for Journals by Title or ISSN
for Articles by Keywords
help
  Subjects -> CHEMISTRY (Total: 909 journals)
    - ANALYTICAL CHEMISTRY (56 journals)
    - CHEMISTRY (643 journals)
    - CRYSTALLOGRAPHY (21 journals)
    - ELECTROCHEMISTRY (28 journals)
    - INORGANIC CHEMISTRY (43 journals)
    - ORGANIC CHEMISTRY (47 journals)
    - PHYSICAL CHEMISTRY (71 journals)

CHEMISTRY (643 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: 31)
ACS Catalysis     Hybrid Journal   (Followers: 53)
ACS Chemical Neuroscience     Hybrid Journal   (Followers: 23)
ACS Combinatorial Science     Hybrid Journal   (Followers: 23)
ACS Macro Letters     Hybrid Journal   (Followers: 28)
ACS Medicinal Chemistry Letters     Hybrid Journal   (Followers: 44)
ACS Nano     Hybrid Journal   (Followers: 328)
ACS Photonics     Hybrid Journal   (Followers: 15)
ACS Symposium Series     Full-text available via subscription  
ACS Synthetic Biology     Hybrid Journal   (Followers: 25)
Acta Chemica Iasi     Open Access   (Followers: 6)
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: 2)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 8)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 9)
Adsorption Science & Technology     Open Access   (Followers: 7)
Advanced Functional Materials     Hybrid Journal   (Followers: 62)
Advanced Science Focus     Free   (Followers: 5)
Advances in Chemical Engineering and Science     Open Access   (Followers: 77)
Advances in Chemical Science     Open Access   (Followers: 21)
Advances in Chemistry     Open Access   (Followers: 27)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 20)
Advances in Drug Research     Full-text available via subscription   (Followers: 26)
Advances in Environmental Chemistry     Open Access   (Followers: 7)
Advances in Enzyme Research     Open Access   (Followers: 11)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 9)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 17)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 12)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 27)
Advances in Nanoparticles     Open Access   (Followers: 17)
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: 4)
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: 69)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 22)
American Journal of Chemistry     Open Access   (Followers: 34)
American Journal of Plant Physiology     Open Access   (Followers: 13)
American Mineralogist     Hybrid Journal   (Followers: 15)
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: 186)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 274)
Annales Universitatis Mariae Curie-Sklodowska, sectio AA – 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: 15)
Antiviral Chemistry and Chemotherapy     Open Access   (Followers: 2)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 9)
Applied Spectroscopy     Full-text available via subscription   (Followers: 26)
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: 4)
Avances en Quimica     Open Access  
Biochemical Pharmacology     Hybrid Journal   (Followers: 11)
Biochemistry     Hybrid Journal   (Followers: 382)
Biochemistry Insights     Open Access   (Followers: 7)
Biochemistry Research International     Open Access   (Followers: 7)
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: 24)
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: 142)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 93)
Bioorganic Chemistry     Hybrid Journal   (Followers: 10)
Biopolymers     Hybrid Journal   (Followers: 20)
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: 25)
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: 12)
Canadian Mineralogist     Full-text available via subscription   (Followers: 7)
Carbohydrate Research     Hybrid Journal   (Followers: 25)
Carbon     Hybrid Journal   (Followers: 70)
Catalysis for Sustainable Energy     Open Access   (Followers: 10)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 10)
Catalysis Science and Technology     Hybrid Journal   (Followers: 10)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 14)
Cellulose     Hybrid Journal   (Followers: 13)
Cereal Chemistry     Full-text available via subscription   (Followers: 5)
ChemBioEng Reviews     Full-text available via subscription   (Followers: 2)
ChemCatChem     Hybrid Journal   (Followers: 8)
Chemical and Engineering News     Free   (Followers: 23)
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: 28)
Chemical Physics Letters : X     Open Access  
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Hybrid Journal   (Followers: 22)
Chemical Reviews     Hybrid Journal   (Followers: 219)
Chemical Science     Open Access   (Followers: 29)
Chemical Technology     Open Access   (Followers: 36)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 5)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 57)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 21)
ChemInform     Hybrid Journal   (Followers: 8)
Chemistry     Open Access  
Chemistry & Biodiversity     Hybrid Journal   (Followers: 7)
Chemistry & Biology     Full-text available via subscription   (Followers: 33)
Chemistry & Industry     Full-text available via subscription   (Followers: 9)
Chemistry - A European Journal     Hybrid Journal   (Followers: 184)
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: 46)
Chemistry of Materials     Hybrid Journal   (Followers: 281)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 10)
Chemistry World     Full-text available via subscription   (Followers: 21)
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: 3)
Chromatography Research International     Open Access   (Followers: 5)
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: 23)
Comments on Inorganic Chemistry: A Journal of Critical Discussion of the Current Literature     Hybrid Journal   (Followers: 2)
Communications Chemistry     Open Access   (Followers: 2)
Composite Interfaces     Hybrid Journal   (Followers: 7)
Comprehensive Chemical Kinetics     Full-text available via subscription   (Followers: 1)
Comptes Rendus Chimie     Full-text available via subscription  
Comptes Rendus Physique     Full-text available via subscription   (Followers: 1)
Computational and Theoretical Chemistry     Hybrid Journal   (Followers: 9)
Computational Biology and Chemistry     Hybrid Journal   (Followers: 13)
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: 2)
Current Metabolomics     Hybrid Journal   (Followers: 6)
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: 77)
Current Topics in Medicinal Chemistry     Hybrid Journal   (Followers: 9)
Current Trends in Biotechnology and Chemical Research     Open Access   (Followers: 2)
Dalton Transactions     Full-text available via subscription   (Followers: 26)

        1 2 3 4 | Last

Similar Journals
Journal Cover
Bioorganic & Medicinal Chemistry Letters
Journal Prestige (SJR): 0.81
Citation Impact (citeScore): 3
Number of Followers: 93  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0960-894X
Published by Elsevier Homepage  [3160 journals]
  • Synthesis and structure activity relationships of a series of
           4-amino-1H-pyrazoles as covalent inhibitors of CDK14
    • Abstract: Publication date: Available online 23 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Fleur M. Ferguson, Zainab M. Doctor, Scott B. Ficarro, Jarrod A. Marto, Nam Doo Kim, Taebo Sim, Nathanael S. Gray The TAIRE family of kinases are an understudied branch of the CDK kinase family, that have been implicated in a number of cancers. This manuscript describes the design, synthesis and SAR of covalent CDK14 inhibitors, culminating in identification of FMF-04-159-2, a potent, covalent CDK14 inhibitor with a TAIRE kinase biased selectivity profile.Graphical abstractGraphical abstract for this article
       
  • Determining the necessity of phenyl ring π-character in warfarin
    • Abstract: Publication date: Available online 23 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Hui Xing, Sevan D. Houston, Xuejie Chen, Da-Yun Jin, G. Paul Savage, Jian-Ke Tie, Craig M. Williams Despite the difficulty in administering a safe dose regimen and reports of emerging resistance, warfarin (1) remains the most widely-used oral anticoagulant for the prevention and treatment of thrombosis in humans globally. Systematic substitution of the warfarin phenyl ring with either 1,3,5,7-cyclooctatetraene (COT) (2), cubane (3), cyclohexane (4) or cyclooctane (5) and subsequent evaluation against the target enzyme, vitamin K epoxide reductase (VKOR), facilitated interrogation of both steric and electronic properties of the phenyl phar-macophore. The tolerance of VKOR to further functional group modification (carboxylate 14, PTAD adduct 15) was also investigated. The results demonstrate the importance of both annulene conferred π-interactions and ring size in the activity of warfarin.Graphical abstractGraphical abstract for this article
       
  • Chemical Conversion of Nicotinamide into Type I Positive Allosteric
           Modulator of α7 nAChRs
    • Abstract: Publication date: Available online 22 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Xin Li, Wenjun Xie, Xintong Wang, Zongze Huang, Xiling Bian, KeWei Wang, Qi Sun Structural modifications of nicotinamide, a form of vitamin B3, gave rise to a series of compounds (8aa−8ce) that exhibit activities as type I positive allosteric modulators (PAMs) of human α7 nAChR expressed in Xenopus ooctyes in two-electrode voltage clamp assay. The compound 8ai was a potent and efficacious PAM with an EC50 = 3.34 ± 1.13 μM and the maximum activation effect of α7 current over 1474 ± 246% in the presence of acetylcholine (100 μM). It is highly specific to α7 nAChR over other subtypes of nAChR and 5-HT3A receptors. The structure−activity relationship analysis identified a key skeleton of nicotinamide nucleus critical for biological activity. Taken together, the 8ai as a type I PAM of α7 nAChR may be beneficial for improvement of cognitive deficit.Graphical abstractGraphical abstract for this article
       
  • Influence of lysine residue in amphipathic helical peptides on targeted
           delivery of RNA into cancer cells
    • Abstract: Publication date: Available online 21 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Shun-ichi Wada, Kohei Taniguchi, Hiroaki Hamazaki, Azusa Yamada, Junsuke Hayashi, Kazuhisa Uchiyama, Hidehito Urata The cRGD-conjugated Aib-containing amphipathic helical peptide, MAP(Aib) derivative (PI), has been reported to be a useful carrier for siRNA delivery into cells. We have conducted a series of structure-activity relationship studies of the influence of the balance between hydrophobicity and basicity on the amphipathicity of PI, and synthesized peptides having a larger number of Lys residues than PI. Increasing the number of basic residues in the amphipathic helix suppressed the ability to deliver siRNA into cells. It was concluded that the balance between hydrophobicity and basicity in the PI helix was important for siRNA delivery into cells. Furthermore, the siRNA delivering ability of PI was specific to cancer cells, such as A549, U-87 MG, and WiDr cells, and was low in normal cells, namely, NIH3T3 cells. Next, we examined the potential of PI as a carrier for the delivery of microRNA-133b (miR-133b), which is known to be an anti-oncomiR. PI enhanced the delivery of miR-133b into WiDr cells, which resulted in the suppression of endogenous protein expression.Graphical abstractGraphical abstract for this article
       
  • Biocompatible G-Quadruplex/BODIPY assembly for cancer cell imaging and the
           attenuation of mitochondria
    • Abstract: Publication date: Available online 21 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Peng-Li Zhang, Zhuo-Kai Wang, Qiu-Yun Chen, Xia Du, Jing Gao The G-quadruplex aptamer is a high-order structure formed by folding of guanine-rich DNA or RNA. The recognition and assembly of G-quadruplex and compounds are important to find biocompatible drugs. Herein, triphenylamine conjugated 4, 4-difluoro-4-bora-3a, 4a-diaza-s-indacene (BODIPY) compound (BPTPA) was synthesized, and the interaction of BPTPA with G4 DNA was studied. It is found that BPTPA selectively binds with G3T3 G4 DNA forming a water-compatible nanocomplex (BPTPA-G3T3). BPTPA-G3T3 can image mitochondria and inhibit the expression of TrxR2. Cytotoxicity results indicate BPTPA-G3T3 can decrease the membrane potential of mitochondria and inhibit the proliferation of BGC-823 cancer cells. Therefore, BPTPA-G3T3 can be the biocompatible attenuator of mitochondria for cancer image and chemotherapy.Graphical abstractGraphical abstract for this article
       
  • Discovery of conolidine derivative DS39201083 as a potent novel analgesic
           without mu opioid agonist activity
    • Abstract: Publication date: Available online 21 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Tsuyoshi Arita, Masayoshi Asano, Kazufumi Kubota, Yuki Domon, Nobuo Machinaga, Kousei Shimada We discovered a novel compound, 5-methyl-1,4,5,7-tetrahydro-2,5-ethanoazocino[4,3-b]indol-6(3H)-one sulfuric acid salt (DS39201083), which was formed by derivatization of a natural product, conolidine. DS39201083 had a unique bicyclic skeleton and was a more potent analgesic than conolidine, as revealed in the acetic acid-induced writhing test and formalin test in ddY mice. The compound showed no agonist activity at the mu opioid receptor.Graphical abstractGraphical abstract for this article
       
  • Anti-HAV evaluation and molecular docking of newly synthesized
           3-benzyl(phenethyl)benzo[g]quinazolines
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 13Author(s): Rashad Al-Salahi, El Hassane Anouar, Mohamed Marzouk, Hatem A. Abuelizz Synthesized 3-benzyl(phenethyl)benzo[g]quinazolines (1–17) were evaluated in vitro to determine their effects against the anti-hepatitis A virus (HAV) using a cytopathic effect inhibition assay. Of the synthesized compounds, 16 and 17 showed considerably high anti-HAV activity, as indicated by their EC50 values of 27.59 and 18 μM, respectively, when compared to that of amantadine (37.3 μM), the standard therapeutic agent. In addition, they exhibited low cytotoxicity as indicated by their CC50 values, 290.63 and 569.45 μM, respectively. Compounds 1, 2, and 5 exhibited remarkable activity compared to the active compounds (16, 17) and amantadine. The selectivity index (SI) values were calculated and applied as a parameter for classifying the activity of the targets. In addition, molecular docking was performed to rationalize the SAR of the target compounds and analyze the binding modes between the docked-selected compounds and amino acid residues in the active site of the HAV-3C proteinase enzyme.Graphical abstractThe target 3-benzyl(phenethyl)benzo[g]quinazolines (16, 17) showed considerably high anti-HAV activity, as indicated by their EC50 values of 27.59 and 18 μM, in relation to amantadine (37.3 μM). This finding suggests that the hydrazine functionality of 16 and 17 could sufficiently display low intrinsic reactivity with the HAV-3C proteinase active site or possess the potential for binding to active site residues of the enzyme.Graphical abstract for this article
       
  • Graphical abstract TOC
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 13Author(s):
       
  • Ultrasonication-ionic liquid synergy for the synthesis of new potent
           anti-tuberculosis 1,2,4-triazol-1-yl-pyrazole based
           spirooxindolopyrrolizidines
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 13Author(s): Vinay Pogaku, Vagolu Siva Krishna, Dharmarajan Sriram, Krishnan Rangan, Srinivas Basavoju The aim of the study is to design and synthesis of a new series of potent anti-TB 1,2,4-triazol-1-yl-pyrazole based spirooxindolopyrrolizidines with their safety profile. A synergetic effect of ultrasonication and ionic liquid was shown successfully as a green methodology for the synthesis of title compounds 6a–t. These derivatives were obtained in shorter reaction time with good yields and well characterized by various spectroscopic methods, single-crystal X-ray diffraction (6f). The in vitro anti-tuberculosis activity for newly-synthesized derivatives has been screened against Mycobacterium tuberculosis. Among all, six compounds 6e, 6k, 6l, 6n, 6q and 6r exhibited equal potent activity compared to standard drug ethambutol (MIC: 1.56 µg/mL) and another compound 6h exhibited outstanding activity (MIC: 0.78 µg/mL) than the standard drug ethambutol. Cytotoxic nature of the anti-TB active compounds was evaluated against RAW 264.7 cells. The 6h, 6e, 6k, 6l, 6n, 6q and 6r exhibited lower toxicity which could be promising hits for anti-tuberculosis.Graphical abstractGraphical abstract for this article
       
  • 2-Pyridineformamide N(4)-ring incorporated thiosemicarbazones inhibit
           MCF-7 cells by inhibiting JNK pathway
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 13Author(s): Bhushan Shakya, Nerina Shahi, Faiz Ahmad, Paras Nath Yadav, Yub Raj Pokharel In an effort to develop a more potent anticancer therapeutic agent, a series of 2-pyridineformamide thiosemicarbazones (R = H, 4-CH3, 5-F, 6-CH3 and Graphical abstract for this article Graphical abstract for this article) have been synthesized and evaluated for their anti-cancer activities against the cancer cells MCF-7 (breast cancer cell line), A-431 and A375 (epidermoid carcinoma cell line), and HeLa (cervical cancer cell line) using MTT assay. All these 2-pyridineformamide thiosemicarbazones exhibited anti-proliferative activities towards these cell lines. 5FAmPyrr possess most profound effects against MCF-7 cells with IC50 of 0.9 µM. In flow cytometry using Propidium Iodide, 5FAmPyrr was found to induce cell death significantly in a dose dependent manner (100 nM–3 µM) and inhibited colony formation of MCF-7 cells. This compound induced pro-apoptotic protein Bax and inhibited anti apoptotic protein Bcl-2 as well as both c-Jun and Jun N-terminal kinase (abbreviated as JNK) in concentration dependent manner. Further pro-caspase 3 and PARP were inhibited by 5FAmPyrr at concentration of 3 µM. The results suggest that 5FAmPyrr exhibit anticancer potency and induced cell death by inhibiting MAPK signaling and inducing intrinsic apoptotic pathway. All these indicate that 2-pyridineformamide thiosemicarbazones could be developed as future therapeutics agents to treat cancer.Graphical abstract for this articleGraphical abstractGraphical abstract for this article
       
  • Design and synthesis of novel tellurodibenzoic acid compounds as
           kidney-type glutaminase (KGA) inhibitors
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 13Author(s): Wei Hou, Yucheng Zhou, Jingjing Rui, Ruisong Bai, Aman K.K. Bhasin, Benfang Helen Ruan Organotellurium compounds have been reported as an immune-modulator sensitizing chemotherapeutics. Herein, we report the design and synthesis of a series of novel tellurodibenzoic acids as mimics of diphenylarsenic acid (DPAA) and potential selective KGA inhibitors. Representative compound 3B exhibited potent inhibition of KGA and glutamine-dependent HCT-116 cells. Stability experiments indicated that 3B has excellent stability under acidic (HCOOH), basic (NH3·H2O) and oxidative (H2O2) conditions, but reacts with β-ME, DTT and lysine which suggested that compound 3B may interact with cysteine or lysine residues. Moreover, molecular docking disclosed that compound 3B binds to the allosteric site of the GAC tetramer containing Arg317-Lys320-Leu321-Phe322-Tyr394-Glu325, which helped to rationalize the SAR and further design and optimization. Taken together, compound 3B could be used as a starting point for the development of new KGA inhibitors.Graphical abstractGraphical abstract for this article
       
  • Dual-targeting GroEL/ES chaperonin and protein tyrosine phosphatase B
           (PtpB) inhibitors: A polypharmacology strategy for treating Mycobacterium
           tuberculosis infections
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 13Author(s): Alex Washburn, Sanofar Abdeen, Yulia Ovechkina, Anne-Marie Ray, Mckayla Stevens, Siddhi Chitre, Jared Sivinski, Yangshin Park, James Johnson, Quyen Q. Hoang, Eli Chapman, Tanya Parish, Steven M. Johnson Current treatments for Mycobacterium tuberculosis infections require long and complicated regimens that can lead to patient non-compliance, increasing incidences of antibiotic-resistant strains, and lack of efficacy against latent stages of disease. Thus, new therapeutics are needed to improve tuberculosis standard of care. One strategy is to target protein homeostasis pathways by inhibiting molecular chaperones such as GroEL/ES (HSP60/10) chaperonin systems. M. tuberculosis has two GroEL homologs: GroEL1 is not essential but is important for cytokine-dependent granuloma formation, while GroEL2 is essential for survival and likely functions as the canonical housekeeping chaperonin for folding proteins. Another strategy is to target the protein tyrosine phosphatase B (PtpB) virulence factor that M. tuberculosis secretes into host cells to help evade immune responses. In the present study, we have identified a series of GroEL/ES inhibitors that inhibit M. tuberculosis growth in liquid culture and biochemical function of PtpB in vitro. With further optimization, such dual-targeting GroEL/ES and PtpB inhibitors could be effective against all stages of tuberculosis – actively replicating bacteria, bacteria evading host cell immune responses, and granuloma formation in latent disease – which would be a significant advance to augment current therapeutics that primarily target actively replicating bacteria.Graphical abstractGraphical abstract for this article
       
  • Synthesis and SAR development of quinoline analogs as novel P2X7 receptor
           antagonists
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 13Author(s): Yufang Xiao, Srinivasa Karra, Andreas Goutopoulos, Noune Tahmassian Morse, Susan Zhang, Mohanraj Dhanabal, Hui Tian, Jeyaprakashnarayanan Seenisamy, Jayashankaran Jayadevan, Richard Caldwell, Justin Potnick, Matthew Bleich, Eugene Chekler, Brian Sherer, Venkataraman Sriraman The P2X7 receptor (P2X7R) plays an important role in diverse conditions associated with tissue damage and inflammation, suggesting that the human P2X7R (hP2X7R) is an attractive therapeutic target. In the present study, the synthesis and structure-activity relationship (SAR) of a novel series of quinoline derivatives as P2X7R antagonists are described herein. These compounds exhibited mechanistic activity (YO PRO) in an engineered HEK293 expressing hP2X7R as well as a functional response (IL-1β) in human THP-1 (hTHP-1) cellular assays. Compound 19 was identified as the most promising compound in this series with excellent cellular potency, low liver microsomal clearance, good permeability and low efflux ratio. In addition, this compound also displayed good pharmacokinetic properties and acceptable brain permeability (Kp,uu of 0.37).Graphical abstractGraphical abstract for this article
       
  • Facile synthesis of carbon-11-labeled sEH/PDE4 dual inhibitors as new
           
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 13Author(s): Limeng Jia, Caihong Miao, Fugui Dong, Wei Li, Min Wang, Qi-Huang Zheng, Zhidong Xu To develop PET tracers for imaging of neuroinflammation, new carbon-11-labeled sEH/PDE4 dual inhibitors have been synthesized. The reference standard N-(4-methoxy-2-(trifluoromethyl)benzyl)benzamide (1) and its corresponding desmethylated precursor N-(4-hydroxy-2-(trifluoromethyl)benzyl)benzamide (2) were synthesized from (4-methoxy-2-(trifluoromethyl)phenyl)methanamine and benzoic acid in one and two steps with 84% and 49% overall chemical yield, respectively. The standard N-(4-methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide (MPPA, 4) and its precursor N-(4-hydroxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide (5) were synthesized from methyl 4-piperidinecarboxylate, propionyl chloride and (4-methoxy-2-(trifluoromethyl)phenyl)methanamine in two and three steps with 62% and 34% overall chemical yield, respectively. The target tracers N-(4-[11C]methoxy-2-(trifluoromethyl)benzyl)benzamide ([11C]1) and N-(4-[11C]methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide ([11C]MPPA, [11C]4) were prepared from their corresponding precursors 2 and 5 with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC combined with SPE in 25–35% radiochemical yield, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was>99%, and the molar activity (AM) at EOB was 370–740 GBq/μmol with a total synthesis time of 35–40-minutes from EOB.Graphical abstractGraphical abstract for this article
       
  • Resistance mechanisms and cross-resistance for a pyridine-pyrimidine amide
           inhibitor of microtubule polymerization
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 13Author(s): J. Chancellor Fox, Alex T. Evans, Michael P. Blomfield, Scout K. Livingstone, Stephen R. Tenney, Jace B. Webster, Katelyn Perry, Jonathon T. Hill, Benjamin T. Bikman, Marc D.H. Hansen Despite their clinical importance, drug resistance remains problematic for microtubule targeting drugs. D4-9-31, a novel microtubule destabilizing agent, has pharmacology that suggests it can overcome common resistance mechanisms and has been shown to remain efficacious in cell and animal models with acquired taxane resistance. To better understand resistance mechanisms and the breadth of cross-resistance with D4-9-31, this study examines the A2780 ovarian cancer cell line as it develops acquired resistance with continuous exposure to D4-9-31. Analyzing cellular responses to D4-9-31 reveals that D4-9-31 resistance is associated with increased mitochondrial respiration, but no cross-resistance to other microtubule targeting agents is observed. Sequencing of transcripts of parental cells and resistant counterparts reveals mutations and altered expression of microtubule-associated genes, but not in genes commonly associated with resistance to microtubule targeting drugs. Additionally, our findings suggest distinct mechanisms drive short- and long-term drug resistance.Graphical abstractGraphical abstract for this article
       
  • Fluorogenic probe for measuring high-mannose type glycan-specific
           endo-β-N-acetylglucosaminidase H activity
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 13Author(s): Nozomi Ishii, Kanae Sano, Ichiro Matsuo We synthesized a fluorogenic probe with a high-mannose type heptasaccharide structure to detect the hydrolytic activity of endo-β-N-acetylglucosaminidase from Streptomyces plicatus (Endo-H). The heptasaccharide derivative (1) was labeled with an N-methylanthraniloyl group as a reporter dye at the branching point of the β-mannoside residue and 2,4-dinitrophenyl group as a quencher molecule at the reducing end, which was hydrolyzed by Endo-H, resulting in increased fluorescence intensity. Thus, Endo-H activities could be evaluated easily and quantitatively by measuring the fluorescence signal. Using both this probe (1) and a previously synthesized pentasaccharide probe, the hydrolysis activity of Endo-H and Endo-M were investigated. The results clearly showed a correlation with the substrate specificity of each enzyme.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and biological evaluation of novel antitumor
           spirodihydrothiopyran-oxindole derivatives
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 13Author(s): Wei Liu, Shuqiang Chen, Fan Zhang, Shipeng He, Shengzheng Wang, Chunquan Sheng Sulfur containing spiroheterocyclic oxindoles are promising privileged scaffolds in medicinal chemistry and drug discovery. Previously, we identified a new class of spirodihydrothiopyran-oxindoles with good in vitro antitumor activity against A549 lung cancer cell line. Herein, various spirooxindole-dihydrothiopyrans with diverse substitutions were synthesized and assayed to investigate the structure-activity relationships. Among the derivatives, compounds 4b, 4i, 4m, 4n and 4q displayed superior or comparable antitumor activity than nutlin-3. Molecular mechanism study revealed this scaffold displayed moderate MDM2 inhibitory activity, significantly induced cancer cell apoptosis and arrested cell cycle at G0/G1 phase, which represented a good lead compound for antitumor drug discovery.Graphical abstractGraphical abstract for this article
       
  • Position of lipidation influences anticancer activity of Smac analogs
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 13Author(s): Ewa D. Micewicz, Christine Nguyen, Alina Micewicz, Alan J. Waring, William H. McBride, Piotr Ruchala A small group of lipid-conjugated Smac mimetics was synthesized to probe the influence of the position of lipidation on overall anti-cancer activity. Specifically, new compounds were modified with lipid(s) in position 3 and C-terminus. Previously described position 2 lipidated analog M11 was also synthesized. The resulting mini library of Smacs lipidated in positions 2, 3 and C-terminus was screened extensively in vitro against a total number of 50 diverse cancer cell lines revealing that both the position of lipidation as well as the type of lipid, influence their anti-cancer activity and cancer type specificity. Moreover, when used in combination therapy with inhibitor of menin–MLL1 protein interactions, position 2 modified analog SM2 showed strong synergistic anti-cancer properties. The most promising lipid-conjugated analogs SM2 and SM6, showed favorable pharmacokinetics and in vivo activity while administered subcutaneously in the preclinical mouse model. Collectively, our findings suggest that lipid modification of Smacs may be a viable approach in the development of anti-cancer therapeutic leads.Graphical abstractGraphical abstract for this article
       
  • Synthesis and preclinical evaluation of [18F]FSL25.1188, a reversible PET
           radioligand for monoamine oxidase-B
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 13Author(s): Kenneth Dahl, Vadim Bernard-Gauthier, Sangram Nag, Katarina Varnäs, Vidya Narayanaswami, Mohammad Mahdi Moein, Ryosuke Arakawa, Neil Vasdev, Christer Halldin Carbon-11 labeled SL25.1188 is a promising reversible monoamine oxidase-B (MAO-B) radioligand that was recently translated for human positron emission tomography (PET) imaging. Herein, we report the development of a novel fluorinated derivative, namely, [18F](S)-3-(6-(3-fluoropropoxy)benzo[d]isoxazol-3-yl)-5-(methoxymethyl)oxazolidin-2-one ([18F]FSL25.1188; [18F]6), as a candidate 18F-labeled MAO-B radioligand, and, its subsequent preclinical evaluation in non-human primates (NHP). [18F]6 was produced and isolated (>6 GBq) with high radiochemical purity (>99%), and molar activity (>100 GBq/µmol at time of injection). Autoradiography studies conducted in post-mortem human brain sections revealed [18F]6 binding in MAO-B rich regions. PET imaging study of [18F]6 in NHP showed high brain uptake (SUV > 2.5) as well as a regional brain radioactivity distribution in accordance with MAO-B expression. [18F]6 displayed favorable in vivo kinetics, with an early peak in the time-activity curve followed by progressive wash-out from the NHP brain. Specificity of [18F]6 was investigated in a pre-treatment study with l-deprenyl (1.0 mg/kg) wherein reduced radioligand uptake was observed in all MAO-B rich regions. Results from the current preclinical investigation suggests [18F]6 is a promising MAO-B PET radioligand. Further evaluation of [18F]6 and structurally related 18F-analogs are underway to identify an optimized candidate for clinical research studies.Graphical abstractGraphical abstract for this article
       
  • Synthesis and biological evaluation of F-18 labeled tetrahydroisoquinoline
           derivatives targeting orexin 1 receptor
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 13Author(s): Hiroyuki Watanabe, Kengo Fukui, Yoichi Shimizu, Yuki Idoko, Yuji Nakamoto, Kaori Togashi, Hideo Saji, Masahiro Ono Orexin 1 receptor (OX1R) is thought to be involved in various body functions, including arousal maintenance and emotional control, but the full details of its function remain unknown. OX1R imaging with positron emission tomography (PET) would be useful in elucidating the orexin system including OX1R, but no PET probes targeting OX1R have been reported. We, therefore, designed and synthesized tetrahydroisoquinoline (THIQ) derivatives as novel PET probes targeting OX1R, and evaluated their utility. In an in vitro competitive binding assay, THIQ-1 and THIQ-2 showed significantly higher binding to OX1R (IC50 = 30 and 31 nM, respectively) than OX2R (IC50 = 160 and 332 nM, respectively). These features were also observed in a cell binding assay using [18F]THIQ-1 and [18F]THIQ-2, demonstrating their OX1R-specific binding property in vitro. In a biodistribution study using normal mice, the brain uptake of [18F]THIQ-1 was higher than that of [18F]THIQ-2, but further improvement is required for in vivo imaging with PET. Taken together, [18F]THIQ-1 and [18F]THIQ-2 have the potential to become useful imaging probes for PET targeting the OX1R, but require additional structural changes to improve their brain uptake.Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC continued
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 13Author(s):
       
  • Discovery of 5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazin-2(1H)-one
           derivatives as new potent PB2 inhibitors
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 13Author(s): Jianhong Yang, Jiatian Du, Chong Huang, Tianqi Wang, Luyi Huang, Shengyong Yang, Linli Li PB2 is an important subunit of influenza RNA-dependent RNA polymerase (RdRP) and has been recognized as a promising target for the treatment of influenza. We herein report the discovery of a new series of PB2 inhibitors containing the skeleton 5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazin-2(1H)-one. Compound 12b is the most potent one, which showed KD values of 0.11 μM and 0.19 μM in surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) assays, respectively. In antiviral activity and cellular cytotoxicity assays, compound 12b showed an EC50 value of 1.025 μM and a CC50 value greater than 100 μM. Molecular docking was also used to predict the binding mode of 12b with PB2. Collectively, this study provides a promising lead compound for subsequent anti-influenza drug discovery targeting PB2.Graphical abstractGraphical abstract for this article
       
  • Discovery of novel phenoxybenzamide analogues as Raf/HDAC dual inhibitors
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 13Author(s): Aixin Geng, Hao Cui, Liyuan Zhang, Xin Chen, Hongmei Li, Tao Lu, Yong Zhu Histone deacetylase (HDAC) inhibitors as an important epigenetic therapeutic strategy affect signaling networks and act synergistically with kinase inhibitors for the treatment of cancer. Herein we presented a series of novel phenoxybenzamide analogues with inhibition of Raf and HDAC. Among them, compound 10e showed potent antiproliferative activities against Hepg2 and MDA-MB-468 in cellular assays. This work may lay the foundation for developing novel dual Raf/HDAC inhibitors as potential anticancer therapeutics.Graphical abstractGraphical abstract for this article
       
  • Towards a TREK-1/2 (TWIK-Related K+ Channel 1 and 2) dual activator tool
           compound: Multi-dimensional optimization of BL-1249
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 13Author(s): Yuzo Iwaki, Kentaro Yashiro, Masaya Kokubo, Takahiro Mori, Joshua M. Wieting, Kevin M. McGowan, Thomas M. Bridges, Darren W. Engers, Jerod S. Denton, Haruto Kurata, Craig W. Lindsley This letter describes a focused, multi-dimensional optimization campaign around BL-1249, a fenamate class non-steroidal anti-inflammatory and a known activator of the K2P potassium channels TREK-1 (K2P2.1) and TREK-2 (K2P10.1). While BL-1249 has been widely profiled in vitro as a dual TREK-1/2 activator, poor physicochemical and DMPK properties have precluded a deeper understanding of the therapeutic potential of these key K2P channels across a broad spectrum of peripheral and central human disease. Here, we report multi-dimensional SAR that led to a novel TREK-1/2 dual activator chemotype, exemplified by ONO-2960632/VU6011992, with improved DMPK properties, representing a new lead for further optimization towards robust in vivo tool compounds.Graphical abstractGraphical abstract for this article
       
  • 1-Aryl-3-(4-methoxybenzyl)ureas as potentially irreversible glycogen
           synthase kinase 3 inhibitors: Synthesis and biological evaluation
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 13Author(s): Jana Venter, Concepción Perez, Willem A.L. van Otterlo, Ana Martínez, Margaret A.L. Blackie Glycogen synthase kinase 3 (GSK-3) has become known for its multifactorial involvement in the pathogenesis of Alzheimer’s disease. In this study, a benzothiazole- and benzimidazole set of 1-aryl-3-(4-methoxybenzyl)ureas were synthesised as proposed Cys199-targeted covalent inhibitors of GSK-3β, through the incorporation of an electrophilic warhead onto their ring scaffolds. The nitrile-substituted benzimidazolylurea 2b (IC50 = 0.086 ± 0.023 µM) and halomethylketone-substituted benzimidazolylurea 9b (IC50 = 0.13 ± 0.060 µM) displayed high GSK-3β inhibitory activity, in comparison to reference inhibitor AR-A014418 (1, IC50 = 0.072 ± 0.043) in our assay. The results suggest further investigation of 2b and 9b as potential covalent inhibitors of GSK-3β, since a targeted interaction might provide improved kinase-selectivity.Graphical abstractGraphical abstract for this article
       
  • A new lateral root growth inhibitor from the sponge-derived fungus
           Aspergillus sp. LS45
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 13Author(s): Liming Huang, Lijian Ding, Xiaohui Li, Ning Wang, Yushan Yan, Mengxiang Yang, Wei Cui, C. Benjamin Naman, Kejun Cheng, Weiyan Zhang, Bin Zhang, Haixiao Jin, Shan He Two new γ-lactones, aspergilactones A (1) and B (2), were discovered along with two known compounds, annularin A (3) and pericoterpenoid A (4), from a culture of the sponge-associated fungus Aspergillus sp. LS45. The planar structures of 1–4 were characterized using comprehensive spectroscopic methods and comparison with literature data. The absolute configurations of 1 and 2 were determined by comparison of electronic circular dichroism (ECD) spectroscopic and optical rotation data with those of known analogues as well as calculated ECD analysis. Compounds 1–4 were tested in a variety of bioassays, and both 1 and 4 exhibited significant inhibition against the lateral root growth of Arabidopsis thaliana Columbia-0 at a concentration of 100 μM. In addition, the in vitro cytotoxic activities of 1–4 against six human cancer cell lines CCRF-CEM, K562, BGC823, AGS, HCT-116 and MDA-MB-231 were evaluated. Compound 4 showed moderate inhibitory effects on CCRF-CEM and K562 cancer cell lines with IC50 values of 13.8 ± 1.6 and 12.9 ± 2.5 μM, respectively. However, compounds 1–4 did not show any notable AChE inhibitory activity in vitro.Graphical abstractGraphical abstract for this article
       
  • Proteolysis targeting chimeras (PROTACs) in ‘beyond rule-of-five’
           chemical space: Recent progress and future challenges
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 13Author(s): Scott D. Edmondson, Bin Yang, Charlene Fallan Proteolysis targeting chimeras (PROTACs) are heterobifunctional compounds with molecular weights and other properties that lie outside the classic ‘rule-of-five’ space. Consequently, PROTACs have unique challenges associated with their development as potential therapeutic agents. This review summarizes and analyzes a representative set of recent PROTACs and highlights some of the potential future challenges facing this promising modality.Graphical abstractGraphical abstract for this article
       
  • Doxycycline, salinomycin, monensin and ivermectin repositioned as cancer
           drugs
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 13Author(s): Anna Markowska, Joanna Kaysiewicz, Janina Markowska, Adam Huczyński Chemotherapy is one of the standard methods for the treatment of malignant tumors. It aims to cause lethal damage to cellular structures, mainly DNA. Noteworthy, in recent years discoveries of novel anticancer agents from well-known antibiotics have opened up new treatment pathways for several cancer diseases. The aim of this review article is to describe new applications for the following antibiotics: doxycycline (DOX), salinomycin (SAL), monensin (MON) and ivermectin (IVR) as they are known to show anti-tumor activity, but have not yet been introduced into standard oncological therapy. To date, these agents have been used for the treatment of a broad-spectrum of bacterial and parasitic infectious diseases and are widely available, which is why they were selected. The data presented here clearly show that the antibiotics mentioned above should be recognised in the near future as novel agents able to eradicate cancer cells and cancer stem cells (CSCs) across several cancer types.Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 13Author(s):
       
  • Revisiting microtubule targeting agents: α-Tubulin and the pironetin
           binding site as unexplored targets for cancer therapeutics
    • Abstract: Publication date: Available online 21 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Sara K. Coulup, Gunda I. Georg Molecules that bind to tubulin and disrupt tubulin dynamics are known as microtubule targeting agents. Treatment with a microtubule targeting agent leads to cell cycle arrest followed by apoptosis. Tubulin inhibitors have been highly effective in the clinical treatment of a variety of tumors and are being investigated for treatment of several other diseases. Currently, all FDA approved microtubule inhibitors bind to β-tubulin. Given the overall success of tubulin-binding agents in anticancer chemotherapy, α-tubulin is an attractive and unexplored target. Herein, we will discuss pironetin, the only compound known to bind α-tubulin, with particular focus on the known biological properties, the total syntheses, exploration of its structure-activity relationship, and future directions.Graphical abstractGraphical abstract for this article
       
  • Discovery of Antichagasic Inhibitors by High-Throughput Screening with
           Trypanosoma cruzi Glucokinase
    • Abstract: Publication date: Available online 20 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Gustavo F. Mercaldi, Edward L.D'Antonio, Annelie Aguessi, Ana Rodriguez, Artur T. Cordeiro A high-throughput screening (HTS) campaign was carried out for Trypanosoma cruzi glucokinase (TcGlcK), a potential drug-target of the pathogenic protozoan parasite.Glycolysis and the pentose phosphate pathway (PPP) are important metabolic pathways for T. cruzi and the inhibition of the glucose kinases (i.e. glucokinase and hexokinase) may be a strategic approach for drug discovery. Glucose kinases phosphorylate D-glucose with co-substrate ATP to yield G6P, and moreover, the produced G6P enters both pathways for catabolism. The TcGlcK – HTS campaign revealed 25 novel enzyme inhibitors that were distributed in nine chemical classes and were discovered from a primary screen of 13,040 compounds. Thirteen of these compounds were found to have low micromolar IC50 enzyme – inhibition values; strikingly, four of those compounds exhibited low toxicity towards NIH-3T3 murine host cells and notable in vitro trypanocidal activity. These compounds were of three chemical classes: (a) the 3-nitro-2-phenyl-2H-chromene scaffold, (b) the N-phenyl-benzenesulfonamide scaffold, and (c) the gossypol scaffold. Two compounds from the 3-nitro-2-phenyl-2H-chromene scaffold were determined to be hit-to-lead candidates that can proceed further down the early-stage drug discovery process.Graphical abstractGraphical abstract for this article
       
  • Gentiopicroside isolated from Gentiana scabra Bge. inhibits adipogenesis
           in 3T3-L1 cells and reduces body weight in diet-induced obese mice
    • Abstract: Publication date: Available online 20 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Ra-Yeong Choi, Sang-Jip Nam, Hae-In Lee, Jihye Lee, Alain S. Leutou, Ju Ri Ham, Mi-Kyung Lee Gentiopicroside is a major active component of the Gentiana scabra Bge., which is commonly used as herbal medicine for the treatment of inflammation in Asia. Gentiopicroside significantly down-regulated expression of key adipogenic transcription factors (PPARγ, C/EBPα, SREBP-1c) and dose-dependently inhibited the lipid uptake-related gene (LPL), fatty acid transport-related gene (FABP4) and triglyceride (TG) synthesis-related gene (DGAT2), as well as fatty acid synthesis-related genes (FAS, SCD1), which resulted in reduced intracellular lipid droplet accumulation and TG content in 3T3-L1 cells. Gentiopicroside also down-regulated expression of inflammatory cytokine genes (NFκB1, TNFα, IL6) compared with vehicle. Oral administration of gentiopicroside (50 mg/kg) in mice fed with high-fat diet for 12 weeks resulted in reduced body weight and visceral fat mass compared with the control group. Overall, the results of this study showed that gentiopicroside had positive anti-obesity effects by regulating the expression of adipogenesis/lipogenesis-related genes and inflammatory genes in 3T3-L1, and that it effectively reduced body weight and visceral fat mass in vivo.Graphical abstractGraphical abstract for this article
       
  • A High Throughput Substrate Binding Assay Reveals Hexachlorophene as an
           Inhibitor of the ER-resident HSP70 Chaperone GRP78
    • Abstract: Publication date: Available online 20 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Andrew J. Ambrose, Christopher J. Zerio, Jared Sivinski, Cody J. Schmidlin, Taoda Shi, Alison B. Ross, Kimberly J. Widrick, Steven M. Johnson, Donna D. Zhang, Eli Chapman Glucose regulated protein 78 (GRP78) is the ER resident 70 kDa heat shock protein 70 (HSP70) and has been hypothesized to be a therapeutic target for various forms of cancer due to its role in mitigating proteotoxic stress in the ER, its elevated expression in some cancers, and the correlation between high levels for GRP78 and a poor prognosis. Herein we report the development and use of a high throughput fluorescence polarization-based peptide binding assay as an initial step toward the discovery and development of GRP78 inhibitors. This assay was used in a pilot screen to discover the anti-infective agent, hexachlorophene, as an inhibitor of GRP78. Through biochemical characterization we show that hexachlorophene is a competitive inhibitor of the GRP78-peptide interaction. Biological investigations showed that this molecule induces the unfolded protein response, induces autophagy, and leads to apoptosis in a colon carcinoma cell model, which is known to be sensitive to GRP78 inhibition.
       
  • Quinoline and thiazolopyridine allosteric inhibitors of MALT1
    • Abstract: Publication date: Available online 20 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): David A. Scott, John M. Hatcher, Hongyan Liu, Mingpeng Fu, Guangyan Du, Lorena Fontán, Ilkay Us, Gabriella Casalena, Qi Qiao, Hao Wu, Ari Melnick, Nathanael S. Gray Quinolines and thiazolopyridines were developed as allosteric inhibitors of MALT1, with good cellular potency and exquisite selectivity. Mouse pharmacokinetic (PK) profiling showed these to have low in vivo clearance, and moderate oral exposure. The thiazolopyridines were less lipophilic than the quinolines, and one thiazolopyridine example was active in our hIL10 mouse pharmacodynamic (PD) model upon oral dosing.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and structure activity relationships of indazole and
           indole derivatives as potent glucagon receptor Antagonists
    • Abstract: Publication date: Available online 18 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Fengbin Song, Guozhang Xu, Michael D. Gaul, Baoping Zhao, Tianbao Lu, Rui Zhang, Renee L. DesJarlais, Karen DiLoreto, Norman Huebert, Brian Shook, Dennis Rentzeperis, Rosie Santulli, Annette Eckardt, Keith Demarest A novel series of indazole/indole derivatives were discovered as glucagon receptor (GCGR) antagonists through scaffold hopping based on two literature leads: MK-0893 and LY-2409021. Further structure-activity relationship (SAR) exploration and optimization led to the discovery of multiple potent GCGR antagonists with excellent pharmacokinetic properties in mice and rats, including low systemic clearance, long elimination half-life, and good oral bioavailability. These potent GCGR antagonists could be used for potential treatment of type II diabetes.Graphical abstractGraphical abstract for this article
       
  • Discovery of ABT-957: 1-Benzyl-5-oxopyrrolidine-2-carboxamides as
           selective calpain inhibitors with enhanced metabolic stability
    • Abstract: Publication date: Available online 18 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Katja Jantos, Andreas Kling, Helmut Mack, Wilfried Hornberger, Achim Moeller, Volker Nimmrich, Yanbin Lao, Marjoleen Nijsen Aberrant activation of calpain has been observed in various pathophysiological disorders including neurodegenerative diseases such as Alzheimeŕs Disease. Here we describe our efforts on ketoamide-based 1-benzyl-5-oxopyrrolidine-2-carboxamides as a novel series of highly selective calpain inhibitors mitigating the metabolic liability of carbonyl reduction. The most advanced compound from this new series, namely A-1212805 (ABT-957, Alicapistat) proceeded to clinical phase I studies.Graphical abstractGraphical abstract for this article
       
  • Development of bivalent compounds as potential neuroprotectants for
           Alzheimer’s disease
    • Abstract: Publication date: Available online 18 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Liu He, Yuqi Jiang, Jakob Green, Hallie Blevins, Shijun Zhang In our efforts to further investigate the impact of the spacer and membrane anchor to the neuroprotective activities, a series of bivalent compounds that contain cholesterol and extended spacers were designed, synthesized and biologically characterized. Our results support previous studies that incorporation of a piperazine ring into the spacer significantly improved the protective potency of bivalent compounds in MC65 cell model. Spacer length beyond 21 atoms does not add further benefits with 21MO being the most potent one with an EC50 of 81.86 ± 11.91 nM. Our results also demonstrated that bivalent compound 21MO suppressed the production of mitochondria reactive oxygen species. Furthermore, our results confirmed that both of the spacer and membrane anchor moiety are essential to metal binding. Collectively, the results provide further evidence and information to guide optimization of such bivalent compounds as potential neuroprotectants for Alzheimer’s disease.Graphical abstractGraphical abstract for this article
       
  • Tool inhibitors and assays to interrogate the biology of the TRAF2 and NCK
           interacting kinase
    • Abstract: Publication date: Available online 18 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Jon Read, Iain T. Collie, Michelle Nguyen-McCarty, Christopher Lucaj, James Robinson, Leslie Conway, Jayanta Mukherjee, Eileen McCall, Gerard Donohoe, Elizabeth Flavell, Karolina Peciak, Juli Warwicker, Carly Dix, Bernard G. Van den Hoven, Andrew Madin, Dean G. Brown, Stephen Moss, Stephen J. Haggarty, Nicholas J. Brandon, Roland W. Bürli The TRAF2 and NCK interacting kinase (TNIK) has been proposed to play a role in cytoskeletal organization and synaptic plasticity and has been linked, among others, to neurological disorders. However, target validation efforts for TNIK have been hampered by the limited kinase selectivity of small molecule probes and possible functional compensation in mouse models. Both issues are at least in part due to its close homology to the kinases MINK1 (or MAP4K6) and MAP4K4 (or HGK). As part of our interest in validating TNIK as a therapeutic target for neurological diseases, we set up a panel of biochemical and cellular assays, which are described herein. We then examined the activity of known amino-pyridine-based TNIK inhibitors (1, 3) and prepared structurally very close analogs that lack the ability to inhibit the target. We also developed a structurally orthogonal, naphthyridine-based TNIK inhibitor (9) and an inactive control molecule of the same chemical series. These validated small-molecule probes will enable dissection of the function of TNIK family in the context of human disease biology.Graphical abstractGraphical abstract for this article
       
  • Synthesis of Isosteviol analogues as potential protective agents against
           Doxorubicin-induced cardiomyopathy in zebrafish embryos
    • Abstract: Publication date: Available online 18 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): R. Jayachandra, Haishan Zhao, Zuchun Cheng, Liping Luo, Tingwei Sun, Wen Tan Doxorubicin (DOX) is a powerful anthracycline antibiotic agent which is widely used to treat various types of cancers. Despite efficacy, it displays severe cardiotoxic side effects. Discovery of novel and effective protective agents against DOX-induced cardiotoxicity has been a subject of great interest. Herein, we report the synthesis of two series of analogues of Isosteviol (ISV) 1 with modifications at C-16, C-19 positions as the first series and at C-15, C-16 positions as the other series. Interestingly second series analogues have shown a potential protective effect against DOX-induced cardiotoxicity in zebrafish embryos in vivo. Further, we have demonstrated that the synthesized new analogues of ISV, prevented the morphological distortions caused due to DOX cardiotoxicity in zebrafish heart and the associated cardiac impairments.Graphical abstractGraphical abstract for this article
       
  • Profiling Interactions of Vaborbactam with Metallo-β-Lactamases
    • Abstract: Publication date: Available online 17 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Gareth W. Langley, Ricky Cain, Jonathan M. Tyrrell, Phillip Hinchliffe, Karina Calvopiña, Catherine Tooke, Emma Widlake, Christopher G. Dowson, James Spencer, Timothy R. Walsh, Christopher J. Schofield, Jürgen Brem β-Lactams are the most successful antibacterials, yet their use is threatened by resistance, importantly as caused by β-lactamases. β-Lactamases fall into two mechanistic groups: the serine β-lactamases that utilise a covalent acyl-enzyme mechanism and the metallo β-lactamases that utilise a zinc-bound water nucleophile. Achieving simultaneous inhibition of both β-lactamase classes remains a challenge in the field. Vaborbactam is a boronate-based inhibitor that reacts with serine-β-lactamases to form covalent complexes that mimic tetrahedral intermediates in catalysis. Vaborbactam has recently been approved for clinical use in combination with the carbapenem meropenem. Here we show that vaborbactam moderately inhibits metallo-β-lactamases from all 3 subclasses (B1, B2 and B3), with a potency of around 20-100 fold below that by which it inhibits its current clinical targets, the Class A serine β-lactamases. This result contrasts with recent investigations of bicyclic boronate inhibitors, which potently inhibit subclass B1 MBLs but which lack activity against B2 and B3 enzymes. These findings indicate that the monocyclic boronate scaffold has the potential to inhibit the full range of β -lactamases and justify further work on the development of boronates as broad-spectrum β-lactamase inhibitors.Graphical abstractGraphical abstract for this article
       
  • Spermine-NBD as fluorescent probe for studies of the polyamine transport
           system in Leishmania donovani
    • Abstract: Publication date: Available online 17 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Elodie Jagu, Sébastien Pomel, Stéphanie Pethe, Jean-Christophe Cintrat, Philippe M. Loiseau, Raphaël Labruère This study describes the synthesis of fluorescent probes as potential substrates for the polyamine transport system (PTS) of Leishmania donovani. A competitive radioassay was used to determine the most efficient probe. We observed that the conjugate spermine-nitrobenzofurazan (Spm-NBD) was able to compete with [3H]-spermidine in L. donovani at a potent IC50 of 60 µM.Graphical abstractGraphical abstract for this article
       
  • Optimization of a Small-Molecule Lipid II binder
    • Abstract: Publication date: Available online 17 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Jay Chauhan, Steven M. Kwasny, Steven Fletcher, Timothy J. Opperman, Erik P.H. de Leeuw Lipid II is an essential precursor of bacterial cell wall biosynthesis and an attractive target for antibiotics. Lipid II is comprised of specialized lipid (bactoprenol) linked to a hydrophilic head group consisting of a peptidoglycan subunit (N-acetylglucosamine (GlcNAc) -N-acetylmuramic acid (MurNAc) disaccharide coupled to a short pentapeptide moiety) via a pyrophosphate. We previously identified a (E)-2,4-bis(4-bromophenyl)-6-(4-(dimethylamino)styryl)pyrylium boron tetrafluoride salt, termed 6jc48-1, that interacts with the MurNAc moiety, the phosphate cage and the isoprenyl tail of Lipid II. Here, we report on the structure-activity relationship of 6jc48-1 derivatives obtained by de novo chemical synthesis. Our results indicate that bacterial killing is positively driven by bi-phenyl stacking with peptidoglycan units. Replacement of bromides by fluorides resulted in activity against S. aureus without affecting Lipid II binding and cytotoxicity. Antibacterial activity was affected negatively by extended interaction of the scaffold with Lipid II isoprenyl units.Graphical abstractGraphical abstract for this article
       
  • SAR Studies in the Sulfonyl Carboxamide Class of HBV Capsid Assembly
           Modulators
    • Abstract: Publication date: Available online 16 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Scott D. Kuduk, Angela M. Lam, Christine Espiritu, Robert Vogel, Vincent Lau, Klaus Klumpp, Osvaldo A. Flores, George D. Hartman The HBV core protein has multiple essential functions in the HBV life cycle to enable chronic HBV infection. The core protein oligomerizes to form the viral capsid, and modulation of the HBV capsid assembly process has shown clinical efficacy in early clinical trials. Herein is described the SAR exploration of NVR 3-778, the first clinical compound in the sulfonyl carboxamide class.Graphical abstractGraphical abstract for this article
       
  • Chemically synthesized LYRM03 could inhibit the metastasis of human breast
           cancer MDA-MB-231 cells in vitro, in vivo
    • Abstract: Publication date: Available online 16 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Yun-kai Yang, Da-dong Shen, Peng He, Liang-dong Du, Ding-jian Wan, Pu Wang, Tao Wang, Mei-qing Feng Aminopeptidase N (APN) belongs to the aminopeptidase family, which is widely distributed throughout the animal and plant kingdoms. APN is thought to be a very important target for cancer therapy as it is linked to cancer progression and metastasis. However, bestatin (Ubenimex) is the only approved drug that targets various aminopeptidases for the treatment of acute myelocytic leukemia and lymphedema. A compound 3-amino-2-hydroxy-4-phenylbutanoylvalylisoleucine (also known as LYRM03), isolated from a Streptomyces strain HCCB10043, exhibited more potent inhibitory activity than bestatin. In this work, we applied a chemical synthesis strategy to generate LYRM03 to overcome the low yields typically achieved from fermentation. Finally, we explored a suite of experiments to determine the bioactivity of LYRM03 and revealed that the metastasis of MDA-MB-231 cells was significantly restrained with LYRM03 treatment or injection both in vitro and in vivo. Because of its anti-metastasis capacity, further structure modifications of LYRM03 will be of interest for its use alone or in combination as a therapy in cancer.Graphical abstractGraphical abstract for this article
       
  • Discovery of piperazic acid peptide deformylase inhibitors with in vivo
           activity for respiratory tract and skin infections
    • Abstract: Publication date: Available online 16 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Jared T. Spletstoser, Jason Dreabit, Andrew N. Knox, Andrew Benowitz, Nino Campobasso, Guanglei Cui, Thomas Lewandowski, Lynn McCloskey, Kelly M. Aubart The discovery of a novel series of peptide deformylase inhibitors incorporating a piperazic acid amino acid found in nature is described. These compounds demonstrated potent in vitro enzymatic potency and antimicrobial activity. Crystal structure analysis revealed the piperazic acid optimized a key contact with the PDF protein that accounted for the increased enzymatic potency of these compounds. We describe lead optimization of the P3’ region of the series that resulted in a compound with good potency against three target organisms. One molecule showed in vivo efficacy in a rat respiratory infection model but ultimately did not meet candidate progression criteria.Graphical abstractGraphical abstract for this article
       
  • VU6005806/AZN-00016130, an advanced M4 positive allosteric modulator (PAM)
           profiled as a potential preclinical development candidate
    • Abstract: Publication date: Available online 16 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Darren W. Engers, Bruce J. Melancon, Allison R. Gregro, Jeanette L. Bertron, Sean R. Bollinger, Andrew S. Felts, Leah C. Konkol, Michael R. Wood, Katrina A. Bollinger, Vincent B. Luscombe, Alice L. Rodriguez, Carrie K. Jones, Michael Bubser, Samantha E. Yohn, Michael W. Wood, Nicholas J. Brandon, Mark E. Dugan, Colleen M. Niswender, P. Jeffrey Conn, Thomas M. Bridges This letter describes progress towards an M4 PAM preclinical candidate that resulted in the discovery of VU6005806/AZN-00016130. While the thieno[2,3-c]pyridazine core has been a consistent feature of key M4 PAMs, no work had previously been reported with respect to alternate functionality at the C3 position of the pyridazine ring. Here, we detail new chemistry and analogs that explored this region, and quickly led to VU6005806/AZN-00016130, which was profiled as a putative candidate. While, the β-amino carboxamide moiety engendered solubility limited absorption in higher species precluding advancement (or requiring extensive pharmaceutical sciences formulation), VU6005806/AZN-00016130 represents a new, high quality preclinical in vivo probe.Graphical abstractGraphical abstract for this article
       
  • Utilizing comprehensive and mini-kinome panels to optimize the selectivity
           of quinoline inhibitors for cyclin G associated kinase (GAK)
    • Abstract: Publication date: Available online 16 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Christopher R.M. Asquith, Daniel K. Treiber, William J. Zuercher We demonstrate an innovative approach for optimization of kinase inhibitor potency and selectivity utilising kinase mini-panels and kinome-wide panels. We present a focused case study on development of a selective inhibitor of cyclin G associated kinase (GAK) using the quin(az)oline inhibitor chemotype. These results exemplify a versatile, efficient approach to drive kinome selectivity during inhibitor development programs.Graphical abstractGraphical abstract for this article
       
  • Design and synthesis of a novel series of cyanoindole derivatives as
           potent γ-secretase modulators
    • Abstract: Publication date: Available online 15 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): François P. Bischoff, Adriana Ingrid Velter, Garrett Minne, Serge Pieters, Didier Berthelot, Michel De Cleyn, Harrie J.M. Gijsen, Gregor Macdonald, Michel Surkyn, Sven Van Brandt, Yves Van Roosbroeck, Chiara Zavattaro, Marc Mercken, Nigel Austin, Deborah Dhuyvetter, Herman Borghys, Ishtiyaque Ahmad, Swapan Kumar Samanta The discovery, design and synthesis of a new series of GSMs is described. The classical imidazole heterocycle has been replaced by a cyano group attached to an indole nucleus. The exploration of this series has led to compound 26-S which combined high in vitro and in vivo potency with an acceptable drug-like profile.Graphical abstractGraphical abstract for this article
       
  • Anticancer saponin OSW-1 is a novel class of selective Golgi stress
           inducer
    • Abstract: Publication date: Available online 15 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Mayu Kimura, Kanae Sasaki, Yosuke Fukutani, Hiderou Yoshida, Ikuroh Ohsawa, Masafumi Yohda, Kaori Sakurai OSW-1 is a plant-derived natural product proposed to selectively kill cancer cells by binding to members of the oxysterol binding protein family, thereby disrupting lipid/sterol homeostasis. However, how these protein-ligand interactions mediate cell death signaling has remained elusive. Here, we discovered that OSW-1 selectively activates the Golgi stress response leading to apoptosis, providing a mechanistic basis for the anticancer activity of OSW-1.Graphical abstractGraphical abstract for this article
       
  • Synthesis and antiviral activity of coumarin derivatives against
           infectious hematopoietic necrosis virus
    • Abstract: Publication date: Available online 14 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Yang Hu, Weichao Chen, Yufeng Shen, Bin Zhu, Gao-Xue Wang Infectious hematopoietic necrosis virus (IHNV) is a highly contagious disease of juvenile salmonid species. However, robust anti-IHNV drugs currently are extremely scarce. For the purpose of seeking out anti-IHNV drugs, here a total of 24 coumarin derivatives are designed, synthesized and evaluated for their anti-viral activities. By comparing the half maximal inhibitory concentrations (IC50) of the 12 screened candidate drugs in epithelioma papulosum cyprini (EPC) cells infected with IHNV, the imidazole coumarin derivative C4 is selected for additional validation studies, with an IC50 of 2.53 μM at 72 h on IHNV glycoprotein. Further experiments revealed that C4 could significantly inhibit apoptosis and cellular morphological damage induced by IHNV. On account of these findings, derivative C4 could be a viable way of controlling IHNV and considered as a promising lead compound for the development of commercial drugs.Graphical abstractGraphical abstract for this article
       
  • Synthesis and biological evaluation of acylthiourea against DUSP1
           inhibition
    • Abstract: Publication date: Available online 14 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Bo Yeon Kim, Ji Hee Yoon, Myeongbin Kim, Jae Nyoung Kim, Hwangseo Park, Seong Eon Ryu, Sangku Lee Structure based virtual screening attempts to discover DUSP1 inhibitors have yielded a scaffold featuring benzoxazole and acylthiourea pharmacophore. A series of its analogues were synthesized to explore structure activity relationship (SAR) of DUSP1 inhibition.Graphical abstractGraphical abstract for this article
       
  • Naturally Occurring Biflavonoids with Amyloid β Aggregation Inhibitory
           Activity for Development of Anti-Alzheimer Agents
    • Abstract: Publication date: Available online 14 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Natchanun Sirimangkalakitti, Lia Dewi Juliawaty, Euis H. Hakim, Irpan Waliana, Naoki Saito, Kiyotaka Koyama, Kaoru Kinoshita Amyloid β (Aβ) aggregation plays an essential role in promoting the progression of Alzheimer's disease (AD). Therefore, the inhibition of Aβ aggregation is a potential therapeutic approach for AD. Herein, twenty-seven biflavonoids with different inter-flavonyl linkages and methoxy substitution patterns were isolated from several plants, and their Aβ40 aggregation inhibitory activity was evaluated by the thioflavin-T fluorescence assay. Amentoflavone (1) and its monomethoxy derivatives (2, 3, and 5) exhibited the most potent inhibitory activity, with IC50 values of approximately 5 μM. It was clarified that increasing the number of methoxy substituents on the biflavonoid structures attenuated the inhibitory activity. Moreover, the linkage and the methoxy substitution pattern had a marked influence on the inhibitory activity. Our investigation strongly supports that biflavonoids can be considered a new type of anti-Alzheimer agents that may be successfully developed for AD patients.Graphical abstractGraphical abstract for this article
       
  • Quercetin-3-Oleoyl Derivatives as New GPR40 Agonists: Molecular Docking
           Studies and Functional Evaluation
    • Abstract: Publication date: Available online 13 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Gabriele Carullo, Mariarita Perri, Fabrizio Manetti, Francesca Aiello, Maria Cristina Caroleo, Erika Cione The G-protein-coupled receptor 40 (GPR40) is an attractive molecular target for the treatment of type 2 diabetes mellitus. Previously, based on the natural oleic acid substrate, an exogenous ligand for this receptor, named AV1, was synthesized. In this context, here we validated the activity of AV1 as a full agonist, while the corresponding catechol analogue, named AV2, was investigated for the first time. The ligand-protein interaction between this new molecule and the receptor was highlighted in the lower portion of the GPR40 groove that generally accommodates DC260126. The functional assays performed have demonstrated that AV2 is a suitable GPR40 partial agonist, showing a therapeutic potential and representing a useful tool in the management of type 2 diabetes.Graphical abstractGraphical abstract for this article
       
  • Dextran-conjugated tetrathiatriarylmethyl radicals as biocompatible spin
           probes for EPR spectroscopy and imaging
    • Abstract: Publication date: Available online 13 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Martin Poncelet, Benoit Driesschaert, Oxana Tseytlin, Mark Tseytlin, Timothy D. Eubank, Valery V. Khramtsov Tetrathiatriarylmethyl (TAM) radicals represent soluble paramagnetic probes for biomedical electron paramagnetic resonance (EPR)-based spectroscopy and imaging. There is an increasing demand in the development of multifunctional, biocompatible and targeted trityl probes hampered by the difficulties in derivatization of the TAM structure. We proposed a new straightforward synthetic strategy using click chemistry for the covalent conjugation of the TAM radical with a water-soluble biocompatible carrier exemplified here by dextran. A set of dextran-grafted probes varied in the degrees of Finland trityl radical loading and dextran modification by polyethelene glycol has been synthesized. The EPR spectrum of the optimized macromolecular probe exhibits a single narrow line with high sensitivity to oxygen and has advantages over the unbound Finland trityl of being insensitive to interactions with albumin. In vivo EPR imaging of tissue oxygenation performed in breast tumor-bearing mouse using dextran-grafted probe demonstrates its utility for preclinical oximetric applications.Graphical abstractGraphical abstract for this article
       
  • Discovery of novel quinoline sulphonamide derivatives as potent, selective
           and orally active RORγ inverse agonists
    • Abstract: Publication date: Available online 9 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Jérôme Amaudrut, Maria A. Argiriadi, Martine Barth, Eric C. Breinlinger, Didier Bressac, Pierre Broqua, David J. Calderwood, Mohamed Chatar, Kevin P. Cusack, Stephen B. Gauld, Sébastien Jacquet, Rajesh V. Kamath, Michael E. Kort, Valérie Lepais, Jean-Michel Luccarini, Philippe Masson, Christian Montalbetti, Laurent Mounier, Dominique Potin, Olivia Poupardin A high-throughput screen against Inventiva’s compound library using a Gal4/RORγ-LBD luciferase reporter gene assay led to the discovery of a new series of quinoline sulphonamides as RORγ inhibitors, eventually giving rise to a lead compound having an interesting in vivo profile after oral administration. This lead was evaluated in a target engagement model in mouse, where it reduced IL-17 cytokine production after immune challenge. It also proved to be active in a multiple sclerosis model (EAE) where it reduced the disease score. The synthesis, structure activity relationship (SAR) and biological activity of these derivatives is described herein.Graphical abstractGraphical abstract for this article
       
  • Synthesis and comparison of substituted 1,2,3-dithiazole and
           1,2,3-thiaselenazole as inhibitors of the feline immunodeficiency virus
           (FIV) nucleocapsid protein as a model for HIV infection
    • Abstract: Publication date: Available online 9 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Christopher R.M. Asquith, Theres Meili, Tuomo Laitinen, Ilia V. Baranovsky, Lidia S. Konstantinova, Antti Poso, Oleg A. Rakitin, Regina Hofmann-Lehmann We report the first biological evaluation the 1,2,3-thiaselenazole class of compound and utilising a concise synthetic approach of sulfur extrusion, selenium insertion of the 1,2,3-dithiazoles. We created a small diverse library of compounds to contrast the two ring systems. This approach has highlighted new structure activity relationship insights and lead to the development of sub-micro molar anti-viral compounds with reduced toxicity. The 1,2,3-thiaselenazole represents a new class of potential compounds for the treatment of FIV and HIV.2019 Elsevier Ltd. All rights reserved.Graphical abstractGraphical abstract for this article
       
  • Generation of C5-desoxy analogs of tetrahydroisoquinoline alkaloids
           exhibiting potent DNA alkylating ability
    • Abstract: Publication date: Available online 9 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Ryo Tanifuji, Kaori Tsukakoshi, Kazunori Ikebukuro, Hideaki Oikawa, Hiroki Oguri C5-desoxy analogs of tetrahydroisoquinoline (THIQ) alkaloids were designed and synthesized as hitherto unexplored structural variants for evaluation of their DNA alkylating activities. While chemical synthesis of the C5-desoxy analogs bearing a phenolic hydroxyl group in the A-ring of the saframycins was assumed to be laborious based on semi-synthetic modifications, a chemo-enzymatic approach allowed for concise access to the analogs. The C5-desoxy analog 7 exhibited greater DNA alkylating ability with a wider tolerance for the sequence variations compared to cyanosafracin B. The C5-desoxy A-ring having a C8 phenolic hydroxyl group, and a C1 substituent in the vicinity of the C21 aminonitrile responsible for DNA alkylation, were demonstrated to play pivotal roles in the interaction between the THIQ alkaloids and DNA.Graphical abstractGraphical abstract for this article
       
  • Synthesis and structure-activity relationship of
           4-alkoxy-thieno[2,3-b]pyridine derivatives as potent alkaline phosphatase
           enhancers for osteoporosis treatment
    • Abstract: Publication date: Available online 9 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Keiji Saito, Tsuyoshi Shinozuka, Akira Nakao, Toshihiro Kiho, Tomonori Kunikata, Takeshi Shiiki, Yoko Nagai, Satoru Naito The synthesis and structure-activity relationships of a novel series of 3-aminothieno[2,3-b]pyridine-2-carboxamides were explored. Our efforts were focused on modifying the C-4 substituent of the thienopyridine ring to develop orally available bone anabolic agents. 4-Alkoxy derivatives were found to be novel ALPase enhancers without inhibitory effect on P450 activity. Among these derivatives, compound 6k was orally administered to ovariectomized rats, and it was found to significantly improve areal bone mineral density at a dose of 30 mg/kg/day.Graphical abstractGraphical abstract for this article
       
  • Fasudil dichloroacetate (FDCA), an orally available agent with potent
           therapeutic efficiency on monocrotaline-induced pulmonary arterial
           hypertension rats
    • Abstract: Publication date: Available online 8 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Lei Qi, Tian Lv, Yusheng Cheng, Min Yu, Honghao Han, Hui Kong, Weiping Xie, Hong Wang, Yihua Zhang, Zhangjian Huang Given the therapeutic efficacy of fasudil hydrochloride (F) and dichloroacetate (DCA) on pulmonary arterial hypertension (PAH), a new salt fasudil dichloroacetate (FDCA) was designed, synthesized and biologically evaluated. FDCA exhibited comparable ROCK II inhibitory activity relative to fasudil hydrochloride, and suppressed the expression of TNF-α and IL-6 in both PDGF-BB and hypoxia-treated pulmonary arterial smooth muscle cells (PASMCs) and endothelial cells (PAECs). Significantly, FDCA lowered mean pulmonary artery pressure (mPAP) and right ventricular systolic pressure (RVSP), and decreased right ventricular hypertrophy (RVH) in monocrotaline (MCT)-induced PAH rats. Meanwhile, FDCA remarkably decreased pulmonary artery medial thickness (PAMT) and hyperplasia, restoring the elasticity of elastic fiber, reduced cardiac hypertrophy, and attenuated fibrosis of heart and lung. Collectively, FDCA exhibited triple activities of pulmonary vasodilation, vascular remodeling inhibition and RVH inhibition, suggesting that it may be a promising agent for PAH intervention.Graphical abstractGraphical abstract for this article
       
  • New phenylpropanoid allopyranosides from the rhizomes of Cimicifuga
           dahurica
    • Abstract: Publication date: Available online 8 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Qing Lu, Hai-bo Li, Qian-qian Pang, Wei-yang Zhang, Zhen-zhen Su, Da-bo Pan, Xin-Sheng Yao, Yang Yu Five new phenylpropanoid allopyranosides (1-5), along with five known compounds (6-10) were isolated from the rhizomes of Cimicifuga dahurica. Their structures were established by means of spectroscopic analyses and chemical methods, as well as comparison with literatures. The anti-inflammatory activities of all isolates were evaluated. Compounds 6, 9 and 10 exhibited inhibitory effects on PGE2 production in LPS stimulated RAW 264.7 macrophages with IC50 values of 19.72, 6.33 and 39.90 µM, respectively.Graphical abstractGraphical abstract for this article
       
  • Design and Synthesis of Functionalized Coumarins as Potential
           Anti-austerity Agents that Eliminates Cancer Cells' Tolerance to Nutrition
           Starvation
    • Abstract: Publication date: Available online 8 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Suresh Awale, Takahiro Okada, Dya Fita Dibwe, Takahiro Maruyama, Satoyuki Takahara, Takuya Okada, Satoshi Endo, Naoki Toyooka Human pancreatic tumor cells have inherent ability to tolerate nutrition starvation which enables them to survive in the hypovascular tumor microenvironment. Discovery of agents that selectively inhibit the cancer cells’ tolerance to nutrition starvation leading to cancer cell death is a new anti-austerity approach in anti-cancer drug discovery. A series of coumarins derivatives were synthesized and evaluated for their anti-austerity activity against PANC-1 human pancreatic cancer cell line. The compound 7-Hydroxy-2-oxo-2H-chromene-3-carboxylic acid (3-phenylpropyl)amide (2c) showed highly potent selective cytotoxicity against PANC-1 cells under nutrient-deprived conditions, with a PC50 value of 0.44 μM, without exhibiting toxicity in normal, nutrient-rich medium. Compound 2c caused dramatic alterations in PANC-1 cell morphology, leading to cell death. The compound 2c was found to inhibit PANC-1 cell migration and colony formation in a concentration-dependent manner. The compound 2c is a lead structure for the anti-austerity drug development against pancreatic cancer.Graphical abstractGraphical abstract for this article
       
  • Discovery of novel pyridazine derivatives as glucose transporter type 4
           (GLUT4) translocation activators
    • Abstract: Publication date: Available online 8 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Takashi Tsuji, Mitsuhiro Yamaguchi, Junichi Kuroyanagi, Shinji Furuzono, Masahiro Konishi, Koji Terayama, Jun Tanaka, Motoko Saito, Yoshiyuki Kobayashi We report herein the synthesis and structure-activity relationships (SAR) of a series of pyridazine derivatives with the activation of glucose transporter type 4 (GLUT4) translocation. Through a cell-based phenotype screening in L6-GLUT4-myc myoblasts and functional glucose uptake assays, lead compound 1a was identified as a functional small molecule. After further derivatization, the thienopyridazine scaffold as the central ring (B-part) was revealed to have potent GLUT4 translocation activities. Consequently, we obtained promising compound 26b, which showed a significant blood glucose lowering effect in the severe diabetic mice model (10-week aged db/db mice) after oral dosing even at 10 mg/kg, implying that our pyridazine derivatives have potential to become novel therapeutic agents for diabetes mellitus.Graphical abstractGraphical abstract for this article
       
  • A pre-targeting strategy for imaging glucose metabolism using
           technetium-99m labelled dibenzocyclooctyne derivative
    • Abstract: Publication date: Available online 8 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Jin Ding, Hang Su, Fan Wang, Taiwei Chu During the last four decades, nuclear medicine has undergone enormous growth, and positron emission tomography (PET) has been in the driving seat for most of the time. 18F-fluorodeoxyglucose (17F-FDG) is the most widely used agent for the detection of hibernating myocardium and metabolically active cancer tissue. But its cost and limited availability are the main limitations. For a long time different researchers and groups of pharmacists have tried to label glucose with a cheaper and long-acting radionuclide like 99mTc. However, they failed to achieve this goal owing to the chemical complexity of 99mTc and the lack of maintaining the physiological activity of diagnostic compounds. A pre-targeting strategy based on strain-promoted [3+2] azide-alkyne cycloaddition (SPAAC) reaction was applied to solve this problem. Functional click synthons were synthesized: 2-azido-2-deoxy-D-glucose (GlucN3) as a glucose analogues, and N- (2- (2- (2- (bis (pyridin-2-ylmethyl) amino) ethoxy) ethoxy) ethyl-2- (6H-11,12-didehydrodibenzo [a,e] cycloocten-5-ylideneaminooxy) acetamide (C7) as a 99mTc(CO)3 labeling and azido-binding group. The results of biodistribution experiments in mice bearing S180 tumor show the relatively high tumor/blood ratio (up to 2.95) and tumor/muscle ratio (up to 6.37), and both of them decreases significantly in the glucose blocking experiment. It indicates that GlucN3 behaves similarly to glucose and that in vivo SPAAC reactions can occur effectively. It is supposed that this pre-targeting strategy can indeed enhance target specificity and may be used for glucose metabolism imaging in tumor diagnosis.Graphical abstractGraphical abstract for this article
       
  • Synthesis and biological evaluation of novel 4,7-dihydroxycoumarin
           derivatives as anticancer agents
    • Abstract: Publication date: Available online 7 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Pilli Govindaiah, Naresh Dumala, Paramjit Grover, M. Jaya Prakash A series of novel 4,7-dihydroxycoumarin based acryloylcyanohydazone derivatives were synthesized and evaluated for antiproliferative activity against four different cancer cell lines (A549, HeLa, SKNSH, and MCF7). Most of the compounds displayed potent cytotoxicity with IC50 values ranging from 3.42 to 31.28 µM against all the tested cancer cell lines. The most active compound, 8h was evaluated for pharmacological mechanistic studies on cell cycle progression and tubulin polymerization inhibition assay. The results revealed that the compound 8h induced the cell cycle arrest at G2/M phase and inhibited tubulin polymerization with IC50 = 6.19 µM. Experimental data of the tubulin polymerization inhibition assay was validated by molecular docking technique and the results exhibited strong hydrogen bonding interactions with amino acids (ASN-101, TYR-224, ASN-228, LYS-254) of tubulin.Graphical abstractGraphical abstract for this article
       
  • Novel benzothiazole hydrazine carboxamide hybrid scaffolds as potential in
           vitro GABA AT enzyme inhibitors: Synthesis, molecular docking and
           antiepileptic evaluation
    • Abstract: Publication date: Available online 7 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Sadaf Jamal Gilani, Mohd. Zaheen Hassan, Syed Sarim Imam, Chandra Kala, Surya Prakash Dixit In the present study, a series of newer benzothiazole derivatives containing thiazolidin-4-one (5a-g) and azetidin-2-one (6a-g), were synthesized by the cyclization of benzothiazolyl arylidene hydrazine carboxamide derivatives with thioglycolic acid and chloroacetyl chloride, respectively. Results of in vivo anticonvulsant screening revealed that compounds having 2,4-dicholoro (5c and 6c) and 4-nitro substituent (5g) at the phenyl ring have promising anticonvulsant activities without any neurotoxicity. Selected compounds were also evaluated for their in vitro GABA AT inhibition. The results indicated that compound 5c (IC50 15.26 μM) exhibited excellent activity as compared to the standard drug vigabatrin (IC50 39.72 μM) suggesting the potential of these benzothiazole analogues as new anticonvulsant agents.Graphical abstractGraphical abstract for this article
       
  • Structure based designing of triazolopyrimidone-based reversible
           inhibitors for kinases involved in NSCLC
    • Abstract: Publication date: Available online 7 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Pankaj Kumar Singh, Dasharath Chaudhari, Sanyog Jain, Om Silakari Secondary acquired mutant EGFR (L858R-T790M) overexpressed NSCLC forms one of the prevalent form of resistant NSCLC. Another subset of resistant NSCLC includes amplified cMET in mutant EGFR derived tumours. Thus, in continuation to our previous work on these two major targets of resistant NSCLC, i.e., EGFR (L858R-T790M) and cMET, we are hereby reporting reversible inhibitors of these kinases. Out of 11 lead molecules reported in our previous study, we selected triazolo-pyrimidone (BAS 09867482) scaffold for further development of small molecule dual and reversible inhibitors. Analogues of lead with different substituents on the side ring were sketched and docked in both the target kinases, followed by molecular dynamic simulations. Analogues maintaining hydrophobic interaction with M790 in secondary acquired mutant EGFR (L858R-T790M) were selected and duly synthesized. In vitro biochemical evaluation of these molecules against EGFR (L858R-T790M) and cMET kinase, along with EGFR (L858R) kinase disclosed that three molecules were having significant dual kinase inhibitory potential with IC50 values well below 100 nM. Further, in vitro anti-proliferative assay against three cell lines (A549, A431 and H460) was performed. Out of all, two compounds were having significant potency against these cell lines.Graphical abstractGraphical abstract for this article
       
  • Design and synthesis of novel
           1-phenyl-3-(5-(pyrimidin-4-ylthio)-1,3,4-thiadiazol- 2-yl)urea derivatives
           with potent anti-CML activity throughout PI3K/AKT signaling pathway
    • Abstract: Publication date: Available online 7 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Weiwei Li, Jianjie Chu, Tingting Fan, Wei Zhang, Minna Yao, Zeqiong Ning, Mingming Wang, Jin Sun, Xian Zhao, Aidong Wen In this investigation, a series of 1-phenyl-3-(5-(pyrimidin-4-ylthio)-1,3,4- thiadiazol-2-yl)urea receptor tyrosine kinase inhibitors were synthesized by a simple and efficient structure-based design. Structure-activity relationship (SAR) analysis of these compounds based on cellular assays led to the discovery of a number of compounds that showed potent activity against human chronic myeloid leukemia (CML) cell line K562, but very weak or no cellular toxicity through monitoring the growth kinetics of K562 cell during a period of 72 hours using the real-time live-cell imaging. Among these compounds, 1-(5-((6-((3-morpholinopropyl) amino)pyrimidin-4-yl)thio)-1,3,4-thiadiazol-2-yl)-3-(4-(trifluoromethyl)phenyl)urea (7) exhibited the least cellular toxicity and better biological activity in cellular assays (K562, IC50: 0.038 μM). Compound 7 also displayed very good induced-apoptosis effect for human CML cell line K562 and exerted its effect via a significantly reduced protein phosphorylation of PI3K/Akt signal pathway by Human phospho-kinase array analysis. In vitro results indicate that 1-phenyl-3-(5-(pyrimidin-4-ylthio)-1,3,4- thiadiazol-2-yl)urea derivatives are lead molecules for further development as treatment of chronic myeloid leukemia and cancer.Graphical abstractGraphical abstract for this article
       
  • First-generation structure-activity relationship studies of
           2,3,4,9-tetrahydro-1H-carbazol-1-amines as CpxA phosphatase inhibitors
    • Abstract: Publication date: Available online 6 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Yangxiong Li, Jessi J. Gardner, Katherine R. Fortney, Inga V. Leus, Vincent Bonifay, Helen I. Zgurskaya, Alexandre A. Pletnev, Sheng Zhang, Zhong-Yin Zhang, Gordon W. Gribble, Stanley M. Spinola, Adam S. Duerfeldt Genetic activation of the bacterial two component signal transduction system, CpxRA, abolishes the virulence of a number of pathogens in human and murine infection models. Recently, 2,3,4,9-tetrahydro-1H-carbazol-1-amines were shown to activate the CpxRA system by inhibiting the phosphatase activity of CpxA. Herein we report the initial structure-activity relationships of this scaffold by focusing on three approaches 1) A-ring substitution, 2) B-ring deconstruction to provide N-arylated amino acid derivatives and 3) C-ring elimination to give 2-ethylamino substituted indoles. These studies demonstrate that the A-ring is amenable to functionalization and provides a promising avenue for continued optimization of this chemotype. Further investigations revealed that the C-ring is not necessary for activity, although it likely provides conformational constraint that is beneficial to potency, and that the (R) stereochemistry is required at the primary amine. Simplification of the scaffold through deconstruction of the B-ring led to inactive compounds, highlighting the importance of the indole core. A new lead compound 26 was identified, which manifests a ∼30-fold improvement in CpxA phosphatase inhibition over the initial hit. Comparison of amino and des-amino derivatives in bacterial strains differing in membrane permeability and efflux capabilities demonstrate that the amine is required not only for target engagement but also for permeation and accumulation in Escherichia coli.Graphical abstractGraphical abstract for this article
       
  • Chemical constituents from the seeds of Cassia obtusefolia and their in
           vitro α-glucosidase inhibitory and antioxidant activities
    • Abstract: Publication date: Available online 3 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Han-Yan Luo, Ri-Xin Guo, Xian-Kuo Yu, Xiao Zhang, Ya-Qi Lu, Hong-wei Wu, Li-Ying Tang, Zhu-ju Wang Basing on chromatographic separation techniques, fifteen aglycones (1-15), including two new anthraquinone aglycones (1, 2) and thirteen known compounds (3-15), were isolated from the small polar fraction of Cassia obtusefolia (petroleum ether extract). Structural elucidations were performed by 1D/2D NMR spectroscopy and mass spectrometry. The in vitro antioxidant and α-glucosidase inhibitory activities of these fifteen compounds were determined. Except compounds 12 (IC50 3.03±0.31 μg/mL, stronger than ascorbic acid, which IC50 was 6.48±2.30 μg/mL) and 13 (IC50 78.40±2.39 μg/mL), the free radical scavenging capacities of other compounds were weak. Compounds 4, 5, 6 and 13 exhibited inhibitory activities on α-glucosidase with IC50 values of 50.60±1.10, 22.57±0.07, 60.09±1.40, and 80.01±2.66 μg/mL separately, however, all the α-glucosidase inhibitory activities were weaker than positive control (acarbose).Graphical abstractGraphical abstract for this article
       
  • Synthesis and Biological Evaluation of
           2-Chloro-3-[(thiazol-2-yl)amino]-1,4-naphthoquinones
    • Abstract: Publication date: Available online 3 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Emmanuel O. Olawode, Roman Tandlich, Earl Prinsloo, Michelle Isaacs, Heinrich Hoppe, Ronnett Seldon, Digby F. Warner, Vanessa Steenkamp, Perry T. Kaye A series of novel, substituted 2-chloro-3-[(thiazol-2-yl)amino]-1,4-naphthoquinones have been prepared and shown to exhibit promising concentration-dependent activity against human SH-SY5Y cells, Plasmodium falciparum, Mycobacterium tuberculosis and P. aeruginosa. Substituent effects on observed bioactivity have been explored; the para-fluorophenyl derivative 3d exhibited activity across the range of the bioassays employed, indicating the potential of the 2-chloro-3-[(4-arylthiazol-2-yl)amino]-1,4-naphthoquinone scaffold in the development of novel, broad spectrum therapeutics.Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC
    • Abstract: Publication date: 15 June 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 12Author(s):
       
  • Graphical abstract TOC continued
    • Abstract: Publication date: 15 June 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 12Author(s):
       
  • Graphical abstract TOC
    • Abstract: Publication date: 15 June 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 12Author(s):
       
  • In vitro inhibitory effects of cirsiliol on IL-6-induced STAT3 activation
           through anti-inflammatory activity
    • Abstract: Publication date: Available online 2 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Hyung Jin Lim, Hyun Jae Jang, Seon Gyeong Bak, Soyoung Lee, Seung Woong Lee, Kang Min Lee, Seung-Jae Lee, Mun-Chual Rho Many studies have identified and described various medicinal effects of cirsiliol. Here, we investigated the signaling pathway involved in the anti-inflammatory effects of cirsiliol on IL-6-induced activity. Cirsiliol showed no cytotoxicity and inhibited pSTAT3-induced luciferase activity. At the molecular level, cirsiliol suppressed the expression of IL-6-induced inflammatory marker genes such as CRP, IL-1β, ICAM-1 and SOCS3, IL-6-induced activation of Jak2, gp130, STAT3 and ERK and nuclear translocation of STAT3, as measured by PCR, immunofluorescence staining and western blot analysis. However, the interaction between IL-6 and its receptor was not affected by cirsiliol treatment. These results indicate that cirsiliol attenuates IL-6-induced cellular signaling by regulating Jak2 phosphorylation. Therefore, cirsiliol could be a therapeutic agent for IL-6-related inflammatory diseases.Graphical abstractGraphical abstract for this article
       
  • Novel Triazine-based pyrimidines suppress glomerular mesangial cells
           proliferation and matrix protein accumulation through a ROS-dependent
           mechanism in the diabetic milieu
    • Abstract: Publication date: Available online 2 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Mira Diab El-Harakeh, Rachel Njeim, Ali Youssef, Natalie Youssef, Assaad A. Eid, Kamal H. Bouhadir Diabetic nephropathy (DN) is one of the most serious complications of diabetes worldwide. It is depicted as the leading cause of end-stage renal disease. Oxidative stress plays a key role in hyperglycemia-induced DN. The preparation and characterization of novel mono-, di-, and trisubstituted-s-triazines endowed with uracil and/or thymine are described in this paper. The synthesis of the title compounds was realized through selective nucleophilic substitution reactions of cyanuric chloride with the corresponding hydrazide nucleobases. In this study, we assessed the effects of these derivatives on the progression of diabetic nephropathy. Our results show that trisubstituted-s-triazines endowed with acylhydrazides attenuate high-glucose induced glomerular mesangial cells proliferation and matrix protein accumulation in vitro. Notably, these derivatives also display anti-oxidative properties. This suggests that the novel trisubstituted-s-triazine derivatives provide renal protection through a reactive oxygen species (ROS)-dependent mechanism. Our data provide evidence that these derivatives may serve as potential therapeutic candidates in the treatment of DN.Graphical abstractGraphical abstract for this article
       
  • Corrigendum to ‘Synthesis and biological evaluation of
           Doxorubicin-containing conjugate targeting PSMA’ [Bioor. Med. Chem.
           Lett. 29/10 (2019) 1246–1255]
    • Abstract: Publication date: Available online 2 May 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Yan A. Ivanenkov, Alexey E. Machulkin, Anastasia S. Garanina, Dmitry A. Skvortsov, Anastasia A. Uspenskaya, Ekaterina V. Deyneka, Alexander V. Trofimenko, Elena K. Beloglazkina, Nikolay V. Zyk, Victor E. Koteliansky, Dmitry S. Bezrukov, Anastasia V. Aladinskaya, Nataliya S. Vorobyeva, Maria M. Puchinina, Grigory K. Ryabykh, Alina A. Sofronova, Alexander S. Malyshev, Alexander G. Majouga
       
  • Lead generation of 1,2-dithiolanes as exon 19 and exon 21 mutant EGFR
           tyrosine kinase inhibitors
    • Abstract: Publication date: Available online 20 April 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Tarek S. Mansour, Vijay Potluri, Ranga R. Pallepati, Vishnu Basetti, Mallaiah Keesara, Ashok G. Moghudula, Pranab MaitiGraphical abstractGraphical abstract for this article
       
  • Synthesis and evaluation of the HIF-1α inhibitory activities of novel
           ursolic acid tetrazole derivatives
    • Abstract: Publication date: Available online 17 April 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Lin-Hao Zhang, Zhi-Hong Zhang, Ming-Yue Li, Zhi-Yu Wei, Xue-Jun Jin, Hu-Ri Piao The hypoxia-inducible factor-1α (HIF-1α) pathway has been implicated in tumor angiogenesis, growth, and metastasis. Therefore, the inhibition of this pathway is an important therapeutic target for the treatment of various types of cancers. Here, we designed and synthesized 31 ursolic acid (UA) derivatives containing a tetrazole moiety and evaluated them for their potential anti-tumor activities as HIF-1α transcriptional inhibitors. Of these, compound 14d (IC50 0.8 ± 0.2 µM) displayed the most potent activity and compounds 14a (IC50 4.7 ± 0.2 µM) exhibited the most promising biological profile. Analysis of the structure–activity relationships of these compounds with HIF-1α suggested that the presence of a tetrazole group located at C-28 of the UA derivatives was critical for their inhibitory activities.Graphical abstractGraphical abstract for this article
       
  • Characterization of the substrate scope of an alcohol dehydrogenase
           commonly used as methanol dehydrogenase
    • Abstract: Publication date: Available online 16 April 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Xiaojia Guo, Yanbin Feng, Xueying Wang, Yuxue Liu, Wujun Liu, Qing Li, Junting Wang, Song Xue, Zongbao K. Zhao Many alcohol dehydrogenases (ADHs) catalyze oxidation of a broad scope of alcohols. When an NAD-dependent ADH oxidizes metahnol, albeit at a poor rate, it may be treated as methanol dehydrogenase (MDH). One ADH from Geobacillus stearothermophilus DSM 2334 (GsADH) has been widely used as MDH, but its actual substrate scope remains less characterized. Here we purified recombinant GsADH from Escherichia coli and determined its crystal structure. We collected kinetics data of this enzyme towards a number of short chain alcohols, and found that iso-propanol is by far the most favorable substrate. Moreover, molecular docking analysis suggested that substrate preference is mainly attributed to the conformer energy of the protein-substrate complex. Our data clarified the substrate scope of GsADH and provided structural insights, which may facilitate more efficient cofactor regeneration and rational metabolic engineering.Graphical abstractGraphical abstract for this article
       
  • Xylo-C-nucleosides with a pyrrolo[2,1-f][1,2,4]triazin-4-amine
           heterocyclic base: Synthesis and antiproliferative properties
    • Abstract: Publication date: Available online 15 April 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Peng Nie, Elisabetta Groaz, Dirk Daelemans, Piet Herdewijn The synthesis of a xylo-C-nucleoside containing pyrrolo[2,1-f][1,2,4]triazin-4-amine as nucleobase along with that of its 1’-cyano analogue is described. Among different experimental conditions explored in order to optimize a key debenzylation step in the presented synthetic route, it was found that palladium catalyzed hydrogen transfer allowed for obtaining the target compounds in good yields. The resulting mixture of epimers was separated and each was characterized by NOESY NMR experiments. In vitro antiproliferative assays showed that the 1’-unsubstituted analogue was active against a panel of tumor cell lines such as the human leukemia HL-60 (IC50 = 1.9 µM) and lung cancer NCI-H460 (IC50 = 2.0 µM) cells.Graphical abstractGraphical abstract for this article
       
  • Structure Guided Drug Design to Develop Kallikrein 5 inhibitors to Treat
           Netherton Syndrome
    • Abstract: Publication date: Available online 12 April 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Ann L. Walker, Ryan P. Bingham, Emma V. Edgar, Alan Ferrie, Duncan S. Holmes, John Liddle, Oxana Polyakova, Monika Rella, Kathrine J. Smith, James H. Thorpe, Yichen Wang, Gemma V. White, Robert J. Young, Alain Hovnanian The connection between Netherton syndrome and overactivation of epidermal / dermal proteases particularly KLK5 has been well established. To treat sufferers of this severe condition we wished to develop a topical KLK5 inhibitor in order to normalise epidermal shedding and reduce the associated inflammation and itching. In this paper we describe structure-based optimisation of a series of brightly coloured weak KLK5 inhibitors into colourless, non-irritant molecules with good KLK5 activity and selectivity over a range of serine proteases.Graphical abstractGraphical abstract for this article
       
  • 3-Substituted Quinolines as RORγt Inverse Agonists
    • Abstract: Publication date: Available online 12 April 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Virginia M. Tanis, Hariharan Venkatesan, Maxwell D. Cummings, Michael Albers, J. Kent Barbay, Krystal Herman, David A. Kummer, Cynthia Milligan, Marina I. Nelen, Rachel Nishimura, Thomas Schlueter, Brian Scott, John Spurlino, Ronald Wolin, Craig Woods, Xiaohua Xue, James P. Edwards, Anne M. Fourie, Kristi Leonard We have previously reported the syntheses of a series of 3,6-disubstituted quinolines as modulators of the retinoic acid receptor-related orphan receptor gamma t (RORγt). These molecules are potent binders but are high molecular weight and they exhibited poor solubility at pH 2 and pH 7. This manuscript details our efforts at improving physical chemical properties for this series of compounds by increasing the diversity at the 3-position (i.e. introducing heteroatoms and lowering the molecular weight). These efforts have led to molecules which are potent binders with improved solubility.Graphical abstractWe have previously reported the syntheses of a series of 3,6-disubstituted quinolines as modulators of the retinoic acid receptor-related orphan receptor gamma t (RORγt). These molecules, such as 1, are potent binders but are high molecular weight and they exhibited poor solubility at pH 2 and pH 7. This manuscript details our efforts at improving physical chemical properties for this series of compounds by increasing the diversity at the 3-position (i.e. introducing heteroatoms and lowering the molecular weight). These efforts have led to molecules such as 27 and 30 which are potent binders with improved solubility.Graphical abstract for this article
       
  • Structure-activity relationship study of antitrypanosomal chalcone
           derivatives using multivariate analysis
    • Abstract: Publication date: Available online 12 April 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Kaio de S. Gomes, Thais A. da Costa-Silva, Igor H. Oliveira, Andrea M. Aguilar, Diogo Oliveira-Silva, Miriam Uemi, Wender A. Silva, Lennine R. Melo, Carlos Kleber Z. Andrade, Andre G. Tempone, João L. Baldim, João Henrique G. Lago Chagas disease represents one of several neglected diseases with reduced number of chemotherapeutical drugs including the highly toxic compounds benznidazole and nifurtimox. In this sense, natural products represent an import scaffold for discovery of new biologically active compounds, in which chalcones are promising representatives due to their antitrypanosomal potential. In this work, a series of 36 chalcone derivatives were synthesized and tested against trypomastigotes of Trypanosoma cruzi. In addition, a detailed investigation on their molecular features was performed. The obtained results suggest that certain molecular features are fundamental for an efficient antitrypanosomal potential of chalcones, such as allylic groups, α,β–unsaturated carbonyl system and aromatic hydroxyl groups. These results were obtained based on the interpretation of machine-learning and multivariate statistical methods, which revealed the essential characteristics of chalcone prototypes against trypomastigotes of T. cruzi.Graphical abstractGraphical abstract for this article
       
  • Potent and selective inhibitors of receptor-interacting protein kinase 1
           that lack an aromatic back pocket group
    • Abstract: Publication date: Available online 11 April 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Gregory L. Hamilton, Huifen Chen, Gauri Deshmukh, Charles Eigenbrot, Rina Fong, Adam Johnson, Pawan Bir Kohli, Patrick J. Lupardus, Bianca M. Liederer, Sreemathy Ramaswamy, Haowei Wang, Jian Wang, Zhaowu Xu, Yunliang Zhu, Domagoj Vucic, Snahel Patel Receptor-interacting protein kinase 1 (RIPK1), a key component of the cellular necroptosis pathway, has gained recognition as an important therapeutic target. Pharmacologic inhibition or genetic inactivation of RIPK1 has shown promise in animal models of disease ranging from acute ischemic conditions, chronic inflammation, and neurodegeneration. We present here a class of RIPK1 inhibitors that is distinguished by a lack of a lipophilic aromatic group present in most literature inhibitors that typically occupies a hydrophobic back pocket of the protein active site. Despite not having this ubiquitous feature of many known RIPK1 inhibitors, we were able to obtain compounds with good potency, kinase selectivity, and pharmacokinetic properties in rats. The use of the lipophilic yet metabolically stable pentafluoroethyl group was critical to balancing the potency and properties of optimized analogsGraphical abstractGraphical abstract for this article
       
  • Design, Synthesis and Biological Activity of Deuterium-Based FFA1 Agonists
           with Improved Pharmacokinetic Profiles
    • Abstract: Publication date: Available online 10 April 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Bing Liu, Liming Deng, Haidong Chen, Ruoxian Liao, Yuyi Li, Xiaohua Zeng, Fengjian Deng, Luyong Zhang, Zheng Li The free fatty acid receptor 1 (FFA1) is considered as a promising anti-diabetic target based on its function of glucose-stimulated insulin secretion. The previously reported compound 2 is a highly potent FFA1 agonist, but it might be suffered from poor pharmacokinetic properties because the phenylpropanoic acid is vulnerable to β-oxidation. To identify orally available analogs, we tried to block the route of β-oxidation by incorporating deuterium at phenylpropionic acid moiety. As expected, the deuterium-based analogs 3 and 4 exhibited better pharmacokinetic properties than parent compound 2. Although the difference of potency between compound 2 and 3 is quite small, the glucose-lowering effect of deuterium analog 3 was better than that of compound 2. Meanwhile, compound 3 docked well into the same binding pocket of TAK-875, and formed almost identical interactions of TAK-875 in binding site. Different from glibenclamide, a lower risk of hypoglycemia was observed in compound 3 even at the high dose of 60 mg/kg.Graphical abstractTo improve PK properties of compound 2, the deuterium strategy was developed to block the β-oxidation of phenylpropionic acid. As expected, the deuterium-based analog 3 exhibited better pharmacokinetic properties and glucose-lowering effect than compound 2.Graphical abstract for this article
       
  • Synthesis and in vitro biological evaluation of new P2X7R radioligands
           [11C]halo-GSK1482160 analogs
    • Abstract: Publication date: Available online 10 April 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Mingzhang Gao, Min Wang, Jill A. Meyer, Paul R. Territo, Gary D. Hutchins, Hamideh Zarrinmayeh, Qi-Huang Zheng The reference standards halo-GSK1482160 (F-, Br-, and I-) and their corresponding precursors desmethyl-halo-GSK1482160 (F-, Br-, and I-) were synthesized from (S)-1-methyl-5-oxopyrrolidine-2-carboxylic acid or (S)-5-oxopyrrolidine-2-carboxylic acid and 2-halo-3-(trifluoromethyl)benzylamine (F-, Br-, and I-) in one step with 45-93% yields. The target tracers [11C]halo-GSK1482160 (F-, Br-, and I-) were prepared from desmethyl-halo-GSK1482160 (F-, Br-, and I-) with [11C]CH3OTf under basic conditions (NaOH-Na2CO3, solid, w/w 1:2) through N-[11C]methylation and isolated by HPLC combined with SPE in 40-50% decay corrected radiochemical yield. The radiochemical purity was>99%, and the molar activity (AM) at end of bombardment (EOB) was 370-740 GBq/μmol. The potency of halo-GSK1482160 (F-, Br-, and I-) in comparison with GSK1482160 (Cl-) was determined by a radioligand competitive binding assay using [11C]GSK1482160, and the binding affinity Ki values for halo-GSK1482160 (F-, Br-, and I-) and GSK1482160 (Cl-) are 54.2, 2.5, 1.9 and 3.1 nM, respectively.Graphical abstractGraphical abstract for this article
       
  • Investigation of biaryl heterocycles as inhibitors of Wee1 kinase
    • Abstract: Publication date: Available online 9 April 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Anthony Mastracchio, Chunqiu Lai, Maricel Torrent, Kenneth Bromberg, Fritz G. Buchanan, Debra Ferguson, Velitchka Bontcheva, Eric F. Johnson, Loren Lasko, David Maag, Nirupama Soni, Alexander R. Shoemaker, Thomas D. Penning Wee1 is a key tyrosine kinase that helps control the G2/M checkpoint by preventing entry into mitosis.1, 2 This is of particular interest for cancer therapy since many cancer cells depend more heavily than do normal cells on a functional G2/M checkpoint for DNA repair.3, 4, 5 This suggests that inhibition of Wee1 could induce premature entry into mitosis of DNA damaged cancer cells leading to mitotic catastrophe and cell death.6, 7 Following on this insight many cancer programs have focused on the development of selective drug-like Wee1 inhibitors.8, 9, 10 AZD1775 (aka MK-1775, adavosertib), the first selective Wee1 inhibitor reported, is currently in clinical trials for the treatment of solid tumors. Clinical results for AZD1775 showed on-target efficacy as a single agent and in combination thus providing additional support for targeting Wee1 in cancer.11, 12, 13Graphical abstractGraphical abstract for this article
       
  • Synthesis and evaluation of histamine H3 receptor ligand based on lactam
           scaffold as agents for treating neuropathic pain
    • Abstract: Publication date: Available online 8 April 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Fei Dou, Xudong Cao, Peng Jing, Chunyan Wu, Yuxin Zhang, Yin Chen, Guisen Zhang The synthesis and H3 receptor ligand of a new series of lactam derivatives are reported. The new compounds were evaluated in vitro in H3 and H1 receptor-binding assays. The structure-activity relationship led us to the promising derivative 2-methyl-7-(3-morpholinopropoxy)-3,4-dihydroisoquinolin-1(2H)-one (11). The compound with highest affinity and greatest selectivity were further profiled, In addition, compound 11 exerted dose-dependent anti-nociceptive effects in the formalin test. These characteristics suggested that the potent and selective compound 11 could be a potent candidate for pain treatment.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis of orally bioavailable novel anaplastic lymphoma kinase
           (ALK) inhibitor diphenylaminopyrimidine analogs and efficacy study on
           NCI-H2228 xenografts mice model
    • Abstract: Publication date: Available online 8 April 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Debasis Das, Jingbing Wang, Yong Li, Jingli Shi, Jian Hong Anaplastic lymphoma kinase (ALK) is an attractive therapeutic target for the treatment of non-small cell lung cancer (NSCLC). Within our ALK drug discovery program, we identified novel deuterated 2,4-diarylamino pyrimidine compounds as potent ALK inhibitors. The compound 11 showed better in vitro activity and in vivo efficacy with good pharmacokinetic profile. In vivo efficacy of compound 11 was better than standard drug ceritinib in NCI-H2228 xenograft mice model.Graphical abstractGraphical abstract for this article
       
  • Discovery of trans-3-(pyridin-3-yl)acrylamide-derived sulfamides as potent
           nicotinamide phosphoribosyltransferase (NAMPT) inhibitors for the
           potential treatment of cancer
    • Abstract: Publication date: Available online 8 April 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Kuojun Zhang, Yong Ni, Jiaxuan Chen, Zhengchao Tu, Xiaoxing Wu, Dong Chen, Hequan Yao, Sheng Jiang Nicotinamide phosphoribosyltransferase (NAMPT) has emerged as a promising target for the discovery of anticancer drugs. Based on NAMPT inhibitor FK866 that has been advanced into phase II trial, we identified a trans-3-(pyridin-3-yl)acrylamide compound 13 incorporating with a biarylsulfanilamide moiety as a new NAMPT inhibitor. Further structure-activity relationship (SAR) exploration led to additional biarylsulfanilamide-derived compounds with high in vitro NAMPT inhibitory potency and antiproliferative activity. In particular, compound 23, the most potent NAMPT inhibitor (IC50 = 5.08 nM), showed single-digit nanomolar antiproliferative activity against DU145, Hela, and H1975 cells with IC50 values of 2.90 nM, 2.34 nM, and 2.24 nM, respectively, and even subnanomolar level against K562, MCF-7, and HUH7 cells with IC50 values of 0.46 nM, 0.23 nM and 0.53 nM, respectively. Our findings provided promising lead compounds for the discovery of more potent NAMPT inhibitors as anticancer drugs.Graphical abstractGraphical abstract for this article
       
  • Microwave-assisted synthesis and in vitro stability of N-benzylamide
           non-steroidal anti-inflammatory drug conjugates for CNS delivery
    • Abstract: Publication date: Available online 8 April 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Brandon D. Eden, Andrew J. Rice, Troy D. Lovett, Olivia M. Toner, Evan P. Geissler, William E. Bowman, Sherri C. Young More effective delivery of non-steroidal anti-inflammatory drugs (NSAIDs) to the brain could treat the underlying inflammatory pathology of a range of CNS diseases and conditions. Use of a blood-brain barrier shuttle such as the N-benzylamide moiety, which has been largely unexplored for this purpose, could improve the brain bioavailabilities of NSAIDs. A series of novel N-benzylamide NSAID conjugates was synthesized via a three-step process with a microwave-assisted bimolecular nucleophilic substitution as the final step. We explored conditions to promote substitution over a competing elimination reaction, which was successfully suppressed with isopropyl alcohol solvent. All molecules exhibit physicochemical properties consistent with those of brain-penetrant molecules. Furthermore, they exhibit long (> 48 hr) half-lives in phosphate buffered saline (PBS; pH 7.4) and short to moderate half-lives in human plasma. N-Benzylamide NSAID conjugates represent promising CNS drug discovery leads.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and structure-activity relationship study of
           aminopyridine derivatives as novel inhibitors of Janus Kinase 2
    • Abstract: Publication date: Available online 6 April 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Wanqi Wang, Yanyan Diao, Wenjie Li, Yating Luo, Tingyuan Yang, Yuyu Zhao, TianTian Qi, Fangling Xu, Xiangyu Ma, Huan Ge, Yingfan Liang, Zhenjiang Zhao, Xin Liang, RuiWang, Lili Zhu, Honglin Li, Yufang Xu Janus Kinase 2 (JAK2) is a kind of intracellular non-receptor protein tyrosine kinase and has been certified as an important target for the treatment of myeloproliferative neoplasms and rheumatoid arthritis. However, the low selectivity and potential safety issues restrict the clinical applications of JAK2 inhibitors. Here we found that crizotinib showed good inhibitory activity against JAK2 by enzymatic assays (IC50 = 27 nM). Then we carried out structure-based drug design and synthesized a series of compounds with an aminopyridine scaffold. Finally, compound 12k and 12l were identified as the promising inhibitors of JAK2, which exhibited high inhibitory activity (IC50 =6 nM and 3 nM, respectively) and selectivity for JAK2 over JAK1 and JAK3, and showed potent antiproliferative activities toward HEL human erythroleukemia cells. Moreover, 12k suppressed symptoms of the collagen-induced arthritis (CIA) model in rats.Graphical abstractGraphical abstract for this article
       
  • Cynaropicrin and inhibition of NF-κB activation: A structure activity
           relationship study
    • Abstract: Publication date: Available online 4 April 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Jing Li, Yusuke Yoshida, Manami Kurita, Toyonobu Usuki Cynaropicrin is a guaianolide sesquiterpene lactone with a 5-7-5 tricyclic skeleton, four exo-olefins, and two hydroxyl groups. This natural product has various biological activities including anti-inflammatory properties and antitrypanosomal activity. It was also found to suppress photoaging of the skin by inhibiting the transcription activity of nuclear factor-kappa B (NF-κB). In this paper, nine chemical derivatives of cynaropicrin were prepared, and the structure activity relationship (SAR) study for NF-κB inhibition by measuring relative light units (RLU) was conducted.Graphical abstractGraphical abstract for this article
       
  • Discovery of a Class of Highly Potent Janus Kinase 1/2 (JAK1/2) Inhibitors
           Demonstrating Effective Cell-Based Blockade of IL-13 Signaling
    • Abstract: Publication date: Available online 4 April 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Mark Zak, Emily J. Hanan, Patrick Lupardus, David G. Brown, Colin Robinson, Michael Siu, Joseph P. Lyssikatos, F. Anthony Romero, Guiling Zhao, Terry Kellar, Rohan Mendonca, Nicholas C. Ray, Simon C. Goodacre, Peter H. Crackett, Neville McLean, Christopher A. Hurley, Po-wai Yuen, Yun-Xing Cheng, Xiongcai Liu, Marya Liimatta Disruption of interleukin-13 (IL-13) signaling with large molecule antibody therapies has shown promise in diseases of allergic inflammation. Given that IL-13 recruits several members of the Janus Kinase family (JAK1, JAK2, and TYK2) to its receptor complex, JAK inhibition may offer an alternate small molecule approach to disrupting IL-13 signaling. Herein we demonstrate that JAK1 is likely the isoform most important to IL-13 signaling. Structure-based design was then used to improve the JAK1 potency of a series of previously reported JAK2 inhibitors. The ability to impede IL-13 signaling was thereby significantly improved, with the best compounds exhibiting single digit nM IC50’s in cell-based assays dependent upon IL-13 signaling. Appropriate substitution was further found to influence inhibition of a key off-target, LRRK2. Finally, the most potent compounds were found to be metabolically labile, which makes them ideal scaffolds for further development as topical agents for IL-13 mediated diseases of the lungs and skin (for example asthma and atopic dermatitis, respectively).Graphical abstractGraphical abstract for this article
       
  • Synthesis and biological evaluation of new HIV-1 protease inhibitors with
           purine bases as P2-ligands
    • Abstract: Publication date: Available online 3 April 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Mei Zhu, Biao Dong, Guo-Ning Zhang, Ju-Xian Wang, Shan Cen, Yu-Cheng Wang Introducing purine bases to P2-ligands might enhance the potency of Human Immunodeficiency Virus-1 (HIV-1) protease inhibitory because of the carbonyl and NH groups promoting the formation of extensive H-bonding interactions. In this work, thirty-three compounds are synthesized and evaluated, among which inhibitors 16a, 16f and 16j containing N-2-(6-substituted-9H-purin-9-yl)acetamide as the P2-ligands along with 4-methoxylphenylsulfonamide as the P2'-ligand, display potent inhibitory effect on the activity of HIV-1 protease with IC50 43 nM, 42 nM and 68 nM in vitro, respectively.Graphical abstractGraphical abstract for this article
       
  • Singlet oxygen-activatable Paclitaxel prodrugs via intermolecular
           activation for combined PDT and chemotherapy
    • Abstract: Publication date: Available online 2 April 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Moses Bio, Kazi Md Mahabubur, Irene Lim, Pallavi Rajaputra, Robert E. Hurst, Youngjae You Systemic side effects and high hydrophobicity are major disadvantages of paclitaxel (PTX), one of the most popular anticancer drugs. Here, we present singlet oxygen (SO)-activatable and mitochondria-targeted PTX prodrugs to overcome these problems and boost the cytotoxic effect of photodynamic therapy (PDT). Three PTX prodrugs were prepared by conjugating PTX with various cationic groups. Hydrophobicity was determined in LogD7.4 value. Mitochondrial localization was confirmed by fluorescence confocal microscopy and uptake of mitochondria-specific fluorescence probe. Dark- and photo-toxicity were measured in AY-27 cells with MTT assay. All three prodrugs showed better hydrophilicity than PTX and improved phototoxicity when combined with protoporphyrin IX (PpIX) PDT. In conclusion, SO-activatable and higher hydrophilic PTX prodrugs were successfully prepared. This approach could be used to improve the antitumor efficacy of PDT without the systemic side effects of PTX.Graphical abstractGraphical abstract for this article
       
  • A cross-linking approach to map small molecule-RNA binding sites in cells
    • Abstract: Publication date: Available online 2 April 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Sai Pradeep Velagapudi, Yue Li, Matthew D. Disney Methods to identify RNAs bound by small molecules in cells are sparse. Herein, an advance to identify the direct RNA targets of small molecules in cells is described. The approach, dubbed Chemical Cross-Linking and Isolation by Pull-down to Map Small Molecule-RNA Binding Sites (Chem-CLIP-Map-Seq), appends a cross-linker and a purification tag onto a small molecule. In cells, the compound binds to RNA and undergoes a proximity-based reaction. The cross-linked RNA is purified and then amplified using a universal reverse transcription (RT) primer and gene-specific PCR primers. At nucleotides proximal to the binding site, RT “stops” are observed. This approach has broad utility in identifying and validating the RNA targets and binding sites of small molecules in the context of a complex cellular system.Graphical abstractGraphical abstract for this article
       
  • Identification and SAR Exploration of a Novel Series of Legumain
           Inhibitors
    • Abstract: Publication date: Available online 29 March 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Sharon L. Eddie, Aaron Gregson, Emma Graham, Stephanie Burton, Timothy Harrison, Roberta Burden, Christopher J. Scott, Paul B. Mullan, Rich Williams This letter describes the development of a series of potent and selective small molecule Legumain inhibitors suitable as chemical probes for in-vitro experiments. Our previous research had identified a dipeptide inhibitor utilizing a semi-reversible cyano warhead that generated 2, a cell active inhibitor. This work explores an alternative P2-P3 linker and further SAR exploration of the P3 group which led to the identification of 16i, a highly potent inhibitor with excellent physiochemical properties.Graphical abstractGraphical abstract for this article
       
 
 
JournalTOCs
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Email: journaltocs@hw.ac.uk
Tel: +00 44 (0)131 4513762
Fax: +00 44 (0)131 4513327
 
About JournalTOCs
API
Help
News (blog, publications)
JournalTOCs on Twitter   JournalTOCs on Facebook

JournalTOCs © 2009-