (Followers: 10)
Coordination Chemistry Reviews     Full-text available via subscription   (Followers: 1)
Copernican Letters     Open Access  
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 5)
Crystal Structure Theory and Applications     Open Access   (Followers: 3)
CrystEngComm     Full-text available via subscription   (Followers: 10)
Current Catalysis     Hybrid Journal   (Followers: 1)
Current Metabolomics     Hybrid Journal   (Followers: 3)
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 8)
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 15)
Current Research in Chemistry     Open Access   (Followers: 8)
Current Science     Open Access   (Followers: 47)
Dalton Transactions     Full-text available via subscription   (Followers: 18)
Detection     Open Access   (Followers: 2)
Developments in Geochemistry     Full-text available via subscription   (Followers: 2)
Diamond and Related Materials     Hybrid Journal   (Followers: 11)
Dislocations in Solids     Full-text available via subscription  
Doklady Chemistry     Hybrid Journal  
Drying Technology: An International Journal     Hybrid Journal   (Followers: 3)
Eclética Química     Open Access   (Followers: 1)
Ecological Chemistry and Engineering S     Open Access   (Followers: 2)
Ecotoxicology and Environmental Contamination     Open Access  
Educación Química     Open Access   (Followers: 1)
Education for Chemical Engineers     Hybrid Journal   (Followers: 5)
EDUSAINS     Open Access  
Elements     Full-text available via subscription   (Followers: 1)
Environmental Chemistry     Hybrid Journal   (Followers: 5)
Environmental Chemistry Letters     Hybrid Journal   (Followers: 2)

        1 2 3 4 | Last

Journal Cover Bioorganic & Medicinal Chemistry
  [SJR: 1.064]   [H-I: 119]   [114 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0968-0896
   Published by Elsevier Homepage  [3039 journals]
  • Quinazolinone derivatives: Synthesis and comparison of inhibitory
           mechanisms on α-glucosidase
    • Authors: Mankun Wei; Wei-Ming Chai; Rui Wang; Qin Yang; Zhihong Deng; Yiyuan Peng
      Pages: 1303 - 1308
      Abstract: Publication date: 15 February 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 4
      Author(s): Mankun Wei, Wei-Ming Chai, Rui Wang, Qin Yang, Zhihong Deng, Yiyuan Peng
      In this study, eight quinazolinone derivatives were designed and synthesized. Their inhibitory activities on α-glucosidase were assessed in vitro. Two compounds: 2-(4-chlorophenyl)-quinazolin-4(3H)-one (CQ) and 2-(4-bromophenyl)-quinazolin-4(3H)-one (BQ) were found to be potent inhibitors of α-glucosidase with IC50 values of 12.5±0.1μM and 15.6±0.2μM, respectively. Spectroscopy methods were performed to analyze the inhibitory mechanisms of both compounds on α-glucosidase. The results revealed that they reversibly inhibited α-glucosidase in a non-competitive manner. CQ and BQ could statically quench the fluorescence spectra by formation of an inhibitor-α-glucosidase complex. The interaction between CQ and α-glucosidase depended on hydrogen bonds, electrostatic and hydrophobic force, while the driving force of the binding between BQ and the enzyme was hydrophobic. The docking results showed that BQ was less active than CQ against α-glucosidase because of its weaker interaction with the enzyme. In brief, the quinazolinone derivatives identified in this work were potentially promising candidates for developing as novel anti-diabetic agents.
      Graphical abstract image

      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2016.09.042
       
  • Probing A-form DNA: A fluorescent aminosugar probe and dual recognition by
           anthraquinone-neomycin conjugates
    • Authors: Derrick Watkins; Changjun Gong; Patrick Kellish; Dev P. Arya
      Pages: 1309 - 1319
      Abstract: Publication date: 15 February 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 4
      Author(s): Derrick Watkins, Changjun Gong, Patrick Kellish, Dev P. Arya
      Nucleic acids adopt a broad array of hydrogen-bonded structures that enable their diverse roles in the cell; even the familiar DNA double helix displays subtle architectural nuances that are sequence dependent. While there have been many approaches for recognition of B-form nucleic acids, A-form DNA recognition has lagged behind. Here, using a tight binding fluorescein-neomycin (F-neo) conjugate that can probe the electrostatic environment of A-form DNA major groove, we developed a fluorescent displacement assay to be used as a screen for DNA duplex-binding compounds. As opposed to intercalating dyes that can significantly perturb DNA structure, the groove binding F-neo allows the probing of native DNA conformation. In combination with the assay development and probing of DNA grooves, we also report the synthesis and binding of a series of neomycin-anthraquinone conjugates, two units with a known preference for binding GC rich DNA. The assay can be used to identify duplex DNA-binding compounds, as well as probe structural features of a target DNA duplex, and can easily be scaled up for high throughput screening of compound libraries.
      Graphical abstract image

      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2016.11.003
       
  • Studies of TAK1-centered polypharmacology with novel covalent TAK1
           inhibitors
    • Authors: Li Tan; Deepak Gurbani; Ellen L. Weisberg; Douglas S. Jones; Suman Rao; William D. Singer; Faviola M. Bernard; Samar Mowafy; Annie Jenney; Guangyan Du; Atsushi Nonami; James D. Griffin; Douglas A. Lauffenburger; Kenneth D. Westover; Peter K. Sorger; Nathanael S. Gray
      Pages: 1320 - 1328
      Abstract: Publication date: 15 February 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 4
      Author(s): Li Tan, Deepak Gurbani, Ellen L. Weisberg, Douglas S. Jones, Suman Rao, William D. Singer, Faviola M. Bernard, Samar Mowafy, Annie Jenney, Guangyan Du, Atsushi Nonami, James D. Griffin, Douglas A. Lauffenburger, Kenneth D. Westover, Peter K. Sorger, Nathanael S. Gray
      Targeted polypharmacology provides an efficient method of treating diseases such as cancer with complex, multigenic causes provided that compounds with advantageous activity profiles can be discovered. Novel covalent TAK1 inhibitors were validated in cellular contexts for their ability to inhibit the TAK1 kinase and for their polypharmacology. Several inhibitors phenocopied reported TAK1 inhibitor 5Z-7-oxozaenol with comparable efficacy and complementary kinase selectivity profiles. Compound 5 exhibited the greatest potency in RAS-mutated and wild-type RAS cell lines from various cancer types. A biotinylated derivative of 5, 27, was used to verify TAK1 binding in cells. The newly described inhibitors constitute useful tools for further development of multi-targeting TAK1-centered inhibitors for cancer and other diseases.
      Graphical abstract image

      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2016.11.034
       
  • Antiprotozoal glutathione derivatives with flagellar membrane binding
           activity against T. brucei rhodesiense
    • Authors: Sylvie Daunes; Vanessa Yardley; Simon L. Croft; Claudius D'Silva
      Pages: 1329 - 1340
      Abstract: Publication date: 15 February 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 4
      Author(s): Sylvie Daunes, Vanessa Yardley, Simon L. Croft, Claudius D'Silva
      A new series of N-substituted S-(2,4-dinitrophenyl)glutathione dibutyl diesters were synthesized to improve in vitro anti-protozoal activity against the pathogenic parasites Trypanosoma brucei rhodesiense, Trypanosoma cruzi and Leishmania donovani. The results obtained indicate that N-substituents enhance the inhibitory properties of glutathione diesters whilst showing reduced toxicity against KB cells as in the cases of compounds 5, 9, 10, 16, 18 and 19. We suggest that the interaction of N-substituted S-(2,4-dinitrophenyl) glutathione dibutyl diesters with T. b. brucei occurs mainly by weak hydrophobic interactions such as London and van der Waals forces. A QSAR study indicated that the inhibitory activity of the peptide is associated negatively with the average number of C atoms, NC and positively to SZX, the ZX shadow a geometric descriptor related to molecular size and orientation of the compound. HPLC-UV studies in conjunction with optical microscopy indicate that the observed selectivity of inhibition of these compounds against bloodstream form T. b. brucei parasites in comparison to L. donovani under the same conditions is due to intracellular uptake via endocytosis in the flagellar pocket.
      Graphical abstract image

      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2016.12.016
       
  • Synthesis, biological evaluation and molecular docking analysis of
           2-phenyl-benzofuran-3-carboxamide derivatives as potential inhibitors of
           Staphylococcus aureus Sortase A
    • Authors: Wan He; Yong Zhang; Jian Bao; Xinxian Deng; Jennifer Batara; Shawn Casey; Qiuyuan Guo; Faqin Jiang; Lei Fu
      Pages: 1341 - 1351
      Abstract: Publication date: 15 February 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 4
      Author(s): Wan He, Yong Zhang, Jian Bao, Xinxian Deng, Jennifer Batara, Shawn Casey, Qiuyuan Guo, Faqin Jiang, Lei Fu
      In Gram-positive bacteria, Sortase A (Srt A) is a critical cysteine transpeptidase that is responsible for recognizing and assembling surface virulence proteins through the recognition of a LPXTG (leucine, proline, X, threonine, and glycine, where X is any amino acid) signal. Mutants lacking genes for Srt A attenuate infections without affecting microbial viability. Here a series of 2-phenyl-benzofuran-3-carboxamide derivatives were synthesized and identified as potent Srt A inhibitors. Activity assays revealed that multiple compounds exhibited excellent inhibitory activity against Srt A compared with known Sortase A inhibitor pHMB (IC50 =130μM). Structural activity relationships (SARs) demonstrated that the amide group at 3-position was essential for inhibitory activity. Replacement of the hydroxyl group at the 2-phenyl position of benzofuran with other substitutions such as a methoxyl, halogen or nitro group reduced the enzyme inhibitory activity in most cases. The compound Ia-22 was found to be the most potent inhibitor against the enzyme with an IC50 value of 30.8μM. Molecular docking studies showed Ia-22 shared similar binding pattern with substrate LPXTG in the binding pocket of Srt A (PDB: 2KID) including i-butyl stretching, L-shape pattern kinking, and H-bond interaction with Srt A functional site residues Cys184, Trp194 and Arg197.
      Graphical abstract image

      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2016.12.030
       
  • Synthesis, anticholinesterase activity and molecular modeling study of
           novel carbamate-substituted thymol/carvacrol derivatives
    • Authors: Belma Zengin Kurt; Isil Gazioglu; Aydan Dag; Ramin Ekhteiari Salmas; Gülru Kayık; Serdar Durdagi; Fatih Sonmez
      Pages: 1352 - 1363
      Abstract: Publication date: 15 February 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 4
      Author(s): Belma Zengin Kurt, Isil Gazioglu, Aydan Dag, Ramin Ekhteiari Salmas, Gülru Kayık, Serdar Durdagi, Fatih Sonmez
      New thymol and carvacrol derivatives with the carbamate moiety were synthesized and their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated. 5-isopropyl-2-methylphenyl(3-fluorophenyl)carbamate (29) was found to be the most potent AChE inhibitor with IC50 values of 2.22μM, and 5-isopropyl-2-methylphenyl (4-fluorophenyl)carbamate (30) exhibited the strongest inhibition against BuChE with IC50 value of 0.02μM. Additionally, the result of H4IIE hepatoma cell toxicity assay for compounds 18, 20, 29, 30 and 35 showed negligible cell death at 0.07–10μM. Moreover in order to better understand the inhibitory profiles of these molecules, molecular modeling studies were applied. Binding poses of studied compounds at the binding pockets of AChE and BuChE targets were determined. Predicted binding energies of these compounds as well as structural and dynamical profiles of molecules at the target sites were estimated using induced fit docking (IFD) algorithms and post-processing molecular dynamics (MD) simulations methods (i.e., Molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) approaches).
      Graphical abstract image

      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2016.12.037
       
  • Synthesis of pharmacologically important naphthoquinones and anticancer
           activity of 2-benzyllawsone through DNA topoisomerase-II inhibition
    • Authors: Balagani Sathish Kumar; Kusumoori Ravi; Amit Kumar Verma; Kaneez Fatima; Mohammad Hasanain; Arjun Singh; Jayanta Sarkar; Suaib Luqman; Debabrata Chanda; Arvind S. Negi
      Pages: 1364 - 1373
      Abstract: Publication date: 15 February 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 4
      Author(s): Balagani Sathish Kumar, Kusumoori Ravi, Amit Kumar Verma, Kaneez Fatima, Mohammad Hasanain, Arjun Singh, Jayanta Sarkar, Suaib Luqman, Debabrata Chanda, Arvind S. Negi
      Naphthoquinones are naturally occurring biologically active entities. Practical de novo syntheses of three naphthoquinones i.e. lawsone (1), lapachol (2), and β-lapachone (3b) have been achieved from commercially available starting materials. The conversion of lapachol (2) to β-lapachone (3b) was achieved through p-TSA/Iodine/BF3-etherate mediated regioselective cyclisation. Further, 2-alkyl and 2-benzyllawsone derivatives have been prepared as possible anticancer agents. Four derivatives exhibited significant anticancer activity and the best analogue i.e. compound 21a exhibited potential anticancer activity (IC50 =5.2μM) against FaDu cell line. Compound 21a induced apoptosis through activation of caspase pathway and exerted cell cycle arrest at S phase in FaDU cells. It also exhibited significant topoisomerase-II inhibition activity. Compound 21a was found to be safe in Swiss albino mice up to 1000mg/kg oral dose.
      Graphical abstract image

      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2016.12.043
       
  • Synthesis of new analogs of AKBA and evaluation of their anti-inflammatory
           activities
    • Authors: Bharani Meka; Suryachandra Rao Ravada; Muthyala Murali Krishna Kumar; Kurre Purna Nagasree; Trimurtulu Golakoti
      Pages: 1374 - 1388
      Abstract: Publication date: 15 February 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 4
      Author(s): Bharani Meka, Suryachandra Rao Ravada, Muthyala Murali Krishna Kumar, Kurre Purna Nagasree, Trimurtulu Golakoti
      A new series of 11-keto-β-boswellic acid and 3-O-acetyl-11-keto-β-boswellic acid analogs (5, 7, 8, 10, 13, 18a-d, 27a-c, 28a-d) were synthesized by modification of hydroxyl and acid functional moieties of boswellic acids. The structures of these analogs were confirmed by spectral data analysis (1H, 13C NMR and mass). Compounds 18b, 27a and 8 showed potent 5-lipoxygenase enzyme inhibitory activity (IC50: 19.53, 20.31 and 44.14μg/mL). The computational studies revealed that selectivity of AKBA is due to its fitment into the 5-LOX receptor, which is missing for the other enzymes like 12-LOX, COX-1 and COX-2. Our study found potentiating effects of 2-formyl and 3-keto substituents in reviving inactive AKBA analogues possessing essential COOH group at 4th position.
      Graphical abstract image

      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2016.12.045
       
  • Development of highly-sensitive detection system in 19F NMR for bioactive
           compounds based on the assembly of paramagnetic complexes with fluorinated
           cubic silsesquioxanes
    • Authors: Takahiro Kakuta; Hayato Narikiyo; Jong-Hwan Jeon; Kazuo Tanaka; Yoshiki Chujo
      Pages: 1389 - 1393
      Abstract: Publication date: 15 February 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 4
      Author(s): Takahiro Kakuta, Hayato Narikiyo, Jong-Hwan Jeon, Kazuo Tanaka, Yoshiki Chujo
      This manuscript reports the detection system with 19F NMR probes for bioactive amine compounds at sub-micro molar concentrations. Water-soluble fluorinated polyhedral oligomeric silsesquioxane (POSS) derivatives were prepared, and the paramagnetic Ni-porphyrin (NiPor) with the fluorinated POSS (F-POSS) was adsorbed in the buffer. By adding the series of amine derivatives to the homogeneous dispersion containing the POSS-NiPor complexes, the changes in the signal intensity were evaluated. It was clearly observed from homogeneous dispersions that the signal intensity of 19F NMR decreased especially in the presence of ethanediamine and hexylamine. From the dynamic light scattering measurements, it was revealed that the assembly of the F-POSS complexes was dramatically induced by the amine compounds when the signal intensity decreased. According to these data, it is proposed that the signal reduction of 19F NMR from the POSS-NiPor complexes could be induced via the strong paramagnetic relaxation enhancement from NiPor in the assembly. Finally, based on the signal reduction by the assembly, we can detect the amine derivatives under 1μM concentration which is similar sensitivity to the conventional fluorescence probes. Our system is valid to monitor the distribution of the bio-active molecules at cellular concentrations.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2016.12.044
       
  • Discovery of a novel series of N-hydroxypyridone derivatives protecting
           astrocytes against hydrogen peroxide-induced toxicity via improved
           mitochondrial functionality
    • Authors: Sarbjit Singh; Ja-Il Goo; Hyojin Noh; Sung Jae Lee; Myoung Woo Kim; Hyejun Park; Hitesh B. Jalani; Kyeong Lee; Chunsook Kim; Won-Ki Kim; Chung Ju; Yongseok Choi
      Pages: 1394 - 1405
      Abstract: Publication date: 15 February 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 4
      Author(s): Sarbjit Singh, Ja-Il Goo, Hyojin Noh, Sung Jae Lee, Myoung Woo Kim, Hyejun Park, Hitesh B. Jalani, Kyeong Lee, Chunsook Kim, Won-Ki Kim, Chung Ju, Yongseok Choi
      Astrocytes play a key role in brain homeostasis, protecting neurons against neurotoxic stimuli such as oxidative stress. Therefore, the neuroprotective therapeutics that enhance astrocytic functionality has been regarded as a promising strategy to reduce brain damage. We previously reported that ciclopirox, a well-known antifungal N-hydroxypyridone compound, protects astrocytes from oxidative stress by enhancing mitochondrial function. Using the N-hydroxypyridone scaffold, we have synthesized a series of cytoprotective derivatives. Mitochondrial activity assay showed that N-hydroxypyridone derivatives with biphenyl group have comparable to better protective effects than ciclopirox in astrocytes exposed to H2O2. N-hydroxypyridone derivatives, especially 11g, inhibited H2O2-induced deterioration of mitochondrial membrane potential and oxygen consumption rate, and significantly improved cell viability of astrocytes. The results indicate that the N-hydroxypyridone motif can provide a novel cytoprotective scaffold for astrocytes via enhancing mitochondrial functionality.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2016.12.052
       
  • Development of 111In-labeled exendin(9-39) derivatives for single-photon
           emission computed tomography imaging of insulinoma
    • Authors: Hiroyuki Kimura; Hirokazu Matsuda; Yu Ogawa; Hiroyuki Fujimoto; Kentaro Toyoda; Naotaka Fujita; Kenji Arimitsu; Keita Hamamatsu; Yusuke Yagi; Masahiro Ono; Nobuya Inagaki; Hideo Saji
      Pages: 1406 - 1412
      Abstract: Publication date: 15 February 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 4
      Author(s): Hiroyuki Kimura, Hirokazu Matsuda, Yu Ogawa, Hiroyuki Fujimoto, Kentaro Toyoda, Naotaka Fujita, Kenji Arimitsu, Keita Hamamatsu, Yusuke Yagi, Masahiro Ono, Nobuya Inagaki, Hideo Saji
      Insulinoma is a tumor derived from pancreatic β-cells, and the resulting hyperinsulinemia leads to characteristic hypoglycemia. Recent studies have reported the frequent overexpression of glucagon-like peptide-1 receptor (GLP-1R) in human insulinomas, suggesting that the binding of a radiolabeled compound to GLP-1R is useful for the imaging of such tumors. Exendin(9-39), a fragment peptide of exendin-3 and -4, binds GLP-1R with high affinity and acts as an antagonist. Accordingly, radiolabeled exendin(9-39) derivatives have also been investigated as insulinoma imaging probes that might be less likely to induce hypoglycemia. In this study, we synthesized a novel indium-111 (111In)-benzyl-diethylenetriaminepentaacetic acid (111In-BnDTPA)-conjugated exendin(9-39), 111In-BnDTPA-exendin(9-39), and evaluated its utility as a probe for the SPECT imaging of insulinoma. natIn-BnDTPA-exendin(9-39) exhibited a high affinity for GLP-1R (IC50 =2.5nM), stability in plasma, and a specific activity that improved following reactions with a solvent and solubilizer. Regarding the in vivo biodistribution of 111In-BnDTPA-exendin(9-39) in INS-1 tumor-bearing mice, high uptake levels were observed in tumors (14.6%ID/g at 15min), with corresponding high tumor-to-blood (T/B), tumor-to-muscle (T/M), and tumor-to-pancreas (T/P) ratios (T/B=2.55, T/M=22.7, T/P=2.7 at 1h). The pre-administration of excess nonradioactive exendin(9-39) significantly reduced accumulation in both the tumor and pancreas (76% and 68% inhibition, respectively) at 1h after 111In-BnDTPA-exendin(9-39) injection, indicating that the GLP-1R mediated a majority of 111In-BnDTPA-exendin(9-39) uptake in the tumor and pancreas. Finally, 111In-BnDTPA-exendin(9-39) SPECT/CT studies in mice yielded clear images of tumors at 30min post-injection. These results suggest that 111In-BnDTPA-exendin(9-39) could be a useful SPECT molecular imaging probe for the detection and exact localization of insulinomas.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2016.12.051
       
  • 3,4-Dihydropyrimidinone-coumarin analogues as a new class of selective
           agent against S. aureus: Synthesis, biological evaluation and molecular
           modelling study
    • Authors: Nirmala S. Naik; Lokesh A. Shastri; Shrinivas D. Joshi; Sheshagiri R. Dixit; Bahubali M. Chougala; S. Samundeeswari; Megharaj Holiyachi; Farzanabi Shaikh; Jyoti Madar; Rashmi Kulkarni; Vinay Sunagar
      Pages: 1413 - 1422
      Abstract: Publication date: 15 February 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 4
      Author(s): Nirmala S. Naik, Lokesh A. Shastri, Shrinivas D. Joshi, Sheshagiri R. Dixit, Bahubali M. Chougala, S. Samundeeswari, Megharaj Holiyachi, Farzanabi Shaikh, Jyoti Madar, Rashmi Kulkarni, Vinay Sunagar
      Bacterial infections are increasingly difficult to combat as bacteria evolve resistance to antibiotic drugs and have severely compromised the arsenal of antibiotic drugs. On the other hand matrix metalloproteinases (MMPs) play a fundamental role in inflammation and extracellular matrix degradation in physiological and pathological conditions. In search of potent antibiotic, taking coumarin and dihydropyrimidinone as lead compound, a green, eco-friendly and efficient protocol has been developed and synthesized the dihydropyrimidin-2(1H)-one/thione derivatives of coumarin 3/4 from substituted 4-formylcoumarins 2 and ethylacetoacetate using urea/thiourea in the presence of catalytic amount of ceric ammonium nitrate is reported. All the synthesized compounds were evaluated for their antibacterial activity against four bacterial strains by broth dilution method. The tested compounds have exhibited promising in vitro potency with low MIC values against the drug susceptive S. aureus strain with low MIC values ranging from 0.2 to 6.25μg/mL. The in vivo anti-inflammatory potency of 3a–e and 4a–e by gelatin zymography is comparable to that of tetracycline. Molecular docking study performed for all the synthesized compounds with S. aureus DNA gyrase and results obtained were quite promising.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.01.001
       
  • Activation of anti-oxidant Nrf2 signaling by substituted trans stilbenes
    • Authors: Lorraine M. Deck; Lisa J. Whalen; Lucy A. Hunsaker; Robert E. Royer; David L. Vander Jagt
      Pages: 1423 - 1430
      Abstract: Publication date: 15 February 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 4
      Author(s): Lorraine M. Deck, Lisa J. Whalen, Lucy A. Hunsaker, Robert E. Royer, David L. Vander Jagt
      Nrf2, which is a member of the cap’n’collar family of transcription factors, is a major regulator of phase II detoxification and anti-oxidant genes as well as anti-inflammatory and neuroprotective genes. The importance of inflammation and oxidative stress in many chronic diseases supports the concept that activation of anti-oxidant Nrf2 signaling may have therapeutic potential. A number of Nrf2 activators have entered into clinical trials. Nrf2 exists in the cytosol in complex with its binding partner Keap1, which is a thiol-rich redox-sensing protein. In response to oxidative and electrophilic stress, select cysteine residues of Keap1 are modified, which locks Keap1 in the Nrf2-Keap1 complex and allows newly synthesized Nrf2 to enter the nucleus. Numerous Nrf2-activating chemicals, including a number of natural products, are electrophiles that modify Keap1, often by Michael addition, leading to activation of Nrf2. One concern with the design of Nrf2 activators that are electrophilic covalent modifiers of Keap1 is the issue of selectivity. In the present study, substituted trans stilbenes were identified as activators of Nrf2. These activators of Nrf2 are not highly electrophilic and therefore are unlikely to activate Nrf2 through covalent modification of Keap1. Dose-response studies demonstrated that a range of substituents on either ring of the trans stilbenes, especially fluorine and methoxy substituents, influenced not only the sensitivity to activation, reflected in EC50 values, but also the extent of activation, which suggests that multiple mechanisms are involved in the activation of Nrf2. The stilbene backbone appears to be a privileged scaffold for development of a new class of Nrf2 activators.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.01.005
       
  • Cystatin C peptidomimetic derivative with antimicrobial properties as a
           potential compound against wound infections
    • Authors: Michał Pikuła; Maria Smużyńska; Adam Krzystyniak; Maciej Zieliński; Paulina Langa; Milena Deptuła; Adriana Schumacher; Jakub Łata; Mirosława Cichorek; Anders Grubb; Piotr Trzonkowski; Franciszek Kasprzykowski; Sylwia Rodziewicz-Motowidło
      Pages: 1431 - 1439
      Abstract: Publication date: 15 February 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 4
      Author(s): Michał Pikuła, Maria Smużyńska, Adam Krzystyniak, Maciej Zieliński, Paulina Langa, Milena Deptuła, Adriana Schumacher, Jakub Łata, Mirosława Cichorek, Anders Grubb, Piotr Trzonkowski, Franciszek Kasprzykowski, Sylwia Rodziewicz-Motowidło
      A peptidomimetic called A20 (Cystapep 1) structurally based upon the N-terminal fragment of human cystatin C is known to have strong antibacterial properties. A20 is characterized by high activity against several bacterial strains often isolated from infected wounds, including methicillin-resistant S. aureus (MRSA). In this work we wanted to explore the therapeutic potential of A20 in the treatment of wound infections. We examined, cytotoxicity, allergenicity and impact of A20 on the proliferation and viability of human keratinocytes. Furthermore, the previously described antimicrobial action of A20has been confirmed here with reference strains of bacteria and extended by several other species. The A20 was highly active against Gram-positive bacteria with minimal inhibitory (MIC) and minimal bactericidal concentrations (MBC) between 8 and 128μg/mL. A20 did not affect proliferation of primary human keratinocytes in concentrations up to 50μg/mL. At the same time, it did not activate Peripheral Blood Mononuclear Cells (PBMCs), including basophils or neutrophils in vitro. Interestingly A20 was found to display immunomodulatory functions as it influences the production of Th2 cytokines (IL-4 and IL-13) by activated PBMCs. It was also resistant to degradation for at least 48h in human plasma. The results indicate that A20 is effective against the multiantibiotic-resistant bacteria and has a high safety profile, which makes it a promising antimicrobial drug candidate.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.01.004
       
  • Synthesis of Ofornine mimics from natural product l-vasicine as
           anti-hypertensive agents
    • Authors: Mushtaq A. Aga; Sheikh Rayees; Abdul Rouf; Brijesh Kumar; Anjna Sharma; P.V.V.S. Nagaraju; Gurdarshan Singh; Subhash C. Taneja
      Pages: 1440 - 1447
      Abstract: Publication date: 15 February 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 4
      Author(s): Mushtaq A. Aga, Sheikh Rayees, Abdul Rouf, Brijesh Kumar, Anjna Sharma, P.V.V.S. Nagaraju, Gurdarshan Singh, Subhash C. Taneja
      We report the chemical synthesis of Ofornine mimics from l-vasicine, structure-activity relationship studies and their in vivo screening for anti-hypertensive action in Wistar rats. It was observed that most of the analogs possessed anti-hypertensive effect; however, the duration of the effect was variable and mostly transient. The results demonstrated that the analogs 12, 13, 14, 15, and 16 showed a sharp and significant decrease in systolic and diastolic blood pressure for 30–60min after intravenous administration. Analog (S)-(3-hydroxypyrrolidin-1-yl)(2-(pyridin-4-ylamino)phenyl)methanone (8) showed a significant decrease in blood pressure in a dose dependent manner whose maximal response lowered to 79.29±4.26mmHg of SBP and 62.55±2.9 of DBP at 10mg/kg intravenous dose. Further, the significant anti-hypertensive effect of 8 lasted for about 2.5h at 10mg/kg dose. We also evaluated the acute toxicity of the analog 8 as per the OECD guidelines and the compound was found to be safe up to the dose of 2000mg/kg body weight. These preclinical findings suggest that the analog 8 could be considered as a promising lead and a durable anti-hypertensive drug candidate and deserves further investigation. The SAR studies clearly showed that the amide, hydroxyl and pyridine ring plays important role in showing the activity.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.01.006
       
  • Molecular docking, discovery, synthesis, and pharmacological properties of
           new 6-substituted-2-(3-phenoxyphenyl)-4-phenyl quinoline derivatives; an
           approach to developing potent DNA gyrase inhibitors/antibacterial agents
    • Authors: Manikandan Alagumuthu; Sivakumar Arumugam
      Pages: 1448 - 1455
      Abstract: Publication date: 15 February 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 4
      Author(s): Manikandan Alagumuthu, Sivakumar Arumugam
      Synthesis and molecular validation of 6-substituted-2-(3-phenoxyphenyl)-4-phenylquinoline derivatives (4a-h) as antibacterial/DNA gyrase inhibitors reported. Primarily, 6-substituted-2-(3-phenoxyphenyl)-4-phenylquinoline derivatives were docked into the active sites of DNA gyrase A&B, to ensure the binding mode of the compounds, and the results were superior on DNA gyrase A over DNA gyrase B. Based on this, S. aureus DNA gyrase A assay was proposed and executed. Most prominent DNA gyrase inhibition showed by 6-fluoro-2-(3-phenoxyphenyl)-4-phenylquinoline (4c), IC50 0.389μg/mL; 2-(3-phenoxyphenyl)-4-phenylquinolin-6-ol (4e), IC50 0.328μg/mL; and 5,7-dichloro-2-(3-phenoxyphenyl)-4-phenylquinolin-6-ol (4h), IC50 0.214μg/mL which were substituted with fluorine ( 4F), nitrile ( 4CN), hydroxyl group ( 4OH) and dichloro-hydroxyl ( 3,5Cl, 4OH) groups in the quinoline scaffold. Antimicrobial activity on Gram−ve bacteria Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 424), and Gram+ve bacteria Staphylococcus aureus (MTCC 96) and Streptococcus pyogenes (MTCC 442) was evaluated. Excellent antibacterial activity showed by S. aureus and S. pyogenes which indicates the activity dominance of 6-substituted-2-(3-phenoxyphenyl)-4-phenylquinoline derivatives on Gram+ve bacteria rather than Gram−ve. Subsequently, the cytotoxicity of 6-substituted-2-(3-phenoxyphenyl)-4-phenylquinoline derivatives was evaluated. Cytotoxicity results of MCF-7 (human breast cancer) and G361 (skin melanoma cancer) cell lines reveals that the 6-substituted-2-(3-phenoxyphenyl)-4-phenylquinoline derivatives are highly toxic to cancer cells. Predicted SAR, Lipinski’s filter, Pharmacokinetic, and ADMET properties were also ensured the druggability probabilities of most favorable compounds among 6-substituted-2-(3-phenoxyphenyl)-4-phenylquinoline derivatives.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.01.007
       
  • Synthesis of isoxazole-containing sulfonamides with potent carbonic
           anhydrase II and VII inhibitory properties
    • Authors: Cevher Altug; Hanife Güneş; Alessio Nocentini; Simona Maria Monti; Martina Buonanno; Claudiu T. Supuran
      Pages: 1456 - 1464
      Abstract: Publication date: 15 February 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 4
      Author(s): Cevher Altug, Hanife Güneş, Alessio Nocentini, Simona Maria Monti, Martina Buonanno, Claudiu T. Supuran
      Two series of benzenesulfonamide containing isoxazole compounds were prepared by using conventional and microwave (MW) methods. 5-Amino-3-aryl-N-(4-sulfamoylphenyl)isoxazole-4-carboxamide derivatives were synthesized by the reaction of hydroxymoyl chlorides with 2-cyano-N-(4-sulfamoylphenyl)acetamide in the presence of triethylamine. The synthesized 5-amino isoxazoles were reacted with various benzoyl chlorides in order to obtain 5-amidoisoxazoles. The novel compounds were screened in vitro as inhibitors of four human (h) isoforms of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1): hCA I, hCA II, hCA IV and hCA VII. The derivatives of the first series were shown to possess excellent inhibitory activity against the cytosolic isoform hCA II, an antiglaucoma drug target, with KIs in the range of 0.5–49.3nM and hCA VII, a recently validated anti-neuropathic pain target with KIs in the range of 4.3–51.9nM.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.01.008
       
  • Design and synthesis of potent substrate-based inhibitors of the
           Trypanosoma cruzi dihydroorotate dehydrogenase
    • Authors: Daniel Ken Inaoka; Maiko Iida; Satoshi Hashimoto; Toshiyuki Tabuchi; Takefumi Kuranaga; Emmanuel Oluwadare Balogun; Teruki Honma; Akiko Tanaka; Shigeharu Harada; Takeshi Nara; Kiyoshi Kita; Masayuki Inoue
      Pages: 1465 - 1470
      Abstract: Publication date: 15 February 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 4
      Author(s): Daniel Ken Inaoka, Maiko Iida, Satoshi Hashimoto, Toshiyuki Tabuchi, Takefumi Kuranaga, Emmanuel Oluwadare Balogun, Teruki Honma, Akiko Tanaka, Shigeharu Harada, Takeshi Nara, Kiyoshi Kita, Masayuki Inoue
      Chagas disease, caused by the parasitic protozoan Trypanosoma cruzi, is the leading cause of heart disease in Latin America. T. cruzi dihydroorotate dehydrogenase (DHODH), which catalyzes the production of orotate, was demonstrated to be essential for T. cruzi survival, and thus has been considered as a potential drug target to combat Chagas disease. Here we report the design and synthesis of 75 compounds based on the orotate structure. A comprehensive structure-activity relationship (SAR) study revealed two 5-substituted orotate analogues (5u and 5v) that exhibit K i app values of several ten nanomolar level and a selectivity of more than 30,000-fold over human DHODH. The information presented here will be invaluable in the search for next-generation drug leads for Chagas disease.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.01.009
       
  • Design, synthesis and evaluation of some N-methylenebenzenamine
           derivatives as selective acetylcholinesterase (AChE) inhibitor and
           antioxidant to enhance learning and memory
    • Authors: Sushant K. Shrivastava; Pavan Srivastava; T.V.R. Upendra; Prabhash Nath Tripathi; Saurabh K. Sinha
      Pages: 1471 - 1480
      Abstract: Publication date: 15 February 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 4
      Author(s): Sushant K. Shrivastava, Pavan Srivastava, T.V.R. Upendra, Prabhash Nath Tripathi, Saurabh K. Sinha
      Series of some 3,5-dimethoxy-N-methylenebenzenamine and 4-(methyleneamino)benzoic acid derivatives comprising of N-methylenebenzenamine nucleus were designed, synthesized, characterized, and assessed for their acetylcholinesterase (AChE), butyrylcholinesterase (BChE) inhibitory, and antioxidant activity thereby improving learning and memory in rats. The IC50 values of all the compound along with standard were determined on AChE and BChE enzyme. The free radical scavenging activity was also assessed by in vitro DPPH (2,2-diphenyl-1-picryl-hydrazyl) and hydrogen peroxide radical scavenging assay. The selective inhibitions of all compounds were observed against AChE in comparison with standard donepezil. The enzyme kinetic study of the most active compound 4 indicated uncompetitive AChE inhibition. The docking studies of compound 4 exhibited the worthy interaction on active-site gorge residues Phe330 and Trp279 responsible for its high affinity towards AChE, whereas lacking of the BChE inhibition was observed due to a wider gorge binding site and absence of important aromatic amino acids interactions. The ex vivo study confirmed AChE inhibition abilities of compound 4 at brain site. Further, a considerable decrease in escape latency period of the compound was observed in comparison with standard donepezil through in vivo Spatial Reference Memory (SRM) and Spatial Working Memory (SWM) models which showed the cognition-enhancing potential of compound 4. The in vivo reduced glutathione (GSH) estimation on rat brain tissue homogenate was also performed to evaluate free radical scavenging activity substantiated the antioxidant activity in learning and memory.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.01.010
       
  • Synthesis of α,β-unsaturated aldehydes as potential substrates
           for bacterial luciferases
    • Authors: Eveline Brodl; Jakov Ivkovic; Chaitanya R. Tabib; Rolf Breinbauer; Peter Macheroux
      Pages: 1487 - 1495
      Abstract: Publication date: 15 February 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 4
      Author(s): Eveline Brodl, Jakov Ivkovic, Chaitanya R. Tabib, Rolf Breinbauer, Peter Macheroux
      Bacterial luciferase catalyzes the monooxygenation of long-chain aldehydes such as tetradecanal to the corresponding acid accompanied by light emission with a maximum at 490nm. In this study even numbered aldehydes with eight, ten, twelve and fourteen carbon atoms were compared with analogs having a double bond at the α,β-position. These α,β-unsaturated aldehydes were synthesized in three steps and were examined as potential substrates in vitro. The luciferase of Photobacterium leiognathi was found to convert these analogs and showed a reduced but significant bioluminescence activity compared to tetradecanal. This study showed the trend that aldehydes, both saturated and unsaturated, with longer chain lengths had higher activity in terms of bioluminescence than shorter chain lengths. The maximal light intensity of (E)-tetradec-2-enal was approximately half with luciferase of P. leiognathi, compared to tetradecanal. Luciferases of Vibrio harveyi and Aliivibrio fisheri accepted these newly synthesized substrates but light emission dropped drastically compared to saturated aldehydes. The onset and the decay rate of bioluminescence were much slower, when using unsaturated substrates, indicating a kinetic effect. As a result the duration of the light emission is doubled. These results suggest that the substrate scope of bacterial luciferases is broader than previously reported.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.01.013
       
  • Novel salicylanilides from 4,5-dihalogenated salicylic acids: Synthesis,
           antimicrobial activity and cytotoxicity
    • Authors: Georgios Paraskevopoulos; Sara Monteiro; Rudolf Vosátka; Martin Krátký; Lucie Navrátilová; František Trejtnar; Jiřina Stolaříková; Jarmila Vinšová
      Pages: 1524 - 1532
      Abstract: Publication date: 15 February 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 4
      Author(s): Georgios Paraskevopoulos, Sara Monteiro, Rudolf Vosátka, Martin Krátký, Lucie Navrátilová, František Trejtnar, Jiřina Stolaříková, Jarmila Vinšová
      Salicylanilides have proved their activity against tuberculosis (TB). One weak electron-withdrawing substituent is favored at the salicylic part, specially Cl or Br atoms at positions 4 or 5. On the other hand, the antimycobacterial activity of salicylanilides is negatively affected when a strong electron-withdrawing substituent (NO2) is present at the same positions. Herein we describe the synthesis and characterization of novel salicylanilides possessing two weak electron-withdrawing groups (halogen atoms) at their salicylic part and compare their antitubercular activity with their monohalogenated analogues. All dihalogenated derivatives proved to possess antitubercular activity at a very narrow micromolar range (MIC=1–4μM), similar with their most active monohalogenated analogues. More importantly, the most active final molecules were further screened against multidrug resistant strains and found to inhibit their growth at the range of 0.5–4μM.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.01.016
       
  • Biological Evaluation of Pyridone Alkaloids on the Endocannabinoid System
    • Authors: Andrea Chicca; Regina Berg; Henning J. Jessen; Nicolas Marck; Fabian Schmid; Patrick Burch; Jürg Gertsch; Karl Gademann
      Abstract: Publication date: Available online 17 February 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Andrea Chicca, Regina Berg, Henning J. Jessen, Nicolas Marck, Fabian Schmid, Patrick Burch, Jürg Gertsch, Karl Gademann
      Naturally occurring pyridone alkaloids as well as synthetic derivatives were previously shown to induce neurite outgrowth. However, the molecular basis for this biological effect remains poorly understood. In this work, we have prepared new pyridones, and tested the effect of thirteen 4-hydroxy-2-pyridone derivatives on the components of the endocannabinoid system. Investigation of binding affinities towards CB1 and CB2 receptors led to the identification of a compound binding selectively to CB1 (12). Compound 12 and a closely related derivative (11) also inhibited anandamide (AEA) hydrolysis by fatty acid amide hydrolase. Interestingly, none of the compounds tested showed any effect on 2-AG hydrolysis by monoacylglycerol lipase at 10 µM. Assessment of AEA uptake did, however, lead to the identification of four inhibitors with IC50 values in the submicromolar range and high selectivity over the other components of the endocannabinoid system.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.02.031
       
  • Synthesis of antisense oligonucleotides containing acyclic alkynyl
           nucleoside analogs and their biophysical and biological properties
    • Authors: Aya Ogata; Yusuke Maeda; Yoshihito Ueno
      Abstract: Publication date: Available online 17 February 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Aya Ogata, Yusuke Maeda, Yoshihito Ueno
      The synthesis of oligonucleotide (ON) analogs, which can be used as antisense molecules, has recently gained much attention. Here, we report the synthesis and properties of an ON analog containing acyclic thymidine and cytidine analogs with a 4-pentyl-1,2-diol instead of the d-ribofuranose moiety. The incorporation of these analogs into the ON improved its nuclease resistance to 3′-exonucleases. Furthermore, it was found that the incorporation of the acyclic thymidine analog into a DNA/RNA duplex accelerates the RNA cleavage of a DNA/RNA duplex by Escherichia coli RNase H.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.01.051
       
  • Synthesis and anti-inflammatory activity of isoquebecol
    • Authors: Sébastien Cardinal; Pierre-Alexandre Paquet-Côté; Jabrane Azelmat; Corinne Bouchard; Daniel Grenier; Normand Voyer
      Abstract: Publication date: Available online 16 February 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Sébastien Cardinal, Pierre-Alexandre Paquet-Côté, Jabrane Azelmat, Corinne Bouchard, Daniel Grenier, Normand Voyer
      We report here the synthesis of isoquebecol, an unprecedented constitutional isomer of quebecol, a polyphenolic compound discovered in maple syrup. The methodology used to prepare isoquebecol involves, as key steps, the formation of a dibromoalkene from an α-ketoester precursor, followed by a double Suzuki-Miyaura reaction. The anti-inflammatory activity of isoquebecol was studied on macrophage cells by monitoring its ability to inhibit LPS-induced IL-6 secretion. Results show that this new compound has an improved bioactivity over that of its natural isomer. Precursors and derivatives of quebecol, isoquebecol and model analog 2,3,3-triphenylpropanol were also prepared and tested in this study. Comparison between the three series of compounds led to establishing new SARs concerning the aryl ring substitution pattern on the triarylpropanol scaffold and substructure functionalization.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.01.050
       
  • Design and synthesis of novel, potent and selective hypoxanthine analogs
           as adenosine A1 receptor antagonists and their biological evaluation
    • Authors: Summon Koul; Vidya Ramdas; Dinesh A. Barawkar; Yogesh B. Waman; Neela Prasad; Santosh Kumar Madadi; Yogesh D. Shejul; Rajesh Bonagiri; Sujay Basu; Suraj Menon; Srinivasa B. Reddy; Sandhya Chaturvedi; Srinivas Rao Chennamaneni; Gaurav Bedse; Rhishikesh Thakare; Jayasagar Gundu; Sumit Chaudhary; Siddhartha De; Ashwinkumar V. Meru; Venkata Palle; Anita Chugh; Kasim A. Mookhtiar
      Abstract: Publication date: Available online 16 February 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Summon Koul, Vidya Ramdas, Dinesh A. Barawkar, Yogesh B. Waman, Neela Prasad, Santosh Kumar Madadi, Yogesh D. Shejul, Rajesh Bonagiri, Sujay Basu, Suraj Menon, Srinivasa B. Reddy, Sandhya Chaturvedi, Srinivas Rao Chennamaneni, Gaurav Bedse, Rhishikesh Thakare, Jayasagar Gundu, Sumit Chaudhary, Siddhartha De, Ashwinkumar V. Meru, Venkata Palle, Anita Chugh, Kasim A. Mookhtiar
      Multipronged approach was used to synthesize a library of diverse C-8 cyclopentyl hypoxanthine analogs from a common intermediate III. Several potent and selective compounds were identified and evaluated for pharmacokinetic (PK) properties in Wistar rats. One of the compounds 14 with acceptable PK parameters was selected for testing in in-vivo primary acute diuresis model. The compound demonstrated significant diuretic activity in this model.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.02.029
       
  • In vivo instability of platensimycin and platencin: Synthesis and
           biological evaluation of urea- and carbamate-platensimycin
    • Authors: Liao-Bin Dong; Jeffrey D. Rudolf; Li Lin; Claudia Ruiz; Michael D. Cameron; Ben Shen
      Abstract: Publication date: Available online 16 February 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Liao-Bin Dong, Jeffrey D. Rudolf, Li Lin, Claudia Ruiz, Michael D. Cameron, Ben Shen
      Platensimycin (PTM) and platencin (PTN), two natural products and promising drug leads that target bacterial and mammalian fatty acid synthases, are known to have unfavorable pharmacokinetic properties. It is not clear, however, what the metabolic fates of PTM and PTN are and no efforts have been reported to address this key roadblock in the development of these compounds as viable drug options. Here we describe the pharmacokinetics of PTM and PTN, and reveal rapid renal clearance as the primary metabolic liability with three additional sites of chemical liability: (i) amide hydrolysis, (ii) glucuronidation, and (iii) oxidation. We determined that hydrolysis is a viable clearance mechanism in vivo and synthesized two PTM analogues to address in vivo hydrolysis. Urea- and carbamate-PTM analogues showed no detectable hydrolysis in vivo, at the expense of antibacterial activity, with no further improvement in systemic exposure. The antibacterial sulfur-containing analogues PTM D1 and PTM ML14 showed significant decreases in renal clearance. These studies set the stage for continued generation of PTM and PTN analogues in an effort to improve their pharmacokinetics while retaining or improving their biological activities.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.02.028
       
  • Novel Pyrrolopyrimidines as Mps1/TTK Kinase Inhibitors for Breast Cancer
    • Authors: Yasuro Sugimoto; Dwitiya B. Sawant; Harold A. Fisk; Liguang Mao; Chenglong Li; Somsundaram Chettiar; Pui-Kai Li; Michael V. Darby; Robert W. Brueggemeier
      Abstract: Publication date: Available online 16 February 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Yasuro Sugimoto, Dwitiya B. Sawant, Harold A. Fisk, Liguang Mao, Chenglong Li, Somsundaram Chettiar, Pui-Kai Li, Michael V. Darby, Robert W. Brueggemeier
      New targeted therapy approaches for certain subtypes of breast cancer, such as triple-negative breast cancers and other aggressive phenotypes, are desired. High levels of the mitotic checkpoint kinase Mps1/TTK have correlated with high histologic grade in breast cancer, suggesting a potential new therapeutic target for aggressive breast cancers (BC). Novel small molecules targeting Mps1 were designed by computer assisted docking analyses, and several candidate compounds were synthesized. These compounds were evaluated in anti-proliferative assays of a panel of 15 breast cancer cell lines and further examined for their ability to inhibit a variety of Mps1-dependent biological functions. The results indicate that the lead compounds have strong anti-proliferative potential through Mps1/TTK inhibition in both basal and luminal BC cell lines, exhibiting IC50 values ranging from 0.05 to 1.0 μM. In addition, the lead compounds 1 and 13 inhibit Mps1 kinase enzymatic activity with IC50 values from 0.356 μM to 0.809 μM, and inhibited Mps1-associated cellular functions such as centrosome duplication and the spindle checkpoint in triple negative breast cancer cells. The most promising analog, compound 13, significantly decreased tumor growth in nude mice containing Cal-51 triple negative breast cancer cell xenografts. Using drug discovery technologies, computational modeling, medicinal chemistry, cell culture and in vivo assays, novel small molecule Mps1/TTK inhibitors have been identified as potential targeted therapies for breast cancers.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.02.030
       
  • Piperazines as nootropic agents: New derivatives of the potent
           cognition-enhancer DM235 carrying hydrophilic substituents
    • Authors: Maria Vittoria Martino; Luca Guandalini; Lorenzo Di Cesare Mannelli; Marta Menicatti; Gianluca Bartolucci; Silvia Dei; Dina Manetti; Elisabetta Teodori; Carla Ghelardini; Maria Novella Romanelli
      Abstract: Publication date: Available online 16 February 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Maria Vittoria Martino, Luca Guandalini, Lorenzo Di Cesare Mannelli, Marta Menicatti, Gianluca Bartolucci, Silvia Dei, Dina Manetti, Elisabetta Teodori, Carla Ghelardini, Maria Novella Romanelli
      The piperazine ring of the potent nootropic drug DM235has been decorated with H-bond donor and acceptor groups (CH2OH, CH2OMe, CH2OCOMe, COOEt); the aim was to insert new functional groups, suitable for further chemical manipulation. The influence of these modifications on nootropic activity was assessed by means of the mouse passive avoidance test; some of the newly synthesized molecules (alcohol 7b, acetate 8b and ester 10d) showed interesting in vivo potency. This makes it possible to use these functional groups for adding other residues, in order to increase molecular diversity, or for anchoring a biotin group, to obtain compounds useful to capture the biological target. Moreover, the new compounds will improve our knowledge of structure activity relationships of this family of drugs.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.02.019
       
  • Comparison of the anion inhibition profiles of the β- and γ-carbonic
           anhydrases from the pathogenic bacterium Burkholderia pseudomallei
    • Authors: Sonia Del Prete; Daniela Vullo; Pietro di Fonzo; Vincenzo Carginale; Claudiu T. Supuran; Clemente Capasso
      Abstract: Publication date: Available online 16 February 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Sonia Del Prete, Daniela Vullo, Pietro di Fonzo, Vincenzo Carginale, Claudiu T. Supuran, Clemente Capasso
      We report the cloning, purification and characterization of BpsβCA, a β-class carbonic anhydrase (CA, EC 4.2.1.1) from the pathogenic bacterium Burkholderia pseudomallei, the etiological agent of melioidosis, and compare its activity and inhibition with those of the γ-CA from the same organism, BpsγCA, recently investigated by our groups. BpsβCA showed a significant catalytic activity for the physiologic, CO2 hydration reaction, with the following kinetic parameters, kcat of 1.6x105 s-1 and kcat/Km of 3.4 x107 M-1x s-1. The inhibition of BpsβCA with a group of anions and small molecules was also investigated. The best inhibitors were sulfamide, sulfamic acid and phenylarsonic acid, which showed KIs in the range of 83 – 92 µM, whereas phenylboronic acid, fluoride, cyanide, azide, bisulfite, tetraborate, perrhenate, perruthenate, peroxydisulfate, perchlorate, tetrafluoroborate, fluorosulfonate and hexafluorophosphate showed KIs> 100 mM. Other inhibitors of this new enzyme were bicarbonate, trithiocarbonate, some complex inorganic anions and N,N-diethyldithiocarbamate, which had inhibition constants of 0.32 – 8.6 mM. As little is known of the life cycle and virulence of this bacterium, this type of study may bring information of interest for the development of novel strategies to fight bacterial infection and drug resistance to commonly used antibiotics
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.02.032
       
  • Identification of A New Class of Potent Cdc7 Inhibitors Designed by
           Putative Pharmacophore Model: Synthesis and Biological Evaluation of
           2,3-Dihydrothieno[3,2-d]pyrimidin-4(1H)-ones
    • Authors: Osamu Kurasawa; Yuya Oguro; Tohru Miyazaki; Misaki Homma; Kouji Mori; Kenichi Iwai; Hideto Hara; Robert Skene; Isaac Hoffman; Akihiro Ohashi; Sei Yoshida; Tomoyasu Ishikawa; Nobuo Cho
      Abstract: Publication date: Available online 16 February 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Osamu Kurasawa, Yuya Oguro, Tohru Miyazaki, Misaki Homma, Kouji Mori, Kenichi Iwai, Hideto Hara, Robert Skene, Isaac Hoffman, Akihiro Ohashi, Sei Yoshida, Tomoyasu Ishikawa, Nobuo Cho
      Cell division cycle 7 (Cdc7) is a serine/threonine kinase that plays important roles in the regulation of DNA replication process. A genetic study indicates that Cdc7 inhibition can induce selective tumor-cell death in a p53-dependent manner, suggesting that Cdc7 is an attractive target for the treatment of cancers. In order to identify a new class of potent Cdc7 inhibitors, we generated a putative pharmacophore model based on in silico docking analysis of a known inhibitor with Cdc7 homology model. The pharmacophore model provided a minimum structural motif of Cdc7 inhibitor, by which preliminary medicinal chemistry efforts identified a dihydrothieno[3,2-d]-pyrimidin-4(1H)-one scaffold having a heteroaromatic hinge-binding moiety. The structure-activity relationship (SAR) studies resulted in the discovery of new, potent, and selective Cdc7 inhibitors 14a,c,e. Furthermore, the high selectivity of 14c,e for Cdc7 over Rho-associated protein kinase 1 (ROCK1) is discussed by utilizing a docking study with Cdc7 and ROCK2 crystal structures.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.02.021
       
  • Synthesis and evaluation of a [18F]BODIPY-labeled Caspase-inhibitor
    • Authors: Christian Paul Ortmeyer; Günter Haufe; Katrin Schwegmann; Sven Hermann; Michael Schäfers; Frederik Börgel; Bernhard Wünsch; Stefan Wagner; Verena Hugenberg
      Abstract: Publication date: Available online 16 February 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Christian Paul Ortmeyer, Günter Haufe, Katrin Schwegmann, Sven Hermann, Michael Schäfers, Frederik Börgel, Bernhard Wünsch, Stefan Wagner, Verena Hugenberg
      BODIPYs (boron dipyrromethenes) are fluorescent dyes which show high stability and quantum yields. They feature the possibility of selective 18F-fluorination at the boron-core. Attached to a bioactive molecule and labeled with [18F]fluorine, the resulting compounds are promising tracers for multimodal imaging in vivo and can be used for PET and fluorescence imaging. A BODIPY containing a phenyl and a hydroxy substituent on boron was synthesized and characterized. Fluorinated and hydroxy substituted dyes were coupled to an isatin-based caspase inhibitor via cycloaddition and the resulting compounds were evaluated in vitro in caspase inhibition assays. The metabolic stability and the formed metabolites were investigated by incubation with mouse liver microsomes and LC-MS analysis. Subsequently the fluorophores were labeled with [18F]fluorine and an in vivo biodistribution study using dynamic PET was performed.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.02.033
       
  • Synthesis and Activity of Nucleoside-Based Antiprotozoan Compounds
    • Authors: Huu-Anh Tran; Zhaoyan Zheng; Xianghui Wen; Srinivasan Manivannan; Arnaud Pastor; Marcel Kaiser; Reto Brun; Floyd F. Snyder; Thomas G. Back
      Abstract: Publication date: Available online 16 February 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Huu-Anh Tran, Zhaoyan Zheng, Xianghui Wen, Srinivasan Manivannan, Arnaud Pastor, Marcel Kaiser, Reto Brun, Floyd F. Snyder, Thomas G. Back
      Parasitic protozoa employ a salvage pathway to synthesize purines and generate essential active nucleotides, whereas mammals are capable of their de novo biosynthesis. This difference provides opportunity for the design of potential new antiprotozoan compounds. A series of 47 adenosine analogues was prepared with modifications at the 2-, 6- and 5’-positions, based on the hypothesis that such compounds would serve as substrates for protozoan nucleoside salvage enzymes, while remaining refractory in mammalian cells. The nucleosides were designed to produce toxic metabolites upon cleavage to the corresponding purine base by the parasite. Three 7-deazaguanosine derivatives were prepared with similar objectives. All of these compounds were tested in vitro against T. brucei (African sleeping sickness), T. cruzi (Chagas’ disease), L. donovani (leishmaniasis) and P. falciparum (malaria). In order to determine the therapeutic selectivity indices (SI) of the antiprotozoan nucleosides, their cytotoxicities toward a rat myoblast cell line were also determined. One adenosine derivative proved highly effective against P. falciparum (IC50 = 110 nM and SI = 1010, while a modified guanosine displayed potent activities against L. donovani (IC50 = 60 nM, SI = 2720) and T. brucei (IC50 = 130 nM, SI = 1250), as well as moderate activity against T. cruzi (IC50 = 3.4 µM, SI = 48). These results provide proof of concept for the nucleoside-based antiprotozoan strategy, as well as potential lead compounds for further optimization and validation.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.02.016
       
  • Multifunctional thioxanthone derivatives with acetylcholinesterase,
           monoamine oxidases and β-amyloid aggregation inhibitory activities as
           potential agents against Alzheimer’s disease
    • Authors: Li Luo; Yan Li; Xiaoming Qiang; Zhongcheng Cao; Rui Xu; Xia Yang; Ganyuan Xiao; Qing Song; Zhenghuai Tan; Yong Deng
      Abstract: Publication date: Available online 14 February 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Li Luo, Yan Li, Xiaoming Qiang, Zhongcheng Cao, Rui Xu, Xia Yang, Ganyuan Xiao, Qing Song, Zhenghuai Tan, Yong Deng
      A series of 1-hydroxyl-3-aminoalkoxy-thioxanthone derivatives were designed, synthesized and evaluated as potential multifunctional agents against Alzheimer’s disease (AD). The results indicated that most of these compounds exhibited good AChE and MAOs inhibitory activities, significant inhibition of self- and Cu2+-induced Aβ 1-42 aggregation, and moderate to good antioxidant activities. Specifically, compound 9e displayed high inhibitory potency toward AChE (IC50 = 0.59 ± 0.02 μM), MAO-A and MAO-B (IC50 = 1.01 ± 0.02 μM and 0.90 ± 0.01 μM respectively), excellent efficiency to block both self- and Cu2+-induced Aβ 1-42 aggregation (74.8 ± 1.2% and 87.7 ± 1.9% at 25 μM, respectively), good metal-chelating property and a low toxicity in SH-SY5Y cells. Furthermore, kinetic and molecular modeling studies revealed that compound 9e binds simultaneously to the catalytic active site and peripheral anionic site of AChE, and could penetrate the BBB. Collectively, these results suggested that 9e might be a potential multifunctional agent for further development in the treatment of AD.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.02.027
       
  • In vitro anticancer activity evaluation of new cationic platinum(II)
           complexes based on imidazole moiety
    • Authors: Isabella Rimoldi; Giorgio Facchetti; Giorgio Lucchini; Elisa Castiglioni; Silvia Marchianò; Nicola Ferri
      Abstract: Publication date: Available online 14 February 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Isabella Rimoldi, Giorgio Facchetti, Giorgio Lucchini, Elisa Castiglioni, Silvia Marchianò, Nicola Ferri
      The development and the synthesis of cationic platinum(II) complexes were realized and their cytotoxic activity was tested on triple negative breast cancer MDA-MB-231 cell line and in two cell lines poorly responsive to cisplatin (DLD-1 and MCF-7). The complex 2c resulted the most potent cytotoxic agent in MDA-MB-231 (IC50=61.9 µM) and more effective than cisplatin on both DLD-1 (IC50=57.4 µM) and MCF-7 (IC50=79.9 µM) cell lines. 2c showed different cellular uptake and pharmacodynamic properties than cisplatin, interfering with the progression of the M phase of the cell cycle. Thus, 2c represents a lead compound of a new class of cytotoxic agents with promising antitumor activity.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.02.010
       
  • Synthesis of 1,3,5-trisubstituted pyrazolines as potential antimalarial
           and antimicrobial agents
    • Authors: Vikash K Mishra; Mitali Mishra; Varsha Kashaw; Sushil K Kashaw
      Abstract: Publication date: Available online 14 February 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Vikash K Mishra, Mitali Mishra, Varsha Kashaw, Sushil K Kashaw
      A series of novel 1,3,5-trisubstituted pyrazolines derivatives have been synthesized from chalcones and nicotinic acid hydrazide in two steps. In first step, chalcones were prepared by treatment of 4-hydroxy acetophenone with different substituted benzaldehyde by Claisen-Schimidt Condensation. In second step, various pyrazoline derivatives were prepared by reflux reaction of chalcones with nicotinic acid hydrazide in ethanolic solution. Compounds were confirmed by elemental analyses, IR, 1H NMR and 13C NMR spectral data and were evaluated for antimalarial and antibacterial activity. Compounds 5n (IC50=0.022 μM for MRC-2 and IC50=0.192 μM for RKL-9) displayed better antiplasmodial activity than the chloroquine (CQ) against chloroquine-sensitive (MRC-2) and chloroquine-resistant (RKL-9) P. falciparum strains. The in vitro cytotoxicity study conducted on the human HepG2 cell line (>30μM) and selectivity index (100-220) indicate that this series presents an interesting selective antiplasmodial profile. Further, in vitro heme crystallization inhibition assay showed compound 5e inhibited formation of β-hematin more efficiently than CQ. In addition, antibacterial and antifungal evaluations were conducted, compounds 5c, 5i and 5j displayed better antibacterial activity against S. aureus, B. subtilis, E. coli and P. aeruginosa than ciproafloxacin. Antifungal activity of compound 5l against A. niger (MIC-3.25μg/ml) and C. albicans (MIC-6.5μg/ml) was found to be better than the standard drug fluconazole.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.02.025
       
  • Iminosugar-based ceramide mimicry for the design of new CERT START domain
           ligands
    • Authors: Cécile Santos; Fabien Stauffert; Stéphanie Ballereau; Cécile Dehoux; Frédéric Rodriguez; Anne Bodlenner; Philippe Compain; Yves Génisson
      Abstract: Publication date: Available online 14 February 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Cécile Santos, Fabien Stauffert, Stéphanie Ballereau, Cécile Dehoux, Frédéric Rodriguez, Anne Bodlenner, Philippe Compain, Yves Génisson
      The enigmatical dichotomy between the two CERT/GPBP protein isoforms, their vast panel of biological implications and the scarcity of known antagonist series call for new ligand chemotypes identification. We report the design of iminosugar-based ceramide mimics for the development of new START domain ligands potentially targeting either protein isoforms. Strategic choice of i) an iminoxylitol core structure and ii) the positioning of two dodecyl residues led to an extent of protein binding comparable to that of the natural cargo lipid ceramide or the archetypical inhibitor HPA-12. Molecular docking study evidenced a possible mode of protein binding fully coherent with the one observed in crystalline co-structures of known ligands. The present study thus paves the way for cellular CERT inhibition activity studies en route to the development of pharmacological tools aiming at deciphering the respective function and therapeutic potential of the two CERT/GPBP protein isoforms.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.02.026
       
  • Human carbonic anhydrase inhibitory profile of mono- and bis-sulfonamides
           synthesized via a direct sulfochlorination of 3-and
           4-(hetero)arylisoxazol-5-amine scaffolds
    • Authors: Mikhail Krasavin; Mikhail Korsakov; Zhanna Zvonaryova; Evgenii Semyonychev; Tiziano Tuccinardi; Stanislav Kalinin; Muhammet Tanç; Claudiu T. Supuran
      Abstract: Publication date: Available online 13 February 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Mikhail Krasavin, Mikhail Korsakov, Zhanna Zvonaryova, Evgenii Semyonychev, Tiziano Tuccinardi, Stanislav Kalinin, Muhammet Tanç, Claudiu T. Supuran
      Three distinct series of isoxazole-based primary mono- and bis-sulfonamides have been synthesized via direct sulfochlorination, each of them delivering nanomolar inhibitors of human carbonic anhydrase. Certain pronounced SAR trends have been established and rationalized by in silico docking. These findings expand the structure-activity knowledge base for heterocycle-containing sulfonamide carbonic anhydrase inhibitors and further validate the power of direct electrophilic sulfochlorination as a means of introducing the pharmacophoric primary sulfonamide group into structurally diverse aromatic precursors.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.02.018
       
  • Investigation on cellular uptake and pharmacodynamics of DOCK2-inhibitory
           peptides conjugated with cell-penetrating peptides
    • Authors: Yusuke Adachi; Kotaro Sakamoto; Tadashi Umemoto; Yasunori Fukuda; Akiyoshi Tani; Taiji Asami
      Abstract: Publication date: Available online 13 February 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Yusuke Adachi, Kotaro Sakamoto, Tadashi Umemoto, Yasunori Fukuda, Akiyoshi Tani, Taiji Asami
      Protein–protein interaction between dedicator of cytokinesis 2 (DOCK2) and Ras-related C3 botulinum toxin substrate 1 (Rac1) is an attractive intracellular target for transplant rejection and inflammatory diseases. Recently, DOCK2-selective inhibitory peptides have been discovered, and conjugation with oligoarginine cell-penetrating peptide (CPP) improved inhibitory activity in a cell migration assay. Although a number of CPPs have been reported, oligoarginine was only one example introduced to the inhibitory peptides. In this study, we aimed to confirm the feasibility of CPP-conjugation approach for DOCK2-inhibitory peptides, and select preferable sequences as CPP moiety. First, we evaluated cell permeability of thirteen known CPPs and partial sequences of influenza A viral protein PB1-F2 using an internalization assay system based on luciferin–luciferase reaction, and then selected four CPPs with efficient cellular uptake. Among four conjugates of these CPPs and a DOCK2-inhibitory peptide, the inhibitory activity of a novel CPP, PB1-F2 fragment 5 (PF5), conjugate was comparable to oligoarginine conjugate and higher than that of the non-conjugated peptide. Finally, internalization assay revealed that oligoarginine and PF5 increased the cellular uptake of inhibitory peptides to the same extent. Hence, we demonstrated that CPP-conjugation approach is applicable to the development of novel anti-inflammatory drugs based on DOCK2 inhibition by investigating both cellular uptake and bioactivity.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.02.022
       
  • Synthesis and Biological Evaluation of Novel N3-substituted
           Dihydropyrimidine Derivatives as T-Type Calcium Channel Blockers and Their
           Efficacy as Analgesics in Mouse Models of Inflammatory Pain
    • Authors: Mohamed Teleb; Fang-Xiong Zhang; Junting Huang; Vinicius M Gadotti; Ahmed M. Farghaly; Omaima M. AboulWafa; Gerald W. Zamponi; Hesham Fahmy
      Abstract: Publication date: Available online 13 February 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Mohamed Teleb, Fang-Xiong Zhang, Junting Huang, Vinicius M Gadotti, Ahmed M. Farghaly, Omaima M. AboulWafa, Gerald W. Zamponi, Hesham Fahmy
      Low-voltage-activated calcium channels are important regulators of neurotransmission and membrane ion conductance. A plethora of intracellular events rely on their modulation. Accordingly, they are implicated in many disorders including epilepsy, Parkinson's disease, pain and other neurological diseases. Among different subfamilies, T-type calcium channels, and in particular the CaV3.2 isoform, were shown to be involved in nociceptive neurotransmission. The role of CaV3.2 in pain modulation was supported by demonstrating selective antisense oligonucleotide-mediated CaV3.2 knockdown, in vivo antinociceptive effects of T-type blockers, and pain attenuation in CaV3.2 knockout formalin-induced pain model. These Emerging investigations have provided new insights into targeting T-type calcium channels for pain management. Within this scope, various T-type calcium channel blockers have been developed such as mibefradil and ethosuximide. Although being active, most of these molecules interact with other receptors as well. This addresses the need for T- selectivity. Few selective T-type channel blockers of diverse chemical classes were developed such as ABT-639 and TTA-P2. Interestingly, R(-) efonidipine which is a dihydropyridine (DHP) showed T-channel selectivity. Systematic modification of 1,4-dihydropyridine scaffold introduced novel derivatives with 40 fold T-type selectivity over L-type calcium channels. Along these lines, substitution of the DHP core with various analogues favored T-selectivity and may serve as novel pharmacophores. Several dihydropyrimidine (DHPM) mimics were introduced by Squibb as potential candidates. As a continuation of this approach, the current study describes the synthesis of Novel N3 substituted DHPMs with structure similarities to the active DHPs. Different functional groups were introduced to the N3 position through a spacer to gain more information about activity and selectivity. Furthermore, the spacer aims at improving the metabolic stability of the molecules. Initial screening data by whole patch clamp technique showed a robust inhibition of Cav3.2 T-type channels by eleven compounds. Interestingly, four compounds of these were efficient selective T-type blockers. Based on selectivity and efficiency, two compounds were selected for in vivo evaluation in mouse models of inflammatory pain. Results showed effective attenuation of nociception and mechanical hypersensitivity.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.02.015
       
  • Structural Insights of SmKDAC8 Inhibitors: Targeting Schistosoma
           Epigenetics Through a Combined Structure-Based 3D QSAR, in vitro and
           Synthesis Strategy
    • Authors: Flavio Ballante; D. Rajasekhar Reddy; Nancy J. Zhou; Garland R. Marshall
      Abstract: Publication date: Available online 13 February 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Flavio Ballante, D. Rajasekhar Reddy, Nancy J. Zhou, Garland R. Marshall
      A predictive structure-based 3D QSAR (COMBINEr 2.0) model of the Schistosoma mansoni lysine deacetylase 8 enzyme (SmKDAC8) was developed, validated and used to perform virtual screening (VS) of the NCI Diversity Set V database (1593 compounds). Three external datasets (with congeneric structures to those experimentally resolved in complexes by X-ray and previously reported as SmKDAC8 inhibitors) were employed to compose and validate the most predictive model. Two series characterized by 104 benzodiazepine derivatives (BZDs) and 60 simplified largazole analogs (SLA), recently reported by our group as human KDAC inhibitors, were tested for their inhibition potency against SmKDAC8 to probe the predictive capability of the quantitative models against compounds with diverse structures. The SmKDAC8 biochemical results confirmed: 1) the benzodiazepine moiety as a valuable scaffold to further investigate when pursuing SmKDAC8 inhibition; 2) the predictive capability of the COMBINEr 2.0 model towards non-congeneric series of compounds, highlighting the most influencing ligand-protein interactions and refining the structure-activity relationships. From the VS investigations, the first 40 top-ranked compounds were obtained and biologically tested for their inhibition potency against SmKDAC8 and hKDACs 1, 3, 6 and 8. Among them, a non-hydroxamic acid benzothiadiazine dioxide derivative (code NSC163639), showed interesting activity and selectivity against SmKDAC8. To further elucidate the structure-activity relationships of NSC163639, two analogs (herein reported as compounds 3 and 4) were synthesized and biologically evaluated. Results suggest the benzothiadiazine dioxide moiety as a promising scaffold to be used in a next step to derive selective SmKDAC8 inhibitors.
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      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.02.020
       
  • 5-Ethynylarylnaphthalimides as Antitumor Agents: Synthesis and Biological
           Evaluation
    • Authors: Patricia Quintana-Espinoza; Pedro Martín-Acosta; Ángel Amesty; Patricia Martín-Rodríguez; Isabel Lorenzo-Castrillejo; Leandro Fernández-Pérez; Félix Machín; Ana Estévez-Braun
      Abstract: Publication date: Available online 13 February 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Patricia Quintana-Espinoza, Pedro Martín-Acosta, Ángel Amesty, Patricia Martín-Rodríguez, Isabel Lorenzo-Castrillejo, Leandro Fernández-Pérez, Félix Machín, Ana Estévez-Braun
      A set of 5-ethynylarylnaphthalimides was synthesized by Sonogashira cross-coupling reactions and evaluated for antiproliferative and antitopoisomerase II in vitro activities. Furthermore docking studies of these molecules as DNA-intercalators were carried out and the in vivo DNA-damaging activity was also determined with the model organism Saccharomyces cerevisiae. From the obtained results three naphthalimides 6, 13 and 14 showed strong topoisomerase II inhibitory activity. These three molecules also presented good docking scores as DNA-intercalators using a self-complementary oligodeoxynucleotide d(ATGCAT)2 as a model, and compounds 13 and 14 were among the most cytotoxic in the in vivo DNA-damaging activity.
      Graphical abstract image

      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.02.024
       
  • Green synthesis of novel spiro-indenoquinoxaline derivatives and their
           cholinesterases inhibition activity
    • Authors: Ammar Maryamabadi; Alireza Hasaninejad; Najmeh Nowrouzi; Gholamhossein Mohebbi
      Abstract: Publication date: Available online 12 February 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Ammar Maryamabadi, Alireza Hasaninejad, Najmeh Nowrouzi, Gholamhossein Mohebbi
      A convenient synthesis of substituted spiroindenoquinoxalines at mild and green conditions was developed. Multicomponent reaction of substituted phenylene diamines, ninhydrin, malononitrile and N,N’-substituted-2-nitroethene-1,1-diamines produced the target compounds. Twelve new spiroindenoquinoxalines were obtained, and their ability in inhibition of acetyl and butyrylcholinesterases were investigated both in-vitro and in-silico. All compounds showed moderate level activity against both acetyl and butyrylcholinesterases.
      Graphical abstract image

      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.02.017
       
  • Synthesis and pharmacological evaluation of
           pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives as potential GABAA-R
           ligands
    • Authors: Guerrini Gabriella; Giovanna Ciciani; Simona Daniele; Lorenzo Di Cesare Mannelli; Carla Ghelardini; Claudia Martini; Silvia Selleri
      Abstract: Publication date: Available online 11 February 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Guerrini Gabriella, Giovanna Ciciani, Simona Daniele, Lorenzo Di Cesare Mannelli, Carla Ghelardini, Claudia Martini, Silvia Selleri
      The synthesis of a new series of 6-phenyl- and 6-benzylpyrazolo[1,5-a]pyrimidin-7(4H)-ones 2a-g and 3a-g, strictly related to derivatives with pyrazolobenzotriazine (PBT) and pyrazoloquinazoline (PQ) scaffold, was realized. The in vitro GABAA-receptor subtype affinity was evaluated and from preliminary pharmacological studies, compound 3g shows anxiolytic-like effect at 10-30 mg/kg.
      Graphical abstract image

      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.02.013
       
  • Design, synthesis and preliminary biological evaluation of
           indole-3-carboxylic acid-based skeleton of Bcl-2/Mcl-1 dual inhibitors
    • Authors: Tingting Liu; Yichao Wan; Renshuai Liu; Lin Ma; Minyong Li; Hao Fang
      Abstract: Publication date: Available online 11 February 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Tingting Liu, Yichao Wan, Renshuai Liu, Lin Ma, Minyong Li, Hao Fang
      The B-cell lymphoma-2 (Bcl-2) family proteins are attractive targets for cancer therapy. In our previous work, the structure-activity relationship of WL-276 was studied. According to the results, rhodanine derivatives show potent binding affinity for Bcl-2 and Mcl-1 protein and show weaker activity against Bcl-XL protein. Based on the previous results, a new class of indole-3-carboxylic acid-based derivatives were designed and synthesized as Bcl-2/Mcl-1 dual inhibitors. Among them, compound 17 has a Ki value of 0.26 μM for Bcl-2 protein and is better than WL-276. Further more, it inhibits the myeloid cell leukemia sequence 1 (Mcl-1) protein with a Ki value of 72 nM. Especially, compound 31 can selectively acting on Bcl-2 and Mcl-1 protein but not Bcl-XL protein, which has great significance for developing dual inhibitors targeting Bcl-2 and Mcl-1 protein, as well as specific antitumor abilities in cells.
      Graphical abstract image

      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.02.014
       
  • Construction of a library of structurally diverse ribonucleopeptides with
           catalytic groups
    • Authors: Tomoki Tamura; Shun Nakano; Eiji Nakata; Takashi Morii
      Abstract: Publication date: Available online 10 February 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Tomoki Tamura, Shun Nakano, Eiji Nakata, Takashi Morii
      Functional screening of structurally diverse libraries consisting of proteins or nucleic acids is an effective method to obtain receptors or aptamers with unique molecular recognition characteristics. However, further modification of these selected receptors to exert a newly desired function is still a challenging task. We have constructed a library of structurally diverse ribonucleopeptides (RNPs) that are modified with a catalytic group, in which the catalytic group aligns with various orientations against the ATP binding pocket of RNA subunit. As a proof-of-principle, the screening of the constructed RNP library for the catalytic reaction of ester hydrolysis was successfully carried out. The size of both the substrate-binding RNA library and the catalytic group modified peptide library are independently expandable, and thus, the size of RNPs library could be enlarged by a combination of these two subunits. We anticipate that the library of functionalized and structurally diverse RNPs would be expanded for various other catalytic reactions.
      Graphical abstract image

      PubDate: 2017-02-19T05:44:31Z
      DOI: 10.1016/j.bmc.2017.02.007
       
  • Design, synthesis, molecular modeling and anti-hyperglycemic evaluation of
           novel quinoxaline derivatives as potential PPARγ and SURs agonists
    • Authors: Mohamed.K. Ibrahim; Ibrahim H. Eissa; AbdallahE. Abdallah; Ahmed M. Metwaly; M.M. and M.A. Radwan ElSohly
      Abstract: Publication date: Available online 16 January 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Mohamed.K. Ibrahim, Ibrahim H. Eissa, AbdallahE. Abdallah, Ahmed M. Metwaly, M.M. and M.A. Radwan ElSohly
      In our effort to develop potent anti-hyperglycemic agents with potential agonistic activities toward PPARγ and SURs, three novel series of quinoxaline derivatives bearing sulfonylurea or sulfonylthiourea moieties with different linkers were designed and synthesized. Some of the newly synthesized compounds were evaluated in vivo for their anti-hyperglycemic activities in STZ-induced hyperglycemic rats. Compounds 15a , 15e, 19b and 24a exhibited the highest anti-hyperglycemic activities with% reduction in blood glucose level of (50.58, 43.84, 45.10 and 49.62, respectively). Additionally, eight compounds revealed potent anti-hyperglycemic activities were further evaluated in vitro for their PPARγ binding affinity and insulin-secreting ability as potential mechanisms for anti-hyperglycemic activity. Four compounds (15a , 15b , 15d and 15e ) significantly bound to PPARγ with IC50 values of 0.482, 0.491, 0.350 and 0.369 μM, respectively. Moreover, Compounds 15a and 15b have demonstrated induction of insulin-secretion with EC50 values of 0.92 and 0.98 μM, respectively. Furthermore, molecular docking and pharmacophore generation techniques were carried out to investigate binding patterns and fit values of the designed compounds with PPARγ and SUR, respectively.
      Graphical abstract image

      PubDate: 2017-01-18T00:53:30Z
      DOI: 10.1016/j.bmc.2017.01.015
       
  • Identification of allosteric binding sites for PI3Kα oncogenic mutant
           specific inhibitor design
    • Authors: Michelle S. Miller; Sweta Maheshwari; Fiona M. McRobb; Kenneth W. Kinzler; L. Mario Amzel; Bert Vogelstein; Sandra B. Gabelli
      Abstract: Publication date: Available online 16 January 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Michelle S. Miller, Sweta Maheshwari, Fiona M. McRobb, Kenneth W. Kinzler, L. Mario Amzel, Bert Vogelstein, Sandra B. Gabelli
      PIK3CA, the gene that encodes the catalytic subunit of phosphatidylinositol 3-kinase α (PI3Kα), is frequently mutated in breast and other types of cancer. A specific inhibitor that targets the mutant forms of PI3Kα could maximize treatment efficiency while minimizing side-effects. Herein we describe the identification of novel binding pockets that may provide an opportunity for the design of mutant selective inhibitors. Using a fragment-based approach, we screened a library of 352 fragments (MW <300 Da) for binding to PI3Kα by X-ray crystallography. Five novel binding pockets were identified, each providing potential opportunities for inhibitor design. Of particular interest was a binding pocket near Glu542, which is located in one of the two most frequently mutated domains.
      Graphical abstract image

      PubDate: 2017-01-18T00:53:30Z
      DOI: 10.1016/j.bmc.2017.01.012
       
  • Synthesis of new spirooxindole-pyrrolothiazoles derivatives: Anti-cancer
           activity and molecular docking
    • Authors: Gehad Lotfy; Mohamed M. Said; El Sayed H. El Ashry; El Sayed H. El Tamany; Abdullah Al-Dhfyan; Yasmine M. Abdel Aziz; Assem Barakat
      Abstract: Publication date: Available online 16 January 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Gehad Lotfy, Mohamed M. Said, El Sayed H. El Ashry, El Sayed H. El Tamany, Abdullah Al-Dhfyan, Yasmine M. Abdel Aziz, Assem Barakat
      The 1,3-dipolar cycloadditions of an azomethine ylide generated from isatin and thiazolidinecarboxylic acid to a series of 2,6-bis[(E)-arylmethylidene]cyclohexanones afforded new di-spiro heterocycles incorporating pyrrolidine and oxindole rings in quantitative yields and chemo-, regio-, and stereoselectively. The newly synthesized compounds were characterized using spectroscopic techniques. Furthermore, the molecular structures of 4a, 4e, and 4n were confirmed by X-ray crystallography. These newly synthesized compounds were screened for their in vitro activity against breast cancer cell line MCF-7 and K562-leukemia. 4k was found to be the most potent compound of this series in targeting MCF-7 breast cancer cells and K562-leukemia, with IC50 values of 15.32 ± 0.02 and 14.74 ± 0.7 μM, respectively. The molecular studies of the synthesized compounds were investigated.
      Graphical abstract image

      PubDate: 2017-01-18T00:53:30Z
      DOI: 10.1016/j.bmc.2017.01.014
       
  • Chiral resolution of serial potent and selective σ1 ligands and
           biological evaluation of (-)-[18F]TZ3108 in rodent and the nonhuman
           primate brain
    • Authors: Xuyi Yue; Hongjun Jin; Zonghua Luo; Hui Liu; Xiang Zhang; Ethan D. McSpadden; Linlin Tian; Hubert P. Flores; Joel S. Perlmutter; Stanley M. Parsons; Zhude Tu
      Abstract: Publication date: Available online 16 January 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Xuyi Yue, Hongjun Jin, Zonghua Luo, Hui Liu, Xiang Zhang, Ethan D. McSpadden, Linlin Tian, Hubert P. Flores, Joel S. Perlmutter, Stanley M. Parsons, Zhude Tu
      Twelve optically pure enantiomers were obtained using either crystallization or chiral high performance liquid chromatography (HPLC) separation methodologies to resolve six racemic sigma-1 (σ 1) receptor ligands. The in vitro binding affinities of each enantiomer for σ 1, σ 2 receptors and vesicular acetylcholine transporter (VAChT) were determined. Out of the 12 optically pure enantiomers, five displayed very high affinities for σ 1 (K i < 2 nM) and high selectivity for σ 1 versus σ 2 and VAChT (>100-fold). The minus enantiomer, (-)-14a ((-)-TZ3108)) (Ki- σ 1 = 1.8 ± 0.4 nM, Ki- σ 2 = 6960 ± 810 nM, Ki-VAChT = 980 ± 87 nM), was chosen for radiolabeling and further in vivo evaluation in rodents and nonhuman primates (NHPs). A biodistribution study in Sprague Dawley rats showed brain uptake (%ID/gram) of (-)-[18F]TZ3108 reached 1.285 ± 0.062 at 5 min and 0.802 ± 0.129 at 120 min. NHP microPET imaging studies revealed higher brain uptake of (-)-[18F]TZ3108 and more favorable pharmacokinetics compared to its racemic counterpart. Pretreatment of the animal using two structurally different σ 1 ligands significantly decreased accumulation of (-)-[18F]TZ3108 in the brain. Together, our in vivo evaluation results suggest that (-)-[18F]TZ3108 is a promising positron emission tomography (PET) tracer for quantifying σ 1 receptor in the brain.
      Graphical abstract image

      PubDate: 2017-01-18T00:53:30Z
      DOI: 10.1016/j.bmc.2017.01.017
       
 
 
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