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  Subjects -> CHEMISTRY (Total: 898 journals)
    - ANALYTICAL CHEMISTRY (55 journals)
    - CHEMISTRY (632 journals)
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    - INORGANIC CHEMISTRY (43 journals)
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CHEMISTRY (632 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: 28)
ACS Catalysis     Hybrid Journal   (Followers: 46)
ACS Chemical Neuroscience     Hybrid Journal   (Followers: 22)
ACS Combinatorial Science     Hybrid Journal   (Followers: 23)
ACS Macro Letters     Hybrid Journal   (Followers: 27)
ACS Medicinal Chemistry Letters     Hybrid Journal   (Followers: 42)
ACS Nano     Hybrid Journal   (Followers: 309)
ACS Photonics     Hybrid Journal   (Followers: 14)
ACS Symposium Series     Full-text available via subscription  
ACS Synthetic Biology     Hybrid Journal   (Followers: 25)
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: 8)
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: 8)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 9)
Adsorption Science & Technology     Open Access   (Followers: 6)
Advanced Functional Materials     Hybrid Journal   (Followers: 60)
Advanced Science Focus     Free   (Followers: 5)
Advances in Chemical Engineering and Science     Open Access   (Followers: 75)
Advances in Chemical Science     Open Access   (Followers: 19)
Advances in Chemistry     Open Access   (Followers: 24)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 19)
Advances in Drug Research     Full-text available via subscription   (Followers: 25)
Advances in Environmental Chemistry     Open Access   (Followers: 7)
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: 16)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 12)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 27)
Advances in Nanoparticles     Open Access   (Followers: 15)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 17)
Advances in Polymer Science     Hybrid Journal   (Followers: 45)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 19)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20)
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: 8)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Al-Kimia : Jurnal Penelitian Sains Kimia     Open Access  
Alchemy : Journal of Chemistry     Open Access   (Followers: 3)
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: 68)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 22)
American Journal of Chemistry     Open Access   (Followers: 32)
American Journal of Plant Physiology     Open Access   (Followers: 13)
American Mineralogist     Hybrid Journal   (Followers: 16)
Anadolu University Journal of Science and Technology A : Applied Sciences and Engineering     Open Access  
Analyst     Full-text available via subscription   (Followers: 37)
Angewandte Chemie     Hybrid Journal   (Followers: 181)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 259)
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: 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     Open Access   (Followers: 2)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 9)
Applied Spectroscopy     Full-text available via subscription   (Followers: 25)
Applied Surface Science     Hybrid Journal   (Followers: 34)
Arabian Journal of Chemistry     Open Access   (Followers: 6)
ARKIVOC     Open Access   (Followers: 1)
Asian Journal of Biochemistry     Open Access   (Followers: 3)
Asian Journal of Chemistry and Pharmaceutical Sciences     Open Access  
Atomization and Sprays     Full-text available via subscription   (Followers: 4)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 7)
Autophagy     Hybrid Journal   (Followers: 3)
Avances en Quimica     Open Access  
Biochemical Pharmacology     Hybrid Journal   (Followers: 11)
Biochemistry     Hybrid Journal   (Followers: 378)
Biochemistry Insights     Open Access   (Followers: 6)
Biochemistry Research International     Open Access   (Followers: 6)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 11)
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     Hybrid Journal   (Followers: 23)
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: 139)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 90)
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: 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: 11)
Canadian Mineralogist     Full-text available via subscription   (Followers: 6)
Carbohydrate Research     Hybrid Journal   (Followers: 25)
Carbon     Hybrid Journal   (Followers: 72)
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: 12)
Cellulose     Hybrid Journal   (Followers: 10)
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: 21)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 75)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 27)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Hybrid Journal   (Followers: 22)
Chemical Reviews     Hybrid Journal   (Followers: 205)
Chemical Science     Open Access   (Followers: 28)
Chemical Technology     Open Access   (Followers: 34)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 5)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 57)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 23)
ChemInform     Hybrid Journal   (Followers: 8)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 7)
Chemistry & Biology     Full-text available via subscription   (Followers: 33)
Chemistry & Industry     Hybrid Journal   (Followers: 8)
Chemistry - A European Journal     Hybrid Journal   (Followers: 168)
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     Open Access   (Followers: 3)
Chemistry Letters     Full-text available via subscription   (Followers: 45)
Chemistry of Materials     Hybrid Journal   (Followers: 268)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
Chemistry World     Full-text available via subscription   (Followers: 20)
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: 3)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 15)
Chemosensors     Open Access  
ChemPhysChem     Hybrid Journal   (Followers: 12)
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: 22)
Chromatography     Open Access   (Followers: 2)
Chromatography Research International     Open Access   (Followers: 6)
Cogent Chemistry     Open Access   (Followers: 2)
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: 7)
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)
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Computational Biology and Chemistry     Hybrid Journal   (Followers: 12)
Computational Chemistry     Open Access   (Followers: 2)
Computers & Chemical Engineering     Hybrid Journal   (Followers: 10)
Coordination Chemistry Reviews     Full-text available via subscription   (Followers: 4)
Copernican Letters     Open Access   (Followers: 1)
Corrosion Series     Full-text available via subscription   (Followers: 7)
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 8)
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   (Followers: 1)
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: 9)
Current Science     Open Access   (Followers: 73)
Current Trends in Biotechnology and Chemical Research     Open Access   (Followers: 2)
Dalton Transactions     Full-text available via subscription   (Followers: 23)
Detection     Open Access   (Followers: 4)
Developments in Geochemistry     Full-text available via subscription   (Followers: 2)

        1 2 3 4 | Last

Journal Cover
Bioorganic & Medicinal Chemistry Letters
Journal Prestige (SJR): 0.81
Citation Impact (citeScore): 3
Number of Followers: 90  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0960-894X
Published by Elsevier Homepage  [3157 journals]
  • Novel PIKK Inhibitor Antibody-Drug Conjugates: Synthesis and Anti-Tumor
           Activity
    • Abstract: Publication date: Available online 11 January 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Dahui Zhou, Jeffrey Casavant, Edmund I. Graziani, Haiyin He, Jeffrey Janso, Frank Loganzo, Sylvia Musto, Nathan Tumey, Christopher J. O'Donnell, Russell Dushin Novel neolymphostin-based antibody-drug conjugate (ADC) precursors were synthesized either through amide couplings between both cleavable and non-cleavable linkers and neolymphostin derivatives, or through Cu(I)-catalyzed acetylene-azide click cycloadditon between non-cleavable linkers and neolymphostin acetal derivatives. These precursors were site-specifically conjugated to cysteine mutant trastuzumab-A114C to provide neolymphostin-based ADCs. Preliminary in vitro data indicated that the corresponding ADCs were active against HER2-expressing tumor cell lines, thus providing a proof-of-concept for using neolymphostin as ADC-based anticancer agents.Graphical abstractGraphical abstract for this article
       
  • Synthesis, Biological Evaluation and Mode of Action Studies of Novel
           Amidinourea Inhibitors of Hepatitis C Virus (HCV)
    • Abstract: Publication date: Available online 11 January 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Andrea Magri, Omar Mokrane, Kate Lauder, Arvind H. Patel, Daniele Castagnolo Novel amidinourea derivatives have been synthesised and evaluated for their antiviral activity against Hepatitis C Virus (HCV). A compound with an amidinourea-spermine chemical structure, different from that of standard anti-HCV drugs, showed micromolar activity against HCV and excellent viability. Studies on the mode of action revealed that the new compound may act against HCV through the inhibition of IRES-mediated translation.Graphical abstractGraphical abstract for this article
       
  • Chemical screening of novel strigolactone agonists that specifically
           interact with DWARF14 protein
    • Abstract: Publication date: Available online 11 January 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Rei Yasui, Yoshiya Seto, Shinsaku Ito, Kojiro Kawada, Kaori Itto-Nakama, Kiyoshi Mashiguchi, Shinjiro Yamaguchi Strigolactones (SLs) are a class of plant hormones that regulate shoot branching as well as being known as root-derived signals for parasitic and symbiotic interactions. The physical interaction between SLs and the DWARF14 (D14) receptor family can be examined by differential scanning fluorimetry (DSF) that monitors the changes in protein melting temperature (Tm). The Tm of D14 is lowered by bioactive SLs in DSF analysis. In this report, we screened the compounds that lower the Tm of Arabidopsis D14 (AtD14) as potential candidates for SL agonists using DSF analysis. Subsequent physiological analyzes revealed that 113D10 acts as a novel SL agonist in a D14-dependent manner. Intriguingly, 113D10 has a chemical structure different from natural SLs in that it does not possess an enol ether bond that connects to a methylbutenolide moiety. Moreover, 113D10 does not stimulate seed germination of root parasitic plants. Accordingly, 113D10 can be a useful tool for SL studies and agricultural applications.Graphical abstractGraphical abstract for this article
       
  • Soluble-type small-molecule CD4 mimics as HIV entry inhibitors
    • Abstract: Publication date: Available online 11 January 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Takuya Kobayakawa, Kiju Konno, Nami Ohashi, Kohei Takahashi, Ami Masuda, Kazuhisa Yoshimura, Shigeyoshi Harada, Hirokazu Tamamura Several small molecule CD4 mimics have been reported previously as HIV-1 entry inhibitors, which block the interaction between the Phe43 cavity of HIV-1 gp120 and the host CD4. Known CD4 mimics such as NBD-556 possess significant anti-HIV activity but are less soluble in water, perhaps due to their hydrophobic aromatic ring-containing structures. Compounds with a pyridinyl group in place of the phenyl group in these molecules have been designed and synthesized in an attempt to increase the hydrophilicity. Some of these new CD4 mimics, containing a tetramethylpiperidine ring show significantly higher water solubility than NBD-556 and have high anti-HIV activity and synergistic anti-HIV activity with a neutralizing antibody. The CD4 mimic that has a cyclohexylpiperidine ring and a 6-fluoropyridin-3-yl ring has high anti-HIV activity and no significant cytotoxicity. The present results will be useful in the future design and development of novel soluble-type molecule CD4 mimics.Graphical abstractGraphical abstract for this article
       
  • Synthesis of the reported structure of homocereulide and its vacuolation
           assay
    • Abstract: Publication date: Available online 10 January 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Toshihito Naka, Yoshihide Hattori, Hiroshi Takenaka, Yoichiro Ohta, Mitsunori Kirihata, Shinji Tanimori Homocereulide, isolated from marine bacterium Bacillus cereus, is an analog of emetic toxin cereulide. There is no report on its structure determination and involvement in B. cereus-associated food poisoning. Homocereulide is a cyclic dodecadepsipeptide composed of L-O-Val-L-Val-D-O-Leu-D-Ala and L-O-allo-Ile-D-Val-D-O-Leu-D-Ala. Here, we synthesized homocereulide using liquid phase fragment condensation. The NMR spectrum of synthesized homocereulide confirmed the intended structure and LC-MS results were consistent with natural products. Morphological evaluation using HEp-2 cells showed higher toxicity with homocereulide (1.39 nM) than cereulide (3.95 nM). Though cereulide is the main component in broth culture, homocereulide is also likely involved in B. cereus-associated food poisoning.Graphical abstractGraphical abstract for this article
       
  • Benzimidazole tethered pyrrolo[3,4-b]quinoline with broad-spectrum
           activity against fungal pathogens
    • Abstract: Publication date: Available online 9 January 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Pedro Villa, Natarajan Arumugam, Abdulrahman I. Almansour, Raju Suresh Kumar, S.M. Mahalingam, Keiji Maruoka, Shankar Thangamani Fungal infections caused by Candida and Cryptococcus are particularly dangerous for immunocompromised individuals. In this study, we identified that benzimidazole fused pyrrolo[3,4-b]quinoline compounds has potent antifungal activity against several clinical isolates of pathogenic fungal strains. Specifically, the compound 6a did not show cytotoxicity against mammalian cells at a concentration that inhibits the growth of fungal strains. In addition, the compound 6a also significantly reduced the metabolic activity of fungal cells in the Candida albicans biofilms. Collectively, our results indicate that benzimidazole fused quinoline compounds has a potential to develop as an antifungal agents.Graphical abstractAntifungal activities of benzimidazole tethered pyrrolo[3, 4-b]quinoline compoundsGraphical abstract for this article
       
  • Discovery of 2-phenylthiazole-4-carboxylic acid, a novel and potent
           scaffold as xanthine oxidase inhibitors
    • Abstract: Publication date: Available online 7 January 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Xue Xu, Liming Deng, Lu Nie, Yueming Chen, Yanzhi Liu, Rongrong Xie, Zheng Li The xanthine oxidase (XO) plays an important role in producing uric acid, and therefore XO inhibitors are considered as one of the promising therapies for hyperuricemia and gout. We have previously reported a series of XO inhibitors with pyrazole scaffold to extend the chemical space of current XO inhibitors. Herein, we describe further structural optimization to explore the optimal heterocycle by replacing the thiazole ring of Febuxostat with 5 heterocycle scaffolds unexplored in this field. All of these efforts resulted in the identification of compound 8, a potent XO inhibitor (IC50 = 48.6 nM) with novel 2-phenylthiazole-4-carboxylic acid scaffold. Moreover, lead compound 8 exhibited hypouricemic effect in potassium oxonate-hypoxanthine-induced hyperuricemic mice. These results promote the understanding of ligand-receptor interaction and might help to design more promising XO inhibitors.Graphical abstractAiming to exploring potent XO inhibitor with optimal heterocycle, we have identified a new 2-phenylthiazole-4-carboxylic acid scaffold by evaluating 5 heterocycle scaffolds unexplored in this field, exemplified by the potent and orally bioavailable XO inhibitor 8.Graphical abstract for this article
       
  • Synthesis and evaluation of novel substituted
           1,2,3-triazolyldihydroquinolines as promising antitubercular agents
    • Abstract: Publication date: Available online 6 January 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Sandeep kumar Marvadi, Vagolu Siva Krishna, Dharmarajan Sriram, Srinivas Kantevari A series of novel substituted 1,2,3-triazolyldihydroquinolines 6a–o was designed and synthesized from 2-acetylthiophene in five-step reaction sequence involving modified Boltzmann-Rahtz reaction of β-Enaminone; Vilsmeier-Haack chloroformylation using DMF/POCl3; Ohira-Bestmann homologation of aldehyde to alkyne as key steps. The reaction of alkyne 4 with various aryl azides in the presence of copper sulfate and sodium ascorbate resulted desired new 1,2,3-triazolyldihydroquinolines 6a-o in excellent yields. In vitro screening of new compounds for anti-mycobacterial activity against Mycobacterium tuberculosis H37Rv (Mtb), resulted in three derivatives 6a (MIC:1.56 µg/mL) and 6d, 6l (MIC:3.12 µg/mL) as promising antitubercular agents with lower cytotoxicity profiles.Graphical abstractGraphical abstract for this article
       
  • A double-headed nucleotide with two cytosines: DNA with condensed
           information and improved duplex stability
    • Abstract: Publication date: Available online 5 January 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Kasper Beck, Charlotte Reslow-Jacobsen, Mick Hornum, Christian Henriksen, Poul Nielsen Double-headed nucleotide monomers are capable of condensing the genetic information of DNA. Herein, a double-headed nucleotide with two cytosine bases (CC) is constructed. The additional cytosine is connected through a methylene linker to the 2́-position of arabinocytidine. The nucleotide is incorporated into oligonucleotides and its effect on duplex stability is studied. For single incorporations, a thermal stabilization of 4.0 °C is found as compared to the unmodified duplex and it is shown that both nucleobases of CC participate in Watson-Crick base pairing. In combination with the previously published UT monomer, it is also shown that multiple incorporations are tolerated. For instance, a 16-mer sequence is targeted by a 13-mer oligonucleotide by using one CC and two UT monomers without compromising the overall duplex stability. Finally, the potential of double-headed nucleotides in triplex forming oligonucleotides is studied, however, with the conclusion that the present design is not well-suited for this function.Graphical abstractA double-headed nucleotide monomer with an additional cytosine base in the 2́-position is prepared and found to behave as a compressed dinucleotide thereby condensing the information in DNA while also stabilizing the resulting duplex.Graphical abstract for this article
       
  • Design, synthesis, and in vitro evaluation of
           N-(3-(3-alkyl-1H-pyrazol-5-yl) phenyl)-aryl amide for selective RAF
           inhibition
    • Abstract: Publication date: Available online 4 January 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Hoyong Jung, Jinwoong Kim, Daseul Im, Hyungwoo Moon, Jung-Mi Hah Notorious oncogenic BRAF V600E plays a significant role in the signal transduction of the MAPK pathway, which is involved in tumor growth, especially in melanoma. Much effort has been made to suppress BRAF V600E through small molecules like vemurafenib and dabrafenib, but the MAPK pathway remains active through paradoxical activation, where CRAF transmits the signal of the MAPK pathway either alone or along with BRAF V600E. Therefore, we designed and synthesized a new series of N-(3-(3-alkyl-1H-pyrazol-5-yl) phenyl)-aryl amide/urea analogues that showed potent inhibitory activities against BRAF V600E and CRAF. Compound 7c exhibited particularly superior selectivity toward BRAF V600E and CRAF over 30 other protein kinases, implying that this chemotype could be investigated as a BRAF paradox breaker. © 2019 Elsevier Ltd. All rights reservedGraphical abstractGraphical abstract for this article
       
  • Design, synthesis, and bioevaluation of a novel class of
           (E)-4-oxo-crotonamide derivatives as potent antituberculosis agents
    • Abstract: Publication date: Available online 3 January 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Jinfeng Ren, Jian Xu, Guoning Zhang, Changliang Xu, LiLi Zhao, XueFu You, Yucheng Wang, Yu Lu, Liyan Yu, Juxian Wang A series of novel (E)-4-oxo-2-crotonamide derivatives were designed and synthesized to find potent antituberculosis agents. All the target compounds were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv(MTB). Results reveal that 4-phenyl moiety at part A and short methyl group at part C were found to be favorable. Most of the derivatives displayed promising activity against MTB with MIC ranging from 0.125 - 4 µg/mL. Especially, compound IIIa16 was found to have the best activity with MIC of 0.125 μg/mL against MTB and with MIC in the range of 0.05 - 0.48 µg/mL against drug-resistant clinical MTB isolates.Graphical abstractGraphical abstract for this article
       
  • Novel 2, 8-bit derivatives of quinolines attenuate Pseudomonas aeruginosa
           virulence and biofilm formation
    • Abstract: Publication date: Available online 3 January 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Man-Na Qiu, Fang Wang, Si-Yu Chen, Peng-Cheng Wang, Yu-Hang Fu, Yuan-Yuan Liu, Xuan Wang, Fan-Bei Wang, Chao Wang, Hong-Wen Yang, Yang Wu, Shi-Ying Zhu, Hai-Bo Zhou, Wei-Min Chen, Jing Lin, Jun-Xia Zheng, Ping-Hua SunGraphical abstractGraphical abstract for this article
       
  • Binding inhibition of various influenza viruses by sialyllactose-modified
           trimer DNAs
    • Abstract: Publication date: Available online 2 January 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Miyuki Yamabe, Kunihiro Kaihatsu, Yasuhito Ebara Sialyllactose (SL)-modified trimer DNAs with a similar SL presentation as their binding sites on influenza virus hemagglutinin (HA) trimer were designed and synthesized. These trimer DNAs showed high affinity for various influenza viruses, including A/Puerto Rico/08/34 (H1N1), A/Beijing/262/95 (H1N1), A/Yokohama/77/2008 (H1N1), and A/Panama/2007/99 (H3N2). Thus, presentation of SL residues on three vertexes of the scaffold as well as sialic acid binding sites on the HA trimer regardless of a tri-branched or triangular scaffold are important for high affinity for influenza viruses. These compounds have the potential for use in detection and as inhibitors of a broad spectrum of influenza viruses.Graphical abstractGraphical abstract for this article
       
  • Fluoromethylcyclopropylamine derivatives as potential in vivo toxicophores
           – a cautionary disclosure
    • Abstract: Publication date: Available online 2 January 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Ben Acton, Helen F. Small, Kate M. Smith, Alison McGonagle, Alexandra I.J. Stowell, Dominic I. James, Niall M. Hamilton, Nicola Hamilton, James R. Hitchin, Colin P. Hutton, Ian D. Waddell, Donald J. Ogilvie, Allan M. Jordan Fluorination of metabolic hotspots in a molecule is a common medicinal chemistry strategy to improve in vivo half-life and exposure and, generally, this strategy offers significant benefits. Here, we report the application of this strategy to a series of poly-ADP ribose glycohydrolase (PARG) inhibitors, resulting in unexpected in vivo toxicity which was attributed to this single-atom modification.Graphical abstractGraphical abstract for this article
       
  • Shape-based virtual screen for the discovery of novel CDK8 inhibitor
           chemotypes
    • Abstract: Publication date: Available online 2 January 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Lian-Jun He, Yi-Bao Zhu, Qing-Zhu Fan, Dong-Dong Miao, Sheng-Peng Zhang, Xiao-Ping Liu, Chao Zhang With the aim of discovering novel cyclin-dependent kinase 8 (CDK8) inhibitors, a combined similarity search and molecular docking approach was employed, which led to 32 hits. Biological tests led to the discovery of several novel submicromolar inhibitors. In particular, compound C768-0769 (ZC0201) showed good CDK8 inhibitory activity, and compound ZC0201 effectively suppressed HCT-116 colorectal cancer cell proliferation by inducing G1/S transition arrest. Furthermore, modulation of phosphorylated signal transducer and activator of transcription 1 (Ser 727) (STAT1SER727), a pharmacodynamic biomarker of CDK8 activity, demonstrated that ZC0201 may cause G1/S transition arrest through CDK8 activity inhibition. Due to its good cellular activity, ZC0201 may be an ideal lead compound for further modification as a potential cancer therapeutic agent.Graphical abstractGraphical abstract for this article
       
  • Identification of selective and reversible LSD1 inhibitors with
           anti-metastasis activity by high-throughput docking
    • Abstract: Publication date: Available online 2 January 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Lijun Li, Ruizhe Li, Yumei Wang The overexpression of lysine specific demethylase 1 (LSD1) has been reported in various human tumors. There is increasing interest in targeting LSD1 with small molecules for cancer treatment. A released structure of an LSD1 kinase domain in complex with FAD was used to set up a low-cost high-throughput docking protocol for quick identification of LSD1 inhibitors. The most promising hit L05 was confirmed to be a potent, selective and reversible LSD1 inhibitor and displayed marked inhibition of colorectal cells migration without significant cytotoxicity.Graphical abstractGraphical abstract for this article
       
  • Modified ribavirin analogues as antiviral agents against Junín virus
    • Abstract: Publication date: Available online 2 January 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Mario Contin, Claudia Sepúlveda, Mirta Fascio, Carlos A. Stortz, Elsa B. Damonte, Norma B. D'Accorso In this work, several ribavirin analogues were synthesized and incorporated into a multivalent arrangement. Both were subsequently modified by the addition of polyhydroxylated residues.Their antiviral activity was tested against Junín virus, etiological agent responsible of Argentine hemorrhagic fever.Some compounds inhibited Junín virus in the range of 13.2–389.1 µM. Two modified ribavirin analogues presented an effective concentration comparable to ribavirin but with a higher selectivity index.Graphical abstractGraphical abstract for this article
       
  • Discovery and evaluation of novel FAAH inhibitors in neuropathic pain
           model
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Debnath Bhuniya, Rajendra K. Kharul, Atul Hajare, Nadim Shaikh, Sandeep Bhosale, Sandip Balwe, Fouzia Begum, Siddhartha De, Sonalee Athavankar, Dhananjay Joshi, Vamsi Madgula, Kaushal Joshi, Amol A. Raje, Ashwinkumar V. Meru, Amol Magdum, Kasim A. Mookhtiar, Rashmi Barbhaiya Conceptual design and modification of urea moiety in chemotype PF-3845/04457845, the bench marking irreversible inhibitor of fatty acid amide hydrolase (FAAH), led to discovery of a novel nicotinamide-based lead 12a having reversible mechanism of action. Focused SAR around the pyridine heterocycle (Ar) in 12a (Tables 1 and 2) resulted into four shortlisted compounds, (−)-12a, (−)-12i, (−)-12l–m. The required (−)-enantiomers were obtained via diastereomeric resolution of a novel chiral dissymmetric intermediate 15. Based on comparative profile of FAAH potency, metabolic stability in liver microsome, liability of inhibiting major hCYP450 isoforms, rat PK, and brain penetration ability, two SAR optimized compounds, (−)-12l and (−)-12m, were selected for efficacy study in rat model of chemotherapy-induced peripheral neuropathy (CIPN). Both the compounds exhibited dose related antihyperalgesic effects, when treated with 3–30 mg/kg po for 7 days. The effects at 30 mg/kg are comparable to that of PF-04457845 (10 mg/kg) and Tramadol (40 mg/kg).Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s):
       
  • Corrigendum to “Eupatilin inhibits angiogenesis-mediated human
           hepatocellular metastasis by reducing MMP-2 and VEGF signaling” [Bioorg.
           Med. Chem. Lett. 28(19) (2018) 3150–3154]
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Jun Yeon Park, Do Hwi Park, Youngsic Jeon, Young-Joo Kim, Jaemin Lee, Myoung-Sook Shin, Ki Sung Kang, Gwi Seo Hwang, Hyun Young Kim, Noriko Yamabe
       
  • The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges
           en route to an mGlu4 PAM development candidate
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Joseph D. Panarese, Darren W. Engers, Yong-Jin Wu, Jason M. Guernon, Aspen Chun, Alison R. Gregro, Aaron M. Bender, Rory A. Capstick, Joshua M. Wieting, Joanne J. Bronson, John E. Macor, Ryan Westphal, Matthew Soars, Julie E. Engers, Andrew S. Felts, Alice L. Rodriguez, Kyle A. Emmitte, Carrie K. Jones, Anna L. Blobaum, P. Jeffrey Conn This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu4 positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled as a preclinical development candidate. Here, we detail the challenges faced in allosteric modulator programs (e.g., steep SAR, as well as subtle structural changes affecting overall physiochemical/DMPK properties and CNS penetration).Graphical abstractGraphical abstract for this article
       
  • Evaluation of neomycin analogues for HIV-1 RRE RNA recognition identifies
           enhanced activity simplified neamine analogues
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Binto Simon, Claire Walmsley, Victoria J. Jackson, Edward P. Garvey, Martin J. Slater, David J. Berrisford, John M. Gardiner Synthetic neamine mimetics have been evaluated for binding to the HIV-1 Rev response element. Modified neamine derivatives, obtained from reductive amination of neamine, led to identification of new 6-amino modified neamine-type ligands with HIV-1 RRE binding affinity up to 20× that of neamine and up to 6× that of the more complex neomycin itself. This provides a noteworthy structure-activity increase and a useful lead to simplified, chemically accessible mimetics.Graphical abstractGraphical abstract for this article
       
  • Discovery and structure-activity relationship of imidazolinylindole
           derivatives as kallikrein 7 inhibitors
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Hidenobu Murafuji, Tsuyoshi Muto, Megumi Goto, Seiichi Imajo, Hajime Sugawara, Yoshiaki Oyama, Yutaka Minamitsuji, Shuji Miyazaki, Kenichi Murai, Hiromichi Fujioka A series of imidazolinylindole derivatives were discovered as novel kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme) inhibitors. Structure-activity relationship (SAR) studies led to the identification of potent human KLK7 inhibitors. By further modification of the benzenesulfonyl moiety to overcome species differences in inhibitory activity, potent inhibitors against both human and mouse KLK7 were identified. Furthermore, the complex structure of 25 with mouse KLK7 could explain the SAR and the cause of the species differences in inhibitory activity.Graphical abstractGraphical abstract for this article
       
  • Synthesis and anti-neuroinflammatory activity of N-heterocyclic analogs
           based on natural biphenyl-neolignan honokiol
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Yue Yuan, Lalita Subedi, Daesung Lim, Jae-Kyung Jung, Sun Yeou Kim, Seung-Yong Seo Novel isoxazole and pyrazole analogs based on natural biphenyl-neolignan honokiol were synthesized and evaluated for their inhibitory activities against nitric oxide production in lipopolysaccharide-activated BV-2 microglial cells. The isoxazole skeleton was constructed via nitrile oxide cycloaddition from oxime 3 and pyrazole was generated by condensation of 4-chromone and alkylhydrazine. Among the analogs, 13b and 14a showed stronger inhibitory activities with IC50 values of 8.9 and 1.2 µM, respectively, than honokiol.Graphical abstractGraphical abstract for this article
       
  • Synthesis and biological activities evaluation of sanjuanolide and its
           analogues
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Jiadai Zhai, Lin Fu, Yuanyuan Li, Rui Zhao, Rui Wang, Hongkuan Deng, Hongliang Liu, Ling Kong, Zhiwei Chen, Feng Sang Sanjuanolide, psorachalcone A and its seven new analogues were synthesized via a combinatorial strategy by aldol reaction. In order to investigate the effect between electron density in π-conjugated systems and biological activities, several electron-withdrawing and electron-donating groups were introduced at C-4 and the phenolic hydroxyl groups of sanjuanolide. The two natural products and its seven new analogues were investigated for their inhibitory effects against five cancer cell lines. Moreover, the hydroxyisoprenyl group may be important to maintain the biological activities of sanjuanolide.Graphical abstractGraphical abstract for this article
       
  • A carbapenem-based fluorescence assay for the screening of
           metallo-β-lactamase inhibitors
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Xiana Qian, Shuangzhan Zhang, Shuyuan Xue, Wuyu Mao, Minqiu Xu, Weipan Xu, Hexin Xie Reported herein is a fluorescence assay for the rapid screening of metallo-β-lactamase (MBL) inhibitors. This assay employs a fluorogenic carbapenem CPC-1 as substrate and is compatible with all MBLs, including B1, B2 and B3 subclass MBLs. The efficiency of this assay was demonstrated by the rapid inhibition screening of a number of molecules against B2 MBL CphA and 2,3-dimercaprol was identified as a potent CphA inhibitor.Graphical abstractGraphical abstract for this article
       
  • Identification of novel triazole inhibitors of Wnt/β-catenin signaling
           based on the Niclosamide chemotype
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Robert A. Mook, Jiangbo Wang, Xiu-Rong Ren, Hailan Piao, H. Kim Lyerly, Wei Chen Dysregulation of the Wnt signaling pathway is an underlying mechanism in multiple diseases, particularly in cancer. Until recently, identifying agents that target this pathway has been difficult and as a result, no approved drugs exist that specifically target this pathway. We reported previously that the anthelmintic drug Niclosamide inhibits the Wnt/β-catenin signaling pathway and suppresses colorectal cancer cell growth in vitro and in vivo. In an effort to build on this finding, we sought to discover new Wnt/β-catenin inhibitors that expanded the chemotype structural diversity. Here, we asked a specific SAR question unresolved in previous SAR studies of Niclosamide’s inhibition of Wnt/β-catenin signaling to identify a new structural class of Wnt/β-catenin signaling inhibitors based on a triazole motif. Similar to Niclosamide, we found that the new triazole derivatives internalized Frizzled-1 GFP receptors, inhibited Wnt/β-catenin signaling in the TOPflash assay and reduced Wnt/β-catenin target gene levels in CRC cells harboring mutations in the Wnt pathway. Moreover, in pilot SAR studies, we found the Wnt/β-catenin SAR trends in the anilide region were generally similar between the two chemical classes of inhibitors. Overall, these studies demonstrate the ability to use the SAR of the Niclosamide salicylanilide chemical class to expand the structural diversity of Wnt/β-catenin inhibitors.Graphical abstractGraphical abstract for this article
       
  • Resorcinol alkyl glucosides as potent tyrosinase inhibitors
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Wakana Ishioka, Sayaka Oonuki, Takehiro Iwadate, Ken-ichi Nihei Resorcinol alkyl glucosides 7–12 were developed as novel tyrosinase inhibitors based on the structure of rhododendrin. These were synthesized from 2,4-dibenzyloxybenzaldehyde using either the Wittig or the Horner-Wadsworth-Emmons reaction with Koenigs-Knorr glycosylation as key steps. The tyrosinase inhibitory activity of 7–12 increased with the length of the alkyl spacer between resorcinol and glucose. The 50% inhibitory concentration (IC50) of tetradecyl derivative 12 was 0.39 μM, making it the most potent of the compounds synthesized. The IC50 of 8 (3.62 μM) with a propyl spacer was ca 10 times that of 7 (35.9 μM) with an ethyl spacer. This significant activity difference suggests that an interaction between resorcinol alkyl glucoside and tyrosinase may increase remarkably if the length of the alkyl spacer exceeds C3.Graphical abstractGraphical abstract for this article
       
  • Synthesis and biological evaluation of clovamide analogues with catechol
           
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Jia-Hao Feng, Xiao-Long Hu, Xian-Yu Lv, Bao-Lin Wang, Jun Lin, Xiao-Qi Zhang, Wen-Cai Ye, Fei Xiong, Hao Wang •In this study, seven clovamide analogues (1–7) were designed and synthesized, and the neuroprotection of 1–7 as well as 8–15 (prepared in our previous work) against H2O2-induced oxidative stress was evaluated in SH-SY5Y cells. Results showed that 1–7 with catechol groups exhibited better neuroprotective effects than 8–15, and their EC50 values ranged from 4.26 to 23.83 μM, especially 1, indicating that the moiety of catechol governed the activities of these compounds. Furthermore, oral administration of 1 (10 or 20 mg/kg) was demonstrated to possess anti-PD effect through alleviating apoptosis and oxidative stress in vitro and in vivo, and to up-regulate the expression of heme oxygenase-1 (HO-1) via PI3K/AKT/mTOR pathway. Finally, the pharmacokinetic (PK) assessment of 1 was determined in rats. These findings suggested that 1 might be an effective candidate for PD therapy.Graphical abstractGraphical abstract for this article
       
  • On the origin of the 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate
           scaffold’s unique group II selectivity for the mGlu receptors
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Junliang Hao, Qi Chen Analogs based on the 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate scaffold showed high potency and selectivity as both group II mGlu receptors orthosteric agonists and antagonists. This scaffold was initially designed to mimic the fully extended glutamate backbone conformation that was hypothesized to be the active conformation for the group II mGlu receptors. With the availability of crystal structures of l-Glu-bound amino terminal domain proteins from multiple mGlu receptor subtypes spanning all three subgroups, a new steric hindrance hypothesis was proposed to account for the scaffold’s unique group II selectivity that explores the subtle distance differences between the α-carbon of l-Glu and the center of the tyrosine phenyl ring from the bottom lobe (e.g. Y216 of mGlu2).Graphical abstractGraphical abstract for this article
       
  • Discovery of novel pyruvate dehydrogenase kinases inhibitors by screening
           of an in-house small molecule library for anti-lung cancer therapeutics
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Fuyun Guo, Shufen Zhao, Xiao'e Li Pyruvate dehydrogenase kinases (PDKs) are widely over-expressed in various human solid cancers, making them attractive therapeutic targets for cancer treatment. Herein, we report the identification of structurally novel PDKs inhibitors by screening of an in-house small molecule library. Biochemical assay indicated that the identified compounds 1–4 inhibited PDK1 activity with EC50 values of 0.50, 1.99, 4.64, and 0.42 µM, respectively. The ITC analysis suggested that the identified compounds 1–4 were pan-isoform PDK inhibitors, which bound to and inhibited the four PDK isoforms. Moreover, 1–4 dose-dependently reduced pyruvate dehydrogenase complex phosphorylation in NCI-H1975 cell. Molecular docking suggested that the most potent compound 4 docked well in the ATP binding pocket of the four PDK isoforms, forming direct hydrogen bond interactions with the conserved amino acids Thr and Asp in ATP binding pocket of PDKs. The cell viability assay demonstrated that 4 potently blocked NCI-H1975 cell proliferation (IC50 = 3.32 µM), but had little effect on human normal lung cell MRC-5 even with the tested concentration up to 40 µM. All the data demonstrated that 4 was a promising lead for the development of structurally novel PDKs inhibitor for the cancer treatment.Graphical abstractGraphical abstract for this article
       
  • Synthesis and biological evaluation of
           1H-pyrrolo[2,3-d]pyrimidine-1,2,3-triazole derivatives as novel
           anti-tubercular agents
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Kasa Shiva Raju, Sandeep AnkiReddy, Gowravaram Sabitha, Vagolu Siva Krishna, Dharmarajan Sriram, Kunduru Bharathi Reddy, Someswar Rao Sagurthi A series of novel 1H-pyrrolo[2,3-d]pyrimidine-1,2,3-triazole derivatives have been synthesized in good to excellent yields. Through the copper-catalyzed azide-alkyne cycloaddition via reaction of 7-(prop-2-ynyl)-7H-pyrrolo[2,3-d]pyrimidine and aryl, heteroaryl and alkyl azides in the presence of CuSO4·5H2O and sodium ascorbate. These compounds were evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv strain. Most of these pyrrolopyrimidine-triazole hybrids exhibited good anti tubercular activity. The antimycobacterial assay results showed that the minimum inhibitory concentration of compounds 4q and 4r were 0.78 µg/mL. The molecular docking results also had shown highest Moldock score for same compounds. These novel compounds exhibited good inhibition activities and further structure-activity studies of the derivatives had shown promising features to use in antitubercular therapy.Graphical abstractGraphical abstract for this article
       
  • A thiol-inducible and quick-response DNA cross-linking agent
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Yuanzhen Xu, Hongbo Wei, Jianjun Chen, Kun Gao Three new 2,4-dinitrobenzenesulfonyl derivatives 1–3 were successfully prepared for the first time using a simple process. They were efficiently triggered by thiols (glutathione and l-cysteine) to release the corresponding phenol derivatives (4–6) within 5 min. The quick response of 1–3 toward thiols was determined by 1H NMR and HPLC. Moreover, our results indicated that 1 could induce DNA cross-linking in the presence of glutathione, probably due to the quinone methide formation of phenol intermediate 4 followed by departure of 2,4-dinitrobenzenesulfonyl group.Graphical abstractGraphical abstract for this article
       
  • Synthesis and evaluation of biological activity for dual-acting
           antibiotics on the basis of azithromycin and glycopeptides
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Anna N. Tevyashova, Elena N. Bychkova, Alexander M. Korolev, Elena B. Isakova, Elena P. Mirchink, Ilya A. Osterman, Réka Erdei, Zsolt Szücs, Gyula Batta One of the promising directions of the combined approach is the design of dual-acting antibiotics – heterodimeric structures on the basis of antimicrobial agents of different classes. In this study a novel series of azithromycin-glycopeptide conjugates were designed and synthesized. The structures of the obtained compounds were confirmed using NMR spectroscopy and mass spectrometry data including MS/MS analysis. All novel hybrid antibiotics were found to be either as active as azithromycin and vancomycin against Gram-positive bacterial strains or have superior activity in comparison with their parent antibiotics. One compound, eremomycin-azithromycin conjugate 16, demonstrated moderate activity against Enterococcus faecium and Enterococcus faecalis strains resistant to vancomycin, and equal to vancomycin’s activity for the treatment of mice with Staphylococcus aureus sepsis.Graphical abstractGraphical abstract for this article
       
  • Synthesis and evaluation of thieno[3,2-d]pyrimidine derivatives
           as novel FMS inhibitors
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Yu-Yon Kim, Jaeyul Choi, Kyungjin Choi, Changhee Park, Young Hoon Kim, Kwee Hyun Suh, Young Jin Ham, Sun Young Jang, Kyu-Hang Lee, Kwang Woo Hwang Colony stimulating factor-1 receptor (CSF-1R or FMS) and it ligand, CSF-1, signaling regulates the differentiation and function of tumor-associated macrophages (TAMs) that play an important role in tumor progression. Derivatives of thieno[3,2-d]pyrimidine were synthesized and evaluated as kinase inhibitors of FMS. The most representative compound 21 showed strong activity (IC50 = 2 nM) against FMS kinase and served as candidate for proof of concept. Anti-tumor activity alone and/or in combination with paclitaxel was examined via a tumor cell growth inhibition assay and via an in vitro tumor invasion assay using human breast adenocarcinoma cells.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and evaluation of N 2,N 4-diaminoquinazoline based
           inhibitors of phosphodiesterase type 5
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Nattakarn Pobsuk, Tamkeen Urooj Paracha, Nattiya Chaichamnong, Nattapas Salaloy, Praphasri Suphakun, Supa Hannongbua, Kiattawee Choowongkomon, Dumrongsak Pekthong, Krongkarn Chootip, Kornkanok Ingkaninan, M. Paul Gleeson We describe the design, synthesis and evaluation of a series of N2,N4-diaminoquinazoline analogs as PDE5 inhibitors. Twenty compounds were prepared and these were assessed in terms of their PDE5 and PDE6 activity, ex-vivo vasodilation response, mammalian cytotoxicity and aqueous solubility. Molecular docking was used to determine the binding mode of the series and this was demonstrated to be consistent with the observed SAR. Compound 15 was the most active PDE5 inhibitor (IC50 = 0.072 ± 0.008 µM) and exhibited 4.6-fold selectivity over PDE6. Ex-vivo assessment of 15 and 22 in a rat pulmonary artery vasodilation model demonstrated EC50s of 1.63 ± 0.72 µM and 2.28 ± 0.74 µM respectively.Graphical abstractGraphical abstract for this article
       
  • Identification of potent bovine viral diarrhea virus inhibitors by a
           structure-based virtual screening approach
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Eliana F. Castro, Juan J. Casal, María J. España de Marco, Leandro Battini, Matías Fabiani, Gabriela A. Fernández, Ana M. Bruno, Lucía V. Cavallaro, Mariela Bollini Bovine viral diarrhea virus (BVDV) is a pestivirus whose infection in cattle is globally distributed. The use of antivirals could complement vaccination as a tool of control and reduce economic losses. The RNA-dependent RNA polymerase (RdRp) of the virus is essential for its genome replication and constitutes an attractive target for the identification of antivirals. With the aim of obtaining selective BVDV inhibitors, the crystal structure of BVDV RdRp was used to perform a virtual screening. Approximately 15,000 small molecules from commercial and in-house databases were evaluated and several structurally different compounds were tested in vitro for antiviral activity. Interestingly, of twelve evaluated compounds, five were active and displayed EC50 values in the sub and low-micromolar range. Time of drug addition experiment and measured intracellular BVDV RNA showed that compound 7 act during RNA synthesis. Molecular Dynamics and MM/PBSA calculation were done to characterize the interaction of the most active compounds with RdRp, which will allow future ligand optimization. These studies highlight the use of in silico screening to identify a new class of BVDV inhibitors.Graphical abstractGraphical abstract for this article
       
  • Triazolopyrimidine and triazolopyridine scaffolds as TDP2 inhibitors
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Carlos J.A. Ribeiro, Jayakanth Kankanala, Jiashu Xie, Jessica Williams, Hideki Aihara, Zhengqiang Wang Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs topoisomerase II (TOP2) mediated DNA damages and causes cellular resistance to clinically used TOP2 poisons. Inhibiting TDP2 can potentially sensitize cancer cells toward TOP2 poisons. Commercial compound P10A10, to which the structure was assigned as 7-phenyl triazolopyrimidine analogue 6a, was previously identified as a TDP2 inhibitor hit in our virtual and fluorescence-based biochemical screening campaign. We report herein that the hit validation through resynthesis and structure elucidation revealed the correct structure of P10A10 (Chembridge ID 7236827) to be the 5-phenyl triazolopyrimidine regioisomer 7a. Subsequent structure–activity relationship (SAR) via the synthesis of a total of 47 analogues of both the 5-phenyl triazolopyrimidine scaffold (7) and its bioisosteric triazolopyridine scaffold (17) identified four derivatives (7a, 17a, 17e, and 17z) with significant TDP2 inhibition (IC50 
       
  • Sanguiin H-11 from Sanguisorbae radix protects HT22 murine hippocampal
           cells against glutamate-induced death
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Ji Hoon Song, Song-Yi Kim, Gwi Seo Hwang, Youn-Sub Kim, Hyun Young Kim, Ki Sung Kang Excessive glutamate level induces neuronal death in acute brain injuries and chronic neurodegenerative diseases. Natural compounds from medicinal and food plants have been attracting interest as a treatment for neurological disorders. Sanguiin H-11 (SH-11), a hydrolysable ellagitannin, inhibits neutrophil movement and nitric oxide -production. However, its neuroprotective effect has not been studied. Therefore, the present study examined the protective effect of SH-11 from Sanguisorbae radix and its mechanism against glutamate-induced death in HT22 cells. Our results showed that SH-11 possessed a strong antioxidant activity and prevented glutamate-induced death in HT22 cells. As a strong antioxidant, SH-11 significantly reduced glutamate-induced increases in intracellular reactive oxygen species accumulation and calcium ion influx. Western blotting analysis showed that glutamate-induced phosphorylation of mitogen-activated protein kinases (MAPKs), including extracellular signal-related kinases 1/2, c-Jun N-terminal kinase, and p38, was significantly decreased by SH-11. Furthermore, SH-11 significantly decreased the number of annexin V-positive HT22 cells, which is indicating apoptotic cell death. In conclusion, our results suggested that SH-11 exerted a potent neuroprotective activity against glutamate-mediated apoptotic cell death by inhibiting oxidative stress-mediated MAPK activation.Graphical abstractGraphical abstract for this article
       
  • Diversity-oriented synthesis of bicyclic fragments containing privileged
           azines
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Nicola Luise, Paul G. Wyatt An innovative and efficient reagent- and scaffold-based diversity oriented synthesis (DOS) of a fragment set was developed for fragment-based drug discovery (FBDD) programs. Twelve diverse, functionalized and bicyclic scaffolds were rapidly accessed by adopting a convenient synthetic toolkit around three privileged azine cores in order to effectively modulate biomolecules. These structures are characterized by both key motifs for interacting with diverse biological targets via hydrogen bonds and useful points of growth for subsequent fragment optimization.Graphical abstractGraphical abstract for this article
       
  • BH3 mimetics derived from Bim-BH3 domain core region show PTP1B inhibitory
           activity
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Xiao Lu, Lijuan Wu, Xiaochun Liu, Shulin Wang, Chuanliang Zhang A series of our previously described BH3 peptide mimetics derived from Bim-BH3 domain core region were found to exhibit weak to potent PTP1B binding affinity and inhibitory activities via target-based drug screening. Among these compounds, a 12-aa Bim-BH3 core sequence peptide conjugated to palmitic acid (SM-6) displayed good PTP1B binding affinity (KD = 8.38 nmol/L), inhibitory activity (IC50 = 1.20 μmol/L) and selectivity against other PTPs (TCPTP, LAR, SHP-1 and SHP-2). Furthermore, SM-6 promoted HepG2 cell glucose uptake and inhibited the expression of PTP1B, indicating that SM-6 could improve the insulin resistance effect in the insulin-resistant HepG2 cell model. These results may indicate a new direction for the application of BH3 peptide mimetics and promising PTP1B peptide inhibitors could be designed and developed based on SM-6.Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC continued
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s):
       
  • Synthesis and antitumor activity of biotinylated camptothecin derivatives
           as potent cytotoxic agents
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Cheng-Ting Zi, Liu Yang, Feng-Qing Xu, Fa-Wu Dong, Rui-Jing Ma, Yan Li, Jun Zhou, Zhong-Tao Ding, Zi-Hua Jiang, Jiang-Miao Hu A series of biotinylated camptothecin derivatives were designed and synthesized. The key to the synthesis was achieved by employing an esterification reaction and click chemistry. All of the new derivatives were tested for cytotoxicity against five human tumor cell lines, including HL-60, SMMC-7721, A-549, MCF-7, and SW480 with IC50 values ranging from 0.13 to 21.53 μM. Most of the derivatives exhibited potent cytotoxicity, especially compound 17 (IC50 = 0.13–3.31 μM) and compound 18 (IC50 = 0.23–1.48 μM), which exhibited the highest potencies. The structure-activity relationships (SARs) of the biotinylated camptothecin derivatives were discussed for exploring novel anticancer agents.Graphical abstractGraphical abstract for this article
       
  • Identification of fluorinated (R)-(−)-aporphine derivatives as potent
           and selective ligands at serotonin 5-HT2C receptor
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Yulong Xu, Anna W. Sromek, John L. Neumeyer A series of novel aporphine derivatives were synthesized for initial screening at the 5-HT2 receptor subtypes. Among them, Compounds 11a and 11b were identified as potent 5-HT2C hit ligands with high selectivity over other 5-HT2 receptor subtypes. Molecular docking study revealed that compounds 11a and 11b formed two key interactions with the binding site of 5-HT2C receptor, including a salt-bridge to D3.32 and a H-bond interaction with N6.55.
       
  • Synthesis and biological evaluation of novel 1-substituted
           3-(3-phenoxyprop-1-yn-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amines as potent
           Bruton's tyrosine kinase (BTK) inhibitors
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Nan Zheng, Qun Hao, Kuaile Lin, Jing Pan, Yingxia Li, Weicheng Zhou A new series of 1-substituted pyrazolopyrimidine derivatives were synthesized as potent BTK inhibitors and they were evaluated by enzyme-based assay and anti-proliferation against multiple B-cell lymphoma cell lines in vitro. Among these compounds, 9h exhibited the highest potency against BTK enzyme, with IC50 value of 4.2 nM. In particular, 8 and 9f performed better inhibition against the proliferation of B lymphoma cell lines DOHH2 and WSU-DLCL2 than the clinical drug ibrutinb. In addition, the test toward the normal PBMC cells showed that 8 possessed low cell cytotoxicity. All these explorations indicated that 8 could serve as a valuable anti-tumor agent for B-cell lymphoblastic leukemia treatment.Graphical abstractGraphical abstract for this article
       
  • Synthesis and evaluation of 2,5-diamino and 2,5-dianilinomethyl pyridine
           analogues as potential CXCR4 antagonists
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Saniya Virani, Zhongxing Liang, Younghyoun Yoon, Hyunsuk Shim, Suazette R. Mooring CXCR4 and its cognate ligand CXCL12 has been linked to various pathways such as cancer metastasis, inflammation, HIV-1 proliferation, and auto-immune diseases. Small molecules have shown potential as CXCR4 inhibitors and modulators, and therefore can mitigate diseases related to the CXCR4-CXCL12 pathway. We have designed and synthesized a series of 2,5-diamino and 2,5-dianilinomethyl pyridine derivatives as potential CXCR4 antagonists. Thirteen compounds have an effective concentration (EC) of 100 nM or less in a binding affinity assay and nine of these have at least 75% inhibition of invasion in Matrigel binding assay. Compounds 3l, 7f, 7j, and 7p show a minimal reduction in inflammation when carrageenan paw edema test is conducted. Overall, these compounds show potential as CXCR4 antagonist.Graphical abstractGraphical abstract for this article
       
  • Prodrugs of the cancer cell selective anti-cancer agent
           (Z)-2-(1H-indol-3-yl)-3-(isoquinolin-5-yl)acrylonitrile (A131) are orally
           efficacious in a mouse model of resistant colon cancer
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Cheng Shang See, Mayumi Kitagawa, Pei-Ju Liao, Kyung Hee Lee, Jasmine Wong, Sang Hyun Lee, Brian W. Dymock A131 (1) possesses a unique cancer cell selective dual mechanism of action where cancer cells are killed but normal cells only undergo growth arrest and are able to regrow after removal of 1. SAR studies of 1 indicate that only the specific structure of 1 elicits the full pharmacological effect. However, application of 1 in mouse models of cancer has been hampered by its low solubility and stability when given orally. In this work we describe the study of various prodrugs based on modification of the indole nitrogen. A range of acyl analogues were prepared as prodrugs which were shown to undergo degradation to the parent drug in plasma. A preferred prodrug fully elicited the pharmacological effects of 1 in cells and led to high aqueous solubility suitable for oral administration. In a mouse model of paclitaxel-resistant colon cancer, compound 10, as a TFA salt, showed 76% tumor growth inhibition when administered at an oral dose of 80 mg/kg twice a day.Graphical abstractGraphical abstract for this article
       
  • 5-Substituted-N-pyridazinylbenzamides as potent and selective LRRK2
           inhibitors: Improved brain unbound fraction enables efficacy
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Xiao Ding, Luigi Piero Stasi, Xuedong Dai, Kai Long, Cheng Peng, Baowei Zhao, Hailong Wang, Changhui Sun, Huan Hu, Zehong Wan, Karamjit S. Jandu, Oliver J. Philps, Yan Chen, Lizhen Wang, Qian Liu, Colin Edge, Yi Li, Kelly Dong, Xiaoming Guan, F. David Tattersall We describe the discovery and optimization of 5-substituted-N-pyridazinylbenzamide derivatives as potent and selective LRRK2 inhibitors. Extensive SAR studies led to the identification of compounds 18 and 23, which demonstrated good in vitro pharmacokinetic profile and excellent selectivity over 140 other kinases. Both compounds demonstrated high unbound fractions in both blood and brain. Compound 18 proved to be brain penetrant, and the high unbound fraction of compound 18 in brain enabled its in vivo efficacy in CNS, wherein a significant inhibition of LRRK2 Ser935 phosphorylation was observed in rat brain following intravenous infusion at 5 mg/kg/h.Graphical abstractGraphical abstract for this article
       
  • Diarylcarbonates are a new class of deubiquitinating enzyme inhibitor
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Marcus J.C. Long, Ann P. Lawson, Rick Baggio, Yu Qian, Lior Rozhansky, Domenico Fasci, Farid El Oualid, Eranthie Weerapana, Lizbeth Hedstrom Promiscuous inhibitors of tyrosine protein kinases, proteases and phosphatases are useful reagents for probing regulatory pathways and stabilizing lysates as well as starting points for the design of more selective agents. Ubiquitination regulates many critical cellular processes, and promiscuous inhibitors of deubiquitinases (DUBs) would be similarly valuable. The currently available promiscuous DUB inhibitors are highly reactive electrophilic compounds that can crosslink proteins. Herein we introduce diarylcarbonate esters as a novel class of promiscuous DUB inhibitors that do not have the liabilities associated with the previously reported compounds. Diarylcarbonates stabilize the high molecular weight ubiquitin pools in cells and lysates. They also elicit cellular phenotypes associated with DUB inhibition, demonstrating their utility in ubiquitin discovery. Diarylcarbonates may also be a useful scaffold for the development of specific DUB inhibitors.Graphical abstractGraphical abstract for this article
       
  • Practical one-step glucuronidation via biotransformation
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Takashi Ohnuki, Masahiko Ejiri, Masaaki Kizuka, Mie Fujiwara, Takahide Nishi We herein report a practical one-step glucuronidation method by biotransformation using Streptomyces sp. SANK 60895. This novel direct method of biotransformation has been shown to be more practical and scalable for glucuronidation than previously reported chemical and enzymatic procedures given its simplicity, high β-selectivity, cost-effectiveness, and reproducibility. We applied the present method to the synthesis of acyl glucuronide and hydroxy-β-glucuronide of mycophenolic acid and compound 4, respectively. This method was also shown to be applicable to the N-glucuronidation of various compounds.Graphical abstractGraphical abstract for this article
       
  • l-Pro-l-Glu+(GPE)+as+neuroprotective+agents&rft.title=Bioorganic+&+Medicinal+Chemistry+Letters&rft.issn=0960-894X&rft.date=&rft.volume=">Synthesis and biological evaluation of novel analogues of Gly-l-Pro-l-Glu
           (GPE) as neuroprotective agents
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Lisa Marinelli, Erika Fornasari, Antonio Di Stefano, Hasan Turkez, Salvatore Genovese, Francesco Epifano, Giuseppe Di Biase, Erica Costantini, Chiara D'Angelo, Marcella Reale, Ivana Cacciatore This study investigated the anti-inflammatory effects of novel pseudotripeptides (GPE 1–3) as potential candidates to counteract neuroinflammation processes in Alzheimer’s disease.GPE 1–3 pseudotripeptides are synthetic derivatives of Gly-l-Pro-l-Glu (GPE), the N-terminal tripeptide of IGF-1, obtained through the introduction of isosteres of the amidic bond (aminomethylene unit) to increase the metabolic stability of the native tripeptide. The results showed that all synthetic derivatives possessed higher half-lives (t1/2 > 4 h) than GPE (t1/2 = 30 min) in human plasma and had good water solubility. The biological results demonstrated that GPE 1–3 had protective properties in several experimental models of treated THP-1 cells. Notably, the novel pseudotripeptides influenced inflammatory cytokine expression (IL-1β, IL-18, and TNF-α) in Aβ25–35-, PMA-, and LPS-treated THP-1 cells. In PMA-differentiated THP-1 macrophages, both GPE 1 and GPE 3 reduced the expression levels of all selected cyto-chemokines, even though GPE 3 showed the best neuroprotective properties.Graphical abstractGraphical abstract for this article
       
  • Semi-synthesis and anti-tumor activity of novel 25-OCH3-PPD derivatives
           incorporating aromatic moiety
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Fan-Zhi Qu, Sheng-Nan Xiao, Xu-De Wang, Yan Zhang, Guang-Yue Su, Yu-Qing Zhao Previously we have reported that 25-OCH3-PPD could suppress the reproduction of cancer cells and cause apoptosis without obvious toxicity. Herein, we aimed to enhance its bioactivity by introducing aromatic groups to its dammarane-type skeleton. These synthesized derivatives were tested for their inhibitory activities against five cancer cell lines. Of them, compounds 3a, 14a and 18a had the strongest antiproliferative activities against tumor cells (IC50 
       
  • Bioactive polyoxygenated cembranoids from a novel Hainan chemotype of the
           soft coral Sinularia flexibilis
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Qihao Wu, Xu-Wen Li, Heng Li, Li-Gong Yao, Wei Tang, Ze-Hong Miao, Hong Wang, Yue-Wei Guo Different chemotypes of Sinularia flexibilis exist in the Hainan island. Thus, a collection of this soft coral from a location different from the one of our previous study afforded three novel cembranoid esters featuring a n-butyl alcohol moiety, a structural element rare in natural products of both terrestrial and marine origin. The structures of the new compounds were elucidated by detailed spectroscopic analysis and by the comparison of their spectroscopic data with those reported in the literature. In addition, the absolute stereochemistry of the previously reported diepoxycembrene (9) was first time determined by the X-ray diffraction analysis. In bioassays, compounds 6–8 exhibited strong anti-inflammatory effect with IC50 values of 2.7, 4.7, and 4.2 μM, respectively, whereas compound 5 displayed cytotoxicity against several cancer cells with IC50 values ranging from 8.9 to 27.4 μM. A preliminary structural-activity relationship (SAR) was also described.Graphical abstractGraphical abstract for this article
       
  • Turning natural products into insecticide candidates: Design and
           semisynthesis of novel fraxinellone-based N-(1,3-thiazol-2-yl)carboxamides
           against two crop-threatening insect pests
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Yong Guo, Jiangping Fan, Qian Zhang, Chongnan Bao, Zhiyan Liu, Ruige Yang To improve the insecticidal activities of fraxinellone, two series of fraxinellone-based N-(1,3-thiazol-2-yl)carboxamides containing 25 compounds were prepared by structural modification. Their structures were determined by melting point, optical rotation, IR, 1H NMR and ESI-MS. The steric configurations of compounds 6i, 7d and 7i were unambiguously confirmed by X-ray diffraction further. The bioassay showed that compounds 6b and 6i exhibited more potent larvicidal and growth inhibitory activities against Plutella xylostella Linnaeus and Mythimna separata Walker, respectively. Moreover, compounds 6b and 6i also displayed low cytotoxicity to noncancerous mammalian cells. The structure–activity relationships (SARs) of all target compounds were also observed.Graphical abstractGraphical abstract for this article
       
  • A novel tetrazole analogue of resveratrol is a potent anticancer agent
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Shobanbabu Bommagani, Narsimha Reddy Penthala, Meenakshisundaram Balasubramaniam, Sudhakiranmayi Kuravi, Eloisi Caldas-Lopes, Monica L. Guzman, Ramesh Balusu, Peter A. Crooks A series of novel tetrazole analogues of resveratrol were synthesized and evaluated for their anti-leukemic activity against an extensive panel of human cancer cell lines and against the MV4-11 AML cell line. These molecules were designed as drug-like derivatives of the resveratrol analogue DMU-212 and its cyano derivatives. Four compounds 8g, 8h, 10a and 10b exhibited LD50 values of 4.60 µM, 0.02 µM, 1.46 µM, and 1.08 µM, respectively, against MV4-11 leukemia cells. The most potent compounds, 8h and 10b, were also found to be active against an extensive panel of human hematological and solid tumor cell lines; compound 8h was the most potent compound with GI50 values
       
  • Synthesis, biological evaluation and molecular docking study of
           1,2,3-1H-triazoles having 4H-pyrano[2,3-d]pyrimidine as potential
           Mycobacterium tuberculosis protein tyrosine phosphatase B inhibitors
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Nguyen Dinh Thanh, Do Son Hai, Nguyen Thi Thu Ha, Do Tien Tung, Cao Thi Le, Hoang Thi Kim Van, Vu Ngoc Toan, Duong Ngoc Toan, Le Hai Dang Some heterocycles, namely 2-amino-4H-pyran-3-carbonitriles, were synthesized in a three-component reaction from substituted benzaldehydes, malononitrile, and ethyl acetoacetate. These heterocycles have been converted subsequently into 4H-pyrano[2,3-d]pyrimidine ring by ring-closing reaction with acetic anhydride in the presence of the concentrated sulfuric acid as catalyst. The successive alkylation reaction of lactam NH bond on pyrimidine-4-one ring was carried out using propargylic bromide in dry acetone in the presence of anhydrous potassium carbonate. The click chemistry of 3-propargyl-4H-pyrano[2,3-d]pyrimidine compounds has been accomplished by reaction with tetra-O-acetyl-α-d-glucopyranosyl azide using the metal-organic framework Cu@MOF-5 as a catalyst in absolute ethanol. All the synthesized 1H-1,2,3-triazoles 8a–y were screened for their in vitro Mycobacterium tuberculosis protein tyrosine phosphatase B (MtbPtpB) inhibition. Kinetic studies of the most active compounds 8v, 8x, and 8y showed their competitive inhibition toward the MtbPtpB enzyme. The detailed structure-activity relationship (SAR) in vitro and in silico studies suggested that the interaction of Arg63 amino acids with anion type of para-hydroxyl group via a salt bridge of iminium cation was essential for strong inhibitory activity against MtbPtpB.Graphical abstractGraphical abstract for this article
       
  • Synthesis of 2′-O-(N-methylcarbamoylethyl) 5-methyl-2-thiouridine and
           its application to splice-switching oligonucleotides
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Yoshiaki Masaki, Keishi Yamamoto, Takeshi Inde, Keita Yoshida, Atsuya Maruyama, Tetsuya Nagata, Jun Tanihata, Shin'ichi Takeda, Mitsuo Sekine, Kohji Seio The effect of 2′-O-(N-methylcarbamoyl)ethyl (MCE) modification on splice-switching oligonucleotides (SSO) was systematically evaluated. The incorporation of five MCE nucleotides at the 5′-termini of SSOs effectively improved the splice switching effect. In addition, the incorporation of 2′-O-(N-methylcarbamoylethyl)-5-methyl-2-thiouridine (s2TMCE), a duplex-stabilizing nucleotide with an MCE modification, into SSOs further improved splice switching. These SSOs may be useful for the treatment of genetic diseases associated with splicing errors.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and characterization of novel
           N-heterocyclic-1-benzyl-1H-benzo[d]imidazole-2-amines as selective TRPC5
           inhibitors leading to the identification of the selective compound, AC1903
           
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Swagat H. Sharma, Juan Lorenzo Pablo, Monica Suarez Montesinos, Anna Greka, Corey R. Hopkins The transient receptor potential cation channel 5 (TRPC5) has been previously shown to affect podocyte survival in the kidney. As such, inhibitors of TRPC5 are interesting candidates for the treatment of chronic kidney disease (CKD). Herein, we report the synthesis and biological characterization of a series of N-heterocyclic-1-benzyl-1H-benzo[d]imidazole-2-amines as selective TRPC5 inhibitors. Work reported here evaluates the benzimidazole scaffold and substituents resulting in the discovery of AC1903, a TRPC5 inhibitor that is active in multiple animal models of CKD.Graphical abstractGraphical abstract for this article
       
  • Dual inhibition of Kif15 by oxindole and quinazolinedione chemical probes
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Megan E. Dumas, Geng-Yuan Chen, Nicole D. Kendrick, George Xu, Scott D. Larsen, Somnath Jana, Alex G. Waterson, Joshua A. Bauer, William Hancock, Gary A. Sulikowski, Ryoma Ohi The mitotic spindle is a microtubule-based machine that segregates a replicated set of chromosomes during cell division. Many cancer drugs alter or disrupt the microtubules that form the mitotic spindle. Microtubule-dependent molecular motors that function during mitosis are logical alternative mitotic targets for drug development. Eg5 (Kinesin-5) and Kif15 (Kinesin-12), in particular, are an attractive pair of motor proteins, as they work in concert to drive centrosome separation and promote spindle bipolarity. Furthermore, we hypothesize that the clinical failure of Eg5 inhibitors may be (in part) due to compensation by Kif15. In order to test this idea, we screened a small library of kinase inhibitors and identified GW108X, an oxindole that inhibits Kif15 in vitro. We show that GW108X has a distinct mechanism of action compared with a commercially available Kif15 inhibitor, Kif15-IN-1 and may serve as a lead with which to further develop Kif15 inhibitors as clinically relevant agents.Graphical abstractGraphical abstract for this article
       
  • Ganocapenoids A–D: Four new aromatic meroterpenoids from
           Ganoderma capense
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Guang-Feng Liao, Ze-Hong Wu, Ying Liu, Yong-Ming Yan, Ru-Mei Lu, Yong-Xian Cheng Four new aromatic meroterpenoids, ganocapenoids A–D (1–4), together with twelve known analogues (5–16) were isolated from the fruiting bodies of Ganoderma capense. The structures of new compounds were determined through spectroscopic methods including 1D and 2D NMR and MS analyses. Their absolute configurations were assigned by ECD calculations and specific rotation comparison. The biological activities of these substances toward regulation of lipid metabolism, neurite outgrowth-promoting activity, and AchE inhibition were assessed. Compound 15 was found to be able to block lipid accumulation at a concentration of 20 μM, and compounds 4a, 4b, and 11 show moderate neurite outgrowth-promoting activity at 10 μM, while compounds 3, 6, 11, and 13 exhibit potent AchE inhibition with the IC50 values of 28.6 ± 1.9, 18.7 ± 1.6, 8.2 ± 0.2, 26.0 ± 2.9 μM, respectively.Graphical abstractFour new aromatic meroterpenoids, ganocapenoids A–D (1–4), together with twelve known analogues (5–16) were isolated from the fruiting bodies of Ganoderma capense. Some of them possess moderate biological activities toward regulation of lipid metabolism, neurite outgrowth-promoting activity, and AchE inhibition. Compound 15 was found to be able to significantly reduce lipid accumulation with a dose-dependent response by inhibiting the synthesis of intracellular cholesterol and promoting the efflux of intracellular cholesterol.Graphical abstract for this article
       
  • Identification of 2-(2′-fluoro-[1,1′-biphenyl]-2-yl)acetamide as a
           Sodium Valproate-like broad spectrum anti-epileptic drug candidate
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Tomoyuki Tanaka, Nana Yajima, Tomoko Kiyoshi, Yoshiki Miura, Yoshifumi Inoue, Takuya Nishimaki, Seiji Iwama By further optimizing compound A [2′-fluoro-N-methyl-[1,1′-biphenyl]-2-sulfonamide], we identified DSP-0565 [2-(2′-fluoro-[1,1′-biphenyl]-2-yl)acetamide, 17a] as a strong, broad-spectrum anti-epileptic drug (AED) candidate. Our efforts mainly focused on finding an alternative polar group for the sulfonamide in order to improve ADME profile of compound A including good metabolic stability and no reactive metabolic production. This led to the identification of biphenyl acetamide as a new scaffold for development of broad-spectrum AED candidates. DSP-0565 showed anti-convulsant activity in various models (scPTZ, MES, 6 Hz and amygdala kindling) with good safety margin, and was therefore selected as a clinical candidate.Graphical abstractGraphical abstract for this article
       
  • Erythrofordins D and E, two new cassaine-type diterpenes from
           Erythrophleum suaveolens
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Tanja Grkovic, Jason R. Evans, Rhone K. Akee, Liang Guo, Myrtle Davis, Johnson Jato, Paul G. Grothaus, Michelle Ahalt-Gottholm, Melinda Hollingshead, Jerry M. Collins, David J. Newman, Barry R. O'Keefe Two new cassaine-type diterpenoids, namely erythrofordins D (1) and E (2), sourced from a Cameroon collection of Erythrophleum suaveolens were isolated and assessed for anti-tumor activity. In the NCI-60 cancer cell assay, erythrofordins D (1) and E (2) were found to be cytotoxic in the low micro molar ranges with a mean GI50 value of 2.45 and 0.71 µM, mean TGI value of 9.77 and 2.29 µM, and a mean LC50 of 26.92 and 11.48 µM for 1 and 2 respectively. Using the COMPARE algorithm, the new compounds were found to have similar NCI-60 response profiles to the known cardiac glycosides hyrcanoside and strophanthin. In addition, in an assay examining the viability and contractile function in human cardiomyocytes derived from induced pluripotent stem-cells, erythrofordins showed cardiotoxicity effects at concentrations as low as 0.03 µg/mL.Graphical abstractGraphical abstract for this article
       
  • New approaches for the treatment of Alzheimer’s disease
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s): Paul V. Fish, David Steadman, Elliott D. Bayle, Paul Whiting Alzheimer’s disease (AD) is the most prevalent chronic neurodegenerative disease. Current approved therapies are symptomatic treatments having some effect on cognitive function. Therapies that target β-amyloid (Aβ) have been the focus of efforts to develop a disease modification treatment for AD but these approaches have failed to show any clinical benefit so far. Beyond the ‘Aβ hypothesis’, there are a number of newer approaches to treat AD with neuroinflammation emerging as a very active area of research based on risk gene analysis. This short review will summarize approved drug therapies, recent clinical trials and new approaches for the treatment of AD.Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2Author(s):
       
  • Novel human adenosine receptor antagonists based on the
           7-amino-thiazolo[5,4-d]pyrimidine scaffold. Structural investigations at
           the 2-, 5- and 7- positions to enhance affinity and tune selectivity
    • Abstract: Publication date: Available online 31 December 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Flavia Varano, Daniela Catarzi, Matteo Falsini, Diego Dal Ben, Michela Buccioni, Gabriella Marucci, Rosaria Volpini, Vittoria Colotta This paper describes the synthesis of novel 7-amino-thiazolo[5,4-d]pyrimidines bearing different substituents at positions 2 , 5 and 7 of the thiazolopyrimidine scaffold. The synthesized compounds 2-27 were evaluated in radioligand binding (A1, A2A and A3) and adenylyl cyclase activity (A2B and A2A) assays, in order to evaluate their affinity and potency at human adenosine receptor subtypes. The current study allowed us to support that affinity and selectivity of 7-amino-thiazolo[5,4-d]pyrimidine derivatives towards the adenosine receptor subtypes can be modulated by the nature of the groups attached at positions 2, 5 and 7 of the bicyclic scaffold. To rationalize the hypothetical binding mode of the newly synthesized compounds, we also performed docking calculations in human A2A, A1 and A3 structures.Graphical abstractGraphical abstract for this article
       
  • Fragment splicing-based design, synthesis and safener activity of novel
           substituted phenyl oxazole derivatives
    • Abstract: Publication date: Available online 29 December 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Ying Fu, Dong Zhang, Tao Kang, You-Yuan Guo, Wen-Geng Chen, Shuang Gao, Fei Ye Fragment splicing is a primary strategy in the design and optimization of leading compound toward new skeleton with target bioactivity. Herein a series of novel substituted phenyl oxazole derivatives were designed via fragment analysis and coupling strategy that led to highly potent and bio-selective herbicide safener. The biological tests showed that most of the compounds could enhance the maize growth index, glutathione content and anti-reverse enzyme glutathione S-transferase activity in vivo. The molecular docking model exhibited that the novel compound could compete with chlorsulfuron binding to the herbicide target enzyme, which consequently attained the herbicide detoxification. Especially compound I-f displayed the best activities than commercial safener isoxadifen-ethyl and other compounds. The present work demonstrates that the synthesized compounds could be developed as potential candidates for the discovery of novel herbicide safeners in the future.Graphical abstractGraphical abstract for this article
       
  • lSynthesis and SAR of 5-aryl-furan-2-carboxamide derivatives as potent
           urotensin-II receptor antagonists
    • Abstract: Publication date: Available online 29 December 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Chae Jo Lim, Nam Hui Kim, Hye Jin Park, Byung Ho Lee, Kwang-Seok Oh, Kyu Yang Yi The synthesis and biological evaluation as potential urotensin-II receptor antagonists of a series of 5-arylfuran-2-carboxamide derivatives 1, bearing a 4-(3-chloro-4-(piperidin-4-yloxy)benzyl)piperazin-1-yl group, are described. The results of a systematic SAR investigation of furan-2-carboxamides with C-5 aryl groups possessing a variety of aryl ring substituents led to identification of the 3,4-difluorophenyl analog 1y as a highly potent UT antagonist with an IC50 value of 6 nM. In addition, this substance was found to display high metabolic stability, and low hERG inhibition and cytotoxicity, and to have an acceptable PK profile.Graphical abstractThe synthesis and SAR of 5-arylfuran-2-carboxamide derivatives as urotensin-II receptor antagonists are described.Graphical abstract for this article
       
  • Design, synthesis, and screening of novel ursolic acid derivatives as
           potential anti-cancer agents that target the HIF-1α pathway
    • Abstract: Publication date: Available online 28 December 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Jie Wu, Zhi-Hong Zhang, Lin-Hao Zhang, Xue-Jun Jin, Juan Ma, Hu-Ri Piao The transcription factor hypoxia-inducible factor-1α (HIF-1α) plays an important role in tumor angiogenesis, growth, and metastasis and is recognized as an important potential therapeutic target for cancer. Here, we designed and synthesized three novel series of ursolic acid derivatives containing an aminoguanidine moiety and evaluated them as HIF-1α inhibitors and anti-cancer agents using human cancer cell lines. Most of the compounds exhibited significant inhibition of HIF-1α transcriptional activity, as measured using a Hep3B cell-based luciferase reporter assay. Among these compounds, 7b was the most potent inhibitor of HIF-1α expression under hypoxic conditions (IC50 4.0 µM) and did not display significant cytotoxicity against any cell lines tested. The mechanism of action of 7b was investigated, we found that 7b downregulated HIF-1α protein expression, possibly by suppressing its synthesis, reduced production of vascular endothelial growth factor, and inhibited the proliferation of cancer cells.Graphical abstractThree novel series of ursolic acid derivatives containing an aminoguanidine moietiy were designed, synthesized, and evaluated for anti-tumor activity as HIF-1α inhibitors.Graphical abstract for this article
       
  • Monodisperse oligoethylene glycols modified Camptothecin,
           10-Hydroxycamptothecin and SN38 prodrugs
    • Abstract: Publication date: Available online 27 December 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Tao Deng, Xianglan Mao, Yan Xiao, Zhigang Yang, Xing Zheng, Zhong-Xing Jiang Camptothecin, which represents a class of natural products with high anticancer activity, suffers low water solubility which hampers its clinic application. To address this issue, monodisperse polyethylene glycols were employed to modify this class of natural products, including Camptothecin, 10-Hydroxycamptothecin, and SN38. Through selective modification with a series of monodisperse polyethylene glycols, 31 Camptothecin derivatives, including 9 ethers and 22 carbonates, were prepared using a macrocyclic sulfate-based strategy with high efficacy. Monodisperse polyethylene glycols modification provided the Camptothecin derivatives with high purity and fine-tunable water solubility. Through the physicochemical and biological assays, a few novel prodrugs with good solubility, cytotoxicity, and valuable drug release profile were identified as promising anticancer drug candidates.Graphical abstractGraphical abstract for this article
       
  • Discovery of an isocoumarin analogue that modulates neuronal functions via
           neurotrophin receptor TrkB
    • Abstract: Publication date: Available online 26 December 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Kasireddy Sudarshan, Boda Arun Kumar, Shalini Dogra, Ishani Bose, Prem Narayan Yadav, Indrapal Singh Aidhen Isocoumarins are lactone ring-containing natural products, are quite abundant in microbes and higher plants, and have been shown to exhibit a broad range of pharmacological properties. However, the molecular mechanism or target of this class of molecules is not known. In this study, we have synthesized 14 isocoumarin derivatives and evaluated for their activity at TrkB receptor in transiently transfected HEK293T cells. We identified 8-hydroxy-3-aryl isocoumarin (1) as a high-affinity agonist at the TrkB receptor. We also demonstrated that isocoumarin 1 activated endogenously TrkB receptor in primary cortical neurons and modulated various markers of synaptic plasticity, and increased dendritic arborization. These results indicate therapeutic potential and molecular target of 8-hydroxy-3-aryl isocoumarin 1 for the treatment of various CNS disorders.Graphical abstractGraphical abstract for this article
       
  • Synthesis and tyrosinase inhibitory activities of 4-oxobutanoate
           derivatives of carvacrol and thymol
    • Abstract: Publication date: 1 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 1Author(s): Nicholas Brotzman, Yiming Xu, Allison Graybill, Alexander Cocolas, Andrew Ressler, Navindra P. Seeram, Hang Ma, Geneive E. Henry Carvacrol (1) and thymol (2) were converted to their alkyl 4-oxobutanoate derivatives (7–20) in three steps, and evaluated for tyrosinase inhibitory activity. The compounds showed structure-dependent activity, with all alkyl 4-oxobutanoates, except 7 and 20, showing better inhibitory activity than the precursor 4-oxobutanoic acids (5 and 6). In general, thymol derivatives exhibited a higher percent inhibitory activity than carvacrol derivatives at 500 μM. Derivatives containing three-carbon and four-carbon alkyl groups gave the strongest activity (carvacrol derivatives 9–12, IC50 = 128.8–244.1 μM; thymol derivatives 16–19, IC50 = 102.3–191.4 μM).Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC
    • Abstract: Publication date: 1 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 1Author(s):
       
  • Synthesis, in vitro and in vivo evaluation of 2-aryl-4H-chromene and
           
    • Abstract: Publication date: 1 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 1Author(s): Alexander A. Spasov, Denis A. Babkov, Dmitry V. Osipov, Vladlen G. Klochkov, Diana R. Prilepskaya, Maxim R. Demidov, Vitaly A. Osyanin, Yuri N. Klimochkin Herein we report a study of novel arylchromene derivatives as analogs of naturally occurring flavonoids with prominent α-glucosidase inhibitory properties. Novel inhibitors were identified via simple stepwise in silico screening, efficient synthesis, and biological evaluation. It is shown that 2-aryl-4H-chromene core retains pharmacophore properties while being readily available synthetically. A lead compound identified through screening inhibits yeast α-glucosidase with IC50 of 62.26 µM and prevents postprandial hyperglycemia in rats at 2.2 mg/kg dose.Graphical abstractGraphical abstract for this article
       
  • Discovery of a novel azetidine scaffold for colony stimulating factor-1
           receptor (CSF-1R) Type II inhibitors by the use of docking models
    • Abstract: Publication date: 1 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 1Author(s): Kazutaka Ikegashira, Taku Ikenogami, Takayuki Yamasaki, Yasunori Hase, Takayuki Yamaguchi, Koji Inagaki, Satoki Doi, Tsuyoshi Adachi, Yoshihisa Koga, Hiromasa Hashimoto We report the discovery of a novel azetidine scaffold for colony stimulating factor-1 receptor (CSF-1R) Type II inhibitors by using a structure-based drug design (SBDD) based on a docking model. The work leads to the representative compound 4a with high CSF-1R inhibitory activity (IC50 = 9.1 nM). The obtained crystal structure of an azetidine compound with CSF-1R, which matched our predicted docking model, demonstrates that the azetidine compounds bind to the DFG-out conformation of the protein as a Type II inhibitor.Graphical abstractGraphical abstract for this article
       
  • Vitamin E-inspired multi-scale imaging agent
    • Abstract: Publication date: 1 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 1Author(s): Mikel Ghelfi, Lucas A. Maddalena, Jeffrey A. Stuart, Jeffrey Atkinson, Thad A. Harroun, Drew Marquardt The production and use of multi-modal imaging agents is on the rise. The vast majority of these imaging agents are limited to a single length scale for the agent (e.g. tissues only), which is typically at the organ or tissue scale. This work explores the synthesis of such an imaging agent and discusses the applications of our vitamin E-inspired multi-modal and multi-length scale imaging agents TB-Toc ((S,E)-5,5-difluoro-7-(2-(5-((6-hydroxy-2,5,7,8-tetramethylchroman-2-yl) methyl) thiophen-2-yl) vinyl)-9-methyl-5H-dipyrrolo-[1,2-c:2’,1’-f][1,3,2]diazaborinin-4-ium-5-uide). We investigate the toxicity of TB-Toc along with the starting materials and lipid based delivery vehicle in mouse myoblasts and fibroblasts. Further we investigate the uptake of TB-Toc delivered to cultured cells in both solvent and liposomes. TB-Toc has low toxicity, and no change in cell viability was observed up to concentrations of 10 mM. TB-Toc shows time-dependent cellular uptake that is complete in about 30 min. This work is the first step in demonstrating our vitamin E derivatives are viable multi-modal and length scale diagnostic tools.Graphical abstractGraphical abstract for this article
       
  • Structure-based design and discovery of potent and selective
           lysine-specific demethylase 1 (LSD1) inhibitors
    • Abstract: Publication date: 1 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 1Author(s): Zhe Nie, Lihong Shi, Chon Lai, Christophe Severin, Jiangchun Xu, Joselyn R. Del Rosario, Ryan K. Stansfield, Robert W. Cho, Toufike Kanouni, James M. Veal, Jeffrey A. Stafford, Young K. Chen The histone demethylase LSD1 is a key enzyme in the epigenetic regulation of gene transcription. Here we present our efforts to discover small molecule reversible inhibitors of LSD1 as an attractive approach to treat hematologic malignancies and certain solid tumors. Using structure-based drug design, we designed and synthesized a novel series of heteroaromatic imidazole inhibitors that demonstrate potent inhibition of the demethylase activity and low nanomolar cell-based activity. This novel LSD1 inhibitor series was further optimized by attenuating the hERG inhibition and improving oral bioavailability.Graphical abstractGraphical abstract for this article
       
  • Synthesis, antituberculosis studies and biological evaluation of new
           quinoline derivatives carrying 1,2,4-oxadiazole moiety
    • Abstract: Publication date: 1 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 1Author(s): T.G. Shruthi, Sumesh Eswaran, Prasad Shivarudraiah, Shridhar Narayanan, Sangeetha Subramanian Tuberculosis is the infectious disease caused by mycobacterium tuberculosis (Mtb), responsible for the utmost number of deaths annually across the world. Herein, twenty-one new substituted 1,2,4-oxadiazol-3-ylmethyl-piperazin-1-yl-quinoline derivatives were designed and synthesized through multistep synthesis followed by in vitro evaluation of their antitubercular potential against Mtb WT H37Rv. The compound QD-18 was found to be promising with MIC value of 0.5 µg/ml and QD-19 to QD-21 were also remarkable with MIC value of 0.25 µg/ml. Additionally, we have carried out experiments to confirm the metabolic stability, cytotoxicity and pharmacokinetics of these compounds along with kill kinetics of QD-18. These compounds were found to be orally bioavailable and highly effective. Altogether, these results indicate that QD-18, QD-19, QD-20 and QD-21 are promising lead compounds for the development of a novel chemical class of antitubercular drugs.Graphical abstractA new series of quinoline carrying 1,2,4-oxadiazole moiety have been synthesized and evaluated for their antituberculosis studies. Majority of them showed moderate to good antituberculosis activity.Graphical abstract for this article
       
  • Rotenoisin A is a novel anti-adipogenic compound
    • Abstract: Publication date: 1 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 1Author(s): Hang-Hee Cho, Hyeon Soo Park, Sun-Hee Jang, Chungkil Won, Hong-Duck Kim, Tae Hoon Kim, Jae-Hyeon Cho The purpose of this study was to investigate the mechanisms underlying the inhibitory effects of rotenoisin A on adipogenesis in 3T3-L1 preadipocytes. 3T3-L1 cells were treated with rotenoisin A for 8 days after the induction of differentiation. Oil-red O staining showed that rotenoisin A significantly inhibited DMI-induced lipid accumulation and adipocyte differentiation. We found that rotenoisin A treatment of 3T3-L1 preadipocytes significantly reduced the mRNA and protein levels of the key adipocyte-specific transcription factors C/EBPβ, C/EBPα, and PPARγ and markedly inhibited the expression of fatty acid-binding protein (aP2), fatty acid synthase (FAS), and lipoprotein lipase (LPL). Furthermore, we observed that rotenoisin A substantially increased the phosphorylation of AMP-activated protein kinase (AMPK) and its downstream target phosphorylated acetyl CoA carboxylase (ACC). However, co-treatment with Compound C, an AMPK inhibitor, reversed the rotenoisin A-induced inhibition of the expression of the adipogenic transcription factors C/EBPα and PPARγ and decreased the levels of phosphorylated AMPK in differentiated 3T3-L1 cells. These results demonstrated that the anti-adipogenesis mechanism involves the down-regulation of critical adipogenic transcription factors, including C/EBPβ, C/EBPα, and PPARγ, through activation of the AMPK signaling pathway by rotenoisin A.Graphical abstractGraphical abstract for this article
       
  • Oxidative nucleophilic substitution selectively produces cambinol
           derivatives with antiproliferative activity on bladder cancer cell lines
    • Abstract: Publication date: 1 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 1Author(s): Lorenzo Botta, Silvia Filippi, Bruno Mattia Bizzarri, Roberta Meschini, Manuela Caputo, Luca Proietti-De-Santis, Concetta Iside, Angela Nebbioso, Giampiero Gualandi, Raffaele Saladino Methyltrioxorhenium mediated oxidative addition/elimination nucleophilic substitution yielded alkylamino and arylamino cambinol derivatives characterized by anti-proliferative activity against wild-type and p53 mutated MGH-U1 and RT112 bladder cancer cell lines. Some of the novel compounds showed an activity higher than that of the lead compound. The reaction was highly regioselective, affording for the first time a panel of C-2 cambinol substitution products. Aliphatic primary and secondary amines, and primary aromatic amines, were used as nitrogen centered nucleophiles. Surprisingly, the antiproliferative activity of C-2 substituted cambinol derivatives was not correlated to the induction of p53 protein, as evaluated by the analysis of the cell viability on wild-type and p53 mutated cancer cell lines, and further confirmed by western blot analyses. These data suggest that they exert their antiproliferative activity by a mechanism completely different from cambinol.Graphical abstractGraphical abstract for this article
       
  • Discovery of naldemedine: A potent and orally available opioid receptor
           antagonist for treatment of opioid-induced adverse effects
    • Abstract: Publication date: 1 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 1Author(s): Masanao Inagaki, Masaharu Kume, Yoshinori Tamura, Shinichiro Hara, Yoshihisa Goto, Nobuhiro Haga, Tsuyoshi Hasegawa, Takashi Nakamura, Katsumi Koike, Shuuichi Oonishi, Toshiyuki Kanemasa, Hiroyuki Kai Structure-activity relationship studies of several morphinan derivatives were conducted to obtain dual antagonists for μ- and δ-opioid receptors. We discovered peripherally restricted dual antagonists for μ/δ-opioid receptors as a new chemotype with a morphinan scaffold, which are orally available and do not easily pass the blood–brain barrier. As we expected, some of these compounds inhibit opioid-induced constipation and emesis/vomiting with limited potential to interfere the analgesic effects of morphine. Among them, naldemedine was selected as a potential drug candidate.Graphical abstractGraphical abstract for this article
       
  • Synthesis, biological evaluation and molecular dynamic simulations of
           novel Benzofuran-tetrazole derivatives as potential agents against
           Alzheimer’s disease
    • Abstract: Publication date: 1 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 1Author(s): Pragati Kushwaha, Soobiya Fatima, Akanksha Upadhyay, Sampa Gupta, Sudha Bhagwati, Tanvi Baghel, M.I. Siddiqi, Aamir Nazir, Koneni V. Sashidhara A series of novel Benzofuran-tetrazole derivatives were successfully synthesised by integrating multicomponent Ugi-azide reaction with the molecular hybridization approach. Interestingly, a number of synthesized derivatives (5c, 5d, 5i, 5l, 5q and 5s) exhibited significant reduction of aggregation of “human” amyloid beta peptide, expressing on transgenic Caenorhabditis elegans (C. elegans) strain CL4176. Further, in silico docking results have evidenced the exquisite interaction of active compounds with the help of TcAChE–E2020 complex. These findings underscore the potential of these hybrids as lead molecules against Alzheimers’s disease.Graphical abstractGraphical abstract for this article
       
  • Discovery and SAR studies of novel 2-anilinopyrimidine-based selective
           inhibitors against triple-negative breast cancer cell line MDA-MB-468
    • Abstract: Publication date: 1 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 1Author(s): Jeyun Jo, Sou Hyun Kim, Heegyu Kim, Myeonggyo Jeong, Jae-Hwan Kwak, Young Taek Han, Jee-Yeong Jeong, Young-Suk Jung, Hwayoung Yun Triple-negative breast cancers (TNBCs) are characterized as an invasive and intractable subtype of breast cancers. Overexpression of epidermal growth factor receptor (EGFR) has been considered to be an important target for TNBC therapy, but efficacies of EGFR inhibitors in clinical trials are elusive. In this study, novel series of 2-anilinopyrimidines were synthesized in an effort to identify selective inhibitors against an EGFR-overexpressing TNBC cell line. Biological evaluation demonstrated that compounds 21 and 38, with a 4-methylpiperidine group and a high ClogP value, exhibited good potency and selectivity for the TNBC cell line. This study has provided evidence to support further development of 2-anilinopyrimidine-based TNBC selective inhibitors and investigation of the targets of compounds 21 and 38.Graphical abstractGraphical abstract for this article
       
  • Towards lead compounds as anti-cancer agents via new phaeosphaeride A
           derivatives
    • Abstract: Publication date: 1 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 1Author(s): Victoria V. Abzianidze, Sofya A. Zakharenkova, Natalia I. Moiseeva, Petr P. Beltyukov, Valeriy A. Polukeev, Yaroslav A. Dubrovskii, Victor A. Kuznetsov, Yuri G. Trishin, Jennifer E. Mejia, Alvin A. Holder New derivatives of phaeosphaeride A (PPA) were synthesized and characterized. Anti-tumor studies were carried out on the U937, HCT-116, PC3, MCF-7, A549, К562, NCI-H929, Jurkat, THP-1, RPMI8228 tumor cell lines, and on the HEF cell line. All the compounds synthesized were found to have better efficacy than PPA towards the tumor cell lines mentioned. Compound 6 (IC50 = 0.59 ± 0.27 µM) was observed to be 11 times more active than PPA (IC50 = 6.5 ± 0.30 µM) towards the NCI-H929 cell line, with a therapeutic index of 18. Compound 6 was determined to be over half and 16 times more active than etoposide towards the NCI-H929 (IC50 = 0.9 ± 0.05 µM) and A549 (IC50 = 100 ± 7.0 µM) cell lines, respectively.Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC
    • Abstract: Publication date: 1 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 1Author(s):
       
  • Discovery of covalent enzyme inhibitors using virtual docking of covalent
           fragments
    • Abstract: Publication date: 1 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 1Author(s): Sandipan Roy Chowdhury, Steven Kennedy, Kai Zhu, Rama Mishra, Patrick Chuong, Alyssa-uyen Nguyen, Stefan G. Kathman, Alexander V. Statsyuk Here we present a virtual docking screen of 1648 commercially available covalent fragments, and identified covalent inhibitors of cysteine protease cathepsin L. These inhibitors did not inhibit closely related protease cathepsin B. Thus, we have established virtual docking of covalent fragments as an approach to discover covalent enzyme inhibitors.Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC
    • Abstract: Publication date: 1 January 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 1Author(s):
       
  • The development of myeloperoxidase inhibitors
    • Abstract: Publication date: Available online 15 November 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Semira Galijasevic Myeloperoxidase (MPO), an abundant hemoprotein present in neutrophils and monocytes, plays a significant role in immune surveillance and host defense mechanisms. However, increased MPO activity has been linked to a number of pathologies with compelling evidence in initiation and progression of inflammatory events. As a result, search for active compounds that can efficiently inhibit MPO activity and subsequently decrease inflammatory events has been focus of the current research.This perspective provides an overview of the development of MPO inhibitors, their mechanism of action and the review of molecules that were in clinical trials as promising MPO inhibitors.Graphical abstractGraphical abstract for this article
       
  • Tetradehydrohalicyclamine B, a new proteasome inhibitor from the marine
           sponge Acanthostrongylophora ingens
    • Abstract: Publication date: Available online 14 November 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Hikaru Kato, Ahmed H. El-Desoky, Yuya Takeishi, Tatsuo Nehira, Esther D. Angkouw, Remy E.P. Mangindaan, Nicole J. de Voogd, Sachiko Tsukamoto A new halicyclamine derivative, tetradehydrohalicyclamine B (1), was isolated from the marine sponge Acanthostrongylophora ingens, along with halicyclamine B (2) as proteasome inhibitors. Compound 1 is the second example found to have a pyridinium ring in the halicyclamine family. Although the relative configuration of 2 was previously determined by X-ray crystallographic analysis, here we determined the absolute configuration of 2 by ECD experiment. Compounds 1 and 2 inhibited the constitutive proteasome as well as the immunoproteasome. The inhibitory activities of 2 were 4- to 10-fold more potent than those of 1.Graphical abstractGraphical abstract for this article
       
  • Molecular Features Characterizing Non-peptide Selectivity to the Human B1
           and B2 Bradykinin Receptors
    • Abstract: Publication date: Available online 14 November 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): B. Rasaeifar, C.S. Lupala, P. Gomez-Gutierrez, Juan J. Perez Bradykinin is produced in response to inflammation, trauma, burns, shock, allergy and some cardiovascular diseases. Actions of this peptide are mediated through two different G-protein coupled receptors, named B1 and B2 that have different pharmacological characteristics. The former is up-regulated during inflammation episodes or tissue trauma whereas, the latter is constitutively expressed in a variety of cell types. In a previous work we have characterized the molecular features that explain the observed structure-activity results for both receptors by means of molecular modeling studies, using diverse ligands for both receptors. These results were summarized in the form of two different pharmacophores that provided new insights to be used for the design of novel molecules with antagonistic profile. In the present work, we compare these pharmacophores to understand the features that characterize ligand selectivity to the two bradykinin receptors. The study shows that most of the residues involved in the binding pocket are similar in both receptors and consequently are the pharmacophores obtained. The main difference between the two pharmacophores remains on point #5 that involves a polar moiety for the B1 receptor and an aromatic ring for the B2 receptor. Accordingly, analysis of the prospective bound conformation of several non-selective small molecule ligands of the bradykinin receptors permits to conclude that fulfilment of point#5 is a requirement to produce selective ligands. However, the study also shows that this is a necessary condition only, since ligands need also to be bulky enough to avoid binding to these receptors in diverse poses. These results provide new insights for a better understanding of the molecular features that ligands are required to exhibit to be selective bradykinin ligands.Graphical abstractGraphical abstract for this article
       
  • Development of hydroxamate-based histone deacetylase inhibitors containing
           1,2,4-oxadiazole moiety core with antitumor activities
    • Abstract: Publication date: Available online 14 November 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Feifei Yang, Peipei Shan, Na Zhao, Di Ge, Kongkai Zhu, Cheng-shi Jiang, Peifeng Li, Hua Zhang Histone deacetylases (HDACs) has proved to be promising target for the development of antitumor drugs. In this study, we reported the design and synthesis of a class of novel hydroxamate-based bis-substituted aromatic amide HDAC inhibitors with 1,2,4-oxadiazole core. Most newly synthesized compounds displayed excellent HDAC1 inhibitory effects and significant anti-proliferative activities. Among them, compounds 11a and 11c increased acetylation of histone H3 and H4 in dose-dependent manner. Furthermore, 11a and 11c remarkably induced apoptosis in HepG2 cancer cells. Finally, the high potency of compound 11a was rationalized by molecular docking studies.Graphical abstractGraphical abstract for this article
       
  • Discovery and optimization of 3,4,5-trimethoxyphenyl substituted
           triazolylthioacetamides as potent tubulin polymerization inhibitors
    • Abstract: Publication date: Available online 13 November 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Fang Yang, Cai-Ping He, Peng-Cheng Diao, Kwon Ho Hong, Jin-Jun Rao, Pei-Liang Zhao Based on our previous research, three series of new triazolylthioacetamides possessing 3,4,5-trimethoxyphenyl moiety were synthesized, and evaluated for antiproliferative activities and inhibition of tubulin polymerization. The most promising compounds 8b and 8j demonstrated more significant antiproliferative activities against MCF-7, HeLa, and HT-29 cell lines than our lead compound 6. Moreover, analogues 8f, 8j, and 8o manifested more potent antiproliferative activities against HeLa cell line with IC50 values of 0.04, 0.05 and 0.16 μM, respectively, representing 100-, 82-, and 25-fold improvements of the activity compared to compound 6. Furthermore, the representative compound, 8j, was found to induce significant cell cycle arrest at the G2/M phase in HeLa cell lines via a concentration-dependent manner. Meanwhile, compound 8b exhibited the most potent tubulin polymerization inhibitory activity with an IC50 value of 5.9 μM, which was almost as active as that of CA-4 (IC50 = 4.2 μM). Additionally, molecular docking analysis suggested that 8b formed stable interactions in the colchicine-binding site of tubulin.Graphical abstractGraphical abstract for this article
       
  • Development and characterization of a CNS-penetrant benzhydryl hydroxamic
           acid class IIa histone deacetylase inhibitor
    • Abstract: Publication date: Available online 13 November 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Christopher A. Luckhurst, Omar Aziz, Vahri Beaumont, Roland W. Bürli, Perla Breccia, Michel C. Maillard, Alan F. Haughan, Marieke Lamers, Phil Leonard, Kim L. Matthews, Gilles Raphy, Andrew J. Stott, Ignacio Munoz-Sanjuan, Beth Thomas, Michael Wall, Grant Wishart, Dawn Yates, Celia Dominguez We have identified a potent, cell permeable and CNS penetrant class IIa histone deacetylase (HDAC) inhibitor 22, with>500-fold selectivity over class I HDACs (1,2,3) and ∼150-fold selectivity over HDAC8 and the class IIb HDAC6 isoform. Dose escalation pharmacokinetic analysis demonstrated that upon oral administration, compound 22 can reach exposure levels in mouse plasma, muscle and brain in excess of cellular class IIa HDAC IC50 levels for ∼ 8 h. Given the interest in aberrant class IIa HDAC function for a number of neurodegenerative, neuromuscular, cardiac and oncology indications, compound 22 (also known as CHDI-390576) provides a selective and potent compound to query the role of class IIa HDAC biology, and the impact of class IIa catalytic site occupancy in vitro and in vivo.Graphical abstractGraphical abstract for this article
       
  • Seco-4-methyl-DCK Derivatives as Potent Chemosensitizers
    • Abstract: Publication date: Available online 12 November 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Yalan Guo, Ke Wang, Xiaoyu Chen, Haihong Li, Qi Wan, Susan Morris-Natschke, Kuo-Hsiung Lee, Ying Chen Twenty-five seco-4-methyl-DCK derivatives were designed, synthesized and evaluated for chemoreversal activity when combined with paclitaxel or vincristine in two drug-resistant cancer cell lines (A2780/T and KB-V) respectively. Most of the new compounds displayed moderate to significant MDR reversal activities in the P-gp overexpressing A2780/T and KB-V cells. Especially, compounds 7o and 7y showed the most potent chemosensitization activities with more than 496 and 735 reversal ratios at a concentration of 10 μM. Unexpectedly the newly synthesized compounds did not show chemosensitization activities observed in a non-P-gp overexpressing cisplatin resistant human ovarian cancer cell line (A2780/CDDP), implying that the MDR reversal effects might be associated with P-gp overexpression. Moreover, these compounds did not exhibit significant antiproliferative activities against nontumorigenic cell lines (HUVEC, HOSEC and T29) compared to the positive control verapamil at the tested concentration, which suggested better safety than verapamil. The pharmacological actions of the compounds will be studied further to explore their merit for development as novel candidates to overcome P-gp mediated MDR cancer.Graphical abstractGraphical abstract for this article
       
  • Targeting Tyrosine Kinase: Development of Acridone – Pyrrole –Oxindole
           Hybrids against Human Breast Cancer
    • Abstract: Publication date: Available online 10 November 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Manpreet Kaur, Palwinder Singh Based on the molecular modelling studies, a rational modification of the lead molecule was made to develop highly potent compounds showing anti-cancer activity against human breast cancer cell lines MCF 7, MD-MB-468 and T-47D. The most potent compounds have Log P and total polar surface area 4.4 – 5.4 and 59.8 Å, respectively and they also exhibited promising ADME profile.Graphical abstractGraphical abstract for this article
       
  • Discovery of 4-alkoxy-6-methylpicolinamide negative allosteric modulators
           of metabotropic glutamate receptor subtype 5
    • Abstract: Publication date: Available online 10 November 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Andrew S. Felts, Katrina A. Bollinger, Christopher J. Brassard, Alice L. Rodriguez, Ryan D. Morrison, J. Scott Daniels, Anna L. Blobaum, Colleen M. Niswender, Carrie K. Jones, P. Jeffrey Conn, Kyle A. Emmitte, Craig W. Lindsley This letter describes the further chemical optimization of VU0424238 (auglurant), an mGlu5 NAM clinical candidate that failed in non-human primate (NHP) 28 day toxicology due to accumulation of a species-specific aldehyde oxidase (AO) metabolite of the pyrimidine head group. Here, we excised the pyrimidine moiety, identified the minimum pharmacophore, and then developed a new series of saturated ether head groups that ablated any AO contribution to metabolism. Putative back-up compounds in this novel series provided increased sp3 character, uniform CYP450-mediated metabolism across species, good functional potency and high CNS penetration. Key to the optimization was a combination of matrix and iterative libraries that allowed rapid surveillance of multiple domains of the allosteric ligand.Graphical abstractGraphical abstract for this article
       
  • Novel monoamine oxidase inhibitors based on the privileged 2-imidazoline
           molecular framework
    • Abstract: Publication date: Available online 9 November 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Anton Shetnev, Angelina Osipyan, Sergey Baykov, Alexander Sapegin, Zhanna Chirkova, Michail Korsakov, Anél Petzer, Idalet Engelbrecht, Jacobus P. Petzer Series of structurally diverse 2-imidazoline derivatives have been synthesized by condensation of substituted aldehydes with ethylenediamine, Pd-catalyzed N-arylation of 2-imidazolines and by the formation of 1,2,4-oxadiazoles and benzoxazepines from 2-imidazoline-containing precursors. The 2-imidazoline derivatives were evaluated as potential inhibitors of human monoamine oxidase (MAO) A and B. Among the 2-imidazolines, good potency inhibitors were discovered with compound 9p (IC50 = 0.012 µM) being the most potent MAO-B inhibitor, while compound 9d (IC50 = 0.751 µM) was the most potent MAO-A inhibitor of the series. These potencies are in the same range as those of reference MAO inhibitors used in the clinic. Among 33 compounds evaluated, 13 exhibited IC50 values in the submicromolar range for the inhibition of an MAO isoform. It is postulated that the imidazoline moieties of some of these inhibitors may be recognized by the imidazoline I2-binding site of MAO. Good potency MAO inhibitors may be useful for the treatment of neuropsychiatric and neurodegenerative disorders such as depression and Parkinson’s disease, and future application for the treatment of prostate cancer, congestive heart failure and Alzheimer’s disease. In addition, high potency 2-imidazoline-derived MAO inhibitors may be used as potential probes for the imidazoline binding sites of the MAOs, as well as to determine alternative binding regions of imidazoline within the MAO active site.Graphical abstractGraphical abstract for this article
       
  • Synthesis and Biological Evaluation of Ginsenoside Compound K Analogues as
           a Novel Class of Anti-asthmatic Agents
    • Abstract: Publication date: Available online 9 November 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Sumei Ren, Ruiqi Liu, Yujie Wang, Ning Ding, Yingxia Li Ginsenoside Compound K (CK) showed potent activity against IgE for the treatment of asthma. A series of CK analogues were then synthesized by straightforward procedures. The in vivo anti-IgE activity evaluations using the OVA-induced asthmatic mouse model revealed preliminary SARs of the CK analogues, which showed that the sugar type, modifications on A-ring and the C20 side chain of CK all affected much on the activities. Primary SARs optimization led to the discovery of compounds T1, T2, T3, T8 and T12, which displayed superior or comparable anti-asthmatic effects (IgE value = 1237.11±106.28, 975.82±160.32, 1136.96±121.85, 1191.08±107.59 and 1258.27±148.70 ng/mL, respectively) in comparison with CK (1501.85±184.66 ng/mL). These potent compounds could serve as leads for further development.Graphical abstractGinsenoside Compound K (CK) showed potent activity against IgE for the treatment of asthma. A series of CK analogues were then synthesized by straightforward procedures. The in vivo anti-IgE activity evaluations using the OVA-induced asthmatic mouse model revealed preliminary SARs of the CK analogues, which showed that the sugar type, modifications on A-ring and the C20 side chain of CK all affected much on the activities. Primary SARs optimization led to the discovery of compounds T1, T2, T3, T8 and T12, which displayed superior or comparable anti-asthmatic effects (IgE value = 1237.11±106.28, 975.82±160.32, 1136.96±121.85, 1191.08±107.59 and 1258.27±148.70 ng/mL, respectively) in comparison with CK (1501.85±184.66 ng/mL).Graphical abstract for this article
       
 
 
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