for Journals by Title or ISSN
for Articles by Keywords
help
  Subjects -> CHEMISTRY (Total: 852 journals)
    - ANALYTICAL CHEMISTRY (52 journals)
    - CHEMISTRY (598 journals)
    - CRYSTALLOGRAPHY (21 journals)
    - ELECTROCHEMISTRY (25 journals)
    - INORGANIC CHEMISTRY (41 journals)
    - ORGANIC CHEMISTRY (46 journals)
    - PHYSICAL CHEMISTRY (69 journals)

CHEMISTRY (598 journals)                  1 2 3 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 10)
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: 38)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 18)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 23)
ACS Macro Letters     Full-text available via subscription   (Followers: 24)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 39)
ACS Nano     Full-text available via subscription   (Followers: 251)
ACS Photonics     Full-text available via subscription   (Followers: 12)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 23)
Acta Chemica Iasi     Open Access   (Followers: 2)
Acta Chimica Sinica     Full-text available via subscription   (Followers: 1)
Acta Chimica Slovaca     Open Access   (Followers: 1)
Acta Chimica Slovenica     Open Access  
Acta Chromatographica     Full-text available via subscription   (Followers: 9)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 5)
Acta Scientifica Naturalis     Open Access   (Followers: 2)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 5)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 8)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 5)
Advanced Functional Materials     Hybrid Journal   (Followers: 51)
Advanced Science Focus     Free   (Followers: 3)
Advances in Chemical Engineering and Science     Open Access   (Followers: 57)
Advances in Chemical Science     Open Access   (Followers: 13)
Advances in Chemistry     Open Access   (Followers: 15)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 18)
Advances in Drug Research     Full-text available via subscription   (Followers: 22)
Advances in Enzyme Research     Open Access   (Followers: 9)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 16)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 9)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 21)
Advances in Nanoparticles     Open Access   (Followers: 15)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15)
Advances in Polymer Science     Hybrid Journal   (Followers: 41)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5)
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: 2)
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: 3)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 66)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 15)
American Journal of Chemistry     Open Access   (Followers: 27)
American Journal of Plant Physiology     Open Access   (Followers: 14)
American Mineralogist     Hybrid Journal   (Followers: 14)
Analyst     Full-text available via subscription   (Followers: 39)
Angewandte Chemie     Hybrid Journal   (Followers: 177)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 229)
Annales UMCS, Chemia     Open Access   (Followers: 1)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 4)
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: 8)
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: 16)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antiviral Chemistry and Chemotherapy     Hybrid Journal   (Followers: 1)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 7)
Applied Spectroscopy     Full-text available via subscription   (Followers: 22)
Applied Surface Science     Hybrid Journal   (Followers: 28)
Arabian Journal of Chemistry     Open Access   (Followers: 6)
ARKIVOC     Open Access   (Followers: 2)
Asian Journal of Biochemistry     Open Access   (Followers: 1)
Atomization and Sprays     Full-text available via subscription   (Followers: 4)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 7)
Autophagy     Hybrid Journal   (Followers: 2)
Avances en Quimica     Open Access   (Followers: 1)
Biochemical Pharmacology     Hybrid Journal   (Followers: 10)
Biochemistry     Full-text available via subscription   (Followers: 325)
Biochemistry Insights     Open Access   (Followers: 6)
Biochemistry Research International     Open Access   (Followers: 6)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 9)
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: 1)
Biomacromolecules     Full-text available via subscription   (Followers: 19)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 10)
Biomedical Chromatography     Hybrid Journal   (Followers: 6)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 3)
BioNanoScience     Partially Free   (Followers: 5)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 122)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 84)
Bioorganic Chemistry     Hybrid Journal   (Followers: 10)
Biopolymers     Hybrid Journal   (Followers: 18)
Biosensors     Open Access   (Followers: 2)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 1)
Bitácora Digital     Open Access  
Boletin de la Sociedad Chilena de Quimica     Open Access  
Bulletin of the Chemical Society of Ethiopia     Open Access   (Followers: 2)
Bulletin of the Chemical Society of Japan     Full-text available via subscription   (Followers: 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: 3)
Canadian Journal of Chemistry     Hybrid Journal   (Followers: 10)
Canadian Mineralogist     Full-text available via subscription   (Followers: 5)
Carbohydrate Research     Hybrid Journal   (Followers: 26)
Carbon     Hybrid Journal   (Followers: 68)
Catalysis for Sustainable Energy     Open Access   (Followers: 7)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 8)
Catalysis Science and Technology     Free   (Followers: 7)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 8)
Cellulose     Hybrid Journal   (Followers: 7)
Cereal Chemistry     Full-text available via subscription   (Followers: 5)
ChemBioEng Reviews     Full-text available via subscription   (Followers: 1)
ChemCatChem     Hybrid Journal   (Followers: 8)
Chemical and Engineering News     Free   (Followers: 15)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 70)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 25)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 21)
Chemical Reviews     Full-text available via subscription   (Followers: 183)
Chemical Science     Open Access   (Followers: 22)
Chemical Technology     Open Access   (Followers: 16)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 5)
Chemical Week     Full-text available via subscription   (Followers: 8)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 56)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 24)
ChemInform     Hybrid Journal   (Followers: 8)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 6)
Chemistry & Biology     Full-text available via subscription   (Followers: 30)
Chemistry & Industry     Hybrid Journal   (Followers: 5)
Chemistry - A European Journal     Hybrid Journal   (Followers: 146)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 15)
Chemistry and Materials Research     Open Access   (Followers: 20)
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: 42)
Chemistry of Materials     Full-text available via subscription   (Followers: 246)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
Chemistry World     Full-text available via subscription   (Followers: 22)
Chemistry-Didactics-Ecology-Metrology     Open Access   (Followers: 1)
ChemistryOpen     Open Access   (Followers: 2)
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: 10)
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: 10)
Chromatographia     Hybrid Journal   (Followers: 24)
Clay Minerals     Full-text available via subscription   (Followers: 10)
Cogent Chemistry     Open Access  
Colloid and Interface Science Communications     Open Access  
Colloid and Polymer Science     Hybrid Journal   (Followers: 10)
Colloids and Surfaces B: Biointerfaces     Hybrid Journal   (Followers: 6)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 4)
Combustion Science and Technology     Hybrid Journal   (Followers: 19)
Comments on Inorganic Chemistry: A Journal of Critical Discussion of the Current Literature     Hybrid Journal   (Followers: 2)
Composite Interfaces     Hybrid Journal   (Followers: 6)
Comprehensive Chemical Kinetics     Full-text available via subscription   (Followers: 2)
Comptes Rendus Chimie     Full-text available via subscription  
Comptes Rendus Physique     Full-text available via subscription   (Followers: 1)
Computational and Theoretical Chemistry     Hybrid Journal   (Followers: 9)
Computational Biology and Chemistry     Hybrid Journal   (Followers: 11)
Computational Chemistry     Open Access   (Followers: 2)
Computers & Chemical Engineering     Hybrid Journal   (Followers: 9)
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 Metabolomics     Hybrid Journal   (Followers: 5)
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 9)
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 18)
Current Research in Chemistry     Open Access   (Followers: 8)
Current Science     Open Access   (Followers: 64)
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  
Doklady Chemistry     Hybrid Journal  
Drying Technology: An International Journal     Hybrid Journal   (Followers: 4)
Eclética Química     Open Access   (Followers: 1)
Ecological Chemistry and Engineering S     Open Access   (Followers: 3)
Ecotoxicology and Environmental Contamination     Open Access  
Educación Química     Open Access   (Followers: 1)
Education for Chemical Engineers     Hybrid Journal   (Followers: 5)
EJNMMI Radiopharmacy and Chemistry     Open Access  

        1 2 3 | Last

Journal Cover Bioorganic & Medicinal Chemistry Letters
  [SJR: 0.952]   [H-I: 112]   [84 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0960-894X
   Published by Elsevier Homepage  [3118 journals]
  • Recent encounters with atropisomerism in drug discovery
    • Authors: Peter W. Glunz
      Pages: 53 - 60
      Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2
      Author(s): Peter W. Glunz
      Atropisomerism is stereochemistry arising from restricted bond rotation that creates a chiral axis. Atropisomers are subject to time-dependent inversion of chirality via bond rotation, a property which in drug molecules introduces complexity and challenges for drug discovery and development processes. Greater recognition of the occurrence of atropisomerism and improved characterization techniques have helped medicinal chemists successfully advance atropisomeric drug molecules. This review provides recent examples of atropisomerism encountered in medicinal chemistry efforts and the strategies used to address the accompanying challenges.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.11.050
       
  • Breakthroughs in neuroactive steroid drug discovery
    • Authors: Maria-Jesus Blanco; Daniel La; Quinn Coughlin; Caitlin A. Newman; Andrew M. Griffin; Boyd L. Harrison; Francesco G. Salituro
      Pages: 61 - 70
      Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2
      Author(s): Maria-Jesus Blanco, Daniel La, Quinn Coughlin, Caitlin A. Newman, Andrew M. Griffin, Boyd L. Harrison, Francesco G. Salituro
      Endogenous and synthetic neuroactive steroids (NASs) or neurosteroids are effective modulators of multiple signaling pathways including receptors for the γ-aminobutyric acid A (GABAA) and glutamate, in particular N-methyl-d-aspartate (NMDA). These receptors are the major inhibitory and excitatory neurotransmitters in the central nervous system (CNS), and there is growing evidence suggesting that dysregulation of neurosteroid production plays a role in numerous neurological disorders. The significant unmet medical need for treatment of CNS disorders has increased the interest for these types of compounds. In this review, we highlight recent progress in the clinical development of NAS drug candidates, in addition to preclinical breakthroughs in the identification of novel NASs, mainly for GABAA and NMDA receptor modulation.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.11.043
       
  • Identification of bicyclic hexafluoroisopropyl alcohol sulfonamides as
           retinoic acid receptor-related orphan receptor gamma (RORγ/RORc) inverse
           agonists. Employing structure-based drug design to improve pregnane X
           receptor (PXR) selectivity
    • Authors: Hua Gong; David S. Weinstein; Zhonghui Lu; James J.-W. Duan; Sylwia Stachura; Lauren Haque; Ananta Karmakar; Hemalatha Hemagiri; Dhanya Kumar Raut; Arun Kumar Gupta; Javed Khan; Dan Camac; John S. Sack; Andrew Pudzianowski; Dauh-Rurng Wu; Melissa Yarde; Ding-Ren Shen; Virna Borowski; Jenny H. Xie; Huadong Sun; Celia D'Arienzo; Marta Dabros; Michael A. Galella; Faye Wang; Carolyn A. Weigelt; Qihong Zhao; William Foster; John E. Somerville; Luisa M. Salter-Cid; Joel C. Barrish; Percy H. Carter; T.G. Murali Dhar
      Pages: 85 - 93
      Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2
      Author(s): Hua Gong, David S. Weinstein, Zhonghui Lu, James J.-W. Duan, Sylwia Stachura, Lauren Haque, Ananta Karmakar, Hemalatha Hemagiri, Dhanya Kumar Raut, Arun Kumar Gupta, Javed Khan, Dan Camac, John S. Sack, Andrew Pudzianowski, Dauh-Rurng Wu, Melissa Yarde, Ding-Ren Shen, Virna Borowski, Jenny H. Xie, Huadong Sun, Celia D'Arienzo, Marta Dabros, Michael A. Galella, Faye Wang, Carolyn A. Weigelt, Qihong Zhao, William Foster, John E. Somerville, Luisa M. Salter-Cid, Joel C. Barrish, Percy H. Carter, T.G. Murali Dhar
      We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Ymax in the PXR assay for long term preclinical pharmacokinetic (PK) studies.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.12.006
       
  • Design, synthesis and structure-activity relationship evaluation of novel
           LpxC inhibitors as Gram-negative antibacterial agents
    • Authors: Shi Ding; Rui-Yang Dai; Wen-Ke Wang; Qiao Cao; Le-Fu Lan; Xian-Li Zhou; Yu-She Yang
      Pages: 94 - 102
      Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2
      Author(s): Shi Ding, Rui-Yang Dai, Wen-Ke Wang, Qiao Cao, Le-Fu Lan, Xian-Li Zhou, Yu-She Yang
      LpxC inhibitors are new-type antibacterial agents developed in the last twenty years, mainly against Gram-negative bacteria infections. To develop novel LpxC inhibitors with good antibacterial activities and biological metabolism, we summarized the basic skeleton of reported LpxC inhibitors, designed and synthesized several series of compounds and tested their antibacterial activities against Escherichial coli and Pseudomonas aeruginosa in vitro. Structure-activity relationships have been discussed in this article. The metabolism stability of YDL-2, YDL-5, YDL-8, YDL-14, YDL-20–YDL-23 have been evaluated in liver microsomes, which indicated that the 2-amino isopropyl group may be a preferred structure than the 2-hydroxy ethyl group in the design of LpxC inhibitors.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.12.005
       
  • Cytotoxic quinazoline alkaloids from the seeds of Peganum harmala
    • Authors: Sheng-Ge Li; Kai-Bo Wang; Chi Gong; Yu Bao; Ning-Bo Qin; Da-Hong Li; Zhan-Lin Li; Jiao Bai; Hui-Ming Hua
      Pages: 103 - 106
      Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2
      Author(s): Sheng-Ge Li, Kai-Bo Wang, Chi Gong, Yu Bao, Ning-Bo Qin, Da-Hong Li, Zhan-Lin Li, Jiao Bai, Hui-Ming Hua
      Seventeen quinazoline alkaloids and derivatives, containing two pairs of new epimers, named as (S)- and (R)-1-(2-aminobenzyl)-3-hydroxypyrrolidin-2-one β-d-glucopyranosyl-(1 → 6)-β-d-glucopyranoside (1, 2), (S)- and (R)-vasicinone β-d-glucopyranosyl-(1 → 6)-β-d-glucopyranoside (3, 4), and a new enantiomer (12b), together with six known ones (5–8, 10, and 12a), and three pairs of known enantiomers (9, 11, and 13), were isolated from the ethanol extracts of the seeds of Peganum harmala L.. Their structures including the absolute configuration were elucidated by using 1D and 2D NMR, and ECD calculation approaches. The cytotoxic activities of all isolated compounds were evaluated. 11 showed moderate cytotoxicity against PC-3 cells with an IC50 value of 15.41 μM.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.12.003
       
  • Protective effects of 6-ureido/thioureido-2,4,5-trimethylpyridin-3-ols
           against 4-hydroxynonenal-induced cell death in adult retinal pigment
           epithelial-19 cells
    • Authors: Dawon Bae; Jaya Gautam; Hyeonjin Jang; Suhrid Banskota; Sang Yeul Lee; Min-Ji Jeong; A-Sol Kim; Hong Chul Kim; Iyn-Hyang Lee; Tae-gyu Nam; Jung-Ae Kim; Byeong-Seon Jeong
      Pages: 107 - 112
      Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2
      Author(s): Dawon Bae, Jaya Gautam, Hyeonjin Jang, Suhrid Banskota, Sang Yeul Lee, Min-Ji Jeong, A-Sol Kim, Hong Chul Kim, Iyn-Hyang Lee, Tae-gyu Nam, Jung-Ae Kim, Byeong-Seon Jeong
      Dysfunction or progressive degeneration of retinal pigment epithelium (RPE) contributes in the initial pathogenesis of age-related macular degeneration (AMD) causing irreversible vision loss, which makes RPE the prime target of the disease. The present study aimed to identify compounds to protect 4-hydroxynonenal (4-HNE)-induced RPE cell death by inhibiting NADPH oxidase 4 (NOX4) activity, not just as free radical scavengers, using ARPE-19, a human adult retinal pigment epithelial cell line, as a RPE representative. Novel thirty-two 6-ureido/thioureido-2,4,5-trimethylpyridin-3-ol derivatives 17 were synthesized and tested. We found that there was a strong correlation between level of protective effect of compounds 17 against 4-HNE-induced APRE-19 cell death and that of inhibitory activity against 4-HNE-induced superoxide production, and that most of the compounds 17 showed minimal DPPH radical scavenging activity. Compound 17–28 showed the best protective activity against 4-HNE-induced superoxide production (79.5% inhibition) and cell death (85.1% recovery) at 10 μM concentration, which was better than that of VAS2870, a NOX2/4 inhibitor. In addition, compound 17–28 blocked 4-HNE-induced apoptosis of ARPE-19 cells in a concentration-dependent manner. The results indicate that compound 17–28 may be a lead compound to develop AMD therapeutics.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.11.046
       
  • Synthesis, in vitro α-glucosidase inhibitory activity and docking studies
           of novel chromone-isatin derivatives
    • Authors: Guangcheng Wang; Ming Chen; Jie Qiu; Zhenzhen Xie; Anbai Cao
      Pages: 113 - 116
      Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2
      Author(s): Guangcheng Wang, Ming Chen, Jie Qiu, Zhenzhen Xie, Anbai Cao
      A novel series of chromone-isatin derivatives 6a–6p were designed, synthesized and characterized by 1H NMR, 13C NMR and HRMS. These novel synthetic compounds were evaluated for inhibitory activity against yeast α-glucosidase enzyme. The results of biological test have shown that all tested compounds exhibited excellent to potent inhibitory activity in the range of IC50 = 3.18 ± 0.12–16.59 ± 0.17 μM as compared to the standard drug acarbose (IC50 = 817.38 ± 6.27 μM). Compound 6j (IC50 = 3.18 ± 0.12 μM) with a hydroxyl group at the 7-position of chromone and a 4-bromobenzyl group at the N1-positions of isatin, was found to be the most active compound among the series. Furthermore, molecular docking study was performed to help understand binding interactions of the most active analogs with α-glucosidase enzyme. These results indicated that this class of compounds had potential for the development of anti-diabetic agents.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.11.047
       
  • Synthesis and evaluation of a class of 1,4,7-triazacyclononane derivatives
           as iron depletion antitumor agents
    • Authors: Sheng Wang; Yongkang Gai; Shasha Zhang; Lei Ke; Xiang Ma; Guangya Xiang
      Pages: 117 - 121
      Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2
      Author(s): Sheng Wang, Yongkang Gai, Shasha Zhang, Lei Ke, Xiang Ma, Guangya Xiang
      Iron depletion has been confirmed as an efficient strategy for cancer treatment. In the current study, a series of 1,4,7-triazacyclononane derivatives HE-NO2A, HP-NO2A and NE2P2A, as well as the bifunctional chelators p-NO2-PhPr-NE3TA and p-NH2-PhPr-NE3TA were synthesized and evaluated as iron-depleting agents for the potential anti-cancer therapy against human hepatocellular carcinoma. The cytotoxicity of these chelators was measured using hepatocellular cancer cells and compared with the clinically available iron depletion agent DFO and the universal metal chelator DTPA. All these 1,4,7-triazacyclononane-based chelators exhibited much stronger antiproliferative activity than DFO and DTPA. Among them, chelators with phenylpropyl side chains, represented by p-NO2-PhPr-NE3TA and p-NH2-PhPr-NE3TA, displayed the highest antiproliferative activity against HepG2 cells. Hence, these compounds are attractive candidates for the advanced study as iron depletion agents for the potential anti-cancer therapy, and could be further in conjugation with a targeting moiety for the future development in targeted iron depletion therapy.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.11.048
       
  • (−)-9′-O-(α-l-Rhamnopyranosyl)lyoniresinol from Lespedeza cuneata
           suppresses ovarian cancer cell proliferation through induction of
           apoptosis
    • Authors: Jiwon Baek; Dahae Lee; Tae Kyoung Lee; Ji Hoon Song; Ju Sung Lee; Seong Lee; Sang-Woo Yoo; Ki Sung Kang; Eunjung Moon; Sanghyun Lee; Ki Hyun Kim
      Pages: 122 - 128
      Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2
      Author(s): Jiwon Baek, Dahae Lee, Tae Kyoung Lee, Ji Hoon Song, Ju Sung Lee, Seong Lee, Sang-Woo Yoo, Ki Sung Kang, Eunjung Moon, Sanghyun Lee, Ki Hyun Kim
      Lespedeza cuneata (Dum. Cours.) G. Don. (Fabaceae), known as Chinese bushclover or sericea lespedeza, has been used in traditional medicine to treat diabetes, hematuria, and insomnia, and it has been reported that bioactive compounds from L. cuneata possess various pharmacological properties. However, there has been no study to determine the active compounds from L. cuneata with potential activity against ovarian cancer. This study aimed to isolate cytotoxic compounds from L. cuneata and identify the molecular mechanisms underlying the apoptosis pathway in ovarian cancer cells. Based on cytotoxic activity identified in the screening test, chemical investigation of the active fraction of L. cuneata led to the isolation of nine compounds including four lignanosides (1–4), three flavonoid glycosides (5–7), and two phenolics (8–9). Cytotoxicity and the molecular mechanism were examined by methyl thiazolyl tetrazolium (MTT) assay and Western blot analysis. Of the isolated compounds, (−)-9′-O-(α-l-rhamnopyranosyl)lyoniresinol (3) demonstrated the strongest effect in suppressing A2780 human ovarian carcinoma cell proliferation in a dose-dependent manner, with an IC50 value of 35.40 ± 2.78 μM. Control A2780 cells had normal morphology, whereas cell blebbing, shrinkage, and condensation were observed after treatment with compound 3. Western blotting analysis showed that compound 3 inhibited A2780 human ovarian cancer cell viability by activating caspase-8, caspase-3, and PARP, which contributed to apoptotic cell death. These results suggest that (−)-9′-O-(α-l-rhamnopyranosyl)lyoniresinol (3) has potent anticancer activities against A2780 human ovarian carcinoma cells through the extrinsic apoptotic pathway. Therefore, (−)-9′-O-(α-l-rhamnopyranosyl)lyoniresinol is an excellent candidate for the development of novel chemotherapeutics.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.11.045
       
  • Rational modification of semaxanib and sunitinib for developing a tumor
           growth inhibitor targeting ATP binding site of tyrosine kinase
    • Authors: Jagroop Kaur; Baljit Kaur; Palwinder Singh
      Pages: 129 - 133
      Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2
      Author(s): Jagroop Kaur, Baljit Kaur, Palwinder Singh
      Analysis of the crystal structure of tyrosine kinase in complexation with an ATP analogue, supplemented with the molecular docking studies of semaxanib and sunitinib in the ATP binding site of the enzyme enabled us to make design of a series of tyrosine kinase inhibitors. The combination of pyrrole and indolinone in one molecule and placement of appropriate substituent thereof made the molecule compatible for the hydrophobic sub-pocket of the enzyme. Screening of the compounds over 60 cell line panel of human tumor cell lines identified compound 3a that exhibited GI50 35 nM and 63 nM against MCF7 and MDA-MB-468 cell lines of breast cancer.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.11.049
       
  • Small molecule inhibitors of anthrax edema factor
    • Authors: Guan-Sheng Jiao; Seongjin Kim; Mahtab Moayeri; April Thai; Lynne Cregar-Hernandez; Linda McKasson; Sean O'Malley; Stephen H. Leppla; Alan T. Johnson
      Pages: 134 - 139
      Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2
      Author(s): Guan-Sheng Jiao, Seongjin Kim, Mahtab Moayeri, April Thai, Lynne Cregar-Hernandez, Linda McKasson, Sean O'Malley, Stephen H. Leppla, Alan T. Johnson
      Anthrax is a highly lethal disease caused by the Gram-(+) bacteria Bacillus anthracis. Edema toxin (ET) is a major contributor to the pathogenesis of disease in humans exposed to B. anthracis. ET is a bipartite toxin composed of two proteins secreted by the vegetative bacteria, edema factor (EF) and protective antigen (PA). Our work towards identifying a small molecule inhibitor of anthrax edema factor is the subject of this letter. First we demonstrate that the small molecule probe 5′-Fluorosulfonylbenzoyl 5′-adenosine (FSBA) reacts irreversibly with EF and blocks enzymatic activity. We then show that the adenosine portion of FSBA can be replaced to provide more drug-like molecules which are up to 1000-fold more potent against EF relative to FSBA, display low cross reactivity when tested against a panel of kinases, and are nanomolar inhibitors of EF in a cell-based assay of cAMP production.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.11.040
       
  • Anti-neuroinflammatory effects of sesquiterpenoids isolated from
           Nardostachys jatamansi
    • Authors: Chi-Su Yoon; Kwan-Woo Kim; Sang-Chan Lee; Youn-Chul Kim; Hyuncheol Oh
      Pages: 140 - 144
      Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2
      Author(s): Chi-Su Yoon, Kwan-Woo Kim, Sang-Chan Lee, Youn-Chul Kim, Hyuncheol Oh
      Two new nardosinone-type sesquiterpenoids, namely kanshone J (1) and kanshone K (2) along with seven known terpenoids (3–9) were isolated from the rhizomes and roots of Nardostachys jatamansi DC (Valerianaceae). The structures of these compounds were determined mainly by analysis of 1D-, 2D-NMR and MS data. In addition, the absolute configuration of compound 1 was assigned by application of the modified Mosher’s method. In an initial assay to evaluate their anti-neuroinflammatory effects, compounds 1–5 and 9 exhibited dose-dependent inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in BV2 cells, with IC50 values ranging from 2.43 to 46.54 μM. Particularly, desoxo-narchinol A (3) and narchinol B (4) significantly inhibited LPS-induced NO overproduction in BV2 cells with IC50 values of 3.48 ± 0.47 and 2.43 ± 0.23 μM, respectively. Furthermore, compounds 3 and 4 exhibited anti-neuroinflammatory effects by inhibiting the production of pro-inflammatory mediators, including prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) proteins, and pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF)-α, in LPS-stimulated BV2 and primary microglial cells.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.11.041
       
  • Design and synthesis of novel pyrimidine analogs as highly selective,
           non-covalent BTK inhibitors
    • Authors: Wataru Kawahata; Tokiko Asami; Takayuki Irie; Masaaki Sawa
      Pages: 145 - 151
      Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2
      Author(s): Wataru Kawahata, Tokiko Asami, Takayuki Irie, Masaaki Sawa
      BTK is a promising target for the treatment of multiple diseases such as B cell malignances, asthma, and rheumatoid arthritis. Here, we report the discovery of a series of novel pyrimidine analogs as potent, highly selective, non-covalent inhibitors of BTK. Compound 25d demonstrated higher affinity to an unactivated conformation of BTK that resulted in an excellent kinase selectivity. Compound 25d showed a good oral bioavailability in mice, and significantly inhibits the PCA reaction in mice.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.11.037
       
  • Synthesis, antitumor activity, and cytotoxicity of 4-substituted
           1-benzyl-5-diphenylstibano-1H-1,2,3-triazoles
    • Authors: Mizuki Yamada; Tsutomu Takahashi; Mai Hasegawa; Mio Matsumura; Kanna Ono; Ryota Fujimoto; Yuki Kitamura; Yuki Murata; Naoki Kakusawa; Motohiro Tanaka; Tohru Obata; Yasuyuki Fujiwara; Shuji Yasuike
      Pages: 152 - 154
      Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2
      Author(s): Mizuki Yamada, Tsutomu Takahashi, Mai Hasegawa, Mio Matsumura, Kanna Ono, Ryota Fujimoto, Yuki Kitamura, Yuki Murata, Naoki Kakusawa, Motohiro Tanaka, Tohru Obata, Yasuyuki Fujiwara, Shuji Yasuike
      Trisubstituted 5-organostibano-1H-1,2,3-triazoles (3a–f) were synthesized by the Cu-catalyzed azide-alkyne cycloaddition of various ethynylstibanes (1) with benzylazide (2) in the presence of CuBr (5 mol%) under aerobic conditions. The reaction of 5-stibanotriazoles with HCl afforded C5-unsubstituted 1,2,3-triazoles (4a–f). The antitumor activity of trisubstituted 5-organostibano-1H-1,2,3-triazoles (3a–f) and their 5-unsubstituted 1,2,3-triazoles (4a–f) were evaluated in several tumor cell lines. All 5-stibanotriazoles (3a–f) exerted an excellent antitumor activity. On the contrary, 5-unsubstituted 1,2,3-triazoles (4a–f) without a diphenylantimony group in the molecule exhibited very low antitumor activity compared with 5-stibanotriazoles (3a–f). In compounds of both the series, the substituted 4-butyl group appeared to decrease antitumor activity. However, results suggested that organometal (antimony) in the molecule was required for greater antitumor activity. In addition, all 5-stibanotriazoles (3a–f), but not all 5-unsubstituted 1,2,3-triazoles (4a–f), exhibited cytotoxicity in normal vascular endothelial cells derived from bovine aorta. Among the compounds (3b–e) that exhibited excellent antitumor activity, those with 4-methylphenyl (3b) and 1-cyclohexenyl (3e) showed relatively low cytotoxicity to vascular endothelial cells. Together, these results suggest that trisubstituted 5-organostibano-1H-1,2,3-triazoles, including compounds 3b and 3e, may serve as potential anticancer therapeutic drugs in the future.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.11.038
       
  • Towards smart biocide-free anti-biofilm strategies: Click-based synthesis
           of cinnamide analogues as anti-biofilm compounds against marine bacteria
    • Authors: C. Sall; M. Ayé; O. Bottzeck; A. Praud; Y. Blache
      Pages: 155 - 159
      Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2
      Author(s): C. Sall, M. Ayé, O. Bottzeck, A. Praud, Y. Blache
      A set of triazole-based analogues of N-coumaroyltyramine was designed to discover potential leads that may help in the control of bacterial biofilms. the most potent compounds act as inhibitors of biofilm development with EC50 closed to ampicillin (EC50 = 11 μM) without toxic effect on bacterial growth even at high concentrations(100 μM).
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.11.039
       
  • Discovery of new GSK-3β inhibitors through structure-based virtual
           screening
    • Authors: Xiaodong Dou; Lan Jiang; Yanxing Wang; Hongwei Jin; Zhenming Liu; Liangren Zhang
      Pages: 160 - 166
      Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2
      Author(s): Xiaodong Dou, Lan Jiang, Yanxing Wang, Hongwei Jin, Zhenming Liu, Liangren Zhang
      Glycogen synthase kinase-3β (GSK-3β) is an attractive therapeutic target for human diseases, such as diabetes, cancer, neurodegenerative diseases, and inflammation. Thus, structure-based virtual screening was performed to identify novel scaffolds of GSK-3β inhibitors, and we observed that conserved water molecules of GSK-3β were suitable for virtual screening. We found 14 hits and D1 (IC50 of 0.71 μM) were identified. Furthermore, the neuroprotection activity of D1–D3 was validated on a cellular level. 2D similarity searches were used to find derivatives of high inhibitory compounds and an enriched structure–activity relationship suggested that these skeletons were worthy of study as potent GSK-3β inhibitors.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.11.036
       
  • Histone H3 peptides incorporating modified lysine residues as
           lysine-specific demethylase 1 inhibitors
    • Authors: Taeko Kakizawa; Yosuke Ota; Yukihiro Itoh; Takayoshi Suzuki
      Pages: 167 - 169
      Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2
      Author(s): Taeko Kakizawa, Yosuke Ota, Yukihiro Itoh, Takayoshi Suzuki
      Lysine-specific demethylase 1 (LSD1) is a flavin-dependent enzyme that removes methyl groups from mono- or dimethylated lysine residues at the fourth position of histone H3. We have previously reported several histone H3 peptides containing an LSD1 inactivator motif at Lys-4. In this study, histone H3 peptides having a trans-2-phenylcyclopropylamine (PCPA), a 2,5-dihydro-1H-pyrrole, and a 1,2,3,6-tetrahydropyridine moiety at Lys-4 were prepared along with related compounds possessing a shorter side chain at the fourth position. Enzymatic assays showed that PCPA peptides containing a longer side chain, which can react with FAD in the active site, are potent LSD1-selective inhibitors.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.11.035
       
  • Effect of side chain hydrophobicity and cationic charge on antimicrobial
           activity and cytotoxicity of helical peptoids
    • Authors: Jiyoun Lee; Dahyun Kang; Jieun Choi; Wei Huang; Mayken Wadman; Annelise E. Barron; Jiwon Seo
      Pages: 170 - 173
      Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2
      Author(s): Jiyoun Lee, Dahyun Kang, Jieun Choi, Wei Huang, Mayken Wadman, Annelise E. Barron, Jiwon Seo
      Peptoids are peptidomimetic polymers that are resistant to proteolysis and less prone to immune responses; thus, they can provide a practical alternative to peptides. Among the various therapeutic applications that have been explored, cationic amphipathic peptoids have demonstrated broad-spectrum antibacterial activity, including activity towards drug-resistant bacterial strains. While their potency and activity spectrum can be manipulated by sequence variations, bacterial selectivity and systemic toxicity need to be improved for further clinical development. To this aim, we incorporated various hydrophobic or cationic residues to improve the selectivity of the previously developed antibacterial peptoid 1. The analogs with hydrophobic residues demonstrated non-specific cytotoxicity, while those with an additional cationic residue showed improved selectivity and comparable antibacterial activity. Specifically, compared to 1, peptoid 7 showed much lower hemolysis and cytotoxicity, while maintaining the antibacterial activity. Therefore, we believe that peptoid 7 has the potential to serve as a promising alternative to current antimicrobial therapies.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.11.034
       
  • Discovery of molecular mechanism of a clinical herbal formula upregulating
           serum HDL-c levels in treatment of metabolic syndrome by in vivo and
           computational studies
    • Authors: Meimei Chen; Fafu Yang; Jie Kang; Huijuan Gan; Xinmei Lai; Yuxing Gao
      Pages: 174 - 180
      Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2
      Author(s): Meimei Chen, Fafu Yang, Jie Kang, Huijuan Gan, Xinmei Lai, Yuxing Gao
      Decreased HDL cholesterol (HDL-c) is considered as an independent risk factor of cardiovascular disease in metabolic syndrome (Mets). Wendan decoction (WDD), a famous clinical traditional Chinese medicine formula in Mets in China, which can obviously up-regulate serum HDL-c levels in Mets. However, till now, the molecular mechanism of up-regulation still remained unclear. In this study, an integrated approach that combined serum ABCA1 in vivo assay, QSAR modeling and molecular docking was developed to explore the molecular mechanism and chemical substance basis of WDD upregulating HDL-c levels. Compared with Mets model group, serum ABCA1 and HDL-c levels intervened by two different doses of WDD for two weeks were significantly up-regulated. Then, kohonen and LDA were applied to develop QSAR models for ABCA1 up-regulators based flavonoids. The derived QSAR model produced the overall accuracy of 100%, a very powerful tool for screening ABCA1 up-regulators. The QSAR model prediction revealed 67 flavonoids in WDD were ABCA1 up-regulators. Finally, they were subjected to the molecular docking to understand their roles in up-regulating ABCA1 expression, which led to discovery of 23 ABCA1 up-regulators targeting LXR beta. Overall, QSAR modeling and docking studies well accounted for the observed in vivo activities of ABCA1 affected by WDD.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.11.033
       
  • Discovery of benzotriazole-azo-phenol/aniline derivatives as antifungal
           agents
    • Authors: Min Lv; Jingchun Ma; Qin Li; Hui Xu
      Pages: 181 - 187
      Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2
      Author(s): Min Lv, Jingchun Ma, Qin Li, Hui Xu
      A series of benzotriazole-azo-phenol/aniline derivatives were prepared and evaluated for their antifungal activities against six phytopathogenic fungi such as Fusarium graminearum, Fusarium solani, Alternaria alternate, Valsa mali, Botrytis cinerea, and Curvularia lunata. Among them, compounds IIf, IIn, and IIr showed a broad-spectrum of potent antifungal activities. Especially some compounds displayed 3.5–10.8 folds more potent activities than carbendazim against A. alternata and C. lunata. Notably, compounds IIc, IIm, and IIr exhibited good protective and therapeutic effects against B. cinerea at 200 μg/mL. Their structure-activity relationships were also discussed.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.11.032
       
  • Structure-based design, synthesis, and binding mode analysis of novel and
           potent chymase inhibitors
    • Authors: Junko Futamura-Takahashi; Taisaku Tanaka; Hajime Sugawara; Shinzo Iwashita; Seiichi Imajo; Yoshiaki Oyama; Tsuyoshi Muto
      Pages: 188 - 192
      Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2
      Author(s): Junko Futamura-Takahashi, Taisaku Tanaka, Hajime Sugawara, Shinzo Iwashita, Seiichi Imajo, Yoshiaki Oyama, Tsuyoshi Muto
      Based on insight from the X-ray crystal structure of human chymase in complex with compound 1, a lactam carbonyl of the diazepane core was exchanged with O-substituted oxyimino group, leading to amidoxime derivatives. This modification resulted in highly potent chymase inhibitors, such as O-phenylamidoxime 5f. X-ray crystal structure analysis indicated that compound 5f induced movement of the Leu99 and Tyr94 side chains at the S2 site, and the increase in inhibitory activity of O-phenyl amidoxime derivatives suggested that the O-phenyl moiety interacted with the Tyr94 residue. Surface plasmon resonance experiments showed that compound 5f had slower association and dissociation kinetics and the calculated residence time of compound 5f to human chymase was extended compared to that of amide compound 1.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.11.031
       
  • Synthesis of radioiodinated probes targeted toward matrix
           metalloproteinase-12
    • Authors: Masayori Hagimori; Takashi Temma; Shinji Kudo; Kohei Sano; Naoya Kondo; Takahiro Mukai
      Pages: 193 - 195
      Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2
      Author(s): Masayori Hagimori, Takashi Temma, Shinji Kudo, Kohei Sano, Naoya Kondo, Takahiro Mukai
      Matrix metalloproteinase-12 (MMP-12, macrophage elastase) is a member of the MMP family that is responsible for the degradation of extracellular matrix, and is associated with the inflammatory process of chronic obstructive pulmonary disease (COPD). COPD, characterized by progressive and irreversible airflow obstruction, is recently a major cause of mortality and morbidity worldwide. Herein, to develop radioiodinated probes for the early diagnosis of COPD, we designed and synthesized novel MMP-12-targeted dibenzofuran compounds (1–3) with a variety of linker structures (carbamate, amide, and sulfonamide). In competitive enzyme activity assays, it was revealed that the linker structures significantly affected the inhibitory activity against and selectivity for MMP-12. Compound 1, with carbamate linker, demonstrated potent MMP-12 inhibitory activity (IC50 = 8.5 nM) compared to compound 2, with amide linker, and compound 3, with sulfonamide linker. Using bromo-substituted carbamate 13 as a radioiodination precursor, [125I]1 was successfully prepared to high radiochemical purity (over 98%) and good specific radioactivity (4.1 GBq/μmol). These results suggest that radioiodinated compound 1 is potent as a novel MMP-12-targeted probe.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.11.027
       
  • Synthesis and biological evaluation of 1-amino isochromans from
           2-bromoethyl benzaldehyde and amines in acid medium
    • Authors: Narjis Fatima; B.V. Subba Reddy; Sabitha Gowravaram; J.S. Yadav; Sudhakar Kadari; Chandra Shekar Putta
      Pages: 196 - 201
      Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2
      Author(s): Narjis Fatima, B.V. Subba Reddy, Sabitha Gowravaram, J.S. Yadav, Sudhakar Kadari, Chandra Shekar Putta
      We have developed a facile and efficient synthetic route to substituted isochromans for the first time by reacting 2-(2-bromoethyl)benzaldehyde with a variety of aryl, heteroaryl amines in AcOH. The reaction is catalyst/additive free and takes place at reflux conditions with short reaction time to furnish products in good to excellent yields. All the compounds have been characterized by spectral techniques such as IR, 1H NMR and Mass etc. Synthesized compounds were evaluated for antimicrobial activity against specific bacterial like 1) Staphylococcus strains aureus 2) Bacillus subtilis 3) Escherichia coli 4) Pseudomonas aeruginosa. Compounds 3e, 3n, 3 m, 3 l, 3 k, 3j and 3b showed most potent in vitro activity against bacterial strains.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.11.020
       
  • AMP and adenosine are both ligands for adenosine 2B receptor signaling
    • Authors: Jessica K. Holien; Benjamin Seibt; Veena Roberts; Evelyn Salvaris; Michael W. Parker; Peter J. Cowan; Karen M. Dwyer
      Pages: 202 - 206
      Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2
      Author(s): Jessica K. Holien, Benjamin Seibt, Veena Roberts, Evelyn Salvaris, Michael W. Parker, Peter J. Cowan, Karen M. Dwyer
      Adenosine is considered the canonical ligand for the adenosine 2B receptor (A2BR). A2BR is upregulated following kidney ischemia augmenting post ischemic blood flow and limiting tubular injury. In this context the beneficial effect of A2BR signaling has been attributed to an increase in the pericellular concentration of adenosine. However, following renal ischemia both kidney adenosine monophosphate (AMP) and adenosine levels are substantially increased. Using computational modeling and calcium mobilization assays, we investigated whether AMP could also be a ligand for A2BR. The computational modeling suggested that AMP interacts with more favorable energy to A2BR compared with adenosine. Furthermore, AMPαS, a non-hydrolyzable form of AMP, increased calcium uptake by Chinese hamster ovary (CHO) cells expressing the human A2BR, indicating preferential signaling via the Gq pathway. Therefore, a putative AMP-A2BR interaction is supported by the computational modeling data and the biological results suggest this interaction involves preferential Gq activation. These data provide further insights into the role of purinergic signaling in the pathophysiology of renal IRI.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.11.019
       
  • Assessment of a pretomanid analogue library for African trypanosomiasis:
           Hit-to-lead studies on 6-substituted
           2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides
    • Authors: Andrew M. Thompson; Andrew J. Marshall; Louis Maes; Nigel Yarlett; Cyrus J. Bacchi; Eric Gaukel; Stephen A. Wring; Delphine Launay; Stephanie Braillard; Eric Chatelain; Charles E. Mowbray; William A. Denny
      Pages: 207 - 213
      Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2
      Author(s): Andrew M. Thompson, Andrew J. Marshall, Louis Maes, Nigel Yarlett, Cyrus J. Bacchi, Eric Gaukel, Stephen A. Wring, Delphine Launay, Stephanie Braillard, Eric Chatelain, Charles E. Mowbray, William A. Denny
      A 900 compound nitroimidazole-based library derived from our pretomanid backup program with TB Alliance was screened for utility against human African trypanosomiasis (HAT) by the Drugs for Neglected Diseases initiative. Potent hits included 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides, which surprisingly displayed good metabolic stability and excellent cell permeability. Following comprehensive mouse pharmacokinetic assessments on four hits and determination of the most active chiral form, a thiazine oxide counterpart of pretomanid (24) was identified as the best lead. With once daily oral dosing, this compound delivered complete cures in an acute infection mouse model of HAT and increased survival times in a stage 2 model, implying the need for more prolonged CNS exposure. In preliminary SAR findings, antitrypanosomal activity was reduced by removal of the benzylic methylene but enhanced through a phenylpyridine-based side chain, providing important direction for future studies.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.10.067
       
  • NOTA analogue: A first dithiocarbamate inhibitor of
           metallo-β-lactamases
    • Authors: En Zhang; Ming-Ming Wang; Shu-Chao Huang; Shuai-Min Xu; De-Yun Cui; Yuan-Li Bo; Peng-Yan Bai; Yong-Gang Hua; Chun-Ling Xiao; Shangshang Qin
      Pages: 214 - 221
      Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2
      Author(s): En Zhang, Ming-Ming Wang, Shu-Chao Huang, Shuai-Min Xu, De-Yun Cui, Yuan-Li Bo, Peng-Yan Bai, Yong-Gang Hua, Chun-Ling Xiao, Shangshang Qin
      The emergence of antibiotic drug (like carbapenem) resistance is being a global crisis. Among those resistance factors of the β-lactam antibiotics, the metallo-β-lactamases (MBLs) is one of the most important reasons. In this paper, a series of cyclic dithiocarbamate compounds were synthesized and their inhibition activities against MBLs were initially tested combined with meropenem (MEM) by in vitro antibacterial efficacy tests. Sodium 1,4,7-triazonane-1,4,7-tris(carboxylodithioate) (compound 5) was identified as the most active molecule to restore the activity of MEM. Further anti-bacterial effectiveness assessment, compound 5 restored the activity of MEM against Escherichia coli, Citrobacter freundii, Proteus mirabilis and Klebsiella pneumonia, which carried resistance genes of blaNDM-1 . The compound 5 was non-hemolytic, even at a concentration of 1000 µg/mL. This compound was low toxic toward mammalian cells, which was confirmed by fluorescence microscopy image and the inhibition rate of HeLa cells. The Ki value of compounds 5 against NDM-1 MBL was 5.63 ± 1.27 μM. Zinc ion sensitivity experiments showed that the inhibitory effect of compound 5 as a MBLs inhibitor was influenced by zinc ion. The results of the bactericidal kinetics displayed that compound 5 as an adjuvant assisted MEM to kill all bacteria. These data validated that this NOTA dithiocarbamate analogue is a good inhibitor of MBLs.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.10.074
       
  • Discovery of
           1-(4-((3-(4-methylpiperazin-1-yl)propyl)amino)benzyl)-5-(trifluoromethyl)pyridin-2(1H)-one,
           an orally active multi-target agent for the treatment of diabetic
           nephropathy
    • Authors: Jun Chen; Zhangzhe Peng; Miaomiao Lu; Xuan Xiong; Zhuo Chen; Qianbin Li; Zeneng Cheng; Dejian Jiang; Lijian Tao; Gaoyun Hu
      Pages: 222 - 229
      Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2
      Author(s): Jun Chen, Zhangzhe Peng, Miaomiao Lu, Xuan Xiong, Zhuo Chen, Qianbin Li, Zeneng Cheng, Dejian Jiang, Lijian Tao, Gaoyun Hu
      Oxidative stress, inflammation and fibrosis can cause irreversible damage on cell structure and function of kidney and are key pathological factors in Diabetic Nephropathy (DN). Therefore, multi-target agents are urgently need for the clinical treatment of DN. Using Pirfenidone as a lead compound and based on the previous research, two novel series (5-trifluoromethyl)-2(1H)-pyridone analogs were designed and synthesized. SAR of (5-trifluoromethyl)-2(1H)-pyridone derivatives containing nitrogen heterocyclic ring have been established for in vitro potency. In addition, compound 8, a novel agent that act on multiple targets of anti-DN with IC50 of 90μM in NIH3T3 cell lines, t1/2 of 4.89±1.33h in male rats and LD50 >2000mg/kg in mice, has been advanced to preclinical studies as an oral treatment for DN.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.07.001
       
  • Factors affecting the uncaging efficiency of 500 nm
           light-activatable BODIPY caging group
    • Authors: Minoru Kawatani; Mako Kamiya; Hironori Takahashi; Yasuteru Urano
      Pages: 1 - 5
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1
      Author(s): Minoru Kawatani, Mako Kamiya, Hironori Takahashi, Yasuteru Urano
      Photoremovable protective groups, or caging groups, enable us to regulate the activities of bioactive molecules in living cells upon photoirradiation. Nevertheless, requirement of UV light for activating caging group is a significant limitation due to its cell toxicity and its poor tissue penetration. Our group previously reported a 500 nm light-activatable caging group based on BODIPY scaffold, however, its uncaging efficiency was lower than those of conventional caging groups. Here we show that the uncaging quantum yield (QY) of BODIPY caging group depends upon the driving force of photo-induced electron transfer (PeT). We also found that the uncaging QY increased in less polar solvents. We applied these findings to develop BODIPY-caged capsaicin, which is well localized to low-polarity intracellular compartments, as a tool to stimulate TRPV1 in live cells in response to blue-green light.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.030
       
  • Identification of a 4-fluorobenzyl l-valinate amide benzoxaborole
           (AN11736) as a potential development candidate for the treatment of Animal
           African Trypanosomiasis (AAT)
    • Authors: Tsutomu Akama; Yong-Kang Zhang; Yvonne R. Freund; Pamela Berry; Joanne Lee; Eric E. Easom; Robert T. Jacobs; Jacob J. Plattner; Michael J. Witty; Rosemary Peter; Tim G. Rowan; Kirsten Gillingwater; Reto Brun; Bakela Nare; Luke Mercer; Musheng Xu; Jiangong Wang; Hao Liang
      Pages: 6 - 10
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1
      Author(s): Tsutomu Akama, Yong-Kang Zhang, Yvonne R. Freund, Pamela Berry, Joanne Lee, Eric E. Easom, Robert T. Jacobs, Jacob J. Plattner, Michael J. Witty, Rosemary Peter, Tim G. Rowan, Kirsten Gillingwater, Reto Brun, Bakela Nare, Luke Mercer, Musheng Xu, Jiangong Wang, Hao Liang
      Novel l-valinate amide benzoxaboroles and analogues were designed and synthesized for a structure-activity-relationship (SAR) investigation to optimize the growth inhibitory activity against Trypanosoma congolense (T. congolense) and Trypanosoma vivax (T. vivax) parasites. The study identified 4-fluorobenzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-l-valinate (5, AN11736), which showed IC50 values of 0.15 nM against T. congolense and 1.3 nM against T. vivax, and demonstrated 100% efficacy with a single dose of 10 mg/kg against both T. congolense and T. vivax in mouse models of infection (IP dosing) and in the target animal, cattle, dosed intramuscularly. AN11736 has been advanced to early development studies.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.028
       
  • Isosteric ribavirin analogues: Synthesis and antiviral activities
    • Authors: Nikolay I. Zhurilo; Mikhail V. Chudinov; Andrey V. Matveev; Olga S. Smirnova; Irina D. Konstantinova; Anatoly I. Miroshnikov; Alexander N. Prutkov; Lyubov E. Grebenkina; Natalya V. Pulkova; Vitaly I. Shvets
      Pages: 11 - 14
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1
      Author(s): Nikolay I. Zhurilo, Mikhail V. Chudinov, Andrey V. Matveev, Olga S. Smirnova, Irina D. Konstantinova, Anatoly I. Miroshnikov, Alexander N. Prutkov, Lyubov E. Grebenkina, Natalya V. Pulkova, Vitaly I. Shvets
      The novel isosteric ribavirin analogues were synthesized by two different ways. Some of them showed significant antiviral action against hepatitis C virus (HCV), herpes simplex (HCV-1) and influenza A virus comparable to that of ribavirin itself. The data obtained confirm the proposed theory of the ribavirin possible antiviral activity mechanism related with bioisosterism.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.029
       
  • Design and synthesis of a biaryl series as inhibitors for the bromodomains
           of CBP/P300
    • Authors: Kwong Wah Lai; F. Anthony Romero; Vickie Tsui; Maureen H. Beresini; Gladys de Leon Boenig; Sarah M. Bronner; Kevin Chen; Zhongguo Chen; Edna F. Choo; Terry D. Crawford; Patrick Cyr; Susan Kaufman; Yingjie Li; Jiangpeng Liao; Wenfeng Liu; Justin Ly; Jeremy Murray; Weichao Shen; John Wai; Fei Wang; Caicai Zhu; Xiaoyu Zhu; Steven Magnuson
      Pages: 15 - 23
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1
      Author(s): Kwong Wah Lai, F. Anthony Romero, Vickie Tsui, Maureen H. Beresini, Gladys de Leon Boenig, Sarah M. Bronner, Kevin Chen, Zhongguo Chen, Edna F. Choo, Terry D. Crawford, Patrick Cyr, Susan Kaufman, Yingjie Li, Jiangpeng Liao, Wenfeng Liu, Justin Ly, Jeremy Murray, Weichao Shen, John Wai, Fei Wang, Caicai Zhu, Xiaoyu Zhu, Steven Magnuson
      A novel, potent, and orally bioavailable inhibitor of the bromodomain of CBP, compound 35 (GNE-207), has been identified through SAR investigations focused on optimizing al bicyclic heteroarene to replace the aniline present in the published GNE-272 series. Compound 35 has excellent CBP potency (CBP IC50 = 1 nM, MYC EC50 = 18 nM), a selectively index of >2500-fold against BRD4(1), and exhibits a good pharmacokinetic profile.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.025
       
  • Synthesis and in vitro evaluations of
           6-(hetero)-aryl-imidazo[1,2-b]pyridazine-3-sulfonamide’s as an inhibitor
           of TNF-α production
    • Authors: Shivaji S. Pandit; Mahesh R. Kulkarni; Yashwant B. Pandit; Nitin P. Lad; Vijay M. Khedkar
      Pages: 24 - 30
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1
      Author(s): Shivaji S. Pandit, Mahesh R. Kulkarni, Yashwant B. Pandit, Nitin P. Lad, Vijay M. Khedkar
      Tumor necrosis factor-α is an important pro-inflammatory cytokine having a key role in hosts defensive process of immune systems and its over expression led to a diverse range of inflammatory diseases such as Rheumatoid arthritis, Cronh’s disease, psoriasis, etc. This paper describes our medicinal chemistry efforts on imidazo[1,2-b]pyridazine scaffold: design, synthesis and biological evaluation. By the introducing sulfonamide functionality at 3 positions and substituting 6 positions with (hetero)-aryl groups’, a small library of compounds was prepared. All synthesized compounds were screened for lipopolysaccharide (LPS) mediated TNF-α production inhibitory activity. Biological data revealed that the majority of the compounds of this series showed moderate to potent TNF-α production inhibitory activity. Compound 5u and 5v are the most potent compounds from the series with activity of IC50 = 0.5 µM and 0.3 µM respectively. A short SAR demonstrates that 3-sulfonyl-4-arylpiperidine-4-carbonitrile moiety on imidazo[1,2-b]pyridazine showed better activity compared to the 3-(4-aryllpiperazin-1-yl) sulfonyl) in hPBMC assay. The molecular modeling studies revealed that the potent TNF-α production inhibitory activity 5v due to the extra stability of complex because of an extra pi-pi (π-π) stacking, hydrogen-bonding interactions.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.026
       
  • Discovery of 5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide
           (SBI-425), a potent and orally bioavailable tissue-nonspecific alkaline
           phosphatase (TNAP) inhibitor
    • Authors: Anthony B. Pinkerton; Eduard Sergienko; Yalda Bravo; Russell Dahl; Chen-Ting Ma; Qing Sun; Michael R. Jackson; Nicholas D.P. Cosford; José Luis Millán
      Pages: 31 - 34
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1
      Author(s): Anthony B. Pinkerton, Eduard Sergienko, Yalda Bravo, Russell Dahl, Chen-Ting Ma, Qing Sun, Michael R. Jackson, Nicholas D.P. Cosford, José Luis Millán
      Tissue-nonspecific alkaline phosphatase (TNAP) is an ectoenzyme crucial for bone matrix mineralization via its ability to hydrolyze extracellular inorganic pyrophosphate (ePPi), a potent mineralization inhibitor, to phosphate (Pi). By the controlled hydrolysis of ePPi, TNAP maintains the correct ratio of Pi to ePPi and therefore enables normal skeletal and dental calcification. In other areas of the body low ePPi levels lead to the development of pathological soft-tissue calcification, which can progress to a number of disorders. TNAP inhibitors have been shown to prevent these processes via an increase of ePPi. Herein we describe the use of a whole blood assay to optimize a previously described series of TNAP inhibitors resulting in 5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide (SBI-425), a potent, selective and oral bioavailable compound that robustly inhibits TNAP in vivo.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.024
       
  • Selective incorporation of foreign functionality into fibrin gels through
           a chemically modified DNA aptamer
    • Authors: Hiroto Fujita; Yusuke Inoue; Masayasu Kuwahara
      Pages: 35 - 39
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1
      Author(s): Hiroto Fujita, Yusuke Inoue, Masayasu Kuwahara
      We found for the first time that a thrombin-binding DNA aptamer (TBA) is selectively entrapped in fibrin gels during the gel growth reaction catalyzed by thrombin. Furthermore, using this phenomenon, we successfully demonstrated multiple incorporation of amphiphilic aliphatic groups into fibrin gels via chemically modified TBA.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.022
       
  • Antiplasmodial alkaloids from bulbs of Amaryllis belladonna Steud.
    • Authors: Namki Cho; Yongle Du; Ana Lisa Valenciano; Maria L. Fernández-Murga; Michael Goetz; Jason Clement; Maria B. Cassera; David G.I. Kingston
      Pages: 40 - 42
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1
      Author(s): Namki Cho, Yongle Du, Ana Lisa Valenciano, Maria L. Fernández-Murga, Michael Goetz, Jason Clement, Maria B. Cassera, David G.I. Kingston
      A bioassay-guided fractionation and chemical investigation of Amaryllis belladonna Steud. bulbs resulted in the isolation and identification of the new crinane alkaloid 1,4-dihydroxy-3-methoxy powellan (1), along with the 3 known crinane alkaloids 2–4 and the two lycorane alkaloids 5–6. The structures were elucidated by interpretation of combined HR-ESIMS, CD and 2D NMR spectroscopic data. Among these isolated compounds the lycorane-type alkaloid acetylcaranine (5) exhibited strong antiplasmodial activity, while compounds 3 and 4 were moderately active, and compounds 1 and 6 were inactive.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.021
       
  • The discovery and optimization of naphthalene-linked P2-P4 Macrocycles as
           inhibitors of HCV NS3 protease
    • Authors: Michael Bowsher; Sheldon Hiebert; Rongti Li; Alan X. Wang; Jacques Friborg; Fei Yu; Dennis Hernandez; Ying-Kai Wang; Herbert Klei; Ramkumar Rajamani; Kathy Mosure; Jay O. Knipe; Nicholas A. Meanwell; Fiona McPhee; Paul M. Scola
      Pages: 43 - 48
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1
      Author(s): Michael Bowsher, Sheldon Hiebert, Rongti Li, Alan X. Wang, Jacques Friborg, Fei Yu, Dennis Hernandez, Ying-Kai Wang, Herbert Klei, Ramkumar Rajamani, Kathy Mosure, Jay O. Knipe, Nicholas A. Meanwell, Fiona McPhee, Paul M. Scola
      Naphthalene-linked P2-P4 macrocycles within a tri-peptide-based acyl sulfonamide chemotype have been synthesized and found to inhibit HCV NS3 proteases representing genotypes 1a and 1b with single digit nanomolar potency. The pharmacokinetic profile of compounds in this series was optimized through structural modifications along the macrocycle tether as well as the P1 subsite. Ultimately a compound with oral bioavailability of 100% in rat, and a long half-life in plasma was obtained. However, compounds in this macrocyclic series exhibited cardiac effects in an isolated rabbit heart model and for this reason further optimization efforts were discontinued.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.005
       
  • Synthesis and biological evaluation of water-soluble derivatives of chiral
           gossypol as HIV fusion inhibitors targeting gp41
    • Authors: Jian Yang; Long-Long Li; Ju-Rong Li; Jing-Xiang Yang; Fang Zhang; Gang Chen; Rui Yu; Wen-Jie Ouyang; Shu-Wen Wu
      Pages: 49 - 52
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1
      Author(s): Jian Yang, Long-Long Li, Ju-Rong Li, Jing-Xiang Yang, Fang Zhang, Gang Chen, Rui Yu, Wen-Jie Ouyang, Shu-Wen Wu
      A series of novel or known water-soluble derivatives of chiral gossypol were synthesized and screened in vitro for their anti-HIV-1 activity. (−)-gossypol derivative was more active against HIV-1 than the corresponding (+)-gossypol derivative, respectively. Among these derivatives, d-glucosamine derivative of (−)-gossypol, oligopeptide derivative of (−)-gossypol and taurine derivative of (−)-gossypol, such as compounds 1a, 3a and 14a, showed significant inhibitory activities against HIV-1 replication, HIV-1 mediated cell-cell fusion and HIV gp41 6-helix bundle formation as some amino acid derivatives of (−)-gossypol.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.08.049
       
  • Graphical abstract TOC
    • Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2


      PubDate: 2017-12-27T04:30:13Z
       
  • Graphical abstract TOC
    • Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2


      PubDate: 2017-12-27T04:30:13Z
       
  • Graphical abstract TOC
    • Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2


      PubDate: 2017-12-27T04:30:13Z
       
  • Synthesis of deuterium-labelled analogues of NLRP3 inflammasome inhibitor
           MCC950
    • Authors: Manohar Salla; Mark S. Butler; Nicholas L. Massey; Janet C. Reid; Matthew A. Cooper; Avril A.B. Robertson
      Abstract: Publication date: Available online 26 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters
      Author(s): Manohar Salla, Mark S. Butler, Nicholas L. Massey, Janet C. Reid, Matthew A. Cooper, Avril A.B. Robertson
      This study describes the syntheses of di, tetra and hexa deuterated analogues of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome inhibitor MCC950. In di and tetra deuterated analogues, deuteriums were incorporated into the 1,2,3,5,6,7-hexahydro-s-indacene moiety, whereas in the hexa deuterated MCC950 deuteriums were incorporated into the 2-(furan-3-yl)propan-2-ol moiety. The di deuterated MCC950 analogue was synthesised from 4-amino-3,5,6,7-tetrahydro-s-indacen-1(2H)-one 5. Tetra deuterated analogues were synthesised in 10 chemical steps starting with 5-bromo-2,3-dihydro-1H-inden-1-one 9, whereas the hexa deuterated analogue was synthesised in four chemical steps starting with ethyl-3-furoate 24. All of the compounds exhibited similar activity to MCC950 (IC50 = 8 nM). These deuterated analogues are useful as internal standards in LC-MS analyses of biological samples from in vivo studies.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.12.054
       
  • Benzoxazin-4-ones as novel, easily accessible inhibitors for rhomboid
           proteases
    • Authors: Jian Yang; Marta Barniol-Xicota; Minh T.N. Nguyen; Anezka Ticha; Kvido Strisovsky; Steven H.L. Verhelst
      Abstract: Publication date: Available online 26 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters
      Author(s): Jian Yang, Marta Barniol-Xicota, Minh T.N. Nguyen, Anezka Ticha, Kvido Strisovsky, Steven H.L. Verhelst
      Rhomboid proteases form one of the most widespread intramembrane protease families. They have been implicated in variety of human diseases. The currently reported rhomboid inhibitors display some selectivity, but their construction involves multistep synthesis protocols. Here, we report benzoxazin-4-ones as novel inhibitors of rhomboid proteases with a covalent, but slow reversible inhibition mechanism. Benzoxazin-4-ones can be synthesized from anthranilic acid derivatives in a one-step synthesis, making them easily accessible. We demonstrate that an alkoxy substituent at the 2-position is crucial for potency and results in low micromolar inhibitors of rhomboid proteases. Hence, we expect that these compounds will allow rapid synthesis and optimization of inhibitors of rhomboids from different organisms.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.12.056
       
  • Double-strand cleavage of DNA by a polyamide-phenazine-di-N-oxide
           conjugate
    • Authors: Hang Zhou; Juanhong Gao; Zhaohang Chen; Shan Duan; Chao Li; Renzhong Qiao
      Abstract: Publication date: Available online 26 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters
      Author(s): Hang Zhou, Juanhong Gao, Zhaohang Chen, Shan Duan, Chao Li, Renzhong Qiao
      Phenazine and its derivatives have been widely applied as nucleic acid cleavage agents due to active oxygen activating the C–H bond of the substrate. However, diffusion of oxygen radicals limits their potential applications in the DNA-targeted metal-free drug. Introduction of groove binder moiety such as polyamide enhanced the regional stability of radical molecules and reduced cytotoxicity of the drugs. In this work, we described the design and synthesis of a polyamide-modified phenazine-di-N-oxide as a DNA double-strand cleavage agent. The gel assays showed the hybrid conjugates can effectively break DNA double strands in a non-random manner under physiological conditions. The probable binding mode to DNA was investigated by sufficient spectral experiments, revealing weak interaction between hybrid ligand and nucleic acid molecules. The results of our study have implications on the design of groove-binding hybrid molecules as new artificial nucleases and may provide a strategy for developing efficient and safe DNA cleavage reagents.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.12.058
       
  • Identification of 2-thioxoimidazolidin-4-one derivatives as novel
           noncovalent proteasome and immunoproteasome inhibitors
    • Authors: Rosanna Maccari; Roberta Ettari; Ilenia Adornato; Alexandra Naß; Gerhard Wolber; Alessandra Bitto; Federica Mannino; Federica Aliquò; Giuseppe Bruno; Francesco Nicolò; Santo Previti; Silvana Grasso; Maria Zappalà; Rosaria Ottanà
      Abstract: Publication date: Available online 26 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters
      Author(s): Rosanna Maccari, Roberta Ettari, Ilenia Adornato, Alexandra Naß, Gerhard Wolber, Alessandra Bitto, Federica Mannino, Federica Aliquò, Giuseppe Bruno, Francesco Nicolò, Santo Previti, Silvana Grasso, Maria Zappalà, Rosaria Ottanà
      This paper describes the design, synthesis, and biological evaluation of 2-thioxoimidazolidin-4-one derivatives as inhibitors of proteasome and immunoproteasome, potential targets for the treatment of hematological malignancies. In particular, we focused our efforts on the design of noncovalent inhibitors, which might be a promising therapeutic option potentially devoid of drawbacks and side-effects related to irreversible inhibition. Among all the synthesized compounds, we identified a panel of active inhibitors with K i values towards one or two chymotrypsin-like activities of proteasome (β5c) and immunoproteasome (β5i and β1i subunits) in the low micromolar range. Docking studies suggested a unique binding mode of the molecules in the catalytic site of immunoproteasome proteolytic subunits.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.12.053
       
  • Synthesis, in vitro antimalarial activities and cytotoxicities of
           amino-artemisinin-ferrocene derivatives
    • Authors: Christo de Lange; Dina Coertzen; Frans J. Smit; Johannes F. Wentzel; Ho Ning Wong; Lyn-Marie Birkholtz; Richard K. Haynes; David D. N'Da
      Abstract: Publication date: Available online 26 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters
      Author(s): Christo de Lange, Dina Coertzen, Frans J. Smit, Johannes F. Wentzel, Ho Ning Wong, Lyn-Marie Birkholtz, Richard K. Haynes, David D. N'Da
      Novel derivatives bearing a ferrocene attached via a piperazine linker to C-10 of the artemisinin nucleus were prepared from dihydroartemisinin and screened against chloroquine (CQ) sensitive NF54 and CQ resistant K1 and W2 strains of Plasmodium falciparum (Pf) parasites. The overall aim is to imprint oxidant (from the artemisinin) and redox (from the ferrocene) activities. In a preliminary assessment, these compounds were shown to possess activities in the low nM range with the most active being compound 6 with IC50 values of 2.79 nM against Pf K1 and 3.2 nM against Pf W2. Overall the resistance indices indicate that the compounds have a low potential for cross resistance. Cytotoxicities were determined with Hek293 human embryonic kidney cells and activities against proliferating cells were assessed against A375 human malignant melanoma cells. The selectivity indices of the amino-artemisinin ferrocene derivatives indicate there is overall an appreciably higher selectivity towards the malaria parasite than mammalian cells.
      Graphical abstract image

      PubDate: 2017-12-27T04:30:13Z
      DOI: 10.1016/j.bmcl.2017.12.057
       
  • Synthesis and biological evaluation of
           4β-(thiazol-2-yl)amino-4′-O-demethyl-4-deoxypodophyllotoxins as
           topoisomerase-II inhibitors
    • Authors: Chun-Yan Sang; Heng-Zhi Tian; Yue Chen; Jian-Fei Liu; Shi-Wu Chen; Ling Hui
      Abstract: Publication date: Available online 7 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters
      Author(s): Chun-Yan Sang, Heng-Zhi Tian, Yue Chen, Jian-Fei Liu, Shi-Wu Chen, Ling Hui
      A series of 4β-(thiazol-2-yl)amino-4′-O-demethyl-4-deoxypodophyllotoxins were synthesized, and their cytotoxicities were evaluated against four human cancer cell lines (A549, HepG2, HeLa, and LOVO cells) and normal human diploid fibroblast line WI-38. Some of the compounds exhibited promising antitumor activity and less toxicity than the anticancer drug etoposide. Among them, compounds 15 and 17 were found to be the most potent synthetic derivatives as topo-II inhibitors, and induced DNA double-strand breaks via the p73/ATM pathway as well as the H2AX phosphorylation in A549 cells. These compounds also arrested A549 cells cycle in G2/M phase by regulating cyclinB1/cdc2(p34). Taken together, these results show that a series of compounds are potential anticancer agents.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.12.012
       
  • Facile conversion of ATP-binding RNA aptamer to quencher-free molecular
           aptamer beacon
    • Authors: Yoojin Park; Duangrat Nim-anussornkul; Tirayut Vilaivan; Takashi Morii; Byeang Hyean Kim
      Abstract: Publication date: Available online 6 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters
      Author(s): Yoojin Park, Duangrat Nim-anussornkul, Tirayut Vilaivan, Takashi Morii, Byeang Hyean Kim
      We have developed RNA-based quencher-free molecular aptamer beacons (RNA-based QF-MABs) for the detection of ATP, taking advantage of the conformational changes associated with ATP binding to the ATP-binding RNA aptamer. The RNA aptamer, with its well-defined structure, was readily converted to the fluorescence sensors by incorporating a fluorophore into the loop region of the hairpin structure. These RNA-based QF-MABs exhibited fluorescence signals in the presence of ATP relative to their low background signals in the absence of ATP. The fluorescence emission intensity increased upon formation of a RNA-based QF-MAB·ATP complex.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.12.008
       
  • Investigation of copper-free alkyne/azide 1,3-dipolar cycloadditions using
           microwave irradiation
    • Authors: Lindsay E. Chatkewitz; John F. Halonski; Marshall S. Padilla; Douglas D. Young
      Abstract: Publication date: Available online 6 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters
      Author(s): Lindsay E. Chatkewitz, John F. Halonski, Marshall S. Padilla, Douglas D. Young
      The prevalence of 1,3-dipolar cycloadditions of azides and alkynes within both biology and chemistry highlights the utility of these reactions. However, the use of a copper catalyst can be prohibitive to some applications. Consequently, we have optimized a copper-free microwave assisted reaction to alleviate the necessity for the copper catalyst. A small array of triazoles was prepared to examine the scope of this approach, and the methodology was translated to a protein context through the use of unnatural amino acids to demonstrate one of the first microwave-mediated bioconjugations involving a full length protein.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.12.007
       
 
 
JournalTOCs
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Email: journaltocs@hw.ac.uk
Tel: +00 44 (0)131 4513762
Fax: +00 44 (0)131 4513327
 
About JournalTOCs
API
Help
News (blog, publications)
JournalTOCs on Twitter   JournalTOCs on Facebook

JournalTOCs © 2009-2016