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  Subjects -> CHEMISTRY (Total: 836 journals)
    - ANALYTICAL CHEMISTRY (47 journals)
    - CHEMISTRY (586 journals)
    - CRYSTALLOGRAPHY (22 journals)
    - ELECTROCHEMISTRY (26 journals)
    - INORGANIC CHEMISTRY (41 journals)
    - ORGANIC CHEMISTRY (46 journals)
    - PHYSICAL CHEMISTRY (68 journals)

CHEMISTRY (586 journals)                  1 2 3 4 5 6 | Last

2D Materials     Hybrid Journal   (Followers: 5)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 31)
ACS Catalysis     Full-text available via subscription   (Followers: 27)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 16)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 17)
ACS Macro Letters     Full-text available via subscription   (Followers: 20)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 24)
ACS Nano     Full-text available via subscription   (Followers: 204)
ACS Photonics     Full-text available via subscription   (Followers: 6)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 11)
Acta Chemica Iasi     Open Access  
Acta Chimica Sinica     Full-text available via subscription  
Acta Chimica Slovaca     Open Access   (Followers: 5)
Acta Chromatographica     Full-text available via subscription   (Followers: 9)
Acta Facultatis Medicae Naissensis     Open Access   (Followers: 1)
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 6)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 5)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 5)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 11)
Advanced Functional Materials     Hybrid Journal   (Followers: 40)
Advanced Science Focus     Free   (Followers: 1)
Advances in Chemical Engineering and Science     Open Access   (Followers: 24)
Advances in Chemical Science     Open Access   (Followers: 9)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 15)
Advances in Drug Research     Full-text available via subscription   (Followers: 17)
Advances in Enzyme Research     Open Access  
Advances in Fluorine Science     Full-text available via subscription   (Followers: 7)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 13)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 14)
Advances in Nanoparticles     Open Access   (Followers: 11)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 9)
Advances in Polymer Science     Hybrid Journal   (Followers: 37)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 6)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 10)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6)
African Journal of Chemical Education     Open Access   (Followers: 1)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 5)
Afrique Science : Revue Internationale des Sciences et Technologie     Open Access   (Followers: 1)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 1)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 4)
AMB Express     Open Access  
Ambix     Hybrid Journal   (Followers: 2)
American Journal of Applied Sciences     Open Access   (Followers: 29)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 91)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 11)
American Journal of Chemistry     Open Access   (Followers: 20)
American Journal of Plant Physiology     Open Access   (Followers: 10)
American Mineralogist     Full-text available via subscription   (Followers: 8)
Analyst     Full-text available via subscription   (Followers: 37)
Angewandte Chemie     Hybrid Journal   (Followers: 20)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 141)
Annales UMCS, Chemia     Open Access   (Followers: 2)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access  
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 1)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 2)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 6)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 10)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 12)
Anti-Infective Agents     Hybrid Journal   (Followers: 1)
Antiviral Chemistry and Chemotherapy     Full-text available via subscription  
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 4)
Applied Spectroscopy     Full-text available via subscription   (Followers: 15)
Applied Surface Science     Hybrid Journal   (Followers: 23)
Arabian Journal of Chemistry     Full-text available via subscription   (Followers: 6)
ARKIVOC     Open Access   (Followers: 1)
Asian Journal of Biochemistry     Open Access   (Followers: 1)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 4)
Autophagy     Full-text available via subscription   (Followers: 2)
Avances en Quimica     Open Access   (Followers: 1)
Biochemical Pharmacology     Hybrid Journal   (Followers: 6)
Biochemistry     Full-text available via subscription   (Followers: 162)
Biochemistry Insights     Open Access   (Followers: 4)
Biochemistry Research International     Open Access   (Followers: 4)
BioChip Journal     Hybrid Journal   (Followers: 1)
Bioinorganic Chemistry and Applications     Open Access   (Followers: 4)
Bioinspired Materials     Open Access  
Biointerface Research in Applied Chemistry     Open Access   (Followers: 1)
Biointerphases     Open Access  
Biomacromolecules     Full-text available via subscription   (Followers: 18)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 6)
Biomedical Chromatography     Hybrid Journal   (Followers: 7)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 2)
BioNanoScience     Partially Free   (Followers: 4)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 29)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 23)
Bioorganic Chemistry     Hybrid Journal   (Followers: 5)
Biopolymers     Hybrid Journal   (Followers: 17)
Biosensors     Open Access   (Followers: 3)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 3)
Boletin de la Sociedad Chilena de Quimica     Open Access  
Bulletin of the Chemical Society of Ethiopia     Open Access   (Followers: 2)
Bulletin of the Chemical Society of Japan     Full-text available via subscription   (Followers: 14)
C - Journal of Carbon Research     Open Access  
Canadian Association of Radiologists Journal     Full-text available via subscription   (Followers: 3)
Canadian Journal of Chemistry     Full-text available via subscription   (Followers: 6)
Canadian Mineralogist     Full-text available via subscription   (Followers: 2)
Carbohydrate Research     Hybrid Journal   (Followers: 11)
Carbon     Hybrid Journal   (Followers: 74)
Catalysis for Sustainable Energy     Open Access   (Followers: 3)

        1 2 3 4 5 6 | Last

Journal Cover   Bioorganic & Medicinal Chemistry
  [29 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0968-0896
   Published by Elsevier Homepage  [2812 journals]
  • Hybrid chemistry. Part 4: Discovery of etravirine–VRX-480773 hybrids
           as potent HIV-1 non-nucleoside reverse transcriptase inhibitors
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Zheng-Yong Wan, Yuan Tao, Ya-Feng Wang, Tian-Qi Mao, Hong Yin, Fen-Er Chen, Hu-Ri Piao, Erik De Clercq, Dirk Daelemans, Christophe Pannecouque
      A novel series of etravirine–VRX-480773 hybrids were designed using structure-guided molecular hybridization strategy and fusing the pharmacophore templates of etravirine and VRX-480773. The anti-HIV-1 activity and cytotoxicity was evaluated in MT-4 cell cultures. The most active hybrid compound in this series, N-(2-chlorophenyl)-2-((4-(4-cyano-2,6-dimethylphenoxy)pyrimidin-2-yl)thio)acetamide 3d (EC50 =0.24 , SI>1225), was more potent than delavirdine (EC50 =0.66μM, SI>67) in the anti-HIV-1 in vitro cellular assay. Studies of structure-activity relationships established a correlation between anti-HIV activity and the substitution pattern of the acetanilide group.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
  • 4-(N-Phenyl-N′-substituted
           benzenesulfonyl)-6-(4-hydroxyphenyl)quinolines as inhibitors of mammalian
           target of rapamycin
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Vunnam Venkateswarlu, Anup Singh Pathania, K.A. Aravinda Kumar, Priya Mahajan, Amit Nargotra, Ram A. Vishwakarma, Fayaz A. Malik, Sanghapal D. Sawant
      A series of 4-(N-phenyl-N′-substituted benzenesulfonyl)-6-(4-hydroxyphenyl)quinolines was designed, synthesized and evaluated for their biological potential as anticancer agents by screening the molecules against panel of five human cancer cell lines viz. HL-60, MiaPaCa-2, HCT116, PC-3 and HEP-G2. The series has shown good mTOR inhibitory activity at 0.5μM concentration. The representative compound 7h was found to be most active with the IC50 of 613nM against mTOR. In supportive evidence, the western blotting experiment revealed that compound 7h is more potent in inhibiting p-mTOR (S2448) activity in 2–4h at 5 and 10μM concentrations and was selective and specific towards mTORC1 versus mTORC2. Towards understanding the mechanistic aspects we studied cell cycle analysis, mitochondrial membrane potential loss in MiaPaca-2 cells for compound 7h. The docking study for this series was performed to understand the binding mode of the compounds and its consequent effect in biological activity, the initial interaction studies were found to be useful in design of molecules, where compound 7h has shown additional H-bond interaction with Lys2171 apart from Val2240 and also a small hydrophobic cleft was observed with Leu2185, Met2345 and Ile2356.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
  • Antimitotic and antivascular activity of
           heteroaroyl-2-hydroxy-3,4,5-trimethoxybenzenes
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Hsueh-Yun Lee, Chih-Yi Chang, Mei-Jung Lai, Hsun-Yueh Chuang, Ching-Chuan Kuo, Chi-Yen Chang, Jang-Yang Chang, Jing-Ping Liou
      This study reports the synthesis of a series of heteroaroyl-2-hydroxy-3,4,5-trimethoxybenzenes, which are potent antitubulin agents. Compound 13, (2-hydroxy-3,4,5-trimethoxyphenyl)-(6-methoxy-1H-indol-3-yl)-methanone exhibits marked antiproliferative activity against KB and MKN45 cells with IC50 values of 8.8 and 10.5nM, respectively, binds strongly to the colchicine binding site and leads to inhibition of tubulin polymerization. It also behaves as a vascular disrupting agent which suppresses the formation of capillaries. The C2-OH group in the A-ring of this compound not only retains the biological activity but has valuable physicochemical properties.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
  • Discovery of potent and selective nonplanar tankyrase inhibiting
           nicotinamide mimics
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Yves Nkizinkiko, B.V.S. Suneel Kumar, Variam Ullas Jeankumar, Teemu Haikarainen, Jarkko Koivunen, Chanduri Madhuri, Perumal Yogeeswari, Harikanth Venkannagari, Ezeogo Obaji, Taina Pihlajaniemi, Dharmarajan Sriram, Lari Lehtiö
      Diphtheria toxin-like ADP-ribosyltransferases catalyse a posttranslational modification, ADP-ribosylation and form a protein family of 17 members in humans. Two of the family members, tankyrases 1 and 2, are involved in several cellular processes including mitosis and Wnt/β-catenin signalling pathway. They are often over-expressed in cancer cells and have been linked with the survival of cancer cells making them potential therapeutic targets. In this study, we identified nine tankyrase inhibitors through virtual and in vitro screening. Crystal structures of tankyrase 2 with the compounds showed that they bind to the nicotinamide binding site of the catalytic domain. Based on the co-crystal structures we designed and synthesized a series of tetrahydroquinazolin-4-one and pyridopyrimidin-4-one analogs and were subsequently able to improve the potency of a hit compound almost 100-fold (from 11μM to 150nM). The most potent compounds were selective towards tankyrases over a panel of other human ARTD enzymes. They also inhibited Wnt/β-catenin pathway in a cell-based reporter assay demonstrating the potential usefulness of the identified new scaffolds for further development.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
  • 4,6-Substituted-1,3,5-triazin-2(1H)-ones as monocyclic catalytic
           inhibitors of human DNA topoisomerase IIα targeting the ATP binding
           site
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Barbara Pogorelčnik, Matej Janežič, Izidor Sosič, Stanislav Gobec, Tom Solmajer, Andrej Perdih
      Human DNA topoisomerase IIα (htIIα) is a validated target for the development of novel anticancer agents. Starting from our discovered 4-amino-1,3,5-triazine inhibitors of htIIα, we investigated a library of 2,4,6-trisubstituted-1,3,5-triazines for novel inhibitors that bind to the htIIα ATP binding site using a combination of structure-based and ligand-based pharmacophore models and molecular docking. 4,6-substituted-1,3,5-triazin-2(1H)-ones 8, 9 and 14 were identified as novel inhibitors with activity comparable to the established drug etoposide (1). Compound 8 inhibits the htIIα decatenation in a superior fashion to etoposide. Cleavage assays demonstrated that selected compounds 8 and 14 do not act as poisons and antagonize the poison effect of etoposide. Microscale thermophoresis (MST) confirmed binding of compound 8 to the htIIα ATPase domain and compound 14 effectively inhibits the htIIα mediated ATP hydrolysis. The molecular dynamics simulation study provides further insight into the molecular recognition. The 4,6-disubstituted-1,3,5-triazin-2(1H)-ones represent the first validated monocyclic class of catalytic inhibitors that bind to the to the htIIα ATPase domain.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
  • N-[(2,6-Dimethylphenoxy)alkyl]aminoalkanols—their physicochemical
           and anticonvulsant properties
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Anna M. Waszkielewicz, Marek Cegła, Ewa Żesławska, Wojciech Nitek, Karolina Słoczyńska, Henryk Marona
      Twenty four new N-[(dimethylphenoxy)alkyl]aminoalkanols have been synthesized and evaluated for anticonvulsant activity in a series of in vivo tests: the maximum electroshock (MES), 6Hz, and subcutaneous metrazole (ScMet). The compounds were also evaluated for possible neurotoxicity in the rotarod test. The majority of the achieved compounds exhibit quantified anticonvulsant activity. The most active compound 4: R-(−)-2N-[(2,6-dimethylphenoxy)ethyl]aminopropan-1-ol is active in MES with ED50 =5.34 (male mice, ip), 22.28 (female mice, ip), 51.19 (male mice, po), 7.43 (rats, ip), and 28.60 (rats, po). Thermal analysis proved that its hydrochloride (4a) can exist in polymorphic forms. The compound binds to σ, 5-HT1A, and α2 receptors as well as 5-HT transporter and it does not exhibit mutagenic properties.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
  • Intriguing possibilities and beneficial aspects of transporter-conscious
           drug design
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Toshihiko Tashima
      It has been revealed that many types of drugs interact with transporter proteins within an organism. Transporter proteins absorb or excrete materials, including drugs and nutrients, across the cell membrane. Some hydrophobic drugs are excreted from the cell as xenobiotics by ATP-binding cassette (ABC) transporters. However, solute carrier (SLC) transporters are tissue-specifically expressed and have substrate specificities. Thus, transporter-conscious drug design is an excellent method of delivering drugs to pharmaceutical target organs and provides advantages in absorption, distribution, excretion, and toxicity of drugs (ADMET) due to transport systems. In fact, based on this strategy, the bioavailability of prodrugs designed as peptide transporter 1 (PEPT1) substrates was better than that of the corresponding parent compounds due to the transport system in the small intestine. Furthermore, in central nervous system (CNS) drug developing, drug delivery into brain across the blood–brain barrier (BBB) is a serious problem. However, this problem can be also solved by the use of the transport systems at the BBB. Therefore, transporter-consciously designed drugs not only may effectively elicit activity but also may control adverse side effects caused by off-targets and drug-drug interactions and, consequently, may show good performance in clinical trials. In this review, I introduce possibilities and advantages of transporter-conscious drug designs.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
  • Structural development of stabilized helical peptides as inhibitors of
           estrogen receptor (ER)-mediated transcription
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Yosuke Demizu, Takashi Misawa, Takaya Nagakubo, Yasunari Kanda, Keiichiro Okuhira, Yuko Sekino, Mikihiko Naito, Masaaki Kurihara
      Three types of stabilized helical peptides containing disulfide bonds, C–C cross-linked side chains, or α,α-disubstituted amino acids (2-aminoisobutyric acid (Aib)) were designed and synthesized as inhibitors of estrogen receptor (ER)-coactivator interactions. Furthermore, heptaarginine (R7)-conjugated versions of the peptides were prepared, and their effects on ER-mediated transcription were evaluated at the cellular level (in ER-positive T47D cells). Among them, the R7-conjugated peptides 11 and 12 downregulated the mRNA expression of pS2 (an ER-mediated gene whose expression is upregulated by 17β-estradiol) by 95% (at a dose of 10μM) and 87% (at a dose of 3μM), respectively.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
  • Synthesis, F-18 radiolabeling, and microPET evaluation of
           3-(2,4-dichlorophenyl)-N-alkyl-N-fluoroalkyl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-amines
           as ligands of the corticotropin-releasing factor type-1 (CRF1) receptor
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Jeffrey S. Stehouwer, Matthew S. Birnbaum, Ronald J. Voll, Michael J. Owens, Susan J. Plott, Chase H. Bourke, Michael A. Wassef, Clinton D. Kilts, Mark M. Goodman
      A series of 3-(2,4-dichlorophenyl)-N-alkyl-N-fluoroalkyl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-amines were synthesized and evaluated as potential positron emission tomography (PET) tracers for the corticotropin-releasing factor type-1 (CRF1) receptor. Compounds 27, 28, 29, and 30 all displayed high binding affinity (⩽1.2nM) to the CRF1 receptor when assessed by in vitro competition binding assays at 23°C, whereas a decrease in affinity (⩾10-fold) was observed with compound 26. The log P 7.4 values of [18F]26–[18F]29 were in the range of ∼2.2–2.8 and microPET evaluation of [18F]26–[18F]29 in an anesthetized male cynomolgus monkey demonstrated brain penetrance, but specific binding was not sufficient enough to differentiate regions of high CRF1 receptor density from regions of low CRF1 receptor density. Radioactivity uptake in the skull, and sphenoid bone and/or sphenoid sinus during studies with [18F]28, [18F]28-d 8 , and [18F]29 was attributed to a combination of [18F]fluoride generated by metabolic defluorination of the radiotracer and binding of intact radiotracer to CRF1 receptors expressed on mast cells in the bone marrow. Uptake of [18F]26 and [18F]27 in the skull and sphenoid region was rapid but then steadily washed out which suggests that this behavior was the result of binding to CRF1 receptors expressed on mast cells in the bone marrow with no contribution from [18F]fluoride.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
  • Ring-substituted 8-hydroxyquinoline-2-carboxanilides as potential
           antimycobacterial agents
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Jiri Kos, Iveta Zadrazilova, Eoghan Nevin, Michal Soral, Tomas Gonec, Peter Kollar, Michal Oravec, Aidan Coffey, Jim O’Mahony, Tibor Liptaj, Katarina Kralova, Josef Jampilek
      In this study, a series of twenty-two ring-substituted 8-hydroxyquinoline-2-carboxanilides was prepared and characterized. Primary in vitro screening of the synthesized compounds was performed against Mycobacterium tuberculosis H37Ra, Mycobacterium avium complex and M. avium subsp. paratuberculosis. Some of the tested compounds showed the antimycobacterial activity against M. avium subsp. paratuberculosis comparable with or higher than that of rifampicin. 8-Hydroxy-N-[3-(trifluoromethyl)phenyl]- and 8-hydroxy-N-[4-(trifluoromethyl)phenyl]quinoline-2-carboxamide showed MIC=24μM against all tested mycobacterial strains. 3-Methoxyphenyl- and 3-methylphenyl derivatives expressed MIC=27 or 29μM also against all the tested strains. Their activity against M. avium subsp. paratuberculosis was 4-fold higher than that of rifampicin. 2-Bromophenyl- and 2-(trifluoromethyl)phenyl derivatives had MIC=23 or 24μM against M. tuberculosis. A significant decrease of mycobacterial cell metabolism (viability of M. tuberculosis H37Ra) was observed using MTT assay. Screening of cytotoxicity of the compounds was performed using the THP-1 cells, and no significant lethal effect was observed up to tested concentration 30μM. The structure–activity relationships are discussed.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
  • Inhibition studies of bacterial, fungal and protozoan β-class
           carbonic anhydrases with Schiff bases incorporating sulfonamide moieties
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Mariangela Ceruso, Fabrizio Carta, Sameh M. Osman, Zeid Alothman, Simona Maria Monti, Claudiu T. Supuran
      A series of new Schiff bases derived from sulfanilamide, 3-fluorosulfanilamide or 4-(2-aminoethyl)-benzenesulfonamide containing either a hydrophobic or a hydrophilic tail, have been investigated as inhibitors of three β-carbonic anhydrases (CA, EC 4.2.1.1) from three different microorganisms. Their antifungal, antibacterial and antiprotozoan activities have been determined against the pathogenic fungus Cryptococcus neoformans, the bacterial pathogen Brucella suis and the protozoan parasite Leishmania donovani chagasi, responsible for Leishmaniasis. The results of these inhibition studies show that all three enzymes were efficiently inhibited by the Schiff base sulfonamides with K I values in the nanomolar or submicromolar range, depending on the nature of the tail, coming from the aryl/heteroaryl moiety present in the starting aldehyde employed in the synthesis. Furthermore, the compounds hereby investigated revealed high β-CAs selectivity over the ubiquitous, physiologically relevant and off-target human isoforms (CA I and II) and to be more potent as antifungal and antibacterial than as antiprotozoan potential drugs.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
  • Imidazole clubbed 1,3,4-oxadiazole derivatives as potential antifungal
           agents
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Mohmmad Younus Wani, Aijaz Ahmad, Rayees Ahmad Shiekh, Khalaf J. Al-Ghamdi, Abilio J.F.N. Sobral
      A series of compounds in which 2-(4-ethyl-2-pyridyl)-1H-imidazole was clubbed with substituted 1,3,4-oxadiazole was synthesized and subjected to antifungal activity evaluation. In vitro assays indicated that several clubbed derivatives had excellent antifungal activity against different strains of laboratory and clinically isolated Candida species. Structural Activity Relationship (SAR) studies revealed that the presence and position of substituents on the phenyl ring of the 1,3,4-oxadiazole unit, guides the antifungal potential of the compounds, where compound 4b, 4c and 4g were found to be active against all the tested fungal strains. Impairment of ergosterol biosynthesis upon the concomitant treatment of 4b, 4c and 4g, revealed the possible mechanisms of antifungal action of these compounds. Inhibitors snugly fitting the active site of the target enzyme, as revealed by molecular docking studies, may well explain their excellent inhibitory activity.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
  • In vitro antiplasmodial activity of triazole-linked chloroquinoline
           derivatives synthesized from 7-chloro-N-(prop-2-yn-1-yl)quinolin-4-amine
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Lebusetsa Taleli, Carmen de Kock, Peter J. Smith, Stephen C. Pelly, Margaret A.L. Blackie, Willem A.L. van Otterlo
      The synthesis and in vitro evaluation of novel triazole-linked chloroquinoline derivatives as potential antiplasmodial agents against Plasmodium falciparum is reported. The 15 synthesized target compounds were obtained by means of a copper(I)-mediated click reaction between a variety of 1,2- and 1,3-azidoamines and 7-chloro-N-(prop-2-yn-1-yl)quinolin-4-amine in moderate to good yields (53–85%). The compounds were screened for antiplasmodial activity against NF54 chloroquine-sensitive and Dd2 chloroquine-resistant strains, alongside chloroquine and artesunate as reference compounds. Six of the test compounds revealed a 3–5 fold increase in antiplasmodial activity against chloroquine-resistant strain Dd2 compared to chloroquine. Among the six compounds with good antiplasmodial activity, a reduced cross-resistance relative to artesunate (>3 fold in comparison to chloroquine) was observed, mainly in derivatives that incorporated chloroquine-resistance reversing pharmacophores. A general trend for reduced chloroquine cross-resistance was also detected among 12 out of the 15 compounds tested.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
  • Hedgehog inhibitors from Artocarpus communis and Hyptis suaveolens
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Midori A. Arai, Kyoko Uchida, Samir K. Sadhu, Firoj Ahmed, Takashi Koyano, Thaworn Kowithayakorn, Masami Ishibashi
      The hedgehog (Hh) signaling pathway plays crucial roles in cell maintenance and proliferation during embryonic development. Naturally occurring Hh inhibitors were isolated from Artocarpus communis and Hyptis suaveolens using our previously constructed cell-based assay system. Bioactivity guided fractionation led to the isolation of 15 compounds, including seven new compounds (4, 5, 6, 7, and 9–11). The isolated compounds showed cytotoxicity against a cancer cell line (PANC1) in which Hh signaling was abnormally activated. Several compounds (12–14; GLI1 transcriptional inhibition IC50 =7.6, 4.7, and 4.0μM, respectively) inhibited Hh related protein (BCL2) expression. Moreover, compounds 1, 12, and 13 disrupted GLI1 and DNA complex formation.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
  • Synthesis of new oxadiazole derivatives as α-glucosidase inhibitors
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Muhammad Taha, Nor Hadiani Ismail, Syahrul Imran, Muhammad Qamarruddin Bin Rokei, Syed Muhammad Saad, Khalid Mohammed Khan
      Oxadiazole derivatives (6–28) having hydrazone linkage, were synthesized through condensation reaction between benzohydrazide 5 with various benzaldehydes. The oxadiazoles derivatives (6–28) were evaluated for their α-glucosidase inhibitory activity. The IC50 values for inhibition activity vary in the range between 2.64±0.05 and 460.14±3.25μM. The IC50 values were being compared to the standard acarbose (IC50 =856.45±5.60μM) and it was found that compounds 6–9, 12, 13, 16, 18, 20, 22–28 were found to be more active than acarbose, while other compounds showed no activity. Structure–activity relationship (SAR) studies suggest that oxadiazole benzohydrazones (6–28) inhibitory potential is dependent on substitution of the N-benzylidene part. Compound 18 (IC50 =2.64±0.05μM), which has trihydroxy substitution at C-2′, C-4′, and C-5′ on N-benzylidene moiety, recorded the highest inhibition activity that is three-hundred times more active than the standard drug, acarbose (IC50 =856.45±5.60μM). Compound 23 (IC50 =34.64±0.35μM) was found to be the most active among compounds having single hydroxyl substitution. Shifting hydroxyl from C-2′ to C-4′ (6) and C-3′ (7) reduces inhibitory activity significantly. Compounds with chlorine substituent (compounds 16, 28, and 27) showed potent activities but lower as compared to hydroxyl analogs. Substituent like nitro or methyl groups at any position suppresses enzyme inhibition activity. This reveals the important presence of hydroxyl and halo groups to have enzyme inhibitory potential.
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      PubDate: 2015-07-24T15:43:39Z
       
  • Editorial board
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15




      PubDate: 2015-07-24T15:43:39Z
       
  • Graphical contents list
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15




      PubDate: 2015-07-24T15:43:39Z
       
  • Stereoselective synthesis and pharmacological evaluation of
           [4.3.3]propellan-8-amines as analogs of adamantanamines
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Héctor Torres-Gómez, Kirstin Lehmkuhl, Bastian Frehland, Constantin Daniliuc, Dirk Schepmann, Christina Ehrhardt, Bernhard Wünsch
      Amantadine (1) exerts its anti-Parkinson effects by inhibition of the NMDA associated cation channel and its antiviral activity by inhibition of the M2 protein channel of influenza A viruses. Herein the synthesis, NMDA receptor affinity and anti-influenza activity of analogous propellanamines 3 are reported. The key steps in the synthesis of the diastereomeric propellanamines syn-3 and anti- 3 are diastereoselective reduction of the ketone 7 with L-Selectride to give anti-11, Mitsunobu inversion of the alcohol anti-13 into syn-13, and SN2 substitution of diastereomeric mesylates syn-14 and anti-14 with NaN3. The affinity of the propellanamines syn-3 and anti- 3 to the PCP binding site of the NMDA receptor is similar to that of amantadine (Ki =11μM). However, both propellanamines syn-3 and anti- 3 do not exhibit activity against influenza A viruses. Compared to amantadine (1), the structurally related propellanamines syn-3 and anti- 3 retain the NMDA antagonistic activity but loose the antiviral activity.
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      PubDate: 2015-07-24T15:43:39Z
       
  • Benzoic acid derivatives with improved antifungal activity: Design,
           synthesis, structure–activity relationship (SAR) and CYP53 docking
           studies
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Sabina Berne, Lidija Kovačič, Matej Sova, Nada Kraševec, Stanislav Gobec, Igor Križaj, Radovan Komel
      Previously, we identified CYP53 as a fungal-specific target of natural phenolic antifungal compounds and discovered several inhibitors with antifungal properties. In this study, we performed similarity-based virtual screening and synthesis to obtain benzoic acid-derived compounds and assessed their antifungal activity against Cochliobolus lunatus, Aspergillus niger and Pleurotus ostreatus. In addition, we generated structural models of CYP53 enzyme and used them in docking trials with 40 selected compounds. Finally, we explored CYP53–ligand interactions and identified structural elements conferring increased antifungal activity to facilitate the development of potential new antifungal agents that specifically target CYP53 enzymes of animal and plant pathogenic fungi.
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      PubDate: 2015-07-24T15:43:39Z
       
  • Studies on the preferred uracil–adenine base pair at the cleavage
           site of 10–23 DNAzyme by functional group modifications on adenine
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Junfei Zhu, Zhiwen Li, Zhenjun Yang, Junlin He
      10–23 DNAzyme is capable of catalytically cleaving RNA substrates with the preferred cleavage sites rAU and rGU, in which the common base pair U-dA0 forms between the substrate and the DNAzyme in the cleavage reaction. Here its conservation was studied with base modifications on dA and extra functional groups introduced. The nitrogen atom at 7- or 8-position of adenine was demonstrated to be equally important for the cleavage reaction, although it is not related to the thermal stability of the base pair. Deletion of 6-amino group led to decreased stability of the base pair and a slight slower reaction rate. Extra functional groups through 6-amino group were not favorably accommodated in the cleavage site. From these modifications at the level of functional groups, it demonstrated that the base pair U-dA0 not only contributes to the recognition and binding stability, but also it is involved in the active catalytic center by its functional groups and base stacking. This kind of chemical modifications with 7-substituted 8-aza-7-deaza-2′-deoxyadenosine at dA0 is favorable for the introduction of signal molecules for mechanistic studies and biological applications, without significant loss of the catalytic function and structural destruction.
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      PubDate: 2015-07-24T15:43:39Z
       
  • Anti-growth effect of a novel
           trans-dichloridobis[2-(2-hydroxyethyl)pyridine]platinum (II) complex via
           induction of apoptosis on breast cancer cell lines
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Arzu Yilmaztepe Oral, Buse Cevatemre, Mehmet Sarimahmut, Ceyda Icsel, Veysel Turan Yilmaz, Engin Ulukaya
      Breast cancer still continues to be the leading cause of cancer-related mortality in women worldwide. Although advances have been made in the treatment of this disease during the past decade, new approaches and novel compounds are urgently needed. The aim of this study was to evaluate the cytotoxic activity of trans-[PtCl2(2-hepy)2] [2-hepy=2-(2-hydroxyethyl) pyridine] on breast cancer cell lines, MCF-7 and MDA-MB-231. The platinum (II) complex was synthesized and characterized by our laboratory working group. Anti-growth effect was assayed by the MTT and ATP viability assays and also monitored real-time using xCELLigence system. The mode of cell death was evaluated by using the fluorescence microscopy (Hoechst 33342+Calcein-AM+Propidium iodide staining), Western blotting (cleaved PARP and caspase 3, total caspase 8), flow cytometry (quantitative analysis of live, early/late apoptotic, dead cells and caspase 3/7 activity) and the RT-PCR (the genes analyzed were BCL-2L10, BIK, BAX, BCL-2, FASLG, HRK, TNFRSF10B, and TNFRSF10A). The platinum (II) complex had anti-growth effect in a dose dependent manner in vitro. Cells were killed by apoptosis as evidenced by the pyknotic nuclei, cleavage of poly-(ADP-ribose) polymerase (PARP) and induction of active caspase-3. These results suggest that the complex might represent a potentially active novel drug for the breast cancer treatment and warrants further studies due to its promising cytotoxic activity.
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      PubDate: 2015-07-24T15:43:39Z
       
  • Development of novel DIF-1 derivatives that selectively suppress innate
           immune responses
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Van Hai Nguyen, Haruhisa Kikuchi, Yuzuru Kubohara, Katsunori Takahashi, Yasuhiro Katou, Yoshiteru Oshima
      The multiple pharmacological activities of differentiation-inducing factor-1 (DIF-1) of the cellular slime mold Dictyostelium discoideum led us to examine the use of DIF-1 as a ‘drug template’ to develop promising seed compounds for drug discovery. DIF-1 and its derivatives were synthesized and evaluated for their regulatory activities in innate immune responses. We found two new derivatives (4d and 5e) with highly selective inhibitory activities against production of the antimicrobial peptide attacin in Drosophila S2 cells and against production of interleukin-2 in Jurkat cells.
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      PubDate: 2015-07-24T15:43:39Z
       
  • Synthesis of new fluorinated analogs of GABA, Pregabalin bioisosteres, and
           their effects on [3H]GABA uptake by rat brain nerve terminals
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): T. Borisova, N. Pozdnyakova, E. Shaitanova, I. Gerus, M. Dudarenko, R. Mironets, G. Haufe, V. Kukhar
      Fluorinated analogs of natural substances take an essential place in the design of new biologically active compounds. New fluorinated analogs of γ-aminobutyric acid, that is, β-polyfluoroalkyl-GABAs (FGABAs), were synthesized with substituents: β-CF3-β-OH (1), β-CF3 (2); β-CF2CF2H (3). FGABAs are bioisosteres of Pregabalin (Lyrica®, Pfizer’s blockbuster drug, β-i-Bu-GABA), and have lipophilicity close to this medicine. The effects of synthesized FGABAs on [3H]GABA uptake by isolated rat brain nerve terminals (synaptosomes) were assessed and compared with those of Pregabalin. FGABAs 1–3 (100μM) did not influence the initial velocity of [3H]GABA uptake when applied acutely, whereas an increase in this parameter was found after preliminary incubation of FGABAs with synaptosomes. Pregabalin after preliminary incubation with synaptosomes caused unidirectional changes in the initial velocity of [3H]GABA uptake. Using specific inhibitors of GAT1 and GAT3, NO-711 and SNAP5114, respectively, the ability of FGABAs 1–3 to influence non-GAT1 and non-GAT3 uptake activity of nerve terminals was analyzed, but no specificity was found. Therefore, new synthesized FGABAs are structural but not functional analogs of GABA (because they did not inhibit synaptosomal [3H]GABA uptake). Moreover, FGABAs are able to increase the initial velocity of [3H]GABA uptake by synaptosomes, and this effect is higher than that of Pregabalin.
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      PubDate: 2015-07-24T15:43:39Z
       
  • One-pot synthesis of human metabolites of SAR548304 by fungal
           peroxygenases
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Jan Kiebist, Wolfgang Holla, Johannes Heidrich, Marzena Poraj-Kobielska, Martin Sandvoss, Reiner Simonis, Glenn Gröbe, Jens Atzrodt, Martin Hofrichter, Katrin Scheibner
      Unspecific peroxygenases (UPOs, EC 1.11.2.1) have proved to be stable oxygen-transferring biocatalysts for H2O2-dependent transformation of pharmaceuticals. We have applied UPOs in a drug development program and consider the enzymatic approach in parallel to a conventional chemical synthesis of the human metabolites of the bile acid reabsorption inhibitor SAR548304. Chemical preparation of N,N-di-desmethyl metabolite was realized by a seven-step synthesis starting from a late precursor of SAR548304 and included among others palladium catalysis and laborious chromatographic purification with an overall yield of 27%. The enzymatic approach revealed that the UPO of Marasmius rotula is particularly suitable for selective N-dealkylation of the drug and enabled us to prepare both human metabolites via one-pot conversion with an overall yield of 66% N,N-di-desmethyl metabolite and 49% of N-mono-desmethylated compound in two separated kinetic-controlled reactions.
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      PubDate: 2015-07-24T15:43:39Z
       
  • Discovery of novel N-(5-(tert-butyl)isoxazol-3-yl)-N′-phenylurea
           analogs as potent FLT3 inhibitors and evaluation of their activity against
           acute myeloid leukemia in vitro and in vivo
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Ying Xu, Ning-Yu Wang, Xue-Jiao Song, Qian Lei, Ting-Hong Ye, Xin-Yu You, Wei-Qiong Zuo, Yong Xia, Li-Dan Zhang, Luo-Ting Yu
      FLT3 inhibitors have been explored as a viable therapy for acute myeloid leukemia (AML). However, the clinical outcomes of these FLT3 inhibitors were underwhelming except AC220. Therefore, the development of novel FLT3 inhibitors with high potency against both FLT3-WT and FLT3-ITD mutants are strongly demanded at the present time. In this study, we designed and synthesized a series of novel N-(5-(tert-butyl)isoxazol-3-yl)-N′-phenylurea derivatives as FLT3 inhibitors. SAR studies focused on the fused rings led to the discovery of a series of compounds with high potency against FLT3-ITD-bearing MV4-11 cells and significantly inhibitory activity toward FLT3. Among these compounds, N-(5-(tert-butyl)isoxazol-3-yl)-N′-(4-(7-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl)urea (16i), displayed acceptable aqueous solubility, desirable pharmacokinetic profile and high cytotoxicity selectivity against MV4-11 cells. This compound can inhibit phosphorylation of FLT3 and induce apoptosis in a concentration-dependent manner. Further in vivo antitumor studies showed that 16i led to complete tumor regression in the MV4-11 xenograft model at a dose of 60mg/kg/d while without observable body weight loss. This study had provided us a new chemotype of FLT3 inhibitors as novel therapic candidates for AML.
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      PubDate: 2015-07-24T15:43:39Z
       
  • Pyrrolo[2,3-b]pyridine derivatives as potent Bruton’s tyrosine
           kinase inhibitors
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Xinge Zhao, Wei Huang, Yazhou Wang, Minhang Xin, Qiu Jin, Jianfeng Cai, Feng Tang, Yong Zhao, Hua Xiang
      A series of pyrrolo[2,3-b]pyridine-based derivatives were designed as potent Bruton’s tyrosine kinase (BTK) inhibitors by using a scaffold-hopping strategy. Structure–activity relationship studies identified five compounds (3n, 3p, 3q, 3r, and 3s) with IC50 of less than 10nM in BTK enzyme assay and five compounds (3m, 3n, 3o, 3p, and 3t) with IC50 of less than 20nM in Ramos cell assay. As one of the most potent inhibitors, compound 3p exhibited superior activity to that of compound 1 (RN486) and pyrrolo[2,3-d]pyrimidine derivative 2 in both BTK enzymatic (IC50 =6.0nM) and cellular inhibition (IC50 =14nM) assays. In addition, 3p displayed favorable overall pharmacokinetic profiles compared with 1 and 2.
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      PubDate: 2015-07-24T15:43:39Z
       
  • Antiproliferative activities of halogenated pyrrolo[3,2-d]pyrimidines
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Kartik W. Temburnikar, Christina R. Ross, Gerald M. Wilson, Jan Balzarini, Brian M. Cawrse, Katherine L. Seley-Radtke
      In vitro evaluation of the halogenated pyrrolo[3,2-d]pyrimidines identified antiproliferative activities in compounds 1 and 2 against four different cancer cell lines. Upon screening of a series of pyrrolo[3,2-d]pyrimidines, the 2,4-Cl compound 1 was found to exhibit antiproliferative activity at low micromolar concentrations. Introduction of iodine at C7 resulted in significant enhancement of potency by reducing the IC50 into sub-micromolar levels, thereby suggesting the importance of a halogen at C7. This finding was further supported by an increased antiproliferative effect for 4 as compared to 3. Cell-cycle and apoptosis studies conducted on the two potent compounds 1 and 2 showed differences in their cytotoxic mechanisms in triple negative breast cancer MDA-MB-231 cells, wherein compound 1 induced cells to accumulate at the G2/M stage with little evidence of apoptotic death. In contrast, compound 2 robustly induced apoptosis with concomitant G2/M cell cycle arrest in this cell model.
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      PubDate: 2015-07-24T15:43:39Z
       
  • Design, synthesis and preliminary bioactivity evaluations of substituted
           quinoline hydroxamic acid derivatives as novel histone deacetylase (HDAC)
           inhibitors
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Lei Wang, Xuben Hou, Huansheng Fu, Xiaole Pan, Wenfang Xu, Weiping Tang, Hao Fang
      Inhibition of HDACs activity has become a promising therapeutic strategy in clinical practice to reverse the abnormal epigenetic states of cancer and other diseases. Therefore, HDAC inhibitors become a relatively new class of anti-cancer agent. In the present study, we reported the design and synthesis of a series of novel HDAC inhibitors using various substituted quinoline rings as the cap group. In vitro studies showed that some compounds have good inhibitory activities against HDACs and potent antiproliferative activities in some tumor cell lines. Especially, compound 9w (IC50 =85nM), exhibited better inhibitory effect compared with SAHA (IC50 =161nM).
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      PubDate: 2015-07-24T15:43:39Z
       
  • The twin drug approach for novel nicotinic acetylcholine receptor ligands
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Isabelle Tomassoli, Daniela Gündisch
      The association of two pharmacophoric entities generates so-called ‘twin drugs’ or dimer derivatives. We applied this approach for the design of a small compound library for the interaction with α4β2∗ nicotinic acetylcholine receptors (nAChRs). In this compound series, the nAChR ligand N,N-dimethyl-2-(pyridin-3-yloxy)ethan-1-amine 9 served as one pharmacological entity and it was initially kept constant as one part of the ‘twin’ compound. ‘Twin’ compounds with identical or non-identical entities using the ‘no linker mode’ or ‘overlap’ mode were synthesized and evaluated for their nAChR affinities. Compound 17a showed the highest affinity for the α4β2∗ nAChR subtype (K i =0.188nM) and its (di)fluoro analogs could retain nanomolar affinities, when replacing pyridine as the hydrogen bond acceptor system by mono- or difluoro-phenyls. The ‘twin drug’ approach proved to provide compounds with high affinity and subtype selectivity for α4β2∗ nAChRs.
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      PubDate: 2015-07-24T15:43:39Z
       
  • Synthesis and evaluation of the anti-nociceptive and anti-inflammatory
           activity of 4-aminoquinoline derivatives
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Raquel de Meneses Santos, Pooline Rocha Barros, Janaína Heberle Bortoluzzi, Mario Roberto Meneghetti, Yolanda Karla Cupertino da Silva, Amanda Evelyn da Silva, Mariana da Silva Santos, Magna Suzana Alexandre-Moreira
      In this paper, we describe the synthesis and pharmacological evaluation of a series of 4-aminoquinolines. The compounds were characterised and tested in models of pain and inflammation, using the writhing test with acetic acid, formalin test, peritonitis test by zymosan and arthritis test with Freund’s adjuvant complete assay. The results revealed that all of the 4-aminoquinolines that were prepared promoted anti-nociceptive activity as well as acute and chronic anti-inflammatory effects, with marked activity in the derivates labelled with BAQ and 7-CF3 -MAQ. After 7days of treatment, 7-CF3-MAQ did not induce significant hepatotoxicity, gastrotoxicity or nephrotoxicity.
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      PubDate: 2015-07-24T15:43:39Z
       
  • γ-Benzylidene digoxin derivatives synthesis and molecular modeling:
           Evaluation of anticancer and the Na,K-ATPase activity effect
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Silmara L.G. Alves, Natasha Paixão, Letícia G.R. Ferreira, Felipe R.S. Santos, Luiza D.R. Neves, Gisele C. Oliveira, Vanessa F. Cortes, Kahlil S. Salomé, Andersson Barison, Fabio V. Santos, Gisele Cenzi, Fernando P. Varotti, Soraya M.F. Oliveira, Alex G. Taranto, Moacyr Comar, Luciana M. Silva, François Noël, Luis Eduardo M. Quintas, Leandro A. Barbosa, José A.F.P. Villar
      Cardiotonic steroids (CS), natural compounds with traditional use in cardiology, have been recently suggested to exert potent anticancer effects. However, the repertoire of molecules with Na,K-ATPase activity and anticancer properties is limited. This paper describes the synthesis of 6 new digoxin derivatives substituted (on the C17-butenolide) with γ-benzylidene group and their cytotoxic effect on human fibroblast (WI-26 VA4) and cancer (HeLa and RKO) cell lines as well as their effect on Na,K-ATPase activity and expression. As digoxin, compound BD-4 was almost 100-fold more potent than the other derivatives for cytotoxicity with the three types of cells used and was also the only one able to fully inhibit the Na,K-ATPase of HeLa cells after 24h treatment. No change in the Na,K-ATPase α1 isoform protein expression was detected. On the other hand it was 30–40 fold less potent for direct Na,K-ATPase inhibition, when compared to the most potent derivatives, BD-1 and BD-3, and digoxin. The data presented here demonstrated that the anticancer effect of digoxin derivatives substituted with γ-benzylidene were not related with their inhibition of Na,K-ATPase activity or alteration of its expression, suggesting that this classical molecular mechanism of CS is not involved in the cytotoxic effect of our derivatives.
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      PubDate: 2015-07-24T15:43:39Z
       
  • Cloning, characterization and anion inhibition studies of a new
           γ-carbonic anhydrase from the Antarctic bacterium Pseudoalteromonas
           haloplanktis
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Viviana De Luca, Daniela Vullo, Sonia Del Prete, Vincenzo Carginale, Andrea Scozzafava, Sameh M. Osman, Zeid AlOthman, Claudiu T. Supuran, Clemente Capasso
      A new γ-class carbonic anhydrase (CA, EC 4.2.1.1) was cloned, purified and characterized from the Antarctic bacterium Pseudoalteromonas haloplanktis, PhaCAγ. The enzyme has a medium-low catalytic activity for the physiologic reaction of CO2 hydration to bicarbonate and protons, with a k cat of 1.4×105 s−1 and a k cat/K m of 1.9×106 M−1 s−1. An anion inhibition study of PhaCAγ with inorganic anions and small molecule inhibitors is also reported. Many anions present in sea water, such as chloride, fluoride, sulfate, iodide, but also others such as azide, perchlorate and tetrafluoroborate did not inhibit this enzyme. Pseudohalides such as cyanate, thiocyanate, cyanide, selenocyanide, and also bicarbonate, nitrate, nitrite and many complex inorganic anions showed inhibition in the millimolar range (K I in the range of 1.7–9.3mM). The best PhaCAγ inhibitors detected in this study were diethyldithiocarbamate (K I of 0.96mM) as well as sulfamide, sulfamate, phenylboronic acid and phenylarsonic acid (K I in the range of 82–91μM). Since γ-CAs are poorly understood at this moment, being present in carboxysomes and thus involved in photosynthesis, this study may be relevant for a better understanding of these processes in Antarctic bacteria/cyanobacteria.
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      PubDate: 2015-07-24T15:43:39Z
       
  • Design and biological evaluation of novel 4-(2-fluorophenoxy)quinoline
           derivatives bearing an imidazolone moiety as c-Met kinase inhibitors
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Weike Liao, Gang Hu, Zhuang Guo, Deyu Sun, Lixia Zhang, Yanxin Bu, Yingxiu Li, Yajing Liu, Ping Gong
      A series of 4-(2-fluorophenoxy)quinoline derivatives containing an imidazolone moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and four cancer cell lines (A549, H460, HT-29 and MKN-45). Most compounds showed moderate to excellent activities in enzyme and cellular assays. The most promising analog, 58 (c-Met IC50 =1.42nM), displayed 2.1-, 8.6-fold increase against H460, and MKN-45 cell lines, respectively, compared with foretinib. An analysis of structure–activity relationships revealed that an ortho substituted phenyl ring as well as an N-unsubstituted imidazolone linker is favorable for antitumor activity.
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      PubDate: 2015-07-24T15:43:39Z
       
  • Anti-HIV screening for cell-penetrating peptides using chloroquine and
           identification of anti-HIV peptides derived from matrix proteins
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Takaaki Mizuguchi, Nami Ohashi, Wataru Nomura, Mao Komoriya, Chie Hashimoto, Naoki Yamamoto, Tsutomu Murakami, Hirokazu Tamamura
      Previously, compounds which inhibit the HIV-1 replication cycle were found in overlapping peptide libraries covering the whole sequence of an HIV-1 matrix (MA) protein constructed with the addition of an octa-arginyl group. The two top lead compounds are sequential fragments MA-8L and MA-9L. In the present study, the addition of chloroquine in cell-based anti-HIV assays was proven to be an efficient method with which to find anti-HIV compounds among several peptides conjugated by cell-penetrating signals such as an octa-arginyl group: the conjugation of an octa-arginyl group to individual peptides contained in whole proteins in combination with the addition of chloroquine in cells is a useful assay method to search active peptides. To find more potent fragment peptides, individual peptides between MA-8L and MA-9L, having the same peptide chain length but with sequences shifted by one amino acid residue, were synthesized in this paper and their anti-HIV activity was evaluated with an anti-HIV assay using chloroquine. As a result, the peptides in the C-terminal side of the series, which are relatively close to MA-9L, showed more potent inhibitory activity against both X4-HIV-1 and R5-HIV-1 than the peptides in the N-terminal side.
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      PubDate: 2015-07-24T15:43:39Z
       
  • Synthesis and biological evaluation of isoflavone amide derivatives with
           antihyperlipidemic and preadipocyte antiproliferative activities
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Wenbin Wang, Yi He, Pei Xu, Qidong You, Hong Xiao, Hua Xiang
      A series of isoflavone amides were designed with isoflavone in place of the scaffold of 2-arylbenzoxazole as cholesterol ester transfer protein (CETP) inhibitors. Twelve new compounds were synthesized, and their inhibitory activities of CETP and preadipocyte proliferation were assayed. The hypolipidemic potency of the most effective compound HY-2c was further tested in vivo by hamster. The results indicate that HY-2c exhibited favorable antihyperlipidemic and preadipocyte antiproliferative activities.
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      PubDate: 2015-07-24T15:43:39Z
       
  • Design and synthesis of a potent inhibitor of class 1 DYRK kinases as a
           suppressor of adipogenesis
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): So Masaki, Isao Kii, Yuto Sumida, Tomoe Kato-Sumida, Yasushi Ogawa, Nobutoshi Ito, Mitsuhiro Nakamura, Rie Sonamoto, Naoyuki Kataoka, Takamitsu Hosoya, Masatoshi Hagiwara
      Dysregulation of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) has been demonstrated in several pathological conditions, including Alzheimer’s disease and cancer progression. It has been recently reported that a gain of function-mutation in the human DYRK1B gene exacerbates metabolic syndrome by enhancing obesity. In the previous study, we developed an inhibitor of DYRK family kinases (INDY) and demonstrated that INDY suppresses the pathological phenotypes induced by overexpression of DYRK1A or DYRK1B in cellular and animal models. In this study, we designed and synthesized a novel inhibitor of DYRK family kinases based on the crystal structure of the DYRK1A/INDY complex by replacing the phenol group of INDY with dibenzofuran to produce a derivative, named BINDY. This compound exhibited potent and selective inhibitory activity toward DYRK family kinases in an in vitro assay. Furthermore, treatment of 3T3-L1 pre-adipocytes with BINDY hampered adipogenesis by suppressing gene expression of the critical transcription factors PPARγ and C/EBPα. This study indicates the possibility of BINDY as a potential drug for metabolic syndrome.
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      PubDate: 2015-07-24T15:43:39Z
       
  • Structure-based development of nitroxoline derivatives as potential
           multifunctional anti-Alzheimer agents
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Damijan Knez, Boris Brus, Nicolas Coquelle, Izidor Sosič, Roman Šink, Xavier Brazzolotto, Janez Mravljak, Jacques-Philippe Colletier, Stanislav Gobec
      Tremendous efforts have been dedicated to the development of effective therapeutics against Alzheimer’s disease, which represents the most common debilitating neurodegenerative disease. Multifunctional agents are molecules designed to have simultaneous effects on different pathological processes. Such compounds represent an emerging strategy for the development of effective treatments against Alzheimer’s disease. Here, we report on the synthesis and biological evaluation of a series of nitroxoline-based analogs that were designed by merging the scaffold of 8-hydroxyquinoline with that of a known selective butyrylcholinesterase inhibitor that has promising anti-Alzheimer properties. Most strikingly, compound 8g inhibits self-induced aggregation of the amyloid beta peptide (Aβ1–42), inhibits with sub-micromolar potency butyrylcholinesterase (IC50 =215nM), and also selectively complexes Cu2+. Our study thus designates this compound as a promising multifunctional agent for therapeutic treatment of Alzheimer’s disease. The crystal structure of human butyrylcholinesterase in complex with compound 8g is also solved, which suggests ways to further optimize compounds featuring the 8-hydroxyquinoline scaffold.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
  • BN/CC isosterism in borazaronaphthalenes towards phosphodiesterase 10A
           (PDE10A) inhibitors
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Alexandru Vlasceanu, Mikkel Jessing, John Paul Kilburn
      The application of BN/CC isosterism is explored as a method of expanding the scope of core scaffolds in biologically active compounds. The viability of potential drug candidates incorporating BN-heteroaromatic moieties was investigated through the synthesis of BN-substituted analogs to known phosphodiesterase (PDE10A) inhibitors, namely MP10 and a selection of N-methylanilide analogs. These in some cases revealed unexpectedly potent and relatively stable derivatives, providing further support for the potential of BN-incorporation in medicinal chemistry.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
  • Crystal structures of the apo form and a complex of human LMW-PTP with a
           phosphonic acid provide new evidence of a secondary site potentially
           related to the anchorage of natural substrates
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Emanuella M.B. Fonseca, Daniela B.B. Trivella, Valéria Scorsato, Mariana P. Dias, Natália L. Bazzo, Kishore R. Mandapati, Fábio L. de Oliveira, Carmen V. Ferreira-Halder, Ronaldo A. Pilli, Paulo C.M.L. Miranda, Ricardo Aparicio
      Low molecular weight protein tyrosine phosphatases (LMW-PTP, EC 3.1.3.48) are a family of single-domain enzymes with molecular weight up to 18kDa, expressed in different tissues and considered attractive pharmacological targets for cancer chemotherapy. Despite this, few LMW-PTP inhibitors have been described to date, and the structural information on LMW-PTP druggable binding sites is scarce. In this study, a small series of phosphonic acids were designed based on a new crystallographic structure of LMW-PTP complexed with benzylsulfonic acid, determined at 2.1Å. In silico docking was used as a tool to interpret the structural and enzyme kinetics data, as well as to design new analogs. From the synthesized series, two compounds were found to act as competitive inhibitors, with inhibition constants of 0.124 and 0.047mM. We also report the 2.4Å structure of another complex in which LMW-PTP is bound to benzylphosphonic acid, and a structure of apo LMW-PTP determined at 2.3Å resolution. Although no appreciable conformation changes were observed, in the latter structures, amino acid residues from an expression tag were found bound to a hydrophobic region at the protein surface. This regions is neighbored by positively charged residues, adjacent to the active site pocket, suggesting that this region might be not a mere artefact of crystal contacts but an indication of a possible anchoring region for the natural substrate—which is a phosphorylated protein.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
  • Synthesis of C-5, C-2′ and C-4′-neomycin-conjugated triplex
           forming oligonucleotides and their affinity to DNA-duplexes
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Ville Tähtinen, Lotta Granqvist, Pasi Virta
      Neomycin-conjugated homopyrimidine oligo 2′-deoxyribonucleotides have been synthesized on a solid phase and their potential as triplex forming oligonucleotides (TFOs) with DNA-duplexes has been studied. For the synthesis of the conjugates, C-5, C-2′ and C-4′-tethered alkyne-modified nucleoside derivatives were used as an integral part of the standard automated oligonucleotide chain elongation. An azide-derived neomycin was then conjugated to the incorporated terminal alkynes by Cu(I)-catalyzed 1,3-dipolar cycloaddition (the click chemistry). Concentrated ammonia released the desired conjugates in acceptable purity and yields. The site of conjugation was expectedly important for the Hoogsteen-face recognition: C-5-conjugation showed a notable positive effect, whereas the influence of the C-2′ and C-4′-modification remained marginal. In addition to conventional characterization methods (UV- and CD-spectroscopy), 19F NMR spectroscopy was applied for the monitoring of triplex/duplex/single strand-conversions.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
  • Synthesis and biological evaluation of novel histone deacetylases
           inhibitors with nitric oxide releasing activity
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Wenwen Duan, Jinning Hou, Xiaojing Chu, Xiaoqian Li, Jian Zhang, Jin Li, Wenfang Xu, Yingjie Zhang
      A novel series of histone deacetylases inhibitors (HDACIs) containing benzofuroxan pharmacophore as nitric oxide (NO) donor were designed based on the combination principle and ‘multifunctional drugs’ theory. As a novel study on embedding NO donor into the structure of HDACIs, all designed hybrid compounds, especially 19d and 24d, displayed remarkable HDACs inhibitory activity and outstanding antiproliferative activity on tumor cells. Besides, they could produce high levels of NO in HCT-116 cells; furthermore, their antiproliferative activity on HCT-116 cells could be diminished by pretreatment with hemoglobin, as the NO scavenger, in a dose-dependent manner. All in all, our designed compounds displayed great inhibitory activities and might offer a prospective avenue to discover novel anti-cancer drugs.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
  • Pentamidine analogs as inhibitors of [3H]MK-801 and [3H]ifenprodil binding
           to rat brain NMDA receptors
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Michael L. Berger, Dorota Maciejewska, Jean Jacques Vanden Eynde, Madhusoodanan Mottamal, Jerzy Żabiński, Paweł Kaźmierczak, Mateusz Rezler, Ivana Jarak, Ivo Piantanida, Grace Karminski-Zamola, Annie Mayence, Patrick Rebernik, Arvind Kumar, Mohamed A. Ismail, David W. Boykin, Tien L. Huang
      The anti-protozoal drug pentamidine is active against opportunistic Pneumocystis pneumonia, but in addition has several other biological targets, including the NMDA receptor (NR). Here we describe the inhibitory potencies of 76 pentamidine analogs at 2 binding sites of the NR, the channel binding site labeled with [3H]MK-801 and the [3H]ifenprodil binding site. Most analogs acted weaker at the ifenprodil than at the channel site. The spermine-sensitivity of NR inhibition by the majority of the compounds was reminiscent of other long-chain dicationic NR blockers. The potency of the parent compound as NR blocker was increased by modifying the heteroatoms in the bridge connecting the 2 benzamidine moieties and also by integrating the bridge into a seven-membered ring. Docking of the 45 most spermine-sensitive bisbenzamidines to a recently described acidic interface between the N-terminal domains of GluN1 and GluN2B mediating polyamine stimulation of the NR revealed the domain contributed by GluN1 as the most relevant target.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
  • Selenorhodamine photosensitizers with the Texas-red core for photodynamic
           therapy of cancer cells
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Mark W. Kryman, Kellie S. Davies, Michelle K. Linder, Tymish Y. Ohulchanskyy, Michael R. Detty
      We examined two selenorhodamines with amide and thioamide functionality at the 5-position of a 9-(2-thienyl) substituent on the selenoxanthylium analogue of the Texas-red core for their potential as photosensitizers for photodynamic therapy (PDT) in P-glycoprotein (P-gp)-expressing Colo-26 cells. These compounds were examined for their photophysical properties (absorption, fluorescence, and ability to generate singlet oxygen), for their uptake into Colo-26 cells in the absence or presence of verapamil, for their dark and phototoxicity toward Colo-26 cells, and for their co-localization with mitochondrial-specific agents in Colo-26 cells. Both compounds were extremely effective photosensitizers with values of EC50 ⩽4×10−8 M toward Colo-26 cells with 1.0Jcm−2 laser light delivered at 630±2nm.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
  • Synthesis and evaluation of N-analogs of 1,2-diarylethane as Helicobacter
           pylori urease inhibitors
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Zhu-Ping Xiao, Wei-Kang Shi, Peng-Fei Wang, Wei Wei, Xiao-Tong Zeng, Ji-Rong Zhang, Na Zhu, Miao Peng, Bin Peng, Xiao-Yi Lin, Hui Ouyang, Xiao-Chun Peng, Guang-Cheng Wang, Hai-Liang Zhu
      Therapies based on urease inhibition are now seriously considered as the first line of treatment for infections caused by Helicobacter pylori. However, the present inhibitors are ineffective or unstable in highly acidic gastric juice. Here, we report a series of benzylanilines as effective inhibitors of H. pylori urease. Out of the obtained twenty-one compounds, N-(3,4-dihydroxybenzyl)-4-nitroaniline (4) was evaluated in detail and shows promising features for development as anti-H. pylori agent. Excellent potency against urease in both cell-free extract and intact cell was observed at low concentrations of 4 (IC50 =0.62±0.04 and 1.92±0.09μM), which showed over 29- and 54-fold increase in potency with respect to the positive control AHA. The SAR analysis revealed that protection of 3,4-dihydroxy group of 4 as methoxy or changes of 4-NO2 will result in a moderate to dramatic decrease in potency.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
  • Identification of 5-nitrofuran-2-amide derivatives that induce apoptosis
           in triple negative breast cancer cells by activating C/EBP-homologous
           protein expression
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Hongliang Duan, Yu Li, Hui-Ying Lim, Weidong Wang
      The transcription factor C/EBP-homologous protein (CHOP) is a key component of the terminal unfolded protein response (UPR) that mediates unresolvable endoplasmic reticulum stress-induced apoptosis. CHOP induction is known to cause cancer cell death. Chemicals that induce CHOP expression would thus be valuable as potential cancer therapeutics and as research tools. Here, we identified 5-nitrofuran-2-amide derivatives as small molecule activators of CHOP expression that induced apoptosis in triple negative breast cancer (TNBC) cells. Our preliminary structure–activity relationship studies indicated that compounds with an N-phenyl-5-nitrofuran-2-carboxamide skeleton were particularly potent inducers of TNBC cell apoptosis. The compounds activate CHOP expression via the PERK–eIF2α–ATF4 branch of the UPR. These results indicate that small molecule activators of CHOP expression may have therapeutic potential for TNBC.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
  • Novel inhibitors of RANKL-induced osteoclastogenesis: Design, synthesis,
           and biological evaluation of
           6-(2,4-difluorophenyl)-3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-diones
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Chia-Chung Lee, Fei-Lan Liu, Chun-Liang Chen, Tsung-Chih Chen, Feng-Cheng Liu, Ahmed Atef Ahmed Ali, Deh-Ming Chang, Hsu-Shan Huang
      A series of novel 6-(2,4-difluorophenyl)-3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-dione derivatives were synthesized and evaluated for their inhibitory effects on osteoclast activities by using TRAP-staining assay. Among the tested compounds, 3d and 3h exhibited more potent osteoclast-inhibitory activities than the lead compound NDMC503 (a ring-fused structure of NDMC101), as reported in our previous study. Both 3d and 3h exhibited two-fold increase in activity compared to NDMC503. In addition, our biological results indicated that 3d and 3h could suppress RANKL-induced osteoclastogenesis-related marker genes, such as NFATc1, c-fos, TRAP, and cathepsin K. Notably, 3d could significantly attenuate the bone-resorbing activity of osteoclasts in the pit formation assay. Thus, this study might provide a new class of lead structures that warrant further development as potential anti-resorptive agents.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
  • Structure Based Library Design (SBLD) for new 1,4-dihydropyrimidine
           scaffold as simultaneous COX-1/COX-2 and 5-LOX inhibitors
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Deepak Lokwani, Rajaram Azad, Aniket Sarkate, Pallu Reddanna, Devanand Shinde
      The various scaffolds containing 1,4-dihydropyrimidine ring were designed by considering the environment of the active site of COX-1/COX-2 and 5-LOX enzymes. The structure-based library design approach, including the focused library design (Virtual Combinatorial Library Design) and virtual screening was used to select the 1,4-dihydropyrimidine scaffold for simultaneous inhibition of both enzyme pathways (COX-1/COX-2 and 5-LOX). The virtual library on each 1,4-dihydropyrimidine scaffold was enumerated in two alternative ways. In first way, the chemical reagents at R groups were filtered by docking of scaffold with single position substitution, that is, only at R1, or R2, or R3, … R n on COX-2 enzyme using Glide XP docking mode. The structures that do not dock well were removed and the library was enumerated with filtered chemical reagents. In second alternative way, the single position docking stage was bypassed, and the entire library was enumerated using all chemical reagents by docking on the COX-2 enzyme. The entire library of approximately 15,629 compounds obtained from both ways after screening for drug like properties, were further screened for their binding affinity against COX-1 and 5-LOX enzymes using Virtual Screening Workflow. Finally, 142 hits were obtained and divided into two groups based on their binding affinity for COX-1/COX-2 and for both enzyme pathways (COX-1/COX-2 and 5-LOX). The ten molecules were selected, synthesized and evaluated for their COX-1, COX-2 and 5-LOX inhibiting activity.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
  • Optimization of a novel series of N-phenylindoline-5-sulfonamide-based
           acyl CoA:monoacylglycerol acyltransferase-2 inhibitors: Mitigation of
           CYP3A4 time-dependent inhibition and phototoxic liabilities
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Kenjiro Sato, Hiroki Takahagi, Osamu Kubo, Kousuke Hidaka, Takeshi Yoshikawa, Masahiro Kamaura, Masanori Nakakariya, Nobuyuki Amano, Ryutaro Adachi, Toshiyuki Maki, Kazumi Take, Shiro Takekawa, Tomoyuki Kitazaki, Tsuyoshi Maekawa
      Acyl CoA:monoacylglycerol acyltransferase-2 (MGAT2) has emerged as a potential peripheral target for the treatment of obesity and metabolic disorders. We previously identified a novel series of N-phenylindoline-5-sulfonamide derivatives exemplified by 2 as potent and orally bioavailable MGAT2 inhibitors. Despite its attractive potency, further assessment revealed that this compound exhibited time-dependent inhibition (TDI) of cytochrome P450 3A4 (CYP3A4). To remove the undesirable CYP3A4 TDI activity, structural modification was focused on the 2,4-difluoroaniline moiety on the basis of the assumption that this moiety would be involved in mechanism-based inhibition of CYP3A4 via oxidative metabolism. This led to the finding that the introduction of 4-chloro-2,6-difluoroaniline significantly improved CYP3A4 TDI risk. Further optimization resulted in the discovery of N-(4-chloro-2,6-difluorophenyl)-1-{5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]pyrimidin-2-yl}-7-(2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-indole-5-sulfonamide (27c) with potent MGAT2 inhibitory activity (IC50 =7.8nM) and excellent ADME-Tox profiles including metabolic stability, oral bioavailability, and CYP3A4 TDI. In a mouse oral fat tolerance test, compound 27c effectively and dose-dependently suppressed the elevation of plasma triacylglycerol levels after oral administration at doses of 1 and 3mg/kg. We also discuss mitigation of the phototoxic liability of biaryl derivatives on the basis of the HOMO–LUMO gap hypothesis during the course of optimization efforts.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
  • Potential antibacterial activity of triazine dendrimer: Synthesis and
           controllable drug release properties
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Sandhirakasu Vembu, Srinivasan Pazhamalai, Mannathusamy Gopalakrishnan
      A novel sustained release delivery system of ciprofloxacin was developed. The system consists of a viscosity enhancer plus a penetration enhancer to overcome penetration barriers and loss due to wash-out and thus achieve the desired ciprofloxacin ocular absorption. A macromolecule of piperazine core 1,3,5-triazine dendrimer with eight molecules of ciprofloxacin drug as a surface moiety has been synthesized in five steps. Antibacterial activities of this compound have been investigated for Gram-positive and Gram-negative bacteria like Staphylococcus aureus (mtcc 737), Bacillus subtilis (mtcc 2063), Escherichia coli (mtcc-443), Pseudomonas aeruginosa (mtcc 741) and Proteus mirabilis (mtcc425). It was observed that the influence of hydrophobic and hydrophilic balance per repeat unit of these dendrimer has profound effects for antibacterial activities. The MIC value of the compound very lower at 100μg/mL−1 when compared with standard ciprofloxacin at 500μg/mL−1. The compound (10) exhibits five times higher activity against tested organisms when compared with ciprofloxacin as standard. The structures of the dendrimers were determined by means of MALDI-TOF MS, NMR and IR studies. The in vitro release of ciprofloxacin from obtained dendrimer was investigated.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
  • In vitro evaluation and in silico screening of synthetic
           acetylcholinesterase inhibitors bearing functionalized piperidine
           pharmacophores
    • Abstract: Publication date: 1 August 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 15
      Author(s): Goutam Brahmachari, CheeYan Choo, Pravin Ambure, Kunal Roy
      A series of densely functionalized piperidine (FP) scaffolds was synthesized following a diastereoselective one-pot multicomponent protocol under eco-friendly conditions. The FPs were evaluated in vitro for their acetylcholinesterase (AChE) inhibitory activity, and in silico studies for all the target compounds were carried out using pharmacophore mapping, molecular docking and quantitative structure–activity relationship (QSAR) analysis in order to understand the structural features required for interaction with the AChE enzyme and the key active site residues involved in the intermolecular interactions. Halogenation, nitration or 3,4-methylenedixoxy-substitution at the phenyl ring attached to the 2- and 6-positions of 1,2,5,6-tetrahydropyridine nucleus in compounds 14–17, 19, 20, 24 and 26 greatly enhanced the AChE inhibitory activity. The docking analysis demonstrated that the inhibitors are well-fitted in the active sites. The in silico studies enlighten the future course of studies in modifying the scaffolds for better therapeutic efficacy against the deadly Alzheimer’s disease.
      Graphical abstract image

      PubDate: 2015-07-24T15:43:39Z
       
 
 
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