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  Subjects -> CHEMISTRY (Total: 931 journals)
    - ANALYTICAL CHEMISTRY (58 journals)
    - CHEMISTRY (663 journals)
    - CRYSTALLOGRAPHY (21 journals)
    - ELECTROCHEMISTRY (27 journals)
    - INORGANIC CHEMISTRY (43 journals)
    - ORGANIC CHEMISTRY (48 journals)
    - PHYSICAL CHEMISTRY (71 journals)

CHEMISTRY (663 journals)                  1 2 3 4 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 15)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 31)
ACS Applied Polymer Materials     Hybrid Journal  
ACS Catalysis     Hybrid Journal   (Followers: 55)
ACS Chemical Neuroscience     Hybrid Journal   (Followers: 22)
ACS Combinatorial Science     Hybrid Journal   (Followers: 21)
ACS Macro Letters     Hybrid Journal   (Followers: 29)
ACS Medicinal Chemistry Letters     Hybrid Journal   (Followers: 46)
ACS Nano     Hybrid Journal   (Followers: 380)
ACS Photonics     Hybrid Journal   (Followers: 15)
ACS Symposium Series     Full-text available via subscription   (Followers: 1)
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: 65)
Advanced Science Focus     Free   (Followers: 5)
Advances in Chemical Engineering and Science     Open Access   (Followers: 88)
Advances in Chemistry     Open Access   (Followers: 29)
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: 8)
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: 11)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 29)
Advances in Nanoparticles     Open Access   (Followers: 19)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Polymer Science     Hybrid Journal   (Followers: 49)
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: 13)
Aerosol Science and Engineering     Hybrid Journal  
African Journal of Bacteriology Research     Open Access  
African Journal of Chemical Education     Open Access   (Followers: 5)
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)
Alotrop     Open Access  
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 71)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 22)
American Journal of Chemistry     Open Access   (Followers: 35)
American Journal of Plant Physiology     Open Access   (Followers: 13)
American Mineralogist     Hybrid Journal   (Followers: 14)
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: 192)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 289)
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: 8)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 12)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 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: 33)
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   (Followers: 2)
Atomization and Sprays     Full-text available via subscription   (Followers: 5)
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: 403)
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: 25)
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: 6)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 184)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 91)
Bioorganic Chemistry     Hybrid Journal   (Followers: 10)
Biopolymers     Hybrid Journal   (Followers: 17)
Biosensors     Open Access   (Followers: 3)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 1)
Bitácora Digital     Open Access  
Boletin de la Sociedad Chilena de Quimica     Open Access  
Bulletin of Institute of Chemistry and Chemical Technology, Mongolian Academy of Sciences     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: 24)
Carbon     Hybrid Journal   (Followers: 72)
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: 14)
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: 76)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 27)
Chemical Physics Letters : X     Open Access   (Followers: 2)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Hybrid Journal   (Followers: 24)
Chemical Reviews     Hybrid Journal   (Followers: 233)
Chemical Science     Open Access   (Followers: 33)
Chemical Technology     Open Access   (Followers: 49)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 5)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 56)
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: 32)
Chemistry & Industry     Full-text available via subscription   (Followers: 8)
Chemistry - A European Journal     Hybrid Journal   (Followers: 191)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 17)
Chemistry Africa : A Journal of the Tunisian Chemical Society     Hybrid Journal  
Chemistry and Materials Research     Open Access   (Followers: 22)
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 Heterocyclic Compounds     Hybrid Journal   (Followers: 4)
Chemistry of Materials     Hybrid Journal   (Followers: 283)
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: 12)
Chromatographia     Hybrid Journal   (Followers: 22)
Chromatography     Open Access   (Followers: 3)
Chromatography Research International     Open Access   (Followers: 5)
Clay Minerals     Hybrid Journal   (Followers: 10)
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: 8)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 4)
Combustion Science and Technology     Hybrid Journal   (Followers: 24)
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: 8)
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: 2)
Computational and Theoretical Chemistry     Hybrid Journal   (Followers: 9)
Computational Biology and Chemistry     Hybrid Journal   (Followers: 13)
Computational Chemistry     Open Access   (Followers: 3)
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: 10)

        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: 91  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0960-894X
Published by Elsevier Homepage  [3181 journals]
  • 6-Substituted amiloride derivatives as inhibitors of the urokinase-type
           plasminogen activator for use in metastatic disease
    • Abstract: Publication date: 15 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 24Author(s): Benjamin J. Buckley, Hiwa Majed, Ashraf Aboelela, Elahe Minaei, Longguang Jiang, Karen Fildes, Chen-Yi Cheung, Darren Johnson, Daniel Bachovchin, Gregory M. Cook, Mingdong Huang, Marie Ranson, Michael J. Kelso The oral K+-sparing diuretic amiloride shows anti-cancer side-activities in multiple rodent models. These effects appear to arise, at least in part, through moderate inhibition of the urokinase-type plasminogen activator (uPA, Ki = 2.4 µM), a pro-metastatic trypsin-like serine protease that is upregulated in many aggressive solid malignancies. In applying the selective optimization of side-activity (SOSA) approach, a focused library of twenty two 6-substituted amiloride derivatives were prepared, with multiple examples displaying uPA inhibitory potencies in the nM range. X-ray co-crystal structures revealed that the potency increases relative to amiloride arise from increased occupancy of uPA’s S1β subsite by the appended 6-substituents. Leading compounds were shown to have high selectivity over related trypsin-like serine proteases and no diuretic or anti-kaliuretic effects in rats. Compound 15 showed anti-metastatic effects in a xenografted mouse model of late-stage lung metastasis.Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC
    • Abstract: Publication date: 15 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 24Author(s):
       
  • Design and evaluation of novel tetracyclic benzofurans as palm site
           allosteric inhibitors of HCV NS5B polymerase
    • Abstract: Publication date: 15 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 24Author(s): Hong Liu, Xing Dai, Shuwen He, Linda Brockunier, Karen Marcantonio, Steven W. Ludmerer, Fangbiao Li, Kung-I Feng, Ravi P. Nargund, Anandan Palani Hepatitis C virus (HCV) NS5B polymerase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Several novel and potent HCV NS5B non-nucleoside inhibitors with unique tetracyclic bezonfuran-based structures were prepared and evaluated. Similar to clinical developmental compound MK-8876, N-linked (compounds 1 and 2) and C-linked (compounds 3 and 4) tetracyclic structures maintained broad spectrum anti-replicon potency profiles and demonstrated moderate to excellent oral bioavailability and pharmacokinetic parameters across the three preclinical animal species. To better understand the importance of tetracyclic structures related to pan genotypic potency profiles especially against clinically relevant GT1a variants, the teracycles with different ring size were prepared and in vitro evaluations suggested compounds with six number ring have better overall potency profiles.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis, and biological evaluation of
           2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)sulfonyl)benzamide
           derivatives as potent HIV-1 Vif inhibitors
    • Abstract: Publication date: 15 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 24Author(s): Rong-Hong Zhang, Shan Wang, Rong-Hua Luo, Meng Zhou, Hong Zhang, Guo-Bo Xu, Yong-Long Zhao, Yong-Jun Li, Yong-Lin Wang, Guoyi Yan, Shang-Gao Liao, Yong-Tang Zheng, Rui Li Viral infectivity factor (Vif) is one of the accessory protein of human immunodeficiency virus type I (HIV-1) that inhibits host defense factor, APOBEC3G (A3G), mediated viral cDNA hypermutations. Previous work developed a novel Vif inhibitor 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide (1) with strong antiviral activity. Through optimizations on the two side branches, a series of compound 1 derivatives (2–18) were designed, synthesized and tested in vitro for their antiviral activities. The biological results showed that compound 5 and 16 inhibited the virus replication efficiently with EC50 values of 9.81 and 4.62 μM. Meanwhile, low cytotoxicities on H9 cells were observed for the generated compounds by the MTT assay. The structure–activity relationship of compound 1 was preliminarily clarified, which gave rise to the development of more potent Vif inhibitors.Graphical abstractGraphical abstract for this article
       
  • Functional expression of a highly-reducing polyketide synthase of
           Emericella variecolor IFM42010, an asteltoxin-producing strain, resulted
           in production of two polyenoic β-ketolactones with opposite
           stereochemistry
    • Abstract: Publication date: 15 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 24Author(s): Makoto Hashimoto, Hitomi Ichijo, Kotaro Fujiwara, Hitoshi Sugasawa, Seika Abo, Kimihito Matsudo, Nahoko Uchiyama, Yukihiro Goda, Isao Fujii The asteltoxin-producing fungus Emericella variecolor IFM42010 possesses 22 highly-reducing polyketide synthase (HR-PKS) genes. Of these, an HR-PKS with a methyltransferase domain but lacking an enoylreductase domain could be involved in the biosynthesis of asteltoxin and related compounds. From six such candidate HR-PKS genes, Ev460pks was analyzed by gene disruption in E. variecolor and heterologous expression in Aspergillus oryzae. The Ev460pks-disrupted strain retained asteltoxin production ability, indicating that Ev460pks is not involved in asteltoxin biosynthesis. The A. oryzae transformant harboring the Ev460pks gene produced compounds 1 and 2, along with several unidentified products possibly decomposed from 2. Spectroscopic analyses revealed that 1 was a 4-methyl-β-ketolactone with a methylheptatriene side-chain at the C-5 position, and 2 was also a 4-methyl-β-ketolactone, bearing a dimethyltetradecahexaene side-chain at the same position. The relative configuration at C-4 in compounds 1 and 2 was opposite.Graphical abstractGraphical abstract for this article
       
  • Synthesis, 3D-structure and stability analyses of NRPa-308, a new
           promising anti-cancer agent
    • Abstract: Publication date: 15 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 24Author(s): Etienne Brachet, Aurore Dumond, Wang-Qing Liu, Marie Fabre, Mohamed Selkti, Françoise Raynaud, Olivier Hermine, Rachid Benhida, Philippe Belmont, Christiane Garbay, Yves Lepelletier, Cyril Ronco, Gilles Pagès, Luc Demange We report herein the synthesis of a newly described anti-cancer agent, NRPa-308. This compound antagonizes Neuropilin-1, a multi-partners transmembrane receptor overexpressed in numerous tumors, and thereby validated as promising target in oncology. The preparation of NRPa-308 proved challenging because of the orthogonality of the amide and sulphonamide bonds formation. Nevertheless, we succeeded a gram scale synthesis, according to an expeditious three steps route, without intermediate purification. This latter point is of utmost interest in reducing the ecologic impact and production costs in the perspective of further scale-up processes. The purity of NRPa-308 has been attested by means of conventional structural analyses and its crystallisation allowed a structural assessment by X-Ray diffraction. We also reported the remarkable chemical stability of this molecule in acidic, neutral and basic aqueous media. Eventually, we observed for the first time the accumulation of NRPa-308 in two types of human breast cancer cells MDA-MB231 and BT549.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and biological evaluation of novel desloratadine
           derivatives with anti-inflammatory and H1 antagonize activities
    • Abstract: Publication date: 15 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 24Author(s): Feng Li, Qinlong Xu, Qihua Zhu, Zhaoxing Chu, Gaofeng Lin, Jiajia Mo, Yan Zhao, Jiaming Li, Guangwei He, Yungen Xu To improve the anti-inflammatory activity of desloratadine, we designed and synthesized a series of novel desloratadine derivatives. All compounds were evaluated for their anti-inflammatory and H1 antagonistic activities. Among them, compound 2c showed the strongest H1 antagonistic and anti-inflammatory activity. It also exhibited promising pharmacokinetic profiles and low toxicity. All these results suggest that compound 2c as a novel anti-allergic agent is worthy of further investigation.Graphical abstractTo improve the anti-inflammatory activity of desloratadine, we designed and synthesized a series of novel desloratadine derivatives. All compounds were evaluated for their anti-inflammatory and H1 antagonistic activities. Among them, compound 2c showed the strongest H1 antagonistic and anti-inflammatory activity. It also exhibited promising pharmacokinetic profiles and low toxicity. All these results suggest that compound 2c as a novel anti-allergic agent is worthy of further investigation.Graphical abstract for this article
       
  • Polyfluoroaromatic stavudine (d4T) ProTides exhibit enhanced anti-HIV
           activity
    • Abstract: Publication date: 15 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 24Author(s): Sahar Kandil, Christophe Pannecouque, Fiona M. Chapman, Andrew D. Westwell, Christopher McGuigan Human Immunodeficiency Virus (HIV) damages the immune system and leads to the life-threatening acquired immunodeficiency syndrome (AIDS). Despite the advances in the field of antiretroviral treatment, HIV remains a major public health challenge.Nucleosides represent a prominent chemotherapeutic class for treating viruses, however their cellular uptake, kinase-mediated activation and catabolism are limiting factors. Herein, we report the synthesis and in vitro evaluation of stavudine (d4T) ProTides containing polyfluorinated aryl groups against two strains; HIV-1 (IIIB) and HIV-2 (ROD). ProTide 5d containing a meta-substituted pentafluorosulfanyl (3-SF5) aryl group showed superior antiviral activity over the parent d4T and the nonfluorinated analogue 5a. ProTide 5d has low nanomolar antiviral activity; (IC50 = 30 nM, HIV-1) and (IC50 = 36 nM, HIV-2) which is over tenfold more potent than d4T. Interestingly, ProTide 5d showed a significantly high selectivity indices with SI = 1753 (HIV-1) and 1461 (HIV-2) which is more than twice that of the d4T. All ProTides were screened in wild type as well as thymidine kinase deficient (TK−) cells. Enzymatic activation of ProTide 5d using carboxypeptidase Y enzyme and monitored using both 31P and 19F NMR is presented.Graphical abstractGraphical abstract for this article
       
  • Identification of a new small molecule chemotype of Melanin Concentrating
           Hormone Receptor-1 antagonists using pharmacophore-based virtual screening
           
    • Abstract: Publication date: 15 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 24Author(s): Mohamed A. Helal, Amar G. Chittiboyina, Mitchell A. Avery MCH receptor is a G protein-coupled receptor with two subtypes R1 and R2. Many studies have demonstrated the role of MCH-R1 in feeding and energy homeostasis. It has been proven that oral administration of small molecule MCH-R1 antagonists significantly reduces food intake and causes a dose-dependent weight loss. In this study, two ligand-based pharmacophores were developed and validated based on recently published MCH-R1 antagonists with diverse structures. Successful pharmacophores had one hydrogen bond acceptor, one positive ionizable, one ring aromatic and two or three hydrophobic groups. These 3D-QSAR models were used for virtual screening of the ZINC chemical database resulting in the identification of nine compounds with more than 50% displacement of radiolabeled MCH at a 20 μM concentration. Moreover, four of these compounds showed antagonistic activities in Aequorin functional assay, including MH-3 which is the first MCH-R1 antagonist based on a diazaspiro[4.5]decane scaffold. The most active compounds were also docked into our previously published MCH-R1 homology model to gain insights into their binding determinants. These compounds could represent a viable starting scaffold for the design of potent MCH-R1 antagonists with improved pharmacokinetic properties as an effective treatment for obesity.Graphical abstractGraphical abstract for this article
       
  • Green chemistry appended synthesis, metabolic stability and
           pharmacokinetic assessment of medicinally important chromene
           dihydropyrimidinones
    • Abstract: Publication date: 15 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 24Author(s): Ashutosh K. Dash, Debaraj Mukherjee, Abhijeet Dhulap, Saqlain Haider, Deepak Kumar A green chemistry approach has been developed for the synthesis of chromene dihydropyrimidinone (CDHPM) using recyclable Fe/Al pillared clay catalyst. Pharmacokinetic parameters like aqueous solubility, lipophilicity, P-glycoprotein (P-gp) ATPase activity, permeability, plasma protein binding, red blood cell (RBC) partitioning, metabolic stability in liver microsomes and in silico computations have been studied for the most potent anticancer chromene dihydropyrimidinone hybrid 1. This compound exhibited low solubility, optimum lipophilicity, no P-gp inhibitory activity, intermediate permeability, high plasma protein binding, low RBC partitioning, acceptable metabolic stability in rat liver microsomes (RLM) as well as human liver microsomes (HLM) with transitional hepatic extraction ratio.Graphical abstractGraphical abstract for this article
       
  • SAR optimization studies on a novel series of 2-anilinopyrimidines as
           selective inhibitors against triple-negative breast cancer cell line
           MDA-MB-468
    • Abstract: Publication date: 15 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 24Author(s): Jeyun Jo, Heegyu Kim, Ji Youn Oh, Soyeong Kim, Yeong Hye Park, Hyeonjin Choi, Jee-Yeong Jeong, Young-Suk Jung, Hwayoung Yun Triple-negative breast cancers (TNBCs) account for approximately 15% of breast cancer cases and exhibit an aggressive clinical behavior. In this study, we designed and synthesized two series of 2-anilinopyrimidines based on the structure of our previously reported compound 1 that act as a selective inhibitor of the basal-like TNBC cell line MDA-MB-468. Through the fine-tuning of 1, cyclic and acyclic amines at 4-position of the pyrimidine core were turned out to be crucial for the selectivity. An extensive analysis of structure-activity relationships of the analogs revealed that aminoalkyl groups at the end of the propyl chain are amenable to modification. Among the newly synthesized analogs, compound 38, bearing 4-chloropiperidinyl and cyclohexyl groups, was found to be the most potent and selective, and was about three times more potent and selective than 1 was against the TNBC cells.Graphical abstractGraphical abstract for this article
       
  • Graphical Abstract Contents Continued
    • Abstract: Publication date: 15 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 24Author(s):
       
  • Discovery of potent and selective butyrylcholinesterase inhibitors through
           the use of pharmacophore-based screening
    • Abstract: Publication date: 15 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 24Author(s): Alexander Williams, Shuo Zhou, Chang-Guo Zhan Cholinesterase inhibitors have long been used in the treatment of Alzheimer’s Disease (AD) via the protection of acetylcholine levels. However, recent research has shown that the specific inhibition of butyrylcholinesterase (BChE) could better ameliorate symptoms within patients. In addition, it has recently been shown that selective inhibition of BChE can also significantly attenuate the toxicity and physiological effects of heroin. Currently, there are no specific and potent inhibitors of BChE approved for use in AD or heroin abuse. Through a combined use of in silico and in vitro screening, we have found three compounds with sub-50 nM IC50 values that specifically target BChE. These newly discovered BChE inhibitors can act as the lead scaffolds for future development of the desirably potent and selective BChE inhibitors.Graphical abstractThree potent and selective butyrylcholinesterase inhibitors were discovered through a combination of in silico and in vitro screening of the NCI/DTP Open Chemicals Repository.Graphical abstract for this article
       
  • Synthesis and evaluation of 1,3,5-triazine derivatives as sunscreens
           useful to prevent skin cancer
    • Abstract: Publication date: 15 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 24Author(s): Juliana Santana Reis, Marcos Antonio Corrêa, Clovis Augusto Ribeiro, Jean Leandro Dos Santos The incidence of skin cancers such as non-melanoma skin cancer and malignant melanoma has increased in the last few years mainly because of chronic exposure to ultraviolet (UV) radiation. Sunscreens protect the skin against harmful UV radiations; however, some limitations of these products justify the discovery of new UV filters. Novel 1,3,5-triazine derivatives (12a-h) obtained by the optimization of prototype resveratrol were synthesized and characterized. All compounds exhibited sun protection factor (SPF) and UVA protection factor (UVAPF) in the range of 3–17 and 3–13, respectively. These values were superior to resveratrol and the UV filter ethylhexyl triazone (EHT) currently available on the market. In addition, all compounds demonstrated in vitro antioxidant activity and thermal stability with the decomposition at temperatures above 236 °C. In conclusion, the novel 1,3,5-triazine derivatives have emerged as new UV filters with antioxidant effect useful to prevent skin cancer.Graphical abstractGraphical abstract for this article
       
  • Novel benzimidazole phosphonates as potential inhibitors of protein
           prenylation
    • Abstract: Publication date: 15 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 24Author(s): Nazmul H. Bhuiyan, Michelle L. Varney, David F. Wiemer, Sarah A. Holstein Benzimidazole carboxyphosphonates and bisphosphonates have been prepared and evaluated for their activity as inhibitors of protein prenylation or isoprenoid biosynthesis. The nature of the phosphonate head group was found to dictate enzyme specificity. The lead carboxyphosphonate inhibits geranylgeranyl transferase II while its corresponding bisphosphonate analogue potently inhibits farnesyl diphosphate synthase. The most active inhibitors effectively disrupted protein prenylation in human multiple myeloma cells.Graphical abstractGraphical abstract for this article
       
  • Structure-based analysis and biological characterization of imatinib
           derivatives reveal insights towards the inhibition of wild-type BCR-ABL
           and its mutants
    • Abstract: Publication date: 15 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 24Author(s): Minjian Yang, Qiumu Xi, Wenqiang Jia, Xiaojian Wang To reveal insights into the inhibition of BCR-ABL and its mutants, structure-based computing methods, such as docking, molecular dynamics (MD) simulation, the molecular mechanics generalized born surface area (MMGBSA), and biological characterizations, were employed to analyze two main pharmacophore zones and two related regions of imatinib derivatives. The hydrophobic and halogen interactions formed by the trifluoromethyl, as well as T-shaped π-π interactions formed by the pyrimidine, were confirmed. For the imatinib derivatives, the impacts of the amide moiety (region A) and the pyridine (region B) on the formed interactions were explored. To reveal insights into the inhibition of BCR-ABL mutants, the bioactivities of imatinib, nilotinib and flumatinib against BCR-ABL mutants were evaluated, and a point mutant (Y253F) of BCR-ABL was simulated. The results of our structure-based analysis and biological characterization of imatinib derivatives towards the inhibition of wild-type BCR-ABL and its mutants may provide new ideas for the design of imatinib analogs with potent activity.Graphical abstractGraphical abstract for this article
       
  • Clickable gold nanoparticles for streamlining capture, enrichment and
           release of alkyne-labelled proteins
    • Abstract: Publication date: 15 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 24Author(s): Sho Narita, Naohiro Kobayashi, Kanna Mori, Kaori Sakurai Alkyne-labelled proteins are generated as key intermediates in the chemical probe-based approaches to proteomics analysis. Their efficient and selective detection and isolation is an important problem. We designed and synthesized azide-functionalized gold nanoparticles as new clickable capture reagents to streamline click chemistry-mediated capture, enrichment and release of the alkyne-labelled proteins in one-pot to expedite the post-labelling analysis. Because hydrophobic surface functionalities are known to render gold nanoparticles poorly water-dispersible, hydrophilic PEG linkers with two different lengths were explored to confer colloidal stability to the clickable capture reagents. We demonstrated the ability of the capture reagents to conjugate the alkyne containing proteins at a nanomolar concentration via click chemistry, which can be immediately followed by their enrichment and elution. Furthermore, a bifunctional clickable capture reagent bearing sulforhodamine and azide groups was shown to conveniently attach a fluorophore to the alkyne-labelled protein upon click capture, which facilitated their rapid detection in the gel analysis.Graphical abstractGraphical abstract for this article
       
  • Synthesis and antidepressant-like activity of novel alkoxy-piperidine
           derivatives targeting SSRI/5-HT1A/5-HT7
    • Abstract: Publication date: 15 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 24Author(s): Wen-Tao Wang, Hao Qian, Jian-Wei Wu, Xiao-Wen Chen, Jian-Qi Li A series of novel alkoxy-piperidine derivatives were synthesized and evaluated for their serotonin reuptake inhibitory and binding affinities for 5-HT1A/5-HT7 receptors. In vivo antidepressant activities of the selective compounds were explored using the forced swimming test (FST) and tail suspension test (TST) in mice. The results showed that compounds 7a (reuptake inhibition (RUI), IC50 = 177 nM; 5-HT1A, Ki = 12 nM; 5-HT7, Ki = 25 nM) and 15g (RUI, IC50 = 85 nM; 5-HT1A, Ki = 17 nM; 5-HT7, Ki = 35 nM) were potential antidepressant agents in animal behavioral models with high 5-HT1A/5-HT7 receptor affinities and moderate serotonin reuptake inhibition, and good metabolic stability in vitro.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and evaluation of 2-amino-imidazol-4-one derivatives as
           potent β-site amyloid precursor protein cleaving enzyme 1 (BACE-1)
           inhibitors
    • Abstract: Publication date: 15 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 24Author(s): Tian-Yuan Fan, Wen-Yu Wu, Shao-Peng Yu, Yue Zhong, Chao Zhao, Min Chen, He-Min Li, Nian-Guang Li, Zhi Chen, Sai Chen, Zhi-Hui Sun, Jin-Ao Duan, Zhi-Hao Shi Inhibition of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) to prevent brain β-amyloid (Aβ) peptide’s formation is a potential effective approach to treat Alzheimer’s disease. In this report we described a structure-based optimization of a series of BACE1 inhibitors derived from an iminopyrimidinone scaffold W-41 (IC50 = 7.1 μM) by Wyeth, which had good selectivity and brain permeability but low activity. The results showed that occupying the S3 cavity of BACE1 enzyme could be an effective strategy to increase the biological activity, and five compounds exhibited stronger inhibitory activity and higher liposolubility than W-41, with L-5 was the most potent inhibitor against BACE1 (IC50 = 0.12 μM, logP = 2.49).Graphical abstractGraphical abstract for this article
       
  • Fluorescent sialic derivatives for the specific detection of influenza
           viruses
    • Abstract: Publication date: 15 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 24Author(s): Dandan Liu, Xikai Cui, Abasaheb N. Dhawane, Vasanta Chivukula, Suri S. Iyer Early and accurate diagnosis of influenza viruses can decrease its harmful impact. Here, we have synthesized fluorescent sialic acid derivatives that are cleaved by influenza neuraminidases (NAs) and not by Streptococcus pneumoniae that also inhabits the human olfactory. We have also attempted to develop assays that could differentiate between influenza virus and S. pneumoniae by taking advantage of the structural differences between NAs from these pathogens.Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC
    • Abstract: Publication date: 15 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 24Author(s):
       
  • Synthesis and evaluation of the HIF-1α inhibitory activity of
           3(5)-substituted-4-(quinolin-4-yl)- and 4-(2-phenylpyridin-4-yl)pyrazoles
           as inhibitors of ALK5
    • Abstract: Publication date: Available online 17 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Yan-Wei Li, Xiang-Yu Li, Shanji Li, Li-Min Zhao, Juan Ma, Hu-Ri Piao, Zhe Jiang, Cheng Hua Jin, Xuejun Jin The transcription factor hypoxia-inducible factor-1α (HIF-1α) plays an important role in apoptosis, metastasis, and proliferation and is recognized as an important potential therapeutic target for cancer. Six series of 3(5)-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)pyrazoles (11a–d, 12a–d, and 18a–d) and 3(5)-(6-methylpyridin-2-yl)-4-(2-phenyl-pyridin-4-yl)pyrazoles (19a–d, 20a–d, and 21a–d) were synthesized and evaluated for activin receptor-like kinase 5 (ALK5) and HIF-1α inhibitory activity at the enzyme and cell levels. The effect of the lead compound 20d (J-1012) on HIF-1α activation in HCT116 cells was investigated. J-1012 markedly decreased the hypoxia-induced or TNF-induced accumulation of HIF-1α protein dose-dependently. Analysis revealed that J-1012 inhibited HIF-1α protein synthesis, without affecting the degradation of HIF-1α protein. Furthermore, by inhibiting the activation of HIF-1α, J-1012 suppressed the metastasis and proliferation and promoted apoptosis of HCT116 cells. These results suggest that J-1012 may be a potential therapeutic agent against human colon cancer.Graphical abstractGraphical abstract for this article
       
  • Synthesis, biological evaluation and SAR studies of ursolic acid 3β-ester
           derivatives as novel CETP inhibitors
    • Abstract: Publication date: Available online 17 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Chao Chen, Renhua Sun, Yan Sun, Xuan Chen, Fei Li, Xiaoan Wen, Haoliang Yuan, Dongyin Chen Cholesteryl ester transfer protein (CETP) is an attractive therapeutic target for the prevention and treatment of cardiovascular diseases by lowering low-density lipoprotein cholesterol levels as well as raising high-density lipoprotein cholesterol levels in human plasma. Herein, a series of ursolic acid 3β-ester derivatives were designed, synthesized and evaluated for the CETP inhibiting activities. Among these compounds, the most active compound is U12 with an IC50 value of 2.4 μM in enzymatic assay. The docking studies showed that the possible hydrogen bond interactions between the carboxyl groups at both ends of the molecule skeleton and several polar residues (such as Ser191, Cys13 and Ser230) in the active site region of CETP could significantly enhance the inhibition activity. This study provides structural insight of the interactions between these pentacyclic triterpenoid 3β-ester derivatives and CETP protein for the further modification and optimization.Graphical abstractGraphical abstract for this article
       
  • Synthesis and anticancer activity of novel 9,13-disubstituted berberine
           derivatives
    • Abstract: Publication date: Available online 16 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Zhi-Cheng Wang, Jing Wang, Huang Chen, Jie Tang, Ai-Wu Bian, Ting Liu, Li-Fang Yu, Zhengfang Yi, Fan Yang Novel berberine derivatives with disubstituents on positions C9 and C13 were synthesized and evaluated for antiproliferative activities against human prostate cancer cell lines (PC3 and DU145), breast cancer cell line (MDA-MB-231) and human colon cancer cell lines (HT29 and HCT116). All compounds showed significantly enhanced antiproliferative activities compared with berberine. Notably, compound 18e exhibited the strongest cytotoxicity against PC3 cells with an IC50 value of 0.19 μM, and the highest selectivity index (SIPC3>20). Further studies showed that 18e could arrest the cell cycle at G1 phase, and significantly inhibit tumor cell colony forming and migration even at low concentrations. Interestingly, 18e could significantly induce cytoplasmic vacuolation, suggesting a different mode of action from berberine.Graphical abstractGraphical abstract for this article
       
  • Discovery of a Potent and Selective Adenylyl Cyclase Type 8 Agonist by
           Docking-Based Virtual Screening
    • Abstract: Publication date: Available online 16 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Zhiying Weng, Guowei Xu, Dingyuan Chen, Yaqing Yang, Gao Song, Wen Shen, Shuqun Zhang, LiangLiang Wang, Weimin Yang, Zhili Zuo Adenylyl cyclases (ACs), which are responsible for catalyzing the conversion of adenosine triphosphate (ATP) into the second messenger cyclic adenosine monophosphate (cAMP), play a critical role in cell signal transduction. In this study, a combined approach involving docking-based virtual screening, with the combination of homology modeling followed by an in-vitro, and cell-based biological assay have been performed for discovering a class of novel potent and selective isoform adenylyl cyclase type 8 (AC8) agonist. The computer-aided virtual screening was used to identify fourteen virtual cluster compounds as potential hits which were further subjected to rigorous bioassays. A novel hit compound VHC-7 (ethyl 3-(2,4-dichlorobenzyl)-2-oxoindoline-3-carboxylate) was identified as a highly potent selective AC8 agonist with EC50 value of 0.1052±0.038 µM. Remarkably, the molecule herein reported can be explored further to discover greater number of hit compounds with better pharmacokinetic properties as well as to serve as a promising novel hit agonist of AC8 for the treatment of various central nervous system disorders and its associated diseases.Graphical abstractGraphical abstract for this article
       
  • Synthesis and cytotoxicity evaluation of glycosidic derivatives of lawsone
           against breast cancer cell lines
    • Abstract: Publication date: Available online 16 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Flaviano M. Ottoni, Eliza R Gomes, Rodrigo M. Pádua, Mônica C. Oliveira, Izabella T. Silva, Ricardo J. Alves Breast cancer is the most incident and mortal cancer type in women, with an estimated 2 million new cases expected by 2020 worldwide, with 600,000 deaths. As not all breast cancer types respond to the anti-hormonal therapy, the development of new antineoplastic drugs is necessary. Lawsone (2-hydroxy-1,4-naphtoquinone) is a natural bioactive naphtoquinone displaying a range of activities, with dozens of derivatives described in the literature, including some glycosides possessing antitumor activity. Here, a series of glycosides of lawsone are reported for the first time and all compounds displayed good activity against the SKBR-3 cell line, with IC50 below 10 µM. The most promising derivative was the glycosyl triazole derived from peracetylated D-glucose (11), which showed better cytotoxicity against SKBR-3 (IC50=0.78 µM), being the most selective toward this tumoral cell (SI>20). All compounds described in this work were more active than lawsone, indicating the importance of the carbohydrate and glycosyl triazole moiety for activity.Graphical abstractGraphical abstract for this article
       
  • Discovery of a novel 2,3-dimethylimidazo[1,2-a]pyrazine-6-carboxamide M4
           positive allosteric modulator (PAM) chemotype
    • Abstract: Publication date: Available online 13 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Kayla J. Temple, Julie L. Engers, Madeline F. Long, Katherine J. Watson, Sichen Chang, Vincent B. Luscombe, Matthew T. Jenkins, Alice L. Rodriguez, Colleen M. Niswender, Thomas M. Bridges, P. Jeffrey Conn, Darren W. Engers, Craig W. Lindsley This Letter details our efforts to discover structurally unique M4 PAMs containing 5,6-heteroaryl ring systems. In an attempt to improve the DMPK profiles of the 2,3-dimethyl-2H-indazole-5-carboxamide and 1-methyl-1H-benzo[d][1,2,3]triazole-6-carboxamide cores, we investigated a plethora of core replacements. This exercise identified a novel 2,3-dimethylimidazo[1,2-a]pyrazine-6-carboxamide core that provided improved M4 PAM activity and CNS penetration.Graphical abstractGraphical abstract for this article
       
  • Structure activity relationship, 6-modified purine riboside analogues to
           activate hSTING, stimulator of interferon genes
    • Abstract: Publication date: Available online 12 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Laurent F. Bonnac, Christine D. Dreis, Robert J. Geraghty Twenty-nine nucleoside analogues have been synthesized and evaluated in a cell based assay for their ability to activate the human Stimulator of Interferon Genes (hSTING), a key protein of the innate immune defense. Some 6-O-alkyl nucleoside analogues activate hSTING without associated cytotoxicity. SAR and combination studies were performed to decipher possible activation mechanism. The described nucleoside hSTING activators represent first-in-class modulators of the innate immune defense; a highly relevant target for antiviral, antibacterial, anticancer or Alzheimer’s disease treatments and may present advantages over other types of hSTING activators.Graphical abstractGraphical abstract for this article
       
  • Structure-based design of guanosine analogue inhibitors targeting GTP
           cyclohydrolase IB towards a new class of antibiotics
    • Abstract: Publication date: Available online 12 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): George N. Samaan, Naduni Paranagama, Ayesha Haque, David A. Hecht, Manal A. Swairjo, Byron W. Purse GTP cyclohydrolase (GCYH-I) is an enzyme in the folate biosynthesis pathway that has not been previously exploited as an antibiotic target, although several pathogens including N. gonorrhoeae use a form of the enzyme GCYH-IB that is structurally distinct from the human homologue GCYH-IA. A comparison of the crystal structures of GCYH-IA and -IB with the nM inhibitor 8-oxo-GTP bound shows that the active site of GCYH-IB is larger and differently shaped. Based on this structural information, we designed and synthesized a small set of 8-oxo-G derivatives with ether linkages at O6 and O8 expected to displace water molecules from the expanded active site of GCYH-IB. The most potent of these compounds, G3, is selective for GCYH-IB, supporting the premise that potent and selective inhibitors of GCYH-IB could constitute a new class of small molecule antibiotics.Graphical abstractGraphical abstract for this article
       
  • Synthesis, Anti-plasmodial and Cytotoxic evaluation of
           1H-1,2,3-Triazole/Acyl hydrazide Integrated
           Tetrahydro-β-carboline-4-Aminoquinoline Conjugates
    • Abstract: Publication date: Available online 11 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Bharvi Sharma, Simranjeet Kaur, Jenny Legac, Philip J. Rosenthal, Vipan Kumar A series of 1H-1,2,3-triazole/acylhydrazide-tethered tetrahydro- β -carboline-4-aminoquinoline conjugates was synthesized with an aim to study their anti-plasmodial structure-activity relationship. The presence of 1H-1,2,3-triazole-core along with a flexible alkyl chain length on aminoquinoline core has favourable influence on the anti-plasmodial activity against Chloroquine-resistant W2 strain of P.falciparum while the introduction of hydrazine core not only diminished the activities but also resulted in increased cytotoxicity against mammalian Vero cells.Graphical abstractGraphical abstract for this article
       
  • Novel compounds that reverse the disease phenotype in Type 2 Gaucher
           disease patient-derived cells
    • Abstract: Publication date: Available online 11 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Wayne Childers, Rong Fan, Rogelio Martinez, Dennis J. Colussi, Edward Melenski, Yuxiao Liu, John Gordon, Magid Abou-Gharbia, Marlene A. Jacobson Gaucher disease (GD) results from inherited mutations in the lysosomal enzyme β-glucocerobrosidase (GCase). Currently available treatment options for Type 1 GD are not efficacious for treating neuronopathic Type 2 and 3 GD due to their inability to cross the blood-brain barrier. In an effort to identify small molecules which could be optimized for CNS penetration we identified tamoxifen from a high throughput phenotypic screen on Type 2 GD patient-derived fibroblasts which reversed the disease phenotype. Structure activity studies around this scaffold led to novel molecules that displayed improved potency, efficacy and reduced estrogenic/antiestrogenic activity compared to the original hits. Here we present the design, synthesis and structure activity relationships that led to the lead molecule Compound 31.Graphical abstractGraphical abstract for this article
       
  • Discovery of 2-((4-Resorcinolyl)-5-aryl-1,2,3-triazol-1-yl)acetates as
           potent Hsp90 inhibitors with selectivity over TRAP1
    • Abstract: Publication date: Available online 11 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Sejin Jung, Nam Gu Yoon, Sujae Yang, Darong Kim, Won Seok Lee, Ki Bum Hong, Changwook Lee, Byoung Heon Kang, Ji Hoon Lee, Soosung Kang As the most abundant heat shock protein (HSP), Hsp90 is actively involved in tumor cell growth and various responses to anti-carcinogenic stress. Hsp90 has thus emerged as a potential drug target. A structure-based drug design approach was applied to develop novel resorcinolyltriazole derivatives as Hsp90 inhibitors. Structure-activity relationships (SARs) and molecular docking were investigated to provide a rationale for binding affinity and paralog selectivity. Click chemistry between iodoethynylresorcinol and an azido derivative was used to synthesize a new family of 2-((4-resorcinolyl)-5-aryl-1,2,3-triazol-1-yl) acetates that exhibited Hsp90 binding affinities of 40–100 nM (IC50). Among the synthesized molecules, the triazole alkyl acetates displayed the highest Hsp90 binding affinities. Their potency against Hsp90 was over 100-fold stronger than against TRAP1 and 1∼3-fold stronger than against Grp94. In particular, compounds 18, 19, and 30 had Hsp90 inhibitory activities of ∼45 nM (IC50) and they displayed over 350-fold selectivity for Hsp90 over TRAP1.Graphical abstractGraphical abstract for this article
       
  • Design, synthesisand biological evaluation of novel indole-based oxalamide
           and aminoacetamide derivatives as tubulin polymerization inhibitors
    • Abstract: Publication date: Available online 11 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Peng-Cheng Diao, Xie-Er Jian, Peng Chen, Chuan Huang, Jie Yin, Jie Chun Huang, Jun-Sheng Li, Pei-Liang Zhao A series of novel indole-based oxalamide and aminoacetamide derivatives were designed, synthesized, and evaluated for antiproliferative activities. Preliminary results revealed that compound 8g exhibited significant antiproliferative effect against PC-3, HeLa and HCT-116 cell lines. Flow cytometric analysis of the cell cycle demonstrated the compound 8g induced the cell cycle arrest at G2/M phase in HeLa cell lines. Immunocytochemistry revealed loss of intact microtubule structure in cells treated with 8g and inhibition of tubulin polymerization. Additionally, molecular docking analysis suggested that 8g formed stable interactions in the colchicine-binding site of tubulin. These preliminary results demonstrated that a new class of novel indole-based oxalamide and aminoacetamide derivatives described in the investigation could be developed as potential scaffolds to new anticancer agents.Graphical abstractGraphical abstract for this article
       
  • Development and structure-activity relationship study of SHP2 inhibitor
           containing 3,4,6-trihydroxy-5-oxo-5H-benzo[7]annulene
    • Abstract: Publication date: Available online 11 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Bohee Kim, Seungjin Jo, Sung Bum Park, Chong Hak Chae, Kwangho Lee, Byumseok Koh, Inji Shin SHP2, a non-receptor protein tyrosine phosphatase encoded by PTPN11 gene, plays an important role in the cell growth and proliferation. Activating mutations of SHP2 have been reported as a cause of various human diseases such as solid tumors, leukemia, and Noonan syndrome. The discovery of SHP2 inhibitor can be a potent candidate for the treatment of cancers and SHP2 related human diseases. Several reports on a small molecule targeting SHP2 have published, however, there are limitations on discovery of SHP2 phosphatase inhibitors due to the polar catalytic site environment. Allosteric inhibitor can be an alternative to catalytic site inhibitors. 3,4,6-trihydroxy-5-oxo-5H-benzo[7]annulene 1 was obtained as an initial hit with a 0.097 μM of IC50 from high-throughput screening (HTS) study. After the structure-activity relationship (SAR) study, compound 1 still showed the most potent activity against SHP2. Moreover, 1 and 2j exerted good potency against SHP2 expressing 2D and 3D MDA-MB468.Graphical abstractGraphical abstract for this article
       
  • Design, Synthesis, and Enzymatic Characterization of Quinazoline-Based
           CYP1A2 Inhibitors
    • Abstract: Publication date: Available online 11 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Pedro A Corral, Jordy F Botello, Chengguo Xing Cytochrome P450 isozyme 1A2 (CYP1A2) is one main xenobiotic metabolizing enzyme in humans. It has been associated with the bioactivation of procarcinogens, including 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco specific and potent pulmonary carcinogen. This work describes the computational design and in-silico screening of potential CYP1A2 inhibitors, their chemical synthesis, and enzymatic characterization with the ultimate aim of assessing their potential as cancer chemopreventive agents. To achieve this, a combined classifiers model was used to screen a library of quinazoline-based molecules against known CYP1A2 inhibitors, non-inhibitors, and substrates to predict which quinazoline candidates had a better probability as an inhibitor. Compounds with high probability of CYP1A2 inhibition were further computationally evaluated via Glide docking. Candidates predicted to have selectivity and high binding affinity for CYP1A2 were synthesized and assayed for their enzymatic inhibition of CYP1A2, leading to the discovery of novel and potent quinazoline-based CYP1A2 inhibitors.Graphical abstractGraphical abstract for this article
       
  • Discovery of structurally distinct tricyclic M4 positive allosteric
           modulator (PAM) chemotypes
    • Abstract: Publication date: Available online 11 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Kayla J. Temple, Madeline F. Long, Julie L. Engers, Katherine J. Watson, Sichen Chang, Vincent B. Luscombe, Alice L. Rodriguez, Colleen M. Niswender, Thomas M. Bridges, P. Jeffrey Conn, Darren W. Engers, Craig W. Lindsley This Letter details our efforts to develop new M4 PAM scaffolds with improved pharmacological properties. This endeavor involved replacing the 3,4-dimethylpyridazine core with two novel cores: a 2,3-dimethyl-2H-indazole-5-carboxamide core or a 1-methyl-1H-benzo[d][1,2,3]triazole-6-carboxamide core. Due to shallow SAR, these cores were further evolved into two unique tricyclic cores: an 8,9-dimethyl-8H-pyrazolo[3,4-h]quinazoline core and an 1-methyl-1H-[1,2,3]triazolo[4,5-h]quinazoline core. Both tricyclic cores displayed low nanomolar potency against both human and rat M4.Graphical abstractGraphical abstract for this article
       
  • Upregulation of p53 through Induction of MDM2 Degradation: Amino Acid
           Prodrugs of Anthraquinone Analogs
    • Abstract: Publication date: Available online 11 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Abiodun Anifowose, Zhengnan Yuan, Xiaoxiao Yang, Zhixiang Pan, Yueqin Zheng, Zhongwei Zhang, Binghe Wang Previously, we reported a class of MDM2-MDM4 dimerization inhibitors that upregulate p53 and showed potent anticancer activity in animal models. However, water solubility hinders their further development. Herein we describe our effort to develop a prodrug approach that overcomes the solubility problem. The prodrug of BW-AQ-238, a potent anthraquinone analog, was made by esterification of the hydroxyl group with various natural amino acids. Cytotoxicity of these compounds toward Hela and EU-1 cells, their aqueous solubility, and the release kinetics of these prodrugs in buffer and in the presence of hydrolytic enzymes were studied. The results demonstrate that the amino acid prodrug approach significantly improved the water solubility while maintaining the potency of the parent drug.Graphical abstractGraphical abstract for this article
       
  • Covalent Inactivation of Mycobacterium thermoresistibile
           inosine-5́-monophosphate dehydrogenase (IMPDH)
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Ana Trapero, Angela Pacitto, Daniel Shiu-Hin Chan, Chris Abell, Tom L. Blundell, David B. Ascher, Anthony G. Coyne Inosine-5́-monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme involved in nucleotide biosynthesis. Because of its critical role in purine biosynthesis, IMPDH is a drug design target for immunosuppressive, anticancer, antiviral and antimicrobial chemotherapy. In this study, we use mass spectrometry and X-ray crystallography to show that the inhibitor 6-Cl-purine ribotide forms a covalent adduct with the Cys-341 residue of Mycobacterium thermoresistibile IMPDH.Graphical abstractGraphical abstract for this article
       
  • Inhibition of hedgehog signaling by stereochemically defined des-triazole
           itraconazole analogues
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Jiachen Wen, Kelly A. Teske, M. Kyle Hadden Dysregulation of the hedgehog (Hh) signaling pathway is associated with cancer occurrence and development in various malignancies. Previous structure-activity relationships (SAR) studies have provided potent Itraconazole (ITZ) analogues as Hh pathway antagonists. To further expand on our SAR for the ITZ scaffold, we synthesized and evaluated a series of compounds focused on replacing the triazole. Our results demonstrate that the triazole region is amenable to modification to a variety of different moieties; with a single methyl group representing the most favorable substituent. In addition, nonpolar substituents were more active than polar substituents. These SAR results provide valuable insight into the continued exploration of ITZ analogues as Hh pathway antagonists.Graphical abstractGraphical abstract for this article
       
  • PB-10, a thiazolo[4,5-d] pyrimidine derivative, targets p21-activated
           kinase 4 in human colorectal cancer cells
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Ruijuan Li, Hanxun Wang, Jian Wang, Maosheng Cheng Targeting p21-activated kinase 4 (PAK4) is a potential therapeutic strategy against human colorectal cancer (CRC). In this study, we synthesized a series of novel thiazolo[4,5-d]pyrimidine derivatives (PB-1–12) and identified PB-10 (PAK4 IC50 = 15.12 μM) as a potential and potent PAK4 inhibitor. Our results showed that PB-10 significantly suppressed the proliferation and colony formation of human CRC cells. PB-10 also arrested HCT-116 CRC cells at sub G0/G1 phase while promoting the expression of proapoptotic proteins. In addition, PB-10 inhibited migration, invasion, and adhesion as well as the PAK4 downstream signaling pathway in HCT-116 cells. Molecular docking analysis showed possible binding modes between PB-10 and PAK4. Our study provides a novel compound that may block the PAK4 signaling in CRC cells.Graphical abstractGraphical abstract for this article
       
  • Serendipitous Discovery of Aryl Boronic Acids as β-Lactamase
           Inhibitors
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Shu-Wei Yang, Jianping Pan, Yuriko Root, Giovanna Scapin, Li Xiao, Jing Su High throughput screening for β-lactamase inhibitors afforded biphenyl hits such as 1. Hit confirmation and X-ray soaking experiments with Pseudomonas Aeruginosa AmpC enzyme led to the identification of an aryl boronic acid-serine complex 4, which was formed from phenyl boronic acid 8 (an impurity in compound 1) and ethylene glycol (the cryoprotectant in the soaking experiment).Graphical abstractGraphical abstract for this article
       
  • Heterocycle amide isosteres: an approach to overcoming resistance for
           HIV-1 Integrase strand transfer inhibitors
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Kevin M. Peese, B. Narasimhulu Naidu, Manoj Patel, Chen Li, David R. Langley, Brian Terry, Tricia Protack, Volodymyr Gali, Zeyu Lin, Himadri K. Samanta, Ming Zheng, Susan Jenkins, Ira B. Dicker, Mark R. Krystal, Nicholas A. Meanwell, Michael A. Walker A series of heterocyclic pyrimidinedione-based HIV-1 integrase inhibitors was prepared and screened for activity against purified integrase enzyme and/or viruses modified with the following mutations within integrase: Q148R, Q148H/G140S and N155H. These are mutations that result in resistance to the first generation integrase inhibitors raltegravir and elvitegravir. Based on consideration of drug-target interactions, an approach was undertaken to replace the amide moiety of the first generation pyrimidinedione inhibitor with azole heterocycles that could retain potency against these key resistance mutations. An imidazole moiety was found to be the optimal amide substitute and the observed activity was rationalized with the use of calculated properties and modeling. Rat pharmacokinetic (PK) studies of the lead imidazole compounds demonstrated moderate clearance and moderate exposure.Graphical abstractGraphical abstract for this article
       
  • In vivo comparison of N-11CH3 vs O-11CH3 radiolabeled microtubule targeted
           PET ligands
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): J.S. Dileep Kumar, Jaya Prabhakaran, Naresh Damuka, Justin Wayne Hines, Skylar Norman, Meghana Dodda, J. John Mann, Akiva Mintz, Kiran Kumar Soingapuram Sai Altered dynamics of microtubules (MT) are implicated in the pathophysiology of a number of brain diseases. Therefore, radiolabeled MT targeted ligands that can penetrate the blood brain barrier (BBB) may offer a direct and sensitive approach for diagnosis, and assessing the clinical potential of MT targeted therapeutics using PET imaging. We recently reported two BBB penetrating radioligands, [11C]MPC-6827 and [11C]HD-800a s specific PET ligands for imaging MTs in brain. The major metabolic pathway of the above molecules is anticipated to be via the initial labeling site, O-methyl, compared to the N-methyl group. Herein, we report the radiosynthesis of N-11CH3-MPC-6827 and N-11CH3-HD-800 and a comparison of their in vivo binding with the corresponding O-11CH3 analogues using microPET imaging and biodistribution methods. Both O-11CH3 and N-11CH3 labeled MT tracers exhibit high specific binding and brain. The N-11CH3 labeled PET ligands demonstrated similar in vivo binding characteristics compared with the corresponding O-11CH3 labeled tracers, [11C]MPC-6827 and [11C]HD-800 respectively.Graphical abstractGraphical abstract for this article
       
  • Optimization of cyclic sulfamide derivatives as 11β-hydroxysteroid
           dehydrogenase 1 inhibitors for the potential treatment of ischemic brain
           injury
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Jeong Hyun Lee, Ju Hwan Bok, Sung Bum Park, Haushabhau S. Pagire, Yoon-Ju Na, Eunyoung Rim, Won Hoon Jung, Jin Sook Song, Nam Sook Kang, Ho Won Seo, Kwan-Young Jung, Byung Ho Lee, Ki Young Kim, Jin Hee Ahn The 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a cortisol regenerating enzyme that amplifies tissue glucocorticoid levels, plays an important role in diabetes, obesity, and glaucoma and is recognized as a potential therapeutic target for various disease conditions. Moreover, a recent study demonstrated that selective 11β-HSD1 inhibitor can attenuate ischemic brain injury. This prompted us to optimize cyclic sulfamide derivative for aiming to treat ischemic brain injury. Among the synthesized compounds, 6e has an excellent in vitro activivity with an IC50 value of 1 nM toward human and mouse 11β-HSD1 and showed good 11β-HSD1 inhibition in ex vivo study using brain tissue isolated from mice. Furthermore, in the transient middle cerebral artery occlusion model in mice, 6e treatment significantly attenuated infarct volume and neurological deficit following cerebral ischemia/reperfusion injury. Additionally, binding modes of 6e for human and mouse 11β-HSD1 were suggested.Graphical abstractGraphical abstract for this article
       
  • Further Exploration of the Structure-Activity Relationship of
           Imidazoquinolines; Identification of Potent C7 Substituted
           Imidazoquinolines
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Jordan R. Hunt, Peter A. Kleindl, K. Ryan Moulder, Thomas E. Prisinzano, M. Laird Forrest Small molecule agonists of TLR7/8, such as imidazoquinolines, are validated agonists for the treatment of cancer and for use in vaccine adjuvants. Imidazoquinolines have been extensively modified to understand the structure-activity relationship (SAR) at the N1- and C2-positions resulting in the clinical drug imiquimod, resiquimod, and several other highly potent analogues. However, the SAR of the aryl ring has not been fully elucidated in the literature. This initial study examines the SAR of C7-substituted imidazoquinolines. These compounds not only demonstrated that TLR7/8 tolerate changes at the C7 position but can increase potency and change their cytokine profiles. The most notable TLR7/8 agonists developed from this study 5, 8, and 14 which are up to 4-fold and 2-fold more active than resiquimod for TLR8 and/or TLR7, respectively, and up to 100-fold more active than the FDA approved imiquimod for TLR7.Graphical abstractGraphical abstract for this article
       
  • Early identification of promiscuous attributes of aldose reductase
           inhibitors using a DMSO-perturbation assay
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Keisuke Tomohara, Naoto Hasegawa, Isao Adachi, Yoshikazu Horino, Takeru Nose Aldose reductase (AR) inhibitors are used clinically to treat long-term diabetic complications. Previous studies reported a series of AR inhibitory candidates, but unfortunately the mode of inhibition was poorly described due mainly to the lack of readily available methods for evaluating the specificity. The present study examined the AR inhibitory effects of novel synthetic hydantoins and their structural relatives, some of which were obtained from chemically engineered extracts of natural plants, and discovered several novel AR inhibitors with moderate inhibitory activity. The identified inhibitors were then subjected to a two-step mechanistic characterization using a detergent-addition assay and our novel dimethyl sulfoxide (DMSO)-perturbation assay. The detergent-addition assay revealed aggregation-based inhibitors, and the subsequent DMSO-perturbation assay identified nonspecific binding inhibitors. Thus, the present study demonstrates the usefulness of the DMSO-perturbation screen for identifying nonspecific binding characteristics of AR inhibitors.Graphical abstractGraphical abstract for this article
       
  • Discovery of 1,2,4-triazine-based derivatives as novel neddylation
           inhibitors and anticancer activity studies against gastric cancer MGC-803
           cells
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Jian Song, Xin-Xin Cui, Bo-Wen Wu, Dong Li, Sheng-Hui Wang, Lei Shi, Ting Zhu, Yan-Bing Zhang, Sai-Yang Zhang Neddylation modification is often over-expressed in a variety of human tumor cells. Therefore, targeting neddylation pathway may represent a potential approach to the treatment of human tumors. Herein, we describe the discovery of a hit scaffold from our in-house library and further structure-based optimizations. In this work, compound V11 could block the neddylation and inhibit the activity of NAE (with an EC50 value of 3.56 µM), and a dose-dependent reduction of the Ubc12-NEDD8 conjugations was also observed. Molecular docking results suggest compound V11 could bind tightly to NAE via hydrogen bonds and hydrophobic interactions. Compound V11 showed the best antiproliferative ability with an IC50 value of 8.22 μM against gastric cancer MGC-803 cells. Further anticancer activity studies suggested that compound V11 inhibited MGC-803 cell growth, caused a cell cycle arrestment at G2/M phase and induced apoptosis via extrinsic and intrinsic apoptosis pathways. All the findings suggest that 1,2,4-triazine scaffold might provide a novel scaffold for the further development of neddylation inhibitors and compound V11 might be a potential neddylation inhibitor with anticancer activity.Graphical abstractGraphical abstract for this article
       
  • Design, Synthesis and Biological Evaluation of Phenol-linked Uncialamycin
           Antibody-drug Conjugates
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Yam B. Poudel, Chetana Rao, Srikanth Kotapati, Madhura Deshpande, Lourdes Thevanayagam, Chin Pan, Josephine Cardarelli, Naidu Chowdari, Mahammed Kaspady, Ramesh Samikannu, Prakasam Kuppusamy, Pon Saravanakumar, Pirama N. Arunachalam, Shrikant Deshpande, Vangipuram Rangan, Richard Rampulla, Arvind Mathur, Gregory D. Vite, Sanjeev Gangwar Enediynes are among the most structurally intriguing and biologically active families of natural products isolated from bacterial source. This class of compounds exhibits extremely potent activity against various bacteria and tumor cells. Mechanistic studies have shown that the activity of these natural products stems from their ability to form highly reactive biradical species upon activation in biological system.1 This leads to the cleavage of single or double strands of DNA in living cells, ultimately causing cell death. A number of enediyne natural products have been pursued as cancer therapeutic agents. However, because of their extreme potency, systemic delivery leads to indiscriminate cell killing rendering these compounds unsuitable for use as anticancer agents. Despite this, neocarzinostatin polymer drug conjugate has been approved in Japan for the treatment of several forms of cancer.2 In addition, cancer cell targeted delivery of calicheamicin using a CD33-antibody-drug conjugate was developed by Pfizer and has been approved for the treatment of acute myeloid leukemia.3Graphical abstractGraphical abstract for this article
       
  • Therapeutic potential of coumarin bearing metal complexes: where are we
           headed'
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Sevgi Balcıoğlu, Mert Olgun Karataş, Burhan Ateş, Bülent Alıcı, İsmail Özdemir The successfully application of some metallodrugs such as salvarsan, silver sulfadiazine and cisplatin in modern medicine launched the biological investigation of organometallic and metal-organic complexes. The availability and tunability of various ligands including N-heterocycles, phosphines, N-heterocyclic carbenes present an extended research area to chemists. In recent years, the preparation of the metal complexes of bioactive organic compounds is a new strategy. Coumarin derivatives are one of the classes of compounds used for this purpose, and many complexes of coumarin derivatives were prepared for enhanced biological activity, especially anticancer and antimicrobial. In this paper, we discuss the current situation of this topic.Graphical abstractGraphical abstract for this article
       
  • Virtual Screening to Identify Potent Sepiapterin Reductase Inhibitors
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Hua Gao, Stephen Schneider, Paul Andrews, Kevin Wang, Xin Huang, Brian A. Sparling Sepiapterin reductase has been identified as a potential drug target for neuropathic and inflammatory pain. Virtual screening was executed against a publicly available x-ray crystal structure of sepiapterin reductase. A set of structurally diverse and potent sepiapterin reductase inhibitors was identified. This set of compounds with favorable ligand efficiency and lipophilic efficiency are tractable for further optimization. An SAR follow-up library was synthesized based on one of the virtual screening hits exploring SAR.Graphical abstractGraphical abstract for this article
       
  • Formation of 5α-dihydrotestosterone from 5α-androstane-3α,17β-diol in
           prostate cancer LAPC-4 cells – identifying inhibitors of non-classical
           pathways producing the most potent androgen
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Sophie Boutin, Jenny Roy, René Maltais, Donald Poirier 5α-Dihydrotestosterone (5α-DHT) possesses a great affinity for the androgen receptor (AR), and its binding to AR promotes the proliferation of prostate cancer (PC) cells in androgen-dependent PC. Primarily synthesized from testosterone (T) in testis, 5α-DHT could also be produced from 5α-androstane-3α,17β-diol (3α-diol), an almost inactive androgen, following non-classical pathways. We reported the chemical synthesis of non-commercially available [4-14C]-3α-diol from [4-14C]-T, and the development of a biological assay to identify inhibitors of the 5α-DHT formation from radiolabeled 3α-diol in LAPC-4 PC cell models. We measured the inhibitory potency of 5α-androstane derivatives against the formation of 5α-DHT, and inhibition curves were obtained for the most potent compounds (IC50 = 1.2-14.1 μM). The most potent inhibitor 25 (IC50 = 1.2 μM) possesses a 4-(4-CF3-3-CH3O-benzyl)piperazinylmethyl side chain at C3β and 17β-OH/17α-C≡CH functionalities at C17 of a 5α-androstane core.Graphical abstractGraphical abstract for this article
       
  • Enantioselective total synthesis, divergent optimization and preliminary
           biological evaluation of (indole-N-alkyl)-diketopiperazines
    • Abstract: Publication date: 1 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 23Author(s): Hongjin Bai, Pengcheng Cui, Chuanli Zang, Shengkun Li The first enantioselective total synthesis of the antifungal natural product (indole-N-isoprenyl)-tryptophan-valine diketopiperazine 5 was accomplished. Four stereoisomers of 5 were intentionally prepared, and the (R, R)-isomer is more favorable in enhancing the antifungal bioactivity. Divergent structural optimization of this attractive model was conducted from the chiral pool amino acids. Fine-tuning of the structure protruded the broad-spectrum antifungal 6b, which also showed good preventative efficacy against Sclerotinia scleotiorum. Compound 5d could accelerate both hypocotyl elongation and root growth of Eclipta prostrata even at the concentration of
       
  • Graphical abstract TOC
    • Abstract: Publication date: 1 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 23Author(s):
       
  • Design, synthesis, and biological evaluation of 4-phenoxyquinoline
           derivatives as potent c-Met kinase inhibitor
    • Abstract: Publication date: 1 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 23Author(s): Yifeng Yang, Yingxiu Li, Yunlei Hou, Mingze Qin, Ping Gong, Ju Liu, Yanfang Zhao A series of novel 4-phenoxyquinoline derivatives containing 3-oxo-3,4-dihydro-quinoxaline moiety were synthesized and evaluated for their antiproliferative activity against five human cancer cell lines (A549, H460, HT-29, MKN-45 and U87MG) in vitro. Most of the tested compounds exhibited more potent inhibitory activities than the positive control foretinib. Compound 1b, 1s and 1t were further examined for their inhibitory activity against c-Met kinase. The most promising compound 1s (with c-Met IC50 value of 1.42 nM) showed remarkable cytotoxicity against A549, H460, HT-29, MKN45 and U87MG cell lines with IC50 values of 0.39 μM, 0.18 μM, 0.38 μM, 0.81 μM, respectively. Their preliminary structure-activity relationships (SARs) study indicated that the replacement of the aromatic ring with the cyclohexane improved their antiproliferative activity.Graphical abstractGraphical abstract for this article
       
  • An anthrone-based Kv7.2/7.3 channel blocker with improved properties for
           the investigation of psychiatric and neurodegenerative disorders
    • Abstract: Publication date: 1 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 23Author(s): Jacob D. Porter, Oscar Vivas, C. David Weaver, Abdulmohsen Alsafran, Elliot DiMilo, Leggy A. Arnold, Eamonn J. Dickson, Chris Dockendorff A set of novel Kv7.2/7.3 (KCNQ2/3) channel blockers was synthesized to address several liabilities of the known compounds XE991 (metabolic instability and CYP inhibition) and the clinical compound DMP 543 (acid instability, insolubility, and lipophilicity). Using the anthrone scaffold of the prior channel blockers, alternative heteroarylmethyl substituents were installed via enolate alkylation reactions. Incorporation of a pyridazine and a fluorinated pyridine gave an analog (compound 18, JDP-107) with a promising combination of potency (IC50 = 0.16 μM in a Kv7.2 thallium flux assay), efficacy in a Kv7.2/7.3 patch clamp assay, and drug-like properties.Graphical abstractUnlabelled Image
       
  • Discovery and optimization of covalent Bcl-xL antagonists
    • Abstract: Publication date: 1 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 23Author(s): Herschel Mukherjee, Nancy Su, Matthew A. Belmonte, David Hargreaves, Joe Patel, Sharon Tentarelli, Brian Aquila, Neil P. Grimster Over the last ten years, targeted covalent inhibition has become a key discipline within medicinal chemistry research, most notably in the development of oncology therapeutics. One area where this approach is underrepresented, however, is in targeting protein-protein interactions. This is primarily because these hydrophobic interfaces lack appropriately located cysteine residues to allow for standard conjugate addition chemistry. Herein, we report our development of the first covalent inhibitors of the antiapoptotic protein B-cell lymphoma extra-large (Bcl-xL), utilizing a sulfonyl fluoride (SF) warhead to selectively covalently modify tyrosine 101 of the BH3 domain-binding groove. These compounds display time-dependent inhibition in a biochemical assay and are cellularly active (U266B1). In addition, compound 7 was further elaborated to generate a chemical-biology probe molecule, which may find utility in understanding the intricacies of Bcl-xL biology.Graphical abstractUnlabelled Image
       
  • Design, synthesis and biological evaluation of curcumin analogues as novel
           LSD1 inhibitors
    • Abstract: Publication date: 1 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 23Author(s): Jiming Wang, Xiangyu Zhang, Jiangkun Yan, Wei Li, Qinwen Jiang, Xinran Wang, Dongmei Zhao, Maosheng Cheng Histone lysine-specific demethylase 1 (LSD1) was the first discovered histone demethylase. Inactivating LSD1 or downregulating its expression inhibits cancer-cell development, and thus, it is an attractive molecular target for the development of novel cancer therapeutics. In this study, we worked on the structural optimization of natural products and identified 30 novel LSD1 inhibitors. Utilizing a structure-based drug design strategy, we designed and synthesized a series of curcumin analogues that were shown to be potent LSD1 inhibitors in the enzyme assay. Compound WB07 displayed the most potent LSD1 inhibitory activity, with an IC50 value of 0.8 μM. Moreover, WA20 showed an anticlonogenic effect on A549 cells with an IC50 value of 4.4 μM. Molecular docking simulations were also carried out, and the results indicated that the inhibitors bound to the protein active site located around the key residues of Asp555 and Asp556. These findings suggested that compounds WA20 and WB07 are the first curcumin analogue-based LSD1 inhibitors with remarkable A549 suppressive activity, providing a novel scaffold for the development of LSD1 inhibitors.Graphical abstractUtilizing a structure-based drug design strategy, we designed and synthesized a series of curcumin analogues that were shown to be potent LSD1 inhibitors in the enzyme assay. Compound WB07 displayed the most potent LSD1 inhibitory activity, with an IC50 value of 0.8 μM.Unlabelled Image
       
  • One-pot synthesis of novel tert-butyl-4-substituted
           phenyl-1H-1,2,3-triazolo piperazine/piperidine carboxylates, potential
           GPR119 agonists
    • Abstract: Publication date: 1 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 23Author(s): Nagaraju Bashetti, J.V. Shanmukha Kumar, Naresh Varma Seelam, B. Prasanna, Akiva Mintz, Naresh Damuka, Sriram Devanathan, Kiran Kumar Solingapuram Sai We have synthesized a new series of 1,2,3-triazolo piperazine and piperidine carboxylate derivatives using a simple and one-pot click chemistry with significantly reduced reaction times (~5 min) and enhanced reaction yields (~95–98%). The fourteen novel compounds thus synthesized were tested for ability to target GPR119, a G-protein coupled target receptor that plays critical role in regulation of type-2 diabetes mellitus. Four analogs (3e, 3g, 5e and 5g) demonstrated similar or better EC50 values over previously reported AR231453 activity towards GPR119.Graphical abstractWe have synthesized a new series of 1,2,3-triazolo piperazine and piperidine carboxylate derivatives using a simple and one-pot click chemistry with significantly reduced reaction times (~5 min) and enhanced reaction yields (~95–98%). The fourteen novel compounds thus synthesized were tested for ability to target GPR119, a G-protein coupled target receptor that plays critical role in regulation of type-2 diabetes mellitus. Four analogs (3e, 3g, 5e and 5g) demonstrated similar or better EC50 values over previously reported AR231453 activity towards GPR119.Unlabelled Image
       
  • Synthesis and antidepressant effect of novel aralkyl piperazine and
           piperidine derivatives targeting SSRI/5-HT1A/5-HT7
    • Abstract: Publication date: 1 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 23Author(s): Zheng-Song Gu, Wen-Tao Wang, Hao Qian, Ai-Nan Zhou, Hong-Bin Sun, Qing-Wei Zhang, Jian-Qi Li A series of novel aralkyl piperazine and piperidine derivatives were synthesized, and evaluated for their serotonin reuptake inhibitory and 5-HT1A/5-HT7 receptors affinities activity. Antidepressant activities in vivo of the selective compound were screened using the forced swimming test (FST) and tail suspension test (TST). The results indicated that compound 19a exhibited high affinities for the 5-HT1A/5-HT7 receptors (5-HT1A, Ki = 12 nM; 5-HT7, Ki = 3.2 nM) coupled with potent serotonin reuptake inhibition (IC50 = 14 nM) and showed a marked antidepressant-like effect in the FST and TST models.Graphical abstractUnlabelled Image
       
  • Novel berberine-based derivatives with potent hypoglycemic activity
    • Abstract: Publication date: 1 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 23Author(s): Jian-Ta Wang, Jin-Gang Peng, Ji-Quan Zhang, Zhong-Xiao Wang, Yi Zhang, Xun-Rong Zhou, Jing Miao, Lei Tang Four series of berberine derivatives were designed and synthesized. All the synthetic compounds were screened for in vitro glucose consumption activity in HepG2 cell lines. The results showed that most of the tested compounds exhibited potent hypoglycemic activity, and the most potent compound 20b exhibited its potency by 3.23-fold of berberine, 1.39-fold of metformin and 1.20-fold of rosiglitazone, respectively. Western blot assay indicated these novel berberine-based derivatives executed their glucose-decreasing activity via the activation of AMPK pathway.Graphical abstractGraphical abstract for this article
       
  • Synthesis of analogs of the Gwt1 inhibitor manogepix (APX001A) and in
           vitro evaluation against Cryptococcus spp
    • Abstract: Publication date: 1 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 23Author(s): Michael Trzoss, Jonathan A. Covel, Mili Kapoor, Molly K. Moloney, Quinlyn A. Soltow, Peter J. Webb, Karen Joy Shaw Fosmanogepix (APX001) is a first-in-class prodrug molecule that is currently in Phase 2 clinical trials for invasive fungal infections. The active moiety manogepix (APX001A) inhibits the novel fungal protein Gwt1. Gwt1 catalyzes an early step in the GPI anchor biosynthesis pathway. Here we describe the synthesis and evaluation of 292 new and 24 previously described analogs that were synthesized using a series of advanced intermediates to allow for rapid analoging. Several compounds demonstrated significantly (8- to 32-fold) improved antifungal activity against both Cryptococcus neoformans and C. gattii as compared to manogepix. Further in vitro characterization identified three analogs with a similar preliminary safety and in vitro profile to manogepix and superior activity against Cryptococcus spp.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and biological research of novel
           N-phenylbenzamide-4-methylamine acridine derivatives as potential
           topoisomerase I/II and apoptosis-inducing agents
    • Abstract: Publication date: 1 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 23Author(s): Bin Zhang, Zhende Dou, Zheng Xiong, Ning Wang, Shan He, Xiaojun Yan, Haixiao Jin A series of novel N-phenylbenzamide-4-methylamine acridine derivatives were designed and synthesized based initially on the structure of amsacrine (m-AMSA). Molecular docking suggested that the representative compound 9a had affinity for binding DNA topoisomerase (Topo) II, which was comparable with that of m-AMSA, and furthermore that 9a could have preferential interactions with Topo I. After synthesis of 9a and analogues 9b-9f, these were all tested in vitro and the synthesized compounds displayed potent antiproliferative activity against three different cancer cell lines (K562, CCRF-CEM and U937). Among them, compounds 9b, 9c and 9d exhibiting the highest activity with IC50 value ranging from 0.82 to 0.91 μM against CCRF-CEM cells. In addition, 9b and 9d also showed high antiproliferative activity against U937 cells, with IC50 values of 0.33 and 0.23 μM, respectively. The pharmacological mechanistic studies of these compounds were evaluated by Topo I/II inhibition, western blot assay and cell apoptosis detection. In summary, 9b effectively inhibited the activity of Topo I/II and induced DNA damage in CCRF-CEM cells and, moreover, significantly induced cell apoptosis in a concentration-dependent manner. These observations provide new information and guidance for the structural optimization of more novel acridine derivatives.Graphical abstractGraphical abstract for this article
       
  • Synthesis of 2-arylhydrazinylidene-3-oxo-4,4,4-trifluorobutanoic acids as
           new selective carboxylesterase inhibitors and radical scavengers
    • Abstract: Publication date: 1 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 23Author(s): Olga G. Khudina, Galina F. Makhaeva, Natalia A. Elkina, Natalia P. Boltneva, Olga G. Serebryakova, Evgeny V. Shchegolkov, Elena V. Rudakova, Sofya V. Lushchekina, Yanina V. Burgart, Sergey O. Bachurin, Rudy J. Richardson, Victor I. Saloutin A series of 2-arylhydrazinylidene-3-oxo-4,4,4-trifluorobutanoic acids was synthesized via dealkylation of ethyl 2-arylhydrazinylidene-3-oxo-4,4,4-trifluorobutanoates under the action of a Lewis acid. Under the same conditions, ethyl 2-arylhydrazinylidene-3-oxobutanoates were also found to undergo dealkylation rather than the previously described cyclization into cinnolones. Study of the esterase profile of these compounds showed that trifluoromethyl-containing acids, in contrast to non-fluorinated analogs, were effective and selective inhibitors of carboxylesterase (CES), without substantially inhibiting structurally related cholinesterases (acetylcholinesterase and butyrylcholinesterase). Moreover, both 3-oxo-4,4,4-trifluorobutanoic and 3-oxobutanoic acids having methyl or methoxy substituent in the arylhydrazinylidene fragment showed high antioxidant activity in the ABTS test. Thus, 2-arylhydrazinylidene-3-oxo-4,4,4-trifluorobutanoic acids were found to constitute a new class of effective and selective CES inhibitors that also possess high radical-scavenging activity.Graphical abstractGraphical abstract for this article
       
  • Discovery of novel Cyclophilin D inhibitors starting from three
           dimensional fragments with millimolar potencies
    • Abstract: Publication date: 1 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 23Author(s): Ulrich Grädler, Daniel Schwarz, Michael Blaesse, Birgitta Leuthner, Theresa L. Johnson, Frederic Bernard, Xuliang Jiang, Andreas Marx, Marine Gilardone, Hugues Lemoine, Didier Roche, Catherine Jorand-Lebrun Fragment-based screening by SPR enabled the discovery of chemical diverse fragment hits with millimolar binding affinities to the peptidyl-prolyl isomerase Cyclophilin D (CypD). The CypD protein crystal structures of 6 fragment hits provided the basis for subsequent medicinal chemistry optimization by fragment merging and linking yielding three different chemical series with either urea, oxalyl or amide linkers connecting millimolar fragments in the S1′ and S2 pockets. We successfully improved the in vitro CypD potencies in the biochemical FP and PPIase assays and in the biophysical SPR binding assay from millimolar towards the low micromolar and submicromolar range by>1000-fold for some fragment derivatives. The initial SAR together with the protein crystal structures of our novel CypD inhibitors provide a suitable basis for further hit-to-lead optimization.Graphical abstractGraphical abstract for this article
       
  • Graphical Abstract Contents Continued
    • Abstract: Publication date: 1 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 23Author(s):
       
  • Design, synthesis and evaluation of
           5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione-Based fibrates as potential
           hypolipidemic and hepatoprotective agents
    • Abstract: Publication date: 1 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 23Author(s): Lihua Shao, Yue Bai, Qiutang Wang, Zizhang Chen, Yundong Xie, Xiaoli Bian Six novel target compounds 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT) based fibrates were synthesized and evaluated. All the synthesized compounds were preliminarily screened by using the Triton WR-1339-induecd hyperlipidemia model, in which T1 exhibited more potent hypolipidemic property than positive drug fenofibrate (FF). T1 also significantly decreased serum triglycerides (TG), total cholesterol (TC) and low density lipoprotein cholesterin (LDL) in methionine solution (Mets) induced hyperlipidemic mice. Moreover, hepatic transaminases (AST and ALT) were obviously ameliorated after treatment with T1 and the histological observation indicated that T1 ameliorated the injury in liver tissue and inhibited the hepatic lipid accumulation. In the livers of T1-administrated rat, the levels of PPARα related to lipids metabolism were up-regulated. Additional effects such as antioxidant, anti-inflammatory and H2S releasing action confirmed and reinforced the activity of T1 as a potential multifunctional hypolipidemic and hepatoprotective agent.Graphical abstractGraphical abstract for this article
       
  • Synthesis and biological evaluation of 9-fluorenone derivatives for SPECT
           imaging of α7-nicotinic acetylcholine receptor
    • Abstract: Publication date: 1 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 23Author(s): Hang Gao, Shuxia Wang, Yueheng Qi, Guoxue He, Bingchao Qiang, Sixuan Wang, Huabei Zhang The α7-nicotinic acetylcholine receptor (α7-nAChR) subtype, is found to have a connection with the pathogenesis of a variety of psychiatric and neurological disorders. Herein, we report the development of radioiodinated 9-fluorenone derivatives as single-photon emission computed tomography (SPECT) imaging tracers for α7-nAChRs. Among the derivatives, the best member of the series 10 (Ki = 2.23 nM) were radiolabeled with 125I for in vitro and in vivo studies. The radiotracer [125I]10 exhibited robust brain uptake and specifically labeled α7-nAChRs with a peak uptake value of 9.49 ± 0.87%ID/g in brain. Blocking studies demonstrated that the tracer was highly specific toward α7-nAChR. Furthermore, ex vivo autoradiography and micro-SPECT/CT dynamic imaging in mice confirmed the excellent imaging properties. In addition, molecular docking was also performed to rationalize the potency of the chosen compounds towards α7-nAChRs. To conclude, compound 10 could serve as a promising radiotracer for the α7-nAChRs.Graphical abstractGraphical abstract for this article
       
  • Synthesis and biological evaluation of
           3-acyl-2-phenylamino-1,4-dihydroquinolin-4(1H)-one derivatives as
           potential MERS-CoV inhibitors
    • Abstract: Publication date: 1 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 23Author(s): Ji Hye Yoon, Jun Young Lee, Jihye Lee, Young Sup Shin, Sangeun Jeon, Dong Eon Kim, Jung Sun Min, Jong Hwan Song, Seungtaek Kim, Sunoh Kwon, Young-hee Jin, Min Seong Jang, Hyoung Rae Kim, Chul Min Park 3-Acyl-2-phenylamino-1,4-dihydroquinolin-4(1H)-one derivatives were synthesized and evaluated to show high anti-MERS-CoV inhibitory activities. Among them, 6,8-difluoro-3-isobutyryl-2-((2,3,4-trifluorophenyl)amino)quinolin-4(1H)-one (6u) exhibits high inhibitory effect (IC50 = 86 nM) and low toxicity (CC50 > 25 μM). Moreover, it shows good metabolic stability, low hERG binding affinity, no cytotoxicity, and good in vivo PK properties.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and biological evaluation of novel
           semicarbazone-selenochroman-4-ones hybrids as potent antifungal agents
    • Abstract: Publication date: 1 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 23Author(s): Hang Xu, Xin Su, Xiao-qian Liu, Kai-peng Zhang, Zhuang Hou, Chun Guo A series of novel 2,3-dihydro-4H-1-benzoselenin-4-one (thio)semicarbazone derivatives were designed and synthesized by using molecular hybridization approach. All the target compounds were characterized by HRMS and NMR and evaluated in vitro antifungal activity against five pathogenic strains. In comparison with precursor selenochroman-4-ones, the hybrid molecules in this study showed significant improvement in antifungal activities. Notably, compound B8 showed significant antifungal activity against other strains excluding Aspergillus fumigatus (0.25 μg/mL on Candida albicans, 2 μg/mL on Cryptococcus neoformans, 8 μg/mL on Candida zeylanoides and 2 μg/mL on fluconazole-sensitive strains of Candida albicans). Moreover, compounds B8, B9 and C2 also displayed most potent activities against four fluconazole-resistance strains. Especially the MIC values of the hybrid molecule B8 against fluconazole-resistant strains were in the range of 0.5–2 μg/mL. Therefore, the molecular hybridization approach in this study provided new ideas for the development of antifungal drug.Graphical abstractGraphical abstract for this article
       
  • Discovery and optimization of a series of small-molecule allosteric
           inhibitors of MALT1 protease
    • Abstract: Publication date: 1 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 23Author(s): Tianbao Lu, Peter J. Connolly, Ulrike Philippar, Weimei Sun, Maxwell D. Cummings, Kent Barbay, Luc Gys, Luc Van Nuffel, Nigel Austin, Mariette Bekkers, Fang Shen, Ann Cai, Ricardo Attar, Lieven Meerpoel, James Edwards We describe a series of potent and highly selective small-molecule MALT1 inhibitors, optimized from a High-Throughput Screening hit. Advanced analogues such as compound 40 show high potency (IC50: 0.01 µM) in a biochemical assay measuring MALT1 enzymatic activity, as well as in cellular assays: Jurkat T cell activation (0.05 µM) and IL6/10 secretion (IC50: 0.10/0.06 µM) in the TMD8 B-cell lymphoma line. Compound 40 also inhibited cleavage of the MALT1 substrate RelB (IC50: 0.10 µM). Mechanistic enzymology results suggest that these compounds bind to the known allosteric site of the protease.Graphical abstractGraphical abstract for this article
       
  • Synthesis and antibacterial evaluation of novel oxazolidinone derivatives
           containing a piperidinyl moiety
    • Abstract: Publication date: 1 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 23Author(s): Yunlei Hou, Yuhong Dong, Tianyu Ye, Jia Jiang, Liang Ding, Mingze Qin, Xiudong Ding, Yanfang Zhao In this article, a series of novel oxazolidinone derivatives containing a piperidinyl moiety was designed and synthesized. Their antibacterial activities were measured against S. aureus, MRSA, MSSA, LREF and VRE by MIC assay. Most of them exhibited potent activity against Gram-positive pathogens comparable to linezolid. Among them, compound 9h exhibited comparable activity with linezolid against human MAO-A for safety evaluation and showed moderate metabolism in human liver microsome. The most promising compound 9h, which showed remarkable antibacterial activity against S. aureus, MRSA, MSSA, LREF and VRE pathogens with MIC value of 0.25–1 μg/mL, was an interesting candidate for further investigation.Graphical abstractGraphical abstract for this article
       
  • Mycobacterial tryptophan biosynthesis: A promising target for tuberculosis
           drug development'
    • Abstract: Publication date: 1 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 23Author(s): Sara Consalvi, Cristina Scarpecci, Mariangela Biava, Giovanna Poce The biosynthetic pathways of amino acids are attractive targets for drug development against pathogens with an intracellular behavior like M. tuberculosis (Mtb). Indeed, while in the macrophages Mtb has restricted access to amino acids such as tryptophan (Trp). Auxotrophic Mtb strains, with mutations in the Trp biosynthetic pathway, showed reduced intracellular survival in cultured human and murine macrophages and failed to cause the disease in immunocompetent and immunocompromised mice. Herein we present recent efforts in the discovery of Trp biosynthesis inhibitors.Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC
    • Abstract: Publication date: 1 December 2019Source: Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 23Author(s):
       
  • Design and synthesis of biaryloxazolidinone derivatives containing amide
           or acrylamide moiety as novel antibacterial agents against Gram-positive
           bacteria
    • Abstract: Publication date: Available online 21 October 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Sicong Xu, Jia Jiang, Yinliang Qi, Xiudong Ding, Yachuang Wu, Hong Lei, Yanfang Zhao A series of novel biaryloxazolidinone derivatives containing amide and acrylamide structure were designed, synthesized and evaluated for their antibacterial activity. Most compounds generally exhibited potent antibacterial activity with MIC values of 1 μg/mL against S. aureus, MRSA, MSSA, LREF and VRE pathogens, using linezolid and radezolid as positive controls. Compound 17 exhibited good antibacterial activity with MIC values of 0.5 μg/mL against S. aureus, MRSA, MSSA and VRE and 0.25 μg/mL against LREF. The results indicated that compound 17 might serve as a potential hit-compound for further investigation.Graphical abstractA series of novel biaryloxazolidinone derivatives containing amide or acrylamide structure were designed, synthesized and evaluated for their antibacterial activity.Graphical abstract for this article
       
  • The Identification and Pharmacological Evaluation of Potent, Selective and
           Orally Available ACC1 Inhibitor
    • Abstract: Publication date: Available online 21 October 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Ryo Mizojiri, Moriteru Asano, Masako Sasaki, Yoshihiko Satoh, Yukiko Yamamoto, Hiroyuki Sumi, Hironobu Maezaki In our effort to explore the potential of ACC1-selective inhibitor as in vivo probe molecule, a series of 1,3-benzoxazole derivatives was synthesized. Previously, we reported a series of novel bicyclic and monocyclic ACC1-selective inhibitors. Among them, compound 1a exhibited highly potent cellular activity (acetate uptake IC50 = 0.76 nM) as well as promising in vivo PD efficacy. However, compound 1a caused severe body weight reduction in repeated dose administration in the mouse model. Since 1a showed potent inhibitory activity against mouse ACC1 as well as strong inhibition of mouse ACC2, we further examined a series of 1a analogues in order to reduce undesirable body weight change. The replacement of acetamide moiety with ureido moiety dramatically improved selectivity of mouse ACC1 against ACC2. In addition, analogue 1b displayed favorable bioavailability in mouse cassette dosing PK study, hence in vivo PD studies were also carried out. Oral administration of 1b significantly reduced the concentration of malonyl-CoA in HCT-116 xenograft tumors at doses of more than 30 mg/kg. Furthermore, compound 1b showed significant antitumor efficacy in 786-O xenograft mice at an oral dose of 30 mg/kg (T/C = 0.5%). Accordingly, our novel potent ACC1-selective inhibitor represents a set of useful orally-available research tools, as well as potential therapeutic agents particularly in terms of new cancer therapies.Graphical abstractGraphical abstract for this article
       
  • Discovery of arylamide-5-anilinoquinazoline-8-nitro derivatives as VEGFR-2
           kinase inhibitors: synthesis, in vitro biological evaluation and molecular
           docking
    • Abstract: Publication date: Available online 19 October 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Yongqiang Zhao, Feifei Liu, Guojing He, Ke Li, Changcheng Zhu, Wei Yu, Conghai Zhang, Mingjin Xie, Jun Lin, Jihong Zhang, Yi Jin Herein, we embarked on a structural optimization campaign aiming at the discovery of novel anticancer agents with our previously reported XL-6f as a lead compound. A library of 23 compounds has been synthesized based on the highly conserved active site of VEGFR-2. Several title compounds exhibited selective inhibitory activities against VEGFR-2, which also displayed selective anti-proliferation potency against HepG2 cell. All synthesized compounds were evaluated for anti-angiogenesis capability. Compound 7o showed the most potent anti-angiogenesis ability, the efficient cytotoxic activities (in vitro against HUVEC and HepG2 cell lines with IC50 values of 0.58 and 0.23 µM, respectively). The molecular docking analysis revealed 7o is a Type-II inhibitor of VEGFR-2 kinase. In general, these results indicated these arylamide-5-anilinoquinazoline-8-nitro derivatives are promising inhibitors of VEGFR-2 for the potential treatment of anti-angiogenesis.
       
  • Discovery of a novel bicyclic compound, DS54360155, as an orally potent
           analgesic without mu-opioid receptor agonist activity
    • Abstract: Publication date: Available online 19 October 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Tsuyoshi Arita, Masayoshi Asano, Kazufumi Kubota, Yuki Domon, Nobuo Machinaga, Kousei Shimada We synthesized derivatives of a natural alkaloid, conolidine, and evaluated these derivatives in the acetic acid-induced writhing test and formalin test in ddY mice after oral administration. As a result, we identified (5S)-6-methyl-1,3,4,5,6,8-hexahydro-7H-2,5-methano[1,5]diazonino[7,8-b]indol-7-one sulfate salt, 15a (DS54360155), with a unique and original bicyclic skeleton, as an analgesic more potent than conolidine. Moreover, 15a did not exhibit mu-opioid receptor agonist activity.Graphical abstractGraphical abstract for this article
       
  • Synthesis and structure-activity relationships of novel camphecene
           analogues as anti-influenza agents
    • Abstract: Publication date: Available online 19 October 2019Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Olga I. Yarovaya, Anastasiya S. Sokolova, Iliya Ya. Mainagashev, Alexandrina S. Volobueva, Khristina Lantseva, Sophia S. Borisevich, Anna A. Shtro, Vladimir V. Zarubaev, Nariman F. Salakhutdinov A chemical library was constructed based on the scaffold of camphecene (2-(E)-((1R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene-aminoethanol). The modifications included introduction of mono-and bicyclic heterocyclic moieties in place of the terminal hydroxyl group of camphecene. All compounds were tested for cytotoxicity and anti-viral activity against influenza virus A/Puerto Rico/8/34 (H1N1) in MDCK cells. Among 15 tested compounds 11 demonstrated a selectivity index (SI) higher than 10 and IC50 values in the micromolar range. The antiviral activity and toxicity were shown to strongly depend on the nature of the heterocyclic substituent. Compounds 2 and 14 demonstrated the highest virus-inhibiting activity with SIs of 106 and 183, and bearing pyrrolidine and piperidine moieties, correspondingly. Compound 14 was shown to interfere with viral reproduction at early stages of the viral life cycle (0–2 h post-infection). Taken together, our data suggest potential of camphecene derivatives in particular and camphor-based imine derivatives in general as effective anti-influenza compounds.Graphical abstractGraphical abstract for this article
       
 
 
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