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  Subjects -> CHEMISTRY (Total: 891 journals)
    - ANALYTICAL CHEMISTRY (55 journals)
    - CHEMISTRY (621 journals)
    - CRYSTALLOGRAPHY (21 journals)
    - ELECTROCHEMISTRY (28 journals)
    - INORGANIC CHEMISTRY (45 journals)
    - ORGANIC CHEMISTRY (51 journals)
    - PHYSICAL CHEMISTRY (70 journals)

CHEMISTRY (621 journals)                  1 2 3 4 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 14)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 26)
ACS Catalysis     Full-text available via subscription   (Followers: 43)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 21)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 23)
ACS Macro Letters     Full-text available via subscription   (Followers: 26)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 41)
ACS Nano     Full-text available via subscription   (Followers: 274)
ACS Photonics     Full-text available via subscription   (Followers: 14)
ACS Symposium Series     Full-text available via subscription  
ACS Synthetic Biology     Full-text available via subscription   (Followers: 24)
Acta Chemica Iasi     Open Access   (Followers: 5)
Acta Chimica Slovaca     Open Access   (Followers: 2)
Acta Chimica Slovenica     Open Access   (Followers: 1)
Acta Chromatographica     Full-text available via subscription   (Followers: 9)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 7)
Acta Scientifica Naturalis     Open Access   (Followers: 3)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 6)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 9)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 6)
Advanced Functional Materials     Hybrid Journal   (Followers: 57)
Advanced Science Focus     Free   (Followers: 5)
Advances in Chemical Engineering and Science     Open Access   (Followers: 66)
Advances in Chemical Science     Open Access   (Followers: 18)
Advances in Chemistry     Open Access   (Followers: 21)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 19)
Advances in Drug Research     Full-text available via subscription   (Followers: 23)
Advances in Environmental Chemistry     Open Access   (Followers: 5)
Advances in Enzyme Research     Open Access   (Followers: 10)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 9)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 17)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 11)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 25)
Advances in Nanoparticles     Open Access   (Followers: 15)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 16)
Advances in Polymer Science     Hybrid Journal   (Followers: 43)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 19)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6)
Advances in Science and Technology     Full-text available via subscription   (Followers: 12)
African Journal of Bacteriology Research     Open Access  
African Journal of Chemical Education     Open Access   (Followers: 3)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 7)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Al-Kimia : Jurnal Penelitian Sains Kimia     Open Access  
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 2)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 64)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 17)
American Journal of Chemistry     Open Access   (Followers: 30)
American Journal of Plant Physiology     Open Access   (Followers: 11)
American Mineralogist     Hybrid Journal   (Followers: 15)
Analyst     Full-text available via subscription   (Followers: 38)
Angewandte Chemie     Hybrid Journal   (Followers: 165)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 242)
Annales UMCS, Chemia     Open Access  
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 5)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 3)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 4)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 9)
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: 13)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antiviral Chemistry and Chemotherapy     Hybrid Journal   (Followers: 2)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 9)
Applied Spectroscopy     Full-text available via subscription   (Followers: 23)
Applied Surface Science     Hybrid Journal   (Followers: 31)
Arabian Journal of Chemistry     Open Access   (Followers: 6)
ARKIVOC     Open Access   (Followers: 1)
Asian Journal of Biochemistry     Open Access   (Followers: 2)
Atomization and Sprays     Full-text available via subscription   (Followers: 4)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 7)
Autophagy     Hybrid Journal   (Followers: 2)
Avances en Quimica     Open Access  
Biochemical Pharmacology     Hybrid Journal   (Followers: 10)
Biochemistry     Full-text available via subscription   (Followers: 353)
Biochemistry Insights     Open Access   (Followers: 6)
Biochemistry Research International     Open Access   (Followers: 6)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 10)
Bioinspired Materials     Open Access   (Followers: 5)
Biointerface Research in Applied Chemistry     Open Access   (Followers: 2)
Biointerphases     Open Access   (Followers: 1)
Biology, Medicine, & Natural Product Chemistry     Open Access   (Followers: 2)
Biomacromolecules     Full-text available via subscription   (Followers: 21)
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: 5)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 128)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 87)
Bioorganic Chemistry     Hybrid Journal   (Followers: 10)
Biopolymers     Hybrid Journal   (Followers: 18)
Biosensors     Open Access   (Followers: 2)
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: 1)
Bulletin of the Chemical Society of Japan     Full-text available via subscription   (Followers: 24)
Bulletin of the Korean Chemical Society     Hybrid Journal   (Followers: 1)
C - Journal of Carbon Research     Open Access   (Followers: 3)
Cakra Kimia (Indonesian E-Journal of Applied Chemistry)     Open Access  
Canadian Association of Radiologists Journal     Full-text available via subscription   (Followers: 2)
Canadian Journal of Chemistry     Hybrid Journal   (Followers: 10)
Canadian Mineralogist     Full-text available via subscription   (Followers: 6)
Carbohydrate Research     Hybrid Journal   (Followers: 26)
Carbon     Hybrid Journal   (Followers: 71)
Catalysis for Sustainable Energy     Open Access   (Followers: 8)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 7)
Catalysis Science and Technology     Free   (Followers: 8)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 10)
Cellulose     Hybrid Journal   (Followers: 7)
Cereal Chemistry     Full-text available via subscription   (Followers: 4)
ChemBioEng Reviews     Full-text available via subscription   (Followers: 1)
ChemCatChem     Hybrid Journal   (Followers: 8)
Chemical and Engineering News     Free   (Followers: 18)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 73)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 26)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 22)
Chemical Reviews     Full-text available via subscription   (Followers: 192)
Chemical Science     Open Access   (Followers: 24)
Chemical Technology     Open Access   (Followers: 24)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 5)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 55)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 24)
ChemInform     Hybrid Journal   (Followers: 8)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 7)
Chemistry & Biology     Full-text available via subscription   (Followers: 32)
Chemistry & Industry     Hybrid Journal   (Followers: 7)
Chemistry - A European Journal     Hybrid Journal   (Followers: 162)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 16)
Chemistry and Materials Research     Open Access   (Followers: 21)
Chemistry Central Journal     Open Access   (Followers: 4)
Chemistry Education Research and Practice     Free   (Followers: 5)
Chemistry in Education     Open Access   (Followers: 9)
Chemistry International     Hybrid Journal   (Followers: 2)
Chemistry Letters     Full-text available via subscription   (Followers: 44)
Chemistry of Materials     Full-text available via subscription   (Followers: 255)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
Chemistry World     Full-text available via subscription   (Followers: 19)
Chemistry-Didactics-Ecology-Metrology     Open Access   (Followers: 1)
ChemistryOpen     Open Access   (Followers: 1)
Chemkon - Chemie Konkret, Forum Fuer Unterricht Und Didaktik     Hybrid Journal  
Chemoecology     Hybrid Journal   (Followers: 4)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 14)
Chemosensors     Open Access  
ChemPhysChem     Hybrid Journal   (Followers: 11)
ChemPlusChem     Hybrid Journal   (Followers: 2)
ChemTexts     Hybrid Journal  
CHIMIA International Journal for Chemistry     Full-text available via subscription   (Followers: 2)
Chinese Journal of Chemistry     Hybrid Journal   (Followers: 6)
Chinese Journal of Polymer Science     Hybrid Journal   (Followers: 11)
Chromatographia     Hybrid Journal   (Followers: 24)
Chromatography     Open Access   (Followers: 2)
Chromatography Research International     Open Access   (Followers: 6)
Clay Minerals     Full-text available via subscription   (Followers: 10)
Cogent Chemistry     Open Access   (Followers: 1)
Colloid and Interface Science Communications     Open Access  
Colloid and Polymer Science     Hybrid Journal   (Followers: 11)
Colloids and Interfaces     Open Access  
Colloids and Surfaces B: Biointerfaces     Hybrid Journal   (Followers: 6)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 4)
Combustion Science and Technology     Hybrid Journal   (Followers: 22)
Comments on Inorganic Chemistry: A Journal of Critical Discussion of the Current Literature     Hybrid Journal   (Followers: 2)
Communications Chemistry     Open Access  
Composite Interfaces     Hybrid Journal   (Followers: 7)
Comprehensive Chemical Kinetics     Full-text available via subscription   (Followers: 1)
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: 3)
Copernican Letters     Open Access   (Followers: 1)
Corrosion Series     Full-text available via subscription   (Followers: 6)
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 5)
Croatica Chemica Acta     Open Access  
Crystal Structure Theory and Applications     Open Access   (Followers: 4)
CrystEngComm     Full-text available via subscription   (Followers: 13)
Current Catalysis     Hybrid Journal   (Followers: 2)
Current Chromatography     Hybrid Journal  
Current Green Chemistry     Hybrid Journal  
Current Metabolomics     Hybrid Journal   (Followers: 5)
Current Microwave Chemistry     Hybrid Journal  
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 9)
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 14)
Current Research in Chemistry     Open Access   (Followers: 8)
Current Science     Open Access   (Followers: 69)
Current Trends in Biotechnology and Chemical Research     Open Access   (Followers: 3)
Dalton Transactions     Full-text available via subscription   (Followers: 23)
Detection     Open Access   (Followers: 2)
Developments in Geochemistry     Full-text available via subscription   (Followers: 2)
Diamond and Related Materials     Hybrid Journal   (Followers: 12)
Dislocations in Solids     Full-text available via subscription  

        1 2 3 4 | Last

Journal Cover
Bioorganic & Medicinal Chemistry
Journal Prestige (SJR): 0.871
Citation Impact (citeScore): 3
Number of Followers: 128  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0968-0896
Published by Elsevier Homepage  [3163 journals]
  • The recent progress of isoxazole in medicinal chemistry
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Jie Zhu, Jun Mo, Hong-zhi Lin, Yao Chen, Hao-peng Sun
      Isoxazole compounds exhibit a wide spectrum of targets and broad biological activities. Developing compounds with heterocycle rings has been one of the trends. The integration of isoxazole ring can offer improved physical-chemical properties. Because of the unique profiles, isoxazole ring becomes a popular moiety in compounds design. In this review article, the major focus has been paid to the applications of isoxazole compounds in treating multiple diseases, including anticancer, antimicrobial, anti-inflammatory, etc. Strategies for compounds design for preclinical, clinical, and FDA approved drugs were discussed. Also, the emphasis has been addressed to the future perspectives and trend for the application.
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
  • Design, synthesis and biological evaluation of benzofuran appended
           benzothiazepine derivatives as inhibitors of butyrylcholinesterase and
           antimicrobial agents
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Manizheh Mostofi, Ghodsi Mohammadi Ziarani, Negar Lashgari
      A series of bezofuran appended 1,5-benzothiazepine compounds 7a–v was designed, synthesized and evaluated as cholinesterase inhibitors. The biological assay experiments showed that most of the compounds displayed a clearly selective inhibition for butyrylcholinesterase (BChE), while a weak or no effect towards acetylcholinesterase (AChE) was detected. All analogs exhibited varied BChE inhibitory activity with IC50 value ranging between 1.0 ± 0.01 and 72 ± 2.8 μM when compared with the standard donepezil (IC50, 2.63 ± 0.28 μM). Among the synthesized derivatives, compounds 7l, 7m and 7k exhibited the highest BChE inhibition with IC50 values of 1.0, 1.0 and 1.8 μM, respectively. The results from a Lineweaver-Burk plot indicated a mixed-type inhibition for compound 7l with BChE. In addition, docking studies confirmed the results obtained through in vitro experiments and showed that most potent compounds bind to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of BChE active site. The synthesized compounds were also evaluated for their in vitro antibacterial and antifungal activities. The results indicated that the compounds possessed a broad spectrum of activity against the tested microorganisms and showed high activity against both gram positive and gram negative bacteria and fungi.
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
  • Exploiting polarity and chirality to probe the Hsp90 C-terminus
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Leah K. Forsberg, Rachel E. Davis, Virangika K. Wimalasena, Brian S.J. Blagg
      Inhibition of the Hsp90 C-terminus is an attractive therapeutic approach for the treatment of cancer. Novobiocin, the first Hsp90 C-terminal inhibitor identified, contains a synthetically complex noviose sugar that has limited the generation of structure-activity relationships for this region of the molecule. The work described herein utilizes various ring systems as noviose surrogates to explore the size and nature of the surrounding binding pocket.
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
  • Synthesis and characterization of radioiodinated 3-phenethyl-2-indolinone
           derivatives for SPECT imaging of survivin in tumors
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Natsumi Ishikawa, Takeshi Fuchigami, Tatsuya Mizoguchi, Sakura Yoshida, Mamoru Haratake, Morio Nakayama
      Survivin, overexpressed in most cancers, is associated with poor prognosis and resistance to radiation therapy and chemotherapy. Herein, we report the synthesis of three 3-phenethyl-2-indolinone derivatives and their application as in vivo imaging agents for survivin. Of these, 3-(2-(benzo[d][1,3]dioxol-5-yl)-2-oxoethyl)-3-hydroxy-5- iodoindolin-2-one (IPI-1) showed the highest binding affinity (K d = 68.3 nM) to recombinant human survivin, as determined by quartz crystal microbalance (QCM). In vitro studies demonstrated that the [125I]IPI-1 binding in survivin-positive MDA-MB-231 cells was significantly higher than that in survivin-negative MCF-10A cells. In addition, uptake of [125I]IPI-1 by MDA-MB-231 cells decreased in a dose-dependent manner in the presence of the high-affinity survivin ligand S12; this is indicative of specific binding of [125I]IPI-1 to cellular survivin protein in vitro. Biodistribution studies in MDA-MB-231 tumor-bearing mice demonstrated the moderate uptake of [125I]IPI-1 in the tumor tissue (1.37% ID/g) at 30 min that decreased to 0.32% ID/g at 180 min. Co-injection of S12 (2.5 mg/kg) slightly reduced tumor uptake and the tumor/muscle ratio of [125I]IPI-1. Although further structural modifications are necessary to improve pharmacokinetic properties, our results indicate that PI derivatives may be useful as tumor-imaging probes targeting survivin.
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
  • Design, synthesis and evaluation of vilazodone-tacrine hybrids as
           
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Wenwen Liu, Huan Wang, Xiaokang Li, Yixiang Xu, Jian Zhang, Wei Wang, Qi Gong, Xiaoxia Qiu, Jin Zhu, Fei Mao, Haiyan Zhang, Jian Li
      Depression, a severe mental disease, is greatly difficult to treat and easy to induce other neuropsychiatric symptoms, the most frequent one is cognitive impairment. In this study, a series of novel vilazodone-tacrine hybrids were designed, synthesized and evaluated as multitarget agents against depression with cognitive impairment. Most compounds exhibited good multitarget activities and appropriate blood-brain barrier permeability. Specifically, compounds 1d and 2a exhibited excellent 5-HT1A agonist activities (1d, EC50 = 0.36 ± 0.08 nM; 2a, EC50 = 0.58 ± 0.14 nM) and 5-HT reuptake inhibitory activities (1d, IC50 = 20.42 ± 6.60 nM; 2a, IC50 = 22.10 ± 5.80 nM). In addition, they showed moderate ChE inhibitory activities (1d, AChE IC50 = 1.72 ± 0.217 μM, BuChE IC50 = 0.34 ± 0.03 μM; 2a, AChE IC50 = 2.36 ± 0.34 μM, BuChE IC50 = 0.10 ± 0.01 μM). Good multitarget activities with goodt blood-brain barrier permeability of 1d and 2a make them good lead compounds for the further study of depression with cognitive impairment.
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
  • Osteoblastic differentiation on hydrogels fabricated from Ca2+-responsive
           self-assembling peptides functionalized with bioactive peptides
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Hiroshi Tsutsumi, Megumi Kawamura, Hisakazu Mihara
      We recently developed an amphiphilic peptide, E1Y9 (Ac-E-YEYKYEYKY-NH2), that self-assembles into nanofibers and forms a hydrogel in the presence of Ca2+ ion. Four E1Y9-derivatives (E1Y9-ALK, E1Y9-DGR, E1Y9-PRG and E1Y9-RGD) were designed as conjugates of E1Y9 with bioactive peptide sequences named as ALK (ALKRQGRTLYGF), DGR (DGRDSVAYG), PRG (PRGDSGYRGDS) and RGD (RGDS), respectively, and stimulated osteoblast cells growth as well as differentiation. In this study, E1Y9/E1Y9-derivative mixed hydrogels were constructed to serve as scaffolds for osteoblastic differentiation of MC3T3-E1 cells. E1Y9 and E1Y9-derivatives co-assembled into networked nanofibers and formed hydrogels in response to Ca2+ ion. The pre-osteoblast cell line MC3T3-E1 was cultured and differentiated on mixed hydrogels. An E1Y9/E1Y9-ALK mixed hydrogel exhibited the highest cell proliferation and differentiation activity among the peptide hydrogels. The peptide sequence ALK promoted expression of RUNX2 and osteopontin, a key transcription factor and bone tissue matrix protein, respectively, during the differentiation stage. During the later stage, localization of RUNX2 and osteopontin was regulated in the cytosol and extracellularly, respectively, indicating that the E1Y9/E1Y9-ALK mixed hydrogel controlled the differentiation of MC3T3-E1 cells. Thus, the E1Y9/E1Y9-ALK mixed hydrogel developed in this study showed potential for the culture and regulation of differentiation of osteoblast cells for bone regeneration.
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
  • Structure-activity relationship investigation of Phe-Arg mimetic region of
           human glutaminyl cyclase inhibitors
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Van T.H. Ngo, Van-Hai Hoang, Phuong-Thao Tran, Nguyen Van Manh, Jihyae Ann, Eunhye Kim, Minghua Cui, Sun Choi, Jiyoun Lee, Hee Kim, Hee-Jin Ha, Kwanghyun Choi, Young-Ho Kim, Jeewoo Lee
      Glutamyl cyclase (QC) is a promising therapeutic target because of its involvement in the pathogenesis of Alzheimer’s disease. In this study, we developed novel QC inhibitors that contain 3-aminoalkyloxy-4-methoxyphenyl and 4-aminoalkyloxyphenyl groups to replace the previously developed pharmacophore. Several potent inhibitors were identified, showing IC50 values in a low nanomolar range, and were further studied for in vitro toxicity and in vivo activity. Among these, inhibitors 51 and 53 displayed the most potent AβN3pE−40-lowering effects in in vivo acute model with reasonable BBB penetration, without showing cytotoxicity and hERG inhibition. The molecular modeling analysis of 53 indicated that the salt bridge interaction and the hydrogen bonding in the active site provided a high potency. Given the potent activity and favorable BBB penetration with low cytotoxicity, we believe that compound 53 may serve as a potential candidate for anti-Alzheimer’s agents.
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
  • Novel leucine ureido derivatives as aminopeptidase N inhibitors using
           click chemistry
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Jiangying Cao, Chunhua Ma, Jie Zang, Shuai Gao, Qianwen Gao, Xiujie Kong, Yugang Yan, Xuewu Liang, Qin'ge Ding, Chunlong Zhao, Binghe Wang, Wenfang Xu, Yingjie Zhang
      The over-expression of aminopeptidase N on diverse malignant cells is associated with the tumor angiogenesis and metastasis. In this report, one new series of leucine ureido derivatives containing the triazole moiety was designed, synthesized and evaluated as APN inhibitors. Among them, compound 13v showed the best APN inhibition with an IC50 value of 0.089 ± 0.007 μM, which was two orders of magnitude lower than that of bestatin (IC50 = 9.4 ± 0.5 μM). Compound 13v also showed dose-dependent anti-angiogenesis activities. Even at the lower concentration (10 μM), compound 13v presented similar anti-angiogenesis activity compared with bestatin at 100 μM in both the human umbilical vein endothelial cells (HUVECs) capillary tube formation assay and the rat thoracic aorta rings test. Moreover, compared with bestatin, 13v exhibited comparable, if not better in vivo anti-metastasis activity in a mouse H22 pulmonary metastasis model.
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
  • Novel amidrazone derivatives: Design, synthesis and activity evaluation
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Hua Zhou, Zhi Sen Wang, Xin Hua Liu, Fei Hu Chen
      A series of new 6-styryl-naphthalene-2-amidrazone derivatives were synthesized and evaluated as potential ASIC1a inhibitors. Among them, compound 5e showed the most activity to inhibit [Ca2+]i. elevation in acid-induced articular chondrocytes. Together with the important role of ASIC1a in the pathogenesis of tissue acidification diseases including rheumatoid arthritis, these results might provide a meaningful hint or inspiration in developing drugs targeting at tissue acidification diseases.
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
  • Synthesis, antimycobacterial activity and influence on mycobacterial InhA
           and PknB of 12-membered cyclodepsipeptides
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Katja Laqua, Marcel Klemm, Melissa Richard-Greenblatt, Adrian Richter, Linda Liebe, Tingting Huang, Shuangjun Lin, Ana Guardia, Esther Pérez-Herran, Lluís Ballell, Yossef Av-Gay, Peter Imming
      In recent years, several small natural cyclopeptides and cyclodepsipeptides were reported to have antimycobacterial activity. Following this lead, a synthetic pathway was developed for a small series of 12-membered ring compounds with one amide and two ester bonds (cyclotridepsipeptides). Within the series, the ring system proved to be necessary for growth inhibition of Mycobacterium smegmatis and Mycobacterium tuberculosis in the low micromolar range. Open-chain precursors and analogues were inactive. The compounds modulated autophosphorylation of the mycobacterial protein kinase B (PknB). PknB inhibitors were active at µM concentration against mycobacteria while inducers were inactive. PknB regulates the activity of the mycobacterial reductase InhA, the target of isoniazid. The activity of the series against Mycobacterium bovis BCG InhA overexpressing strains was indistinguishable from that of the parental strain suggesting that they do not inhibit InhA. All substances were not cytotoxic (HeLa > 5 µg/ml) and did not show any significant antiproliferative effect (HUVEC > 5 µg/ml; K-562 > 5 µg/ml). Within the scope of this study, the molecular target of this new type of small cyclodepsipeptide was not identified, but the data suggest interaction with PknB or other kinases may partly cause the activity.
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
  • Novel 8-hydroxyquinoline derivatives targeting β-amyloid aggregation,
           metal chelation and oxidative stress against Alzheimer’s disease
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Xuelian Yang, Pei Cai, Qiaohong Liu, Jiajia Wu, Yong Yin, Xiaobing Wang, Lingyi Kong
      A series of multitargeted 8-hydroxyquinoline derivatives were designed and synthesized for the treatment of Alzheimer’s disease (AD). In vitro studies indicated that most of the prepared compounds exhibited significant inhibitory effects against self-induced Aβ 1−42 aggregation and potential antioxidant properties especially compound 5b (IC50 = 5.64 μM for self-induced Aβ aggregation; the oxygen radical absorbance capacity using fluorescein (ORAC-FL) value is 2.63 Trolox equivalents). Notably, 5b can chelate biometals and inhibit Cu2+/Zn2+-induced Aβ 1−42 aggregation. The cell assays showed that 5b had excellent protective effects against oxidative toxin H2O2 and presented low neurotoxicity in PC12 cells. Furthermore, 5b could penetrate the blood–brain barrier (BBB) in vitro and did not show any acute toxicity in mice at doses up to 2000 mg/kg in vivo. Our findings provide a rationale for the potential application of compound 5b as a lead compound in AD therapy.
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      PubDate: 2018-06-18T08:24:48Z
       
  • Structure-activity relationship of clovamide and its related compounds for
           the inhibition of amyloid β aggregation
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Tatsuhiko Tsunoda, Mio Takase, Hideyuki Shigemori
      Alzheimer’s disease (AD), a neurodegenerative disorder, is characterized by aggregation of amyloid β-protein (Aβ). Aβ aggregates through β-sheet formation and induces cytotoxicity against neuronal cells. Inhibition of Aβ aggregation by naturally occurring compounds is thus a promising strategy for the treatment of AD. We have already reported that caffeoylquinic acids and phenylethanoid glycosides, which possess two or more catechol moieties, strongly inhibited Aβ aggregation. Clovamide (1) containing two catechol moieties, isolated from cacao beans (Theobroma cacao L.), is believed to exhibit preventive effects on Aβ aggregation. To investigate the structure-activity relationship of clovamide (1) for the inhibition of Aβ aggregation, we synthesized 1 and related compounds 2–11 through reaction between l-DOPA, d-DOPA, l-tyrosine, or l-phenylalanine and caffeic acid, p-coumaric acid, or cinnamic acid, and compounds 12 and 13 were derived from 1. Among tested compounds 1–13, those containing one or two catechol moieties exhibited potent anti-aggregation activity, whereas the non-catechol-type related compounds showed little or no activity. This suggests that at least one catechol moiety is essential for inhibition of Aβ42 aggregation, and this activity increases depending on the number of catechol moieties. Consequently, clovamide (1) and its related compounds may be a promising therapeutic option for inhibiting Aβ-mediated pathology in AD.
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      PubDate: 2018-06-18T08:24:48Z
       
  • Applications of a novel biodetection system to saliva using protein
           fingerprints with data processing
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Yuki Tominaga, Kenji Usui, Akiyoshi Hirata, Hiro-O Ito, Kiyoshi Nokihara
      A fundamental method has been developed focusing on a facile and rapid examination of periodontal disease. Periodontal disease is an oral disease thought to affect 80% of adults, and early detection with treatment is desirable for the improvement of the quality of life. Unfortunately conventional methods are not consistent as the disease is caused by a number of undefined bacteria and detection relies on the skills of the dentist. Thus an objective detection system is required. We have performed an experiment on saliva using a novel biodetection system, designated PepTenChip®. A disease model for saliva was prepared using a specimen from a healthy subject and a mixture of hemoglobin (f-Hb) and lactate dehydrogenase (LDH), which is used as a periodontal disease marker protein with healthy saliva. PepTenChip® is a peptide microarray in which fluorescent labelled structured peptides are immobilized on a novel amorphous carbon substrate. Since the peptides used as capture molecules are fluorescently labelled, labeling of analytes is not necessary. The fluorescence intensity change before and after application of analytes are detected rather than the ON/OFF detection common to conventional microarrays using a set of antigen–antibody. The fluorescence intensity value changes according to the concentration of captured protein allowing the generation of protein fingerprint (PFP) and dendrograms. The present method does not rely on a “one to one” interaction, unlike conventional biodetection, and advantages can be envisaged in the case of an undefined or unknown cause of disease. The statistical analyses, such as multivariate analyses, allow classification of the type of proteins added in saliva as mimetics of disease. PepTenChip® system is useful and convenient for examination of periodontal disease in health care.
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      PubDate: 2018-06-18T08:24:48Z
       
  • Synthesis and biological evaluation of 2,4-disubstituted phthalazinones as
           Aurora kinase inhibitors
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Wei Wang, Xiu Feng, Huan-Xiang Liu, Shi-Wu Chen, Ling Hui
      A series of 2,4-disubstituted phthalazinones were synthesized and their biological activities, including antiproliferation, inhibition against Aurora kinases and cell cycle effects were evaluated. Among them, N-cyclohexyl-4-((4-(1-methyl-1H-pyrazol-4-yl)-1-oxophthalazin-2(1H)-yl) methyl) benzamide (12c) exhibited the most potent antiproliferation against five carcinoma cell lines (HeLa, A549, HepG2, LoVo and HCT116 cells) with IC50 values in range of 2.2–4.6 μM, while the IC50 value of reference compound VX-680 was 8.5–15.3 μM. Moreover, Aurora kinase assays exhibited that compound 12c was potent inhibitor of AurA and AurB kinase with the IC50 values were 118 ± 8.1 and 80 ± 4.2 nM, respectively. Molecular docking studies indicated that compound 12c forms better interaction with both AurA and AurB. Furthermore, compound 12c induced G2/M cell cycle arrest in HeLa cells by regulating protein levels of cyclinB1 and cdc2. These results suggested that 12c is a promising pan-Aurora kinase inhibitor for the potential treatment of cancer.
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      PubDate: 2018-06-18T08:24:48Z
       
  • Discovery of tetrahydroindazoles as a novel class of potent and in vivo
           efficacious gamma secretase modulators
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Kai Gerlach, Scott Hobson, Christian Eickmeier, Ulrike Groß, Clemens Braun, Peter Sieger, Michel Garneau, Stefan Hoerer, Niklas Heine
      The identification and optimization of a novel series of centrally efficacious gamma secretase modulators (GSMs) offering an alternative to the privileged aryl imidazole motif is described. Chiral bicyclic tetrahydroindazolyl amine substituted triazolopyridines were identified as structurally distinct novel series of GSMs. Representative compound BI-1408 ( (R)-42) was demonstrated to be centrally efficacious in rats at a 30 mg/kg oral dose.
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      PubDate: 2018-06-18T08:24:48Z
       
  • Design, synthesis and evaluation of benzoheterocycle analogues as potent
           antifungal agents targeting CYP51
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Shizhen Zhao, Peng Wei, Mengya Wu, Xiangqian Zhang, Liyu Zhao, Xiaolin Jiang, Chenzhou Hao, Xin Su, Dongmei Zhao, Maosheng Cheng
      To further enhance the anti-Aspergillus efficacy of our previously discovered antifungal lead compound 1, a series of benzoheterocycle analogues were designed, synthesized and evaluated for their in vitro antifungal activity. The most promising compounds 13s and 14a exhibited excellent antifungal activity against C. albicans, C. neoformans, A. fumigatus and fluconazole-resistant C. albicans strains, that was superior or comparable to those of the reference drugs fluconazole and voriconazole. GC–MS analyses suggested that the novel compound 13s might have a similar mechanism to fluconazole by inhibiting fungal lanosterol 14α-demethylase (CYP51). Furthermore, compounds 13s and 14a exhibited low inhibition profiles for various human cytochrome P450 isoforms as well as excellent blood plasma stability.
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      PubDate: 2018-06-18T08:24:48Z
       
  • Luminescent europium sensors for specific detection of 8-oxo-dGTP by
           time-gated fluorescence
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Yasufumi Fuchi, Takashi Fukuda, Shigeki Sasaki
      The 9-hydroxy-1,3-diazaphenoxazine-2-one unit was conjugated with the Eu3+-cyclen complex through a linker. This diazaphenoxazine group was expected as an antenna unit for the excitation of europium ion, and a selective recognition site for 8-oxo-dGTP base. Among the synthesized three derivatives, the highest fluorescence emission was obtained by the complex constructed of an ethylene linker and the cyclen unit with three N,N-dimethylacetamide groups. The Eu3+-cyclen complex exhibited a selective response to the 8-oxo-dGTP in aqueous media by a time-resolved fluorescence assay.
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      PubDate: 2018-06-18T08:24:48Z
       
  • Discovery of benzimidazole derivatives as orally active renin inhibitors:
           Optimization of 3,5-disubstituted piperidine to improve pharmacokinetic
           profile
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Hidekazu Tokuhara, Yasuhiro Imaeda, Yoshiyuki Fukase, Koichi Iwanaga, Naohiro Taya, Koji Watanabe, Ray Kanagawa, Keisuke Matsuda, Yumiko Kajimoto, Keiji Kusumoto, Mitsuyo Kondo, Gyorgy Snell, Craig A. Behnke, Takanobu Kuroita
      We previously identified 2-tert-butyl-4-[(3-methoxypropyl)amino]-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]pyrimidine-5-carboxamide 3 as a potent renin inhibitor. Since 3 showed unacceptably low bioavailability (BA) in rats, structural modification, using SBDD and focused on physicochemical properties was conducted to improve its PK profile while maintaining renin inhibitory activity. Conversion of the amino group attached at the 4-position of pyrimidine to methylene group improved PK profile and decreased renin inhibitory activity. New central cores with carbon side chains were explored to improve potency. We had designed a series of 5-membered azoles and fused heterocycles that interacted with the lipophilic S3 pocket. In the course of modification, renin inhibitory activity was enhanced by the formation of an additional hydrogen bonding with the hydroxyl group of Thr77. Consequently, a series of novel benzimidazole derivatives were discovered as potent and orally bioavailable renin inhibitors. Among those, compound 13 exhibited more than five-fold of plasma renin inhibition than aliskiren in cynomolgus monkeys at dose ratio.
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      PubDate: 2018-06-18T08:24:48Z
       
  • Efficiency of newly prepared thiazole derivatives against some cutaneous
           fungi
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Salama A. Ouf, Sobhi M. Gomha, Mohamed Eweis, Ahmed S. Ouf, Ihab A. Sharawy
      A series of fourteen novel synthesized arylazothiazole and arylhydrazothiazole derivatives were tested for their antifungal activity and structure-activity relationship. The activity of the compounds depends mainly on the side chains of the nucleus compound. The antifungal activity was more significant when both side chains are aromatic > one aromatic and one aliphatic and substituted aromatic with CH3 or OCH3 > non-substituted > substituted aromatic with chloro- or nitro-groups. Thiazole derivatives 7a, 7c, 7e, 7f, 7 g, 7i, 7 m, and 11a showed the most effective as antifungal compounds and were comparable with fluconazole as antifungal reference drug when investigated against Candida albicans, Microsporum gypseum and Trichophyton mentagrophytes. The minimum inhibitory concentration (MIC) reached 2 µg/mL in the case of C. albicans for compounds 7a, 7b, 7c and 11a and measured 4 µg/mL in the case of M. gypseum and T. mentagrophytes for the same compounds. The minimum fungicidal concentration (MFC) for the same compounds was 4 µg/mL for C. albicans and ranged from 8 to 32 µg/mL for the other two fungi. The results revealed that compounds 7c and 11a were the most antifungal compounds against the test fungi regarding keratinase activity and ergosterol biosynthesis. The in vivo efficacy of synthesized thiazoles 7c and 11a applied at their respective MFC was more effective in the treatment of skin infection of guinea pigs previously inoculated with the test fungi as compared with fluconazole. The Molecular Operating Environment (MOE) software was used to analyze the docking poses and binding energies of compound 11a and keratinase. The computational studies supported the biological activity results.
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      PubDate: 2018-06-18T08:24:48Z
       
  • Design and synthesis of 2,6-disubstituted-8-amino imidazo[1,2a]pyridines,
           a promising privileged structure
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Rajaa Boulahjar, Angela Rincon Arias, Raphaël Bolteau, Nicolas Renault, Mathilde Coevoet, Amélie Barczyk, Romain Duroux, Saïd Yous, Patricia Melnyk, Laurence Agouridas
      Imidazo[1,2a]pyridines have gained much interest in the field of medicinal chemistry research. In the aim of accessing new privileged structure, we decided to design and synthesize 8-aminated-imidazo[1,2a]pyridines substituted on positions 2 and 6. This scaffold, rarely found in the literature, was obtained via palladium-catalyzed coupling reactions (Suzuki reaction or N-hydroxysuccinimidyl activated ester method) and tested on adenosine receptor A2A. We demonstrated how incorporation of an exocyclic amine enhanced affinity towards this receptor while maintaining low cytotoxicity.
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      PubDate: 2018-06-18T08:24:48Z
       
  • Synthesis and evaluation of novel dimethylpyridazine derivatives as
           hedgehog signaling pathway inhibitors
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Chenglin Wang, Mingfei Zhu, Xiuhong Lu, Hong Wang, Weili Zhao, Xiongwen Zhang, Xiaochun Dong
      We report herein the design and synthesis of a series of structural modified dimethylpyridazine compounds as novel hedgehog signaling pathway inhibitors. The bicyclic phthalazine core and 4-methylamino-piperidine moiety of Taladegib were replaced with dimethylpyridazine and different azacycle building blocks, respectively. The in vitro Gli-luciferase assay results demonstrate that the new scaffold still retained potent inhibitory potency. Piperidin-4-amine moiety was found to be the best linker between pharmacophores dimethylpyridazine and fluorine substituted benzoyl group. Furthermore, the optimization of 1-methyl-1H-pyrazol and 4-fluoro-2-(trifluoromethyl)benzamide by different aliphatic or aromatic rings were also investigated and the SAR were described. Several new derivatives were found to show potent Hh signaling inhibitory activity with nanomolar IC50 values. Among these compounds, compound 11c showed the highest inhibitory potency with an IC50 value of 2.33 nM, which was comparable to the lead compound Taladegib. In vivo efficacy of 11c in a ptch+/−p53−/− mouse medulloblastoma allograft model also indicated encouraging results.
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      PubDate: 2018-06-18T08:24:48Z
       
  • Synthesis and structure–activity relationship studies of MI-2
           analogues as MALT1 inhibitors
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Guolin Wu, Haixia Wang, Wenhui Zhou, Bihua Zeng, Wenhui Mo, Kejie Zhu, Rong Liu, Jia Zhou, Ceshi Chen, Haijun Chen
      Recent studies revealed that MALT1 is a promising therapeutic target for the treatment of ABC-DLBCL. Among several reported MALT1 inhibitors, MI-2 as an irreversible inhibitor represents a new class of ABC-DLBCL therapeutics. Due to its inherent potential cross-reactivity, further structure–activity relationship (SAR) study is imperative. In this work, five focused compound libraries based on the chemical structure of MI-2 are designed and synthesized. The systematic SARs revealed that the side chain of 2-methoxyethoxy has little impact on the activity and can be replaced by other functionalized groups, providing new MI-2 analogues with retained or enhanced potency. Compounds 81–83 with terminal hydroxyl group as side chain displayed enhanced activities against MALT1. Replacement of triazole core with pyrazole is also tolerant, while structural modifications on other sites are detrimental. These findings will facilitate further development of small-molecule MALT1 inhibitors.
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      PubDate: 2018-06-18T08:24:48Z
       
  • Discovery of bicyclo[3,3,1]non-2-ene as a novel skeleton for HIF-1
           inhibitors
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Hiroki Ueda, Atsushi Yoshimori, Hiroyuki Nakamura
      Bicyclo[3,3,1]non-2-ene was used as a novel three-dimensional skeleton for the design and synthesis of hypoxia-inducible factor (HIF)-1 inhibitors. Among the compounds synthesized, compound 4b was found to be a potent inhibitor of HIF-1α protein accumulation under hypoxia and inhibited HIF-1α transcriptional activity in HeLa (human cervical carcinoma) cells (half maximal inhibitory concentration [IC50] = 3.0 μM). The inhibition of HIF-1α accumulation induced by compound 4b was attenuated by treating the cells with MG132, a proteasome inhibitor, in a concentration-dependent manner, indicating that the compound 4b induces oxygen-independent proteasomal degradation of HIF-1α.
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      PubDate: 2018-06-18T08:24:48Z
       
  • Conversion of iodine to fluorine-18 based on iodinated chalcone and
           evaluation for β-amyloid PET imaging
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Sho Kaide, Masahiro Ono, Hiroyuki Watanabe, Yoichi Shimizu, Yuji Nakamoto, Kaori Togashi, Aiko Yamaguchi, Hirofumi Hanaoka, Hideo Saji
      In the amyloid cascade hypothesis, β-amyloid (Aβ) plaques is one of the major pathological biomarkers in the Alzheimer’s disease (AD) brain. We report the synthesis and evaluation of novel radiofluorinated chalcones, [18F]4-dimethylamino-4′-fluoro-chalcone ([18F]DMFC) and [18F]4′-fluoro-4-methylamino-chalcone ([18F]FMC), as Aβ imaging probes. The conversion of iodine directly introduced to the chalcone backbone into fluorine was successfully carried out by 18F-labeling via the corresponding boronate precursors, achieving the direct introduction of fluorine-18 into the chalcone backbone to prepare [18F]DMFC and [18F]FMC. In a biodistribution study using normal mice, [18F]DMFC and [18F]FMC showed a higher initial uptake (4.43 and 5.47% ID/g at 2 min postinjection, respectively) into and more rapid clearance (0.52 and 0.66% ID/g at 30 min postinjection, respectively) from the brain than a Food and Drug Administration (FDA)-approved Aβ imaging agent ([18F]Florbetapir), meaning the improvement of the probability of detecting Aβ plaques and the reduction of non-specific binding in the brain. In the in vitro binding studies using aggregates of recombinant Aβ peptides, [18F]DMFC and [18F]FMC showed high binding affinity to recombinant Aβ aggregates at the Kd values of 4.47 and 6.50 nM, respectively. In the in vitro autoradiography (ARG) experiment with AD brain sections, [18F]DMFC and [18F]FMC markedly accumulated only in a region with abundant Aβ plaques, indicating that they clearly recognized human Aβ plaques in vitro. These encouraging results suggest that [18F]DMFC and [18F]FMC may be promising PET probes for the detection of an amyloid pathology and the early diagnosis of AD with marked accuracy.
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      PubDate: 2018-06-18T08:24:48Z
       
  • Lipophilic methylene blue analogues enhance mitochondrial function and
           increase frataxin levels in a cellular model of Friedreich’s ataxia
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Omar M. Khdour, Indrajit Bandyopadhyay, Sandipan Roy Chowdhury, Nishant P. Visavadiya, Sidney M. Hecht
      Friedreich’s ataxia (FRDA) is an autosomal recessive neurodegenerative disorder resulting from reduced expression of the protein frataxin (FXN). Although its function is not fully understood, frataxin appears to help assemble iron sulfur clusters; these are critical for the function of many proteins, including those needed for mitochondrial energy production. Finding ways to increase FXN levels has been a major therapeutic strategy for this disease. Previously, we described a novel series of methylene violet analogues and their structural optimization as potential therapeutic agents for neurodegenerative and mitochondrial disorders. Presently, a series of methylene blue analogues has been synthesized and characterized for their in vitro biochemical and biological properties in cultured Friedreich’s ataxia lymphocytes. Favorable methylene blue analogues were shown to increase frataxin levels and mitochondrial biogenesis, and to improve aconitase activity. The analogues were found to be good ROS scavengers, and able to protect cultured FRDA lymphocytes from oxidative stress resulting from inhibition of complex I and from glutathione depletion. The analogues also preserved mitochondrial membrane potential and augmented ATP production. Our results suggest that analogue 5, emerging from the initial structure of the parent compound methylene blue (MB), represents a promising lead structure and lacks the cytotoxicity associated with the parent compound MB.
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      PubDate: 2018-06-18T08:24:48Z
       
  • Novel oxazolxanthone derivatives as a new type of α-glucosidase
           inhibitor: synthesis, activities, inhibitory modes and synergetic effect
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Sen-Miao Ding, Tian Lan, Gao-Jie Ye, Jia-Jun Huang, You Hu, Yi-Ran Zhu, Bo Wang
      Xanthone derivatives have shown good α-glucosidase inhibitory activity and have drawn increased attention as potential anti-diabetic compounds. In this study, a series of novel oxazolxanthones were designed, synthesized, and investigated as α-glucosidase inhibitors. Inhibition assays indicated that compounds 4–21 bearing oxazole rings exhibited up to 30-fold greater inhibitory activity compared to their corresponding parent compound 1b. Among them, compounds 5–21 (IC50 = 6.3 ± 0.4–38.5 ± 4.6 μM) were more active than 1-deoxynojirimycin (IC50 = 60.2 ± 6.2 μM), a well-known α-glucosidase inhibitor. In addition, the kinetics of enzyme inhibition measured by using Lineweaver–Burk analysis shows that compound 4 is a competitive inhibitor, while compounds 15, 16 and 20 are non-competitive inhibitors. Molecular docking studies showed that compound 4 bound to the active site pocket of the enzyme while compounds 15, 16, and 20 did not. More interestingly, docking simulations reveal that some of the oxazolxanthone derivatives bind to different sites in the enzyme. This prediction was further confirmed by the synergetic inhibition experiment, and the combination of representative compounds 16 and 20 at the optimal ratio of 4:6 led to an IC50 value of 1.9 ± 0.7 μM, better than the IC50 value of 7.1 ± 0.9 μM for compound 16 and 8.6 ± 0.9 μM for compound 20.
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      PubDate: 2018-06-18T08:24:48Z
       
  • Design and synthesis of new antitumor agents with the 1,7-epoxycyclononane
           
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Ángel M. Montaña, Julia Lorenzo, Stefano Ponzano, Maria-Filomena Sanasi
      This article describes the design, synthesis and biological evaluation of a new family of antitumor agents having the 1,7-epoxycyclononane framework. We have developed a versatile synthetic methodology that allows the preparation of a chemical library with structural diversity and in good yield. The synthetic methodology has been scaled up to the multigram level and can be developed in an enantioselective fashion. The study in vitro of a model compound, in front of the cancer cell lines HL-60 and MCF-7, showed a growth inhibitory effect better than that of cisplatin. The observation of cancer cells by fluorescence microscopy showed the presence of apoptotic bodies and a degradation of microtubules. The study of cell cycle and mechanism of death of cancer cells by flow cytometry indicates that the cell cycle arrested at the G0/G1 phase and that the cells died by apoptosis preferably over necrosis. A high percentage of apoptotic cells at the subG0/G1 level was observed. This indicates that our model compound does not behave as an antimitotic agent like nocodazole, used as a reference, which arrests the cell cycle at G2/M phase. The interaction of anticancer agents with DNA molecules was evaluated by atomic force microscopy, circular dichroism and electrophoresis on agarose gel. The results indicate that the model compound has not DNA as a target molecule. The in silico study of the model compound showed a potential good oral bioavailability.
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      PubDate: 2018-06-18T08:24:48Z
       
  • Straightforward hit identification approach in fragment-based discovery of
           bromodomain-containing protein 4 (BRD4) inhibitors
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Petro Borysko, Yurii S. Moroz, Oleksandr V. Vasylchenko, Vasyl V. Hurmach, Anastasia Starodubtseva, Natalia Stefanishena, Kateryna Nesteruk, Sergey Zozulya, Ivan S. Kondratov, Oleksandr O. Grygorenko
      A combination approach of a fragment screening and “SAR by catalog” was used for the discovery of bromodomain-containing protein 4 (BRD4) inhibitors. Initial screening of 3695-fragment library against bromodomain 1 of BRD4 using thermal shift assay (TSA), followed by initial hit validation, resulted in 73 fragment hits, which were used to construct a follow-up library selected from available screening collection. Additionally, analogs of inactive fragments, as well as a set of randomly selected compounds were also prepared (3 × 3200 compounds in total). Screening of the resulting sets using TSA, followed by re-testing at several concentrations, counter-screen, and TR-FRET assay resulted in 18 confirmed hits. Compounds derived from the initial fragment set showed better hit rate as compared to the other two sets. Finally, building dose-response curves revealed three compounds with IC50 = 1.9–7.4 μM. For these compounds, binding sites and conformations in the BRD4 (4UYD) have been determined by docking.
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      PubDate: 2018-06-18T08:24:48Z
       
  • An SAR study of hydroxy-trifluoromethylpyrazolines as inhibitors of
           Orai1-mediated store operated Ca2+ entry in MDA-MB-231 breast cancer cells
           using a convenient Fluorescence Imaging Plate Reader assay
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Ralph J. Stevenson, Iman Azimi, Jack U. Flanagan, Marco Inserra, Irina Vetter, Gregory R. Monteith, William A. Denny
      The proteins Orai1 and STIM1 control store-operated Ca2+ entry (SOCE) into cells. SOCE is important for migration, invasion and metastasis of MDA-MB-231 human triple negative breast cancer (TNBC) cells and has been proposed as a target for cancer drug discovery. Two hit compounds from a medium throughput screen, displayed encouraging inhibition of SOCE in MDA-MB-231 cells, as measured by a Fluorescence Imaging Plate Reader (FLIPR) Ca2+ assay. Following NMR spectroscopic analysis of these hits and reassignment of their structures as 5-hydroxy-5-trifluoromethylpyrazolines, a series of analogues was prepared via thermal condensation reactions between substituted acylhydrazones and trifluoromethyl 1,3-dicarbonyl arenes. Structure-activity relationship (SAR) studies showed that small lipophilic substituents at the 2- and 3-positions of the RHS and 2-, 3- and 4-postions of the LHS terminal benzene rings improved activity, resulting in a novel class of potent and selective inhibitors of SOCE.
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      PubDate: 2018-06-18T08:24:48Z
       
  • Molecular modeling, synthesis, antibacterial and cytotoxicity evaluation
           of sulfonamide derivatives of benzimidazole, indazole, benzothiazole and
           thiazole
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Farha Naaz, Ritika Srivastava, Anuradha Singh, Nidhi Singh, Rajesh Verma, Vishal K. Singh, Ramendra K. Singh
      A new series of heterocyclic molecules bearing sulfonamide linkage has been synthesized and screened for antibacterial activity. During antibacterial screening using broath dilution method, molecules were found to be highly active (MIC value 50–3.1 µg/mL) against different human pathogens, namely B. cerus, S. aureus, E. coli and P. aeruginosa, and most effective against E. coli. A great synergistic effect was observed during determination of FIC where molecules were used in combination with reference drugs chloramphenicol and sulfamethoxazole. The MIC value of the combination – varying concentration of test compounds and ½ MIC of reference drugs or varying concentration of reference drugs and ½ MIC of test compounds, was reduced up to 1/4 or 1/32 of the original value, indicating thereby the combination was 4–32 times more potent than the test molecule. The molecules also showed low degree of cytotoxicity against PBM, CEM and VERO cell lines. The results positively indicated towards the development of lead antibacterials using the combination approach.
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      PubDate: 2018-06-18T08:24:48Z
       
  • Design, synthesis and biological evaluation of phosphopeptides as
           Polo-like kinase 1 Polo-box domain inhibitors
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Tong-yuan Lin, Hong-ping Min, Cheng Jiang, Miao-miao Niu, Fang Yan, Li-li Xu, Bin Di
      Polo-like kinase 1 (Plk1) is an anti-cancer target due to its critical role in mitotic progression. A growing body of evidence has documented that Peptide-Plk1 inhibitors showed high Plk1 binding affinity. However, phosphopeptides-Plk1 inhibitors showed poor cell membranes permeability, which limits their clinical applications. In current study, nine candidate phosphopeptides consisting of non-natural amino acids were rationally designed and then successfully synthesized using an Fmoc-solid phase peptide synthesis (SPPS) strategy. Moreover, the binding affinities and selectivity were evaluated via fluorescence polarization (FP) assay. The results confirmed that the most promising phosphopeptide 6 bound to Plk1 PBD with the IC50 of 38.99 nM, which was approximately 600-fold selectivity over Plk3 PBD (IC50 = 25.44 μM) and nearly no binding to Plk2 PBD. Furthermore the intracellular activities and the cell membrane permeability of phosphopeptide 6 were evalutated. Phosphopeptide 6 demonstrated appropriate cell membrane permeability and arrested HeLa cells cycle in G2/M phase by regulating CyclinB1-CDK1. Further, phosphopeptide 6 showed typical apoptotic morphology and induced caspase-dependent apoptosis. In conclusion, we expect our discovery can provide new insights into the further optimization of Plk1 PBD inhibitors.
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      PubDate: 2018-06-18T08:24:48Z
       
  • Drug efficacy of novel 3-O-methoxy-4-halo disubstituted 5,7-dimethoxy
           chromans; evaluated via DNA gyrase inhibition, bacterial cell wall lesion
           and antibacterial prospective
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Thangarasu Ponnusamy, Manikandan Alagumuthu, S. Thamaraiselvi
      In this study, novel 3-O-methoxy-4-halo, disubstituted-5,7-dimethoxy chromans with bacterial cell wall degrading potentials were synthesized, characterized and evaluated as DNA gyrase inhibitors and antibacterial agents. Compounds were showed a broad spectrum of antimicrobial activity against both Gram+ve bacteria (S. aureus (MTCC 3160), C. diphtheriae (MTCC 116), S. pyogenes (MTCC 442)) and Gram−ve bacteria (E. coli (MTCC 443), P. aeruginosa (MTCC 424), K. pneumoniae (MTCC 530)). Further, a molecular docking study was carried out to get more insight into the binding mode of present study compounds to target proteins (PDB ID: 2XCT (S. aureus DNA gyrase A), PDB ID: 3G75 (S. aureus DNA gyrase B), PDB ID: 3L7L (Teichoic acid polymerase). In the results, 14 > 20 > 24 > 12 > 18 > 17 were found as the most active against almost all executed activities in this study. The predicted Lipinski’s filter scores, SAR, pharmacokinetic/pharmacodynamics, and ADMET properties of these compounds envisioned the druggability prospects and the necessity of further animal model evaluations of 3-O-methoxy-4-halo disubstituted 5,7-dimethoxy chromans to establish them as an effective and future antibiotics.
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
  • Elucidating the inhibition of peptidoglycan biosynthesis in Staphylococcus
           aureus by albocycline, a macrolactone isolated from Streptomyces maizeus
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Hai Liang, Guangfeng Zhou, Yunhui Ge, Elizabeth A. D'Ambrosio, Tess M. Eidem, Catlyn Blanchard, Cindy Shehatou, Vijay K. Chatare, Paul M. Dunman, Ann M. Valentine, Vincent A. Voelz, Catherine L. Grimes, Rodrigo B. Andrade
      Antibiotic resistance is a serious threat to global public health, and methicillin-resistant Staphylococcus aureus (MRSA) is a poignant example. The macrolactone natural product albocycline, derived from various Streptomyces strains, was recently identified as a promising antibiotic candidate for the treatment of both MRSA and vancomycin-resistant S. aureus (VRSA), which is another clinically relevant and antibiotic resistant strain. Moreover, it was hypothesized that albocycline’s antimicrobial activity was derived from the inhibition of peptidoglycan (i.e., bacterial cell wall) biosynthesis. Herein, preliminary mechanistic studies are performed to test the hypothesis that albocycline inhibits MurA, the enzyme that catalyzes the first step of peptidoglycan biosynthesis, using a combination of biological assays alongside molecular modeling and simulation studies. Computational modeling suggests albocycline exists as two conformations in solution, and computational docking of these conformations to an ensemble of simulated receptor structures correctly predicted preferential binding to S. aureus MurA—the enzyme that catalyzes the first step of peptidoglycan biosynthesis—over Escherichia coli (E. coli) MurA. Albocycline isolated from the producing organism (Streptomyces maizeus) weakly inhibited S. aureus MurA (IC50 of 480 μM) but did not inhibit E. coli MurA. The antimicrobial activity of albocycline against resistant S. aureus strains was superior to that of vancomycin, preferentially inhibiting Gram-positive organisms. Albocycline was not toxic to human HepG2 cells in MTT assays. While these studies demonstrate that albocycline is a promising lead candidate against resistant S. aureus, taken together they suggest that MurA is not the primary target, and further work is necessary to identify the major biological target.
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
  • Antidiabetic potential of phytochemicals isolated from the stem bark of
           Myristica fatua Houtt. var. magnifica (Bedd.) Sinclair
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): B. Prabha, S. Neethu, S. Lekshmy Krishnan, D.R. Sherin, M. Madhukrishnan, R. Ananthakrishnan, K.B. Rameshkumar, T.K. Manojkumar, P. Jayamurthy, K.V. Radhakrishnan
      Phytochemical investigation of the stem bark of Myristica fatua Houtt. led to the isolation of a new compound 1 (3-tridecanoylbenzoic acid), along with six known acylphenols (2–7). All the compounds displayed moderate inhibitory activity on α-amylase and significant activity on α-glucosidase; however malabaricone B (6) and C (7) were identified as potent α-glucosidase inhibitors with IC50 values of 63.70 ± 0.546, and 43.61 ± 0.620 µM respectively. Acylphenols (compounds 3–7) also showed significant antiglycation property. The molecular docking and dynamics simulation studies confirmed the efficient binding of malabaricone C with C-terminus of human maltase-glucoamylase (2QMJ). Malabaricone B also enhanced the 2-NBDG [2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxy glucose] uptake in L6 myotubes. These findings demonstrate that acylphenols isolated from Myristica fatua Houtt. can be considered as a lead scaffold for the treatment of type II diabetes mellitus.
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
  • Dual emissive bispyrene peptide probes for highly sensitive measurements
           of trypsin activity and evaluation of trypsin inhibitors
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Daisuke Sato, Takuya Kondo, Tamaki Kato
      Peptide substrates were double labeled with pyrenes to prepare fluorescent probes for highly sensitive detection of protease activity and evaluation of protease inhibitors using pyrene monomer/excimer signals. Two proximate pyrene moieties formed excited state dimers in the probes, and these pyrene excimer formations were dissociated by tryptic digestion. The specificity constant of the optimum bispyrene peptide probe was 2.7 times higher than that of the conventional peptide-4-methylcoumarin amide. Moreover, our probe had high sensitivity with an estimated detection limit for trypsin of 4.11 pM. The half maximal inhibitory concentration and dissociation constant of the Bowman–Birk inhibitor were successfully estimated.
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
  • Design, synthesis and molecular modeling of new 4-phenylcoumarin
           derivatives as tubulin polymerization inhibitors targeting MCF-7 breast
           cancer cells
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Rasha Z. Batran, Asmaa F. Kassem, Eman M.H. Abbas, Samia A. Elseginy, Marwa M. Mounier
      A new set of 4-phenylcoumarin derivatives was designed and synthesized aiming to introduce new tubulin polymerization inhibitors as anti-breast cancer candidates. All the target compounds were evaluated for their cytotoxic effects against MCF-7 cell line, where compounds 2f, 3a, 3b, 3f, 7a and 7b, showed higher cytotoxic effect (IC50 = 4.3–21.2 μg/mL) than the reference drug doxorubicin (IC50 = 26.1 μg/mL), additionally, compounds 1 and 6b exhibited the same potency as doxorubicin (IC50 = 25.2 and 28.0 μg/mL, respectively). The thiazolidinone derivatives 3a, 3b and 3f with potent and selective anticancer effects towards MCF-7 cells (IC50 = 11.1, 16.7 and 21.2 μg/mL) were further assessed for tubulin polymerization inhibition effects which showed that the three compounds were potent tubulin polymerization suppressors with IC50 values of 9.37, 2.89 and 6.13 μM, respectively, compared to the reference drug colchicine (IC50 = 6.93 μM). The mechanistic effects on cell cycle progression and induction of apoptosis in MCF-7 cells were determined for compound 3a due to its potent and selective cytotoxic effects in addition to its promising tubulin polymerization inhibition potency. The results revealed that compound 3a induced cell cycle cessation at G2/M phase and accumulation of cells in pre-G1 phase and prevented its mitotic cycle, in addition to its activation of caspase-7 mediating apoptosis of MCF-7 cells. Molecular modeling studies for compounds 3a, 3b and 3f were carried out on tubulin crystallography, the results indicated that the compounds showed binding mode similar to the co-crystalized ligand; colchicine. Moreover, pharmacophore constructed models and docking studies revealed that thiazolidinone, acetamide and coumarin moieties are crucial for the activity. Molecular dynamics (MD) studies were carried out for the three compounds over 100 ps. MD results of compound 3a showed that it reached the stable state after 30 ps which was in agreement with the calculated potential and kinetic energy of compound 3a.
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
  • Design, synthesis and biological evaluation of pyrimidine derivatives as
           novel CDK2 inhibitors that induce apoptosis and cell cycle arrest in
           breast cancer cells
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Yiting Wang, Yanmei Chen, Xiaoling Cheng, Ke Zhang, Hangyu Wang, Bo Liu, Jinhui Wang
      Cyclin-dependent kinase 2 (CDK2) plays a key role in eukaryotic cell cycle progression which could facilitate the transition from G1 to S phase. The dysregulation of CDK2 is closely related to many cancers. CDK2 is utilized as one of the most studied kinase targets in oncology. In this article, 24 benzamide derivatives were designed, synthesized and investigated for the inhibition activity against CDK2. Our results revealed that the compound 25 is a potent CDK2 inhibitor exhibiting a broad spectrum anti-proliferative activity against several human breast cancer cells. Additionally, compound 25 could block cell cycle at G0 or G1 and induce significant apoptosis in MDA-MB-468 cells. These findings highlight a rationale for further development of CDK2 inhibitors to treat human breast cancer.
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
  • Chiral analogues of (+)-cyclazosin as potent α1B-adrenoceptor
           selective antagonist
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Gianni Sagratini, Michela Buccioni, Gabriella Marucci, Elena Poggesi, Matthew Skorski, Stefano Costanzi, Dario Giardinà
      (+)-Cyclazosin [(+)-1] is one of most selective antagonists of the α1B-adrenoceptor subtype (selectivity ratios, α1B/α1A = 13, α1B/α1D = 38–39). To improve the selectivity, we synthesized and pharmacologically studied the blocking activity against α1-adrenoceptors of several homochiral analogues of (+)-cyclazosin featuring different substituents on the carbonyl or amine groups, namely (−)-2, (+)-3, (−)-4–(−)-8, (+)-9. Moreover, we studied the activity of some their opposite enantiomers, namely (−)-1, (−)-3, (+)-6, and (−)-9, to evaluate the influence of stereochemistry on selectivity. The benzyloxycarbonyl and methyl (4aS,8aR) analogues (+)-3 and (−)-6 improved in a significant way the α1B selectivity of the progenitor compound: 4 and 14 time vs. the α1D subtype and 35 and 77 times vs. the α1A subtype, respectively. The study confirmed the importance of the hydrophobic cis-octahydroquinoxaline moiety of these molecules for the establishment of interactions with the α1-adrenoceptors as well that of their (4aS,8aR) stereochemistry to grant selectivity for the α1B subtype. Hypotheses on the mode of interaction of these compounds were advanced on the basis of molecular modeling studies performed on compound (+)-3.
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
  • Optimized synthesis and antiproliferative activity of desTHPdactylolides
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Guanglin Chen, Rubing Wang, Bao Vue, Manee Patanapongpibul, Qiang Zhang, Shilong Zheng, Guangdi Wang, James D. White, Qiao-Hong Chen
      Dactylolide and certain analogues are attractive targets for study due to their structural resemblance to zampanolide, a very promising anticancer lead compound and a unique covalent-binding microtubule stabilizing agent. The primary goal of this project is identification and synthesis of simplified analogues of dactylolide that would be easier to prepare and could be investigated for antiproliferative activity in comparison with zampanolide. Extension of Almann’s concept of a simplified zampanolide analogue to dactylolide in the form of desTHPdactylolide was attractive not only for reasons of synthetic simplification but also for the prospect that analogues of dactylolide could be prepared in both (17S) and (17R) configurations. Since Altmann’s overall yield for the six-step procedure leading to the C9–C18 fragment of desTHPdactylolide was only 8.7%, a study focused on optimized synthesis and antiproliferative evaluation of each enantiomer of desTHPdactylolide was initiated using Altmann’s route as a framework. To this end, two optimized approaches to this fragment C9–C18 were successfully developed by us using allyl iodide or allyl tosylate as the starting material for a critical Williamson ether synthesis. Both (17S) and (17R) desTHPdactylolides were readily synthesized in our laboratory using optimized methods in yields of 37–43%. Antiproliferative activity of the pair of enantiomeric desTHPdactylolides, together with their analogues, was evaluated in three docetaxel-sensitive and two docetaxel-resistant prostate cancer cell models using a WST-1 cell proliferation assay. Surprisingly, (17R) desTHPdactylolide was identified as the eutomer in the prostate cancer cell models. It was found that (17S) and (17R) desTHPdactylolide exhibit equivalent antiproliferative potency towards both docetaxel-sensitive (PC-3 and DU145) and docetaxel-resistant prostate cancer cell lines (PC-3/DTX and DU145/DTX).
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
  • Synthesis of 4′-C-aminoalkyl-2′-O-methyl modified RNA and
           their biological properties
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Kana Koizumi, Yusuke Maeda, Toshifumi Kano, Hisae Yoshida, Taiichi Sakamoto, Kenji Yamagishi, Yoshihito Ueno
      In this paper, we describe the synthesis of 4′-C-aminoalkyl-2′-O-methylnucleosides and the properties of RNAs containing these analogs. Phosphoramidites of 4′-C-aminoethyl and 4′-C-aminopropyl-2′-O-methyluridines were prepared using glucose as starting material, and RNAs containing the analogs were synthesized using the phosphoramidites. Thermal denaturation studies revealed that these nucleoside analogs decreased the thermal stabilities of double-stranded RNAs (dsRNAs). Results of NMR, molecular modeling, and CD spectra measurements suggested that 4′-C-aminoalkyl-2′-O-methyluridine adopts an C2′-endo sugar puckering in dsRNA. The 4′-C-aminoalkyl modifications in the passenger strand and the guide strand outside the seed region were well tolerated for RNAi activity of siRNAs. Single-stranded RNAs (ssRNAs) and siRNAs containing the 4′-C-aminoethyl and 4′-C-aminopropyl analogs showed high stability in buffer containing bovine serum. Thus, siRNAs containing the 4′-C-aminoethyl and 4′-C-aminopropyl analogs are good candidates for the development of therapeutic siRNA molecules.
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
  • Novel carbamate-linked quaternary ammonium lipids containing unsaturated
           hydrophobic chains for gene delivery
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Hengjun Zhou, Jian Yang, Yanyan Du, Shuang Fu, Chenxi Song, Defu Zhi, Yinan Zhao, Huiying Chen, Shubiao Zhang, Shufen Zhang
      In this paper, two novel carbamate-linked quaternary ammonium lipids (MU18: a lipid with a mono-ammonium head; GU18: a lipid with a Gemini-ammonium head) containing unsaturated hydrophobic chains were designed and synthesized. The chemical structures of the synthetic lipids were characterized by infrared spectrum, ESI-MS, 1H NMR, 13C NMR, and HPLC. For investigating the effect of unsaturation on gene delivery, the previous reported saturated cationic liposomes (MS18 and GS18) were used as comparison. Cationic liposomes were prepared by using these cationic lipids and neutral lipid DOPE at the molar ratio of 1:1. Particle sizes and zeta potentials of the cationic liposomes were studied to show that they were suitable for gene transfection. The binding abilities of the cationic liposomes were investigated by gel electrophoresis at various N/P ratios from 0.5/1 to 8/1. The results indicated that the binding ability of GU18 was much better than MU18 and the saturated cationic liposomes (MS18 and GS18). DNA transfection of these liposomes comparable to commercially available reagent (DOTAP) was achieved in vitro against Hela, HepG-2 and NCI-H460 cell lines. GU18 showed higher transfection at the N/P ratio of 3/1 than other cationic liposomes and the positive control, DOTAP. All of the liposomes presented a relatively low cytotoxicity, which was measured by MTT. Therefore, the synthetic lipids bearing unsaturated hydrophobic chains and Gemini-head could be promising candidates for gene delivery.
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
  • Anthranilic diamides derivatives as potential ryanodine receptor
           modulators: Synthesis, biological evaluation and structure activity
           relationship
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Jing-Bo Liu, Feng-Yun Li, Jing-Yue Dong, Yu-Xin Li, Xiu-Lan Zhang, Yuan-Hong Wang, Li-Xia Xiong, Zheng-Ming Li
      A series of novel anthranilic diamides derivatives (7a–s) containing halogen, trifluoromethyl group and cyano group were designed, synthesized, and characterized by melting point, 1H NMR, 13C NMR and elemental analyses. The bioactivity revealed that most of them showed moderate to excellent activities against oriental armyworm (Mythimna separata) and diamondback moth (Plutella xylostella). Above all, the larvicidal activity of 7o against oriental armyworm was 100% and 40% at 0.25 and 0.1 mg L−1, comparable to that of the standard chlorantraniliprole (100%, 0.25 mg L−1 and 20%, 0.1 mg L−1). What is more, 7o against diamondback moth displayed 90% insecticidal activity at 0.01 mg L−1, superior to chlorantraniliprole (45%, 0.01 mg L−1). The experiments 7o on the American cockroach (Periplaneta Americana) heart beating rates (Dorsal vessel) and contractile force were compared with chlorantraniliprole. In addition, 7o could affect the calcium homeostasis in the central neurons of the third larvae of oriental armyworm, which revealed that the ryanodine receptor is the potential target of 7o. The density functional theory (DFT) calculation results revealed the amide bridge, the benzene ring of anthraniloyl moiety and pyrazole ring might play an important role in the insecticidal activity through hydrophobic interactions and π-π conjugations.
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
  • Vinyldiaminotriazine-acridine conjugate as G-quadruplex alkylating agent
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Madoka E. Hazemi, Kazumitsu Onizuka, Tomohito Kobayashi, Akira Usami, Norihiro Sato, Fumi Nagatsugi
      Higher-order structures of nucleic acids have become widely noted for their biological consequences and the discovery of an alkylating small molecule for these structures has been of interest due to its therapeutic potential. We previously developed the vinyldiaminotriazine (VDAT)-acridine conjugate as a T-T mismatch alkylating agent. In this report, we focused on the finding of the alkylation to the G-quadruplex (G4) DNA with VDAT-acridine conjugates. The VDAT-acridine conjugates exhibited a considerable alkylation ability to G4 under mild conditions. Moreover, the investigation of properties with the alkylated G4 revealed that alkylation by this conjugate significantly increased the stability of the G4 structure. This study provides a starting point in the further development of selective G4 alkylating small molecules.
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
  • Discovery and synthesis of
           6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-one-based novel chemotype CCR2
           antagonists via scaffold hopping strategy
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Li-Huai Qin, Zhi-Long Wang, Xin Xie, Ya-Qiu Long
      The chemokine CC receptor subtype 2 (CCR2) has attracted intensive interest for drug development in diverse therapeutic areas, including chronic inflammatory diseases, diabetes, neuropathic pain, atherogenesis and cancer. By employing a cut-and-sew scaffold hopping strategy, we identified an active scaffold of 3,4-dihydro-2,6-naphthyridin-1(2H)-one as the central pharmacophore to derive novel CCR2 antagonists. Systematic structure–activity relationship study with respect to the ring size and the substitution on the naphthyridinone ring gave birth to 1-arylamino-6-alkylheterocycle-6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-ones as a brand new chemotype of CCR2 antagonists with nanomolar inhibitory activity. The best antagonism activity in this series was exemplified by compound 13a, which combined the optimal substitutions of 3,4-dichlorophenylamino at C-1 and 3-(4-(N-methylmethylsulfonamido)piperidin-1-yl)propyl at N-6 position, leading to an IC50 value of 61 nM and 10-fold selectivity for CCR2 over CCR5. Efficient and general synthesis was established to construct the innovative core structure and derive the compound collections. This is the first report on our designed 6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-one as novel CCR2 antagonist scaffold and its synthesis.
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
  • Facilely accessible quinoline derivatives as potent antibacterial agents
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Peng Teng, Chunhui Li, Zhong Peng, Vanderschouw Anne Marie, Alekhya Nimmagadda, Ma Su, Yaqiong Li, Xingmin Sun, Jianfeng Cai
      Quinoline compounds have been extensively explored as anti-malaria and anti-cancer agents for decades and show profound functional bioactivities, however, the studies of these compounds in other medicinal fields have lagged dramatically. In this study, we report the development of a series of facilely accessible quinoline derivatives that display potent antibacterial activity against a panel of multidrug-resistant Gram-positive bacterial strains, especially C. difficile. We also demonstrated that these molecules are effective in vivo against C. difficile. These results revealed that these types of quinoline compounds could serve as prototypes for the development of an appealing class of antibiotic agents used to combat Gram-positive drug-resistant bacterial strains, including C. difficile.
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
  • Synthesis, molecular modelling studies and biological evaluation of new
           oxoeicosanoid receptor 1 agonists
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Tomasz Maciej Stepniewski, Mariona Torrens-Fontanals, Ismael Rodríguez-Espigares, Toni Giorgino, Karoline G. Primdahl, Anders Vik, Yngve Stenstrøm, Jana Selent, Trond Vidar Hansen
      The oxoeicosanoid receptor 1 (OXER1) is a member of the G-protein coupled receptors (GPCR) family, and is involved in inflammatory processes and oncogenesis. As such it is an attractive target for pharmacological intervention. The present study aimed to shed light on the molecular fundaments of OXER1 modulation using chemical probes structurally related to the natural agonist 5-oxo-ETE. In a first step, 5-oxo-ETE and its closely related derivatives (5-oxo-EPE and 4-oxo-DHA) were obtained by conducting concise and high-yielding syntheses. The biological activity of obtained compounds was assessed in terms of potency (EC50) and efficacy (Emax) for arrestin recruitment. Finally, molecular modelling and simulation were used to explore binding characteristics of 5-oxo-ETE and derivatives with the aim to rationalize biological activity. Our data suggest that the tested 5-oxo-ETE derivatives (i) insert quickly into the membrane, (ii) access the receptor via transmembrane helices (TMs) 5 and 6 from the membrane side and (iii) drive potency and efficacy by differential interaction with TM5 and 7. Most importantly, we found that the methyl ester of 5-oxo-ETE (1a) showed even a higher maximum response than the natural agonist (1). In contrast, shifting the 5-oxo group into position 4 results in inactive compounds (4-oxo DHA compounds (3) and (3a)). All in all, our study provides relevant structural data that help understanding better OXER1 functionality and its modulation. The structural information presented herein will be useful for designing new lead compounds with desired signalling profiles.
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
  • Pyrroloquinoline scaffold-based 5-HT6R ligands: Synthesis, quantum
           chemical and molecular dynamic studies, and influence of nitrogen atom
           position in the scaffold on affinity
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Katarzyna Grychowska, Rafał Kurczab, Paweł Śliwa, Grzegorz Satała, Krzysztof Dubiel, Mikołaj Matłoka, Rafał Moszczyński-Pętkowski, Jerzy Pieczykolan, Andrzej J. Bojarski, Paweł Zajdel
      Based on pyrroloquinoline scaffold bearing 5-HT2C agonists, a series of arylsulfonamide derivatives of 1H-pyrrolo[2,3-f]quinoline and 1H-pyrrolo[3,2-h]quinoline, substituted at position 3 with tetrahydropyridine, were synthesized and evaluated in vitro for their affinity for 5-HT6 receptors. A structure–activity relationship study showed that the 1H-pyrrolo[3,2-h]quinoline scaffold was more favorable for 5-HT6R binding than the 1H-pyrrolo[2,3-f]quinoline one, suggesting dependence upon the type of condensation of the pyrrole and quinoline rings. As revealed by quantum-chemical calculations and molecular dynamic studies, position of the quinoline nitrogen atom in the planar pyrroloquinoline skeleton might affect the spatial orientation of the arylsulfonyl fragment, as a result of structure stabilization by internal hydrogen bonds.
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
  • Expedient synthesis and biological evaluation of alkenyl acyclic
           nucleoside phosphonate prodrugs
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Elisa Pileggi, Michaela Serpi, Graciela Andrei, Dominique Schols, Robert Snoeck, Fabrizio Pertusati
      The importance of phosphonoamidate prodrugs (ProTides) of acyclic nucleoside phosphonate (ANPs) is highlighted by the approval of Tenofovir Alafenamide Fumarate for the treatment of HIV and HBV infections. In the present paper we are reporting an expedient, one-pot, two-steps synthesis of allyl phosphonoamidates and diamidates that offers a time saving strategy when compared to literature methods. The use of these substrates in the cross metathesis reactions with alkenyl functionalised thymine and uracil nucleobases is reported. ANPs prodrugs synthesized via this methodology were evaluated for their antiviral activities against DNA and RNA viruses. It is anticipated that the use of 5,6,7,8-tetrahydro-1-napthyl as aryloxy moiety is capable to confer antiviral activity among a series of otherwise inactive uracil ProTides.
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
  • Access to new highly potent antileukemia, antiviral and antimalarial
           agents via hybridization of natural products (homo)egonol, thymoquinone
           and artemisinin
    • Abstract: Publication date: 23 July 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
      Author(s): Aysun Çapcı Karagöz, Christoph Reiter, Ean-Jeong Seo, Lisa Gruber, Friedrich Hahn, Maria Leidenberger, Volker Klein, Frank Hampel, Oliver Friedrich, Manfred Marschall, Barbara Kappes, Thomas Efferth, Svetlana B. Tsogoeva
      Hybridization of natural products has high potential to further improve their activities and may produce synergistic effects between linked pharmacophores. Here we report synthesis of nine new hybrids of natural products egonol, homoegonol, thymoquinone and artemisinin and evaluation of their activities against P. falciparum 3D7 parasites, human cytomegalovirus, sensitive and multidrug-resistant human leukemia cells. Most of the new hybrids exceed their parent compounds in antimalarial, antiviral and antileukemia activities and in some cases show higher in vitro efficacy than clinically used reference drugs chloroquine, ganciclovir and doxorubicin. Combined, our findings stress the high potency of these hybrids and encourages further use of the hybridization concept in applied pharmacological research.
      Graphical abstract image

      PubDate: 2018-06-18T08:24:48Z
       
 
 
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