Chemical Biology & Drug Design

Cover image for Vol. 86 Issue 2

Early View (Online Version of Record published before inclusion in an issue)

Edited By: David Selwood

Impact Factor: 2.485

ISI Journal Citation Reports © Ranking: 2014: 28/59 (Chemistry Medicinal); 164/289 (Biochemistry & Molecular Biology)

Online ISSN: 1747-0285

VIEW

  1. 1 - 100
  2. 101 - 122
  1. Research Articles

    1. RNAi-Mediated Silencing of EIF3D Alleviates Proliferation and Migration of Glioma U251 and U87MG Cells

      Mingliang Ren, Chun Zhou, Hong Liang, Xuhui Wang and Lunshan Xu

      Article first published online: 28 JUL 2015 | DOI: 10.1111/cbdd.12542

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      In this study, we found EIF3D expression was positively correlated with WHO grades of gliomas. Knockdown of EIF3D by lentivirus-mediated RNAi caused a significant reduction in growth and migration of glioma cells. EIF3D may serve as a potential therapeutic target in glioma.

  2. Research Letters

    1. Microscale Adaptation of In Vitro Transcription/Translation for High-Throughput Screening of Natural Product Extract Libraries

      Andrew N. Lowell, Nicholas Santoro, Steven M. Swaney, Thomas J. McQuade, Pamela J. Schultz, Martha J. Larsen and David H. Sherman

      Article first published online: 25 JUL 2015 | DOI: 10.1111/cbdd.12614

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      A coupled transcription/translation high-throughput screening assay was miniaturized and shown to be effective at detecting known classes of ribosome-inhibiting antibiotics. This luciferase-based assay was successfully applied to a natural product extract library of 30 000 compounds with a hit-rate of 4.6%, a %CV value of 8.5% and a Z’ value of 0.74. Selected hits were retested in triplicate to confirm authenticity, subjected to a secondary screen to remove luciferase inhibitors, and are moving forward in the discovery process..

  3. Research Articles

    1. Synthesis, Biological Evaluation and Molecular Modeling Studies of New 2,3-Diheteroaryl Thiazolidin-4-Ones as NNRTIs

      Utsab Debnath, Saroj Verma, Pankaj Singh, Kavita Rawat, Satish K. Gupta, Raj K. Tripathi, Hefazat H. Siddiqui, Seturam B. Katti and Yenamandra S. Prabhakar

      Article first published online: 22 JUL 2015 | DOI: 10.1111/cbdd.12591

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      Thiazolidin-4-ones with different C-2 and N-3 substituent groups were synthesized and evaluated as non-nucleoside reverse transcriptase inhibitors of HIV-1. This has led to new active compounds sporting heteroaryls at both C-2 and N-3 positions prompting to view them in the backdrop of nevirapine. The most active compounds (7d and 7f) shared spatial features with nevirapine. Molecular dynamics simulations carried out on HIV-1 reverse transcriptase – compound (7d and 7f) complex identified avenues to design new 2,3-diheteroaryl thiazolidinon-4-one against HIV-1.

  4. Research Letters

    1. Synthesis and Antiproliferative Activity of Silybin Conjugates with Salinomycin and Monensin

      Michał Antoszczak, Greta Klejborowska, Monika Kruszyk, Ewa Maj, Joanna Wietrzyk and Adam Huczyński

      Article first published online: 22 JUL 2015 | DOI: 10.1111/cbdd.12602

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      The conjugates of hepatoprotective natural compound silybin (SIL) and two natural polyether ionophores monensin (MON) and salinomycin (SAL) displayed interesting antiproliferative activity in various human cancer cells, including MDR cells at low micromolar concentrations. The anticancer activity is connected with high selectivity indexes (SI) and low toxicity against normal cells.

  5. Research Articles

    1. RNAi Silencing of IL-1β and TNF-α in the Treatment of Post-traumatic Arthritis in Rabbits

      Qiang Tang, Liang Hao, Yuanxiang Peng, Yating Zheng, Kuo Sun, Feng Cai, Chunlong Liu and Qi Liao

      Article first published online: 20 JUL 2015 | DOI: 10.1111/cbdd.12611

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      We concluded that lentivirus-mediated RNA interference can knock down the expression of IL-1β and TNF-α in joint fluid and, in a synergistic effect when two siRNAs are co-transfected, ease cartilage degeneration. This may indicate a new direction for the use of gene silencing in the treatment of post-traumatic arthritis.

    2. Design, Synthesis, Biological Evaluation, and Docking Study of Acetylcholinesterase Inhibitors: New Acridone-1,2,4-oxadiazole-1,2,3-triazole Hybrids

      Maryam Mohammadi-Khanaposhtani, Mohammad Mahdavi, Mina Saeedi, Reyhaneh Sabourian, Maliheh Safavi, Mahnaz Khanavi, Alireza Foroumadi, Abbas Shafiee and Tahmineh Akbarzadeh

      Article first published online: 20 JUL 2015 | DOI: 10.1111/cbdd.12609

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      A novel series of acridone-1,2,4-oxadiazole-1,2,3-triazole hybrids were synthesized and evaluated in vitro for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities.

    3. Synthesis and Anticholinergic Activity of 4-hydroxycoumarin Derivatives Containing Substituted Benzyl-1,2,3-triazole Moiety

      Sahar Mohammad Bagheri, Mehdi Khoobi, Hamid Nadri, Alireza Moradi, Saeed Emami, Leili Jalili-Baleh, Farnaz Jafarpour, Farshad Homayouni Moghadam, Alireza Foroumadi and Abbas Shafiee

      Article first published online: 20 JUL 2015 | DOI: 10.1111/cbdd.12588

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      A series of 4-hydroxycoumarin derivatives 8a-p containing N-benzyl-1,2,3-triazole motif were designed and synthesized as AChE inhibitors. Among them, 2-chlorobenzyl derivative 8k showed the most potent activity against AChE (IC50 = 0.18 µm).

  6. Research Letters

    1. Site-specific Substitutions Eliminate Aggregation Properties of Hemopressin

      Benben Song, Patrick D. Kibler, Aaron N. Endsley, Surendra K. Nayak, Amit K. Galande and Kalyani Jambunathan

      Article first published online: 20 JUL 2015 | DOI: 10.1111/cbdd.12610

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      Aggregation properties of naturally occurring peptide hemopressin and its 25 synthetic analogs were analyzed using the principle of dynamic light scattering.

  7. Research Articles

    1. Elucidating the Mechanism of Action of the Clinically Approved Taxanes: A Comprehensive Comparison of Local and Allosteric Effects

      Cassandra D. M. Churchill, Mariusz Klobukowski and Jack A. Tuszynski

      Article first published online: 14 JUL 2015 | DOI: 10.1111/cbdd.12595

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      Interactions between the tubulin heterodimer and the clinically approved taxanes (paclitaxel, docetaxel and cabazitaxel) are examined. These drugs have variable effects on tubulin at the taxane binding site. Instead, a common mechanism of action of these drugs is identified, with the taxanes having an allosteric effect on tubulin that is traced from the taxane binding site across the entire tubulin heterodimer.

    2. Comparative Analysis of Pharmacophore Features and Quantitative Structure–Activity Relationships for CD38 Covalent and Non-covalent Inhibitors

      Shuang Zhang, Xiwen Xue, Liangren Zhang, Lihe Zhang and Zhenming Liu

      Article first published online: 14 JUL 2015 | DOI: 10.1111/cbdd.12606

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      A comparative analysis of pharmacophore features and quantitative structure–activity relationships for CD38 inhibitors with systemic summarizations and analysis given about the binding characteristics and quantitative structure–activity relationships for known CD38 covalent and non-covalent inhibitors, which will be helpful for further CD38 inhibitors design.

    3. Enrichment Assessment of Multiple Virtual Screening Strategies for Toll-Like Receptor 8 Agonists Based on a Maximal Unbiased Benchmarking Data Set

      Fen Pei, Hongwei Jin, Xin Zhou, Jie Xia, Lidan Sun, Zhenming Liu and Liangren Zhang

      Article first published online: 14 JUL 2015 | DOI: 10.1111/cbdd.12590

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      A comprehensive assessment of multiple virtual screening strategies for toll-like receptor 8 agonists including knowledge-based pharmacophore, shape-based 3D similarity search and combined strategies against a maximum-unbiased benchmarking data set specialized for toll-like receptor 8 agonists. The enrichment assessment demonstrated a considerable performance through our selected three-layer virtual screening strategy: knowledge-based pharmacophore (Phar1) screening, followed by shape-based 3D similarity search (Q4_combo), and then a Gold docking screening. This virtual screening strategy could be further employed to perform large-scale database screening and to discover novel toll-like receptor 8 agonists.

    4. Integrating Pharmacophore into Membrane Molecular Dynamics Simulations to Improve Homology Modeling of G Protein-coupled Receptors with Ligand Selectivity: A2A Adenosine Receptor as an Example

      Lingxiao Zeng, Mengxin Guan, Hongwei Jin, Zhenming Liu and Liangren Zhang

      Article first published online: 14 JUL 2015 | DOI: 10.1111/cbdd.12607

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      We propose a novel strategy by integrating pharmacophore and membrane MD simulations together to improve homology modeling of GPCRs with ligand selectivity. To validate this integrated strategy, the A2A adenosine receptor (A2AAR), whose structures in both active and inactive state have been established, has been chosen as an example. This integrated strategy can be further investigated in homology modeling and expand its applicability to other GPCR modeling, which should aid in the discovery of more effective and selective GPCR ligands.

    5. Synthesis and Biological Evaluation of Benzo[d][1,3]Dioxol-5-yl Chalcones as Antiproliferating Agents

      Ahmed Kamal, Moku Balakrishna, Velatooru Loka Reddy, Syed Riyaz, Chandrakant Bagul, Bethu Murali Satyanarayana and Janapala Venkateswar Rao

      Article first published online: 14 JUL 2015 | DOI: 10.1111/cbdd.12597

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      A series of chalcone derivatives were designed synthesized and evaluated for their cytotoxic potential and mechanistic studies were also carried out for active compounds.

    6. 5-Arylaminouracil Derivatives: New Inhibitors of Mycobacterium tuberculosis

      Elena Matyugina, Mikhail Novikov, Denis Babkov, Alexander Ozerov, Larisa Chernousova, Sofia Andreevskaya, Tatiana Smirnova, Inna Karpenko, Alexander Chizhov, Pravin Murthu, Stefan Lutz, Sergei Kochetkov, Katherine L. Seley-Radtke and Anastasia L. Khandazhinskaya

      Article first published online: 14 JUL 2015 | DOI: 10.1111/cbdd.12603

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      Three series of 5-arylaminouracil derivatives were synthesized and screened for potential antimicrobial activity. Most of compounds had a negative effect on the growth of the M. tuberculosis H37Rv strain, with 100% inhibition observed at concentrations between 5 and 40 μg/mL. Of those, 1-(4′-hydroxy-2′-cyclopenten-1′-yl)-3-(4‴-hydroxy-2‴-cyclopenten-1‴-yl)-5-(4″-butyloxyphenylamino)uracil proved to be the most active among tested compounds against the M. tuberculosis multidrug-resistant strain MS-115 (MIC90 5 μg/mL).

    7. Synthesis and Biological Evaluation of Novel Ursolic acid Derivatives as Potential Anticancer Prodrugs

      Xiang Yang, Yuanfang Li, Wei Jiang, Minrui Ou, Yali Chen, Yu Xu, Qiong Wu, Qing Zheng, Fuqiang Wu, Lue Wang, Wentao Zou, Yitong J. Zhang and Jingwei Shao

      Article first published online: 14 JUL 2015 | DOI: 10.1111/cbdd.12608

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      A series of UA piperazine derivatives were designed and synthesized to improve the anticancer activity and to explore the structure-activity relationships. The effects of the most potent compound 5b on cell proliferation, apoptosis induction and cell cycle were evaluated. Furthermore, we also analyzed the protein-ligand interaction with 5b by using molecular modelling studies.

    8. Synthesis, Biological Evaluation, and Docking of Dihydropyrazole Sulfonamide Containing 2-hydroxyphenyl Moiety: A Series of Novel MMP-2 Inhibitors

      Peng-Fei Wang, Han-Yue Qiu, Shahla Karim Baloch, Hai-Bin Gong, Zhong-Chang Wang and Hai-Liang Zhu

      Article first published online: 14 JUL 2015 | DOI: 10.1111/cbdd.12604

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      A series of dihydropyrazole sulfonamide derivatives containing 2-hydroxyphenyl moiety were designed and synthesized as antitumor agent to target the matrix metalloproteinase-2 (MMP-2). All of the synthesized compounds were examined by bioactivity assays, and structure-activity relationship analysis was also performed to discuss how structural changes could impact the bioactivity.

    9. Changing Blue Fluorescent Protein to Green Fluorescent Protein Using Chemical RNA Editing as a Novel Strategy in Genetic Restoration

      Luyen T. Vu, Thanh T. K. Nguyen, Shafiul Alam, Takashi Sakamoto, Kenzo Fujimoto, Hitoshi Suzuki and Toshifumi Tsukahara

      Article first published online: 23 JUN 2015 | DOI: 10.1111/cbdd.12592

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      By using the transition from cytosine of BFP gene to uridine of GFP gene at position 199 as a model, we successfully controlled photochemical RNA editing to effect site-directed deamination of cytidine to uridine. Western-blotting and fluorescence-analysis results revealed that the transition-GFP protein was synthesized from mRNAs after site-directed RNA editing.

    10. Synthesis of Novel 3-aryl-1-oxa-2,8-diazaspiro[4.5]dec-2-ene Derivatives and Their Biological Evaluation Against Protein Tyrosine Phosphatase 1B

      Wen-Long Wang, Xia Chen, Li-Xin Gao, Li Sheng, Jing-Ya Li, Jia Li and Bainian Feng

      Article first published online: 23 JUN 2015 | DOI: 10.1111/cbdd.12587

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      A series of novel 3-aryl-1-oxa-2,8-diazaspiro[4.5]dec-2-ene derivatives were designed, synthesized, and evaluated as a new class of inhibitors against PTP1B. Among them, compound 6f displayed moderate inhibitory activity with IC50 of 2.87 ± 0.24 μm and can be used as a novel lead compound for the design of inhibitors of PTP1B.

    11. Novel 4-Heteroaryl-Antipyrines as DPP-IV Inhibitors

      Sobhi M. Gomha, Taha M. A. Eldebss, Mohamed G. Badrey, Mohamed M. Abdulla and Abdelrahman S. Mayhoub

      Article first published online: 23 JUN 2015 | DOI: 10.1111/cbdd.12593

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      Novel 4-Heteroaryl-Antipyrines were synthesized and evaluated as a novel scaffold in the field of DPP-IV Inhibitors.

    12. Discovery of New 4-Alkoxyquinazoline-Based Derivatives as Potent VEGFR2 Inhibitors

      Yong Yin, Shao Sha, Yan-Ting Wang, Xun Wu, She-Feng Wang, Fang Qiao, Peng-Cheng Lv and Hai-Liang Zhu

      Article first published online: 23 JUN 2015 | DOI: 10.1111/cbdd.12596

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      Twenty-one 4-alkoxyquinazoline-based derivatives as vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors have been designed and synthesized, and their biological activities were evaluated. Of these compounds, compound 3h exhibited the most potent inhibitory activities against VEGFR2 tyrosine kinase and cell proliferation, with the IC50 values of 2.89 nm (for VEGFR2) and 0.25 μm (for MCF-7).

    13. Design, Synthesis, and Antitumor Activity of (E,Z)-1-(dihydrobenzofuran-5-yl)-3-phenyl-2-(1,2,4-triazol-1-yl)-2-propen-1-ones

      Wan Li, Zi-Hui Yang, Ai-Xi Hu, Xiao-Wei Yan, Na Ding and Jiao Ye

      Article first published online: 23 JUN 2015 | DOI: 10.1111/cbdd.12601

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      A series of (E,Z)-1-(dihydrobenzofuran-5-yl)-3-phenyl-2-(1,2,4-triazol-1-yl)-2-propen-1-ones were designed and synthesized, and their biological activities against tumor cell lines were evaluated in vitro. Compounds (E,Z)-C24 with para-nitro group exhibited the most consistently potent activities against three neoplastic cells, with IC50 ranging from 3.2 to 7.1 μm. Further researches showed that compounds (E,Z)-C24 could induce cell apoptosis and arrest cells cycle at the G2/M and S phases.

    14. Transmembrane Helix Assembly by Max–Min Ant System Algorithm

      Kanon Sujaree, Sunan Kitjaruwankul, Panisak Boonamnaj, Chirayut Supunyabut and Pornthep Sompornpisut

      Article first published online: 23 JUN 2015 | DOI: 10.1111/cbdd.12600

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      A novel efficient algorithm called max–min ant system was designed for solving an assembly of transmembrane proteins. It show noticeably superior convergence performance compared to simulated annealing Monte Carlo and genetic algorithm. The algorithm gives a promising approach for solving structure with low-resolution data.

    15. Antimalarial Effect of 3-Methoxy-1,2-Dioxetanes on the Erythrocytic Cycle of Plasmodium falciparum

      Nicolas S. Lopes, Ariane M. Yoshitake, Adriana F. Silva, Vani X. Oliveira Jr, Leandro S. Silva, Ana A. S. Pinheiro and Luiz Francisco M. L. Ciscato

      Article first published online: 20 JUN 2015 | DOI: 10.1111/cbdd.12599

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      The antimalarial activity of 3-methoxy-1,2-dioxetanes was determined, and is at a similar level as artemisinin; also, their reactivity towards iron(II) correlate linearly with their antimalarial activity.

    16. Cationic Albumin-Conjugated Chelating Agent as a Novel Brain Drug Delivery System in Neurodegeneration

      Golnaz Kamalinia, Fariba Khodagholi, Fatemeh Shaerzadeh, Faranak Tavssolian, Farkhondeh Chaharband, Fatemeh Atyabi, Mohammad Sharifzadeh, Mohsen Amini and Rassoul Dinarvand

      Article first published online: 17 JUN 2015 | DOI: 10.1111/cbdd.12586

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      This manuscript reports a novel cationized albumin-conjugated drug formulation followed by characterization and physicochemical evaluation, cell culture studies for evaluating any related neuroprotective effect as well as the residing molecular mechanisms behind it and an in vivo evaluation of its capability in attenuating Aβ-induced learning and memory deficits. We have demonstrated that cationized albumin-conjugated deferasirox can be exploited as a brain drug delivery system in neurodegenerative disorders by reducing apoptotic and enhancing autophagic pathways.

    17. Characterizing the Free-Energy Landscape of MDM2 Protein–Ligand Interactions by Steered Molecular Dynamics Simulations

      Guodong Hu, Shicai Xu and Jihua Wang

      Article first published online: 15 JUN 2015 | DOI: 10.1111/cbdd.12598

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      Four ligands were dragged out from their MDM2 protein-binding pocket. The differences in free energies calculated by BD-FDT are in agreement with the experimental data. We further found that different binding mechanisms among different ligands are associated with H-bond with Lys51 and Glu25.

  8. Research Letters

    1. 2-Pyridinyl-4(3H)-Quinazolinone: A Scaffold for Anti-influenza A Virus Compounds

      Shixu Liu, Wei Wang, Long Jiang, Shengbiao Wan, Lijuan Zhang, Rilei Yu and Tao Jiang

      Article first published online: 15 JUN 2015 | DOI: 10.1111/cbdd.12589

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      A series of 2-pyridinyl-3-substituted-4(3H)-quinazolinones were designed based on the scaffold of 2-pyridinyl-4(3H)-quinazolinone and their anti-IVA (H1N1) activities and underlying molecular mechanisms were investigated. The results revealed that several compounds exhibited high anti-IVA activities, and are comparable or even better than that of the marketed drug, ribavirin.

  9. Research Articles

    1. Bongkrekic Acid Analogue, Lacking One of the Carboxylic Groups of its Parent Compound, Shows Moderate but pH-insensitive Inhibitory Effects on the Mitochondrial ADP/ATP Carrier

      Atsushi Yamamoto, Keisuke Hasui, Hiroshi Matsuo, Katsuhiro Okuda, Masato Abe, Kenji Matsumoto, Kazuki Harada, Yuya Yoshimura, Takenori Yamamoto, Kazuto Ohkura, Mitsuru Shindo and Yasuo Shinohara

      Article first published online: 13 JUN 2015 | DOI: 10.1111/cbdd.12594

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      Inhibitory effects of 17 bongkrekic acid analogues derived from the intermediates obtained during its total synthesis, on the mitochondrial ATP/ATP carrier were examined. One compound, KH-7, lacking one of the carboxylic groups of its parent compound, showed moderate but pH-intensive inhibitory effects on the mitochondrial ADP/ATP carrier.

  10. Reviews

    1. Heat-Shock Protein 90 (Hsp90) as Anticancer Target for Drug Discovery: An Ample Computational Perspective

      Hezekiel M. Kumalo, Soumendranath Bhakat and Mahmoud E. Soliman

      Article first published online: 11 JUN 2015 | DOI: 10.1111/cbdd.12582

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      In this review, we provide an up-to-date systematic overview on the different computational models implemented toward the design of Hsp90 inhibitors as anticancer agents. This article encompasses on a broad range of topics including background and current statistics of cancer, different anticancer targets including Hsp90, and the structure and function of Hsp90 from an experimental perspective, for example, X-ray and NMR to get a comprehensive overview on this emerging drug target. We believe that the information, computational methods, and perspectives highlighted in this report would assist researchers in the discovery of potential anticancer agents.

  11. Research Articles

    1. Targeting Of miR9/NOTCH1 Interaction Reduces Metastatic Behavior in Triple-negative Breast Cancer

      Samira Mohammadi-Yeganeh, Ardalan Mansouri and Mahdi Paryan

      Article first published online: 3 JUN 2015 | DOI: 10.1111/cbdd.12584

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      miR-9 correlation with NOTCH1 play a role in Notch signaling pathway and is involved in metastatic breast cancer. So, inhibition of NOTCH1 signaling by miR-9 can propose as a new therapeutic approach.

    2. Synthesis and Anti-neuroinflammatory Activity of Lactone Benzoyl Hydrazine and 2-nitro-1-phenyl-1H-Indole Derivatives as p38α MAPK Inhibitors

      Bao Cheng, Yongsheng Lin, Ming Kuang, Sai Fang, Qiong Gu, Jun Xu and Laiyou Wang

      Article first published online: 1 JUN 2015 | DOI: 10.1111/cbdd.12581

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      We designed, synthesized and evaluated two series lactone benzoyl hydrazine and 2-nitro-1-phenyl-1H-Indole derivatives for novel promising chemical lead p38α MAPK inhibitors as anti-neuroinflammatory agents in fighting against Alzheimer's diseases.

    3. Structural Basis of Non-Steroidal Anti-Inflammatory Drug Diclofenac Binding to Human Serum Albumin

      Yao Zhang, Philbert Lee, Shichu Liang, Zuping Zhou, Xiaoyang Wu, Feng Yang and Hong Liang

      Article first published online: 28 MAY 2015 | DOI: 10.1111/cbdd.12583

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      Three DIC molecules bind to HSA main through hydrophobic interactions and hydrogen bond. One is located in IB subdomain, the others co-bind to big hydrophobic pocket in IIA subdomain. Interestingly, the DIC binding in side chamber of binding pocket projects into cleft of IIA and IIIA subdomain.

    4. Amino Acid-Based Cationic Lipids With α-Tocopherol Hydrophobic Tail for Efficient Gene Delivery

      Wen-Jing Yi, Li-Ting Zheng, Rong-Chuan Su, Qiang Liu and Zhi-Gang Zhao

      Article first published online: 28 MAY 2015 | DOI: 10.1111/cbdd.12585

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      Biocompatible amino acid-based cationic lipids with α-tocopherol hydrophobic tails were synthesized and applied as non-viral gene vectors.

    5. Syntheses, Cholinesterases Inhibition, and Molecular Docking Studies of Pyrido[2,3-b]pyrazine Derivatives

      Abdul Hameed, Syeda T. Zehra, Syed J. A. Shah, Khalid M. Khan, Rima D. Alharthy, Norbert Furtmann, Jürgen Bajorath, Muhammad N. Tahir and Jamshed Iqbal

      Article first published online: 28 MAY 2015 | DOI: 10.1111/cbdd.12579

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      A series of pyrido[2,3-b]pyrazine (6a-6q) derivatives has been synthesized and evaluated for inhibitory activities against cholinesterases; acetylcholinesterase, and butyrylcholinesterase. Molecular docking of active compounds was also performed to suggest the putative binding modes with cholinesterases.

    6. Synthesis and Evaluation of Derivatives of the Proteasome Deubiquitinase Inhibitor b-AP15

      Xin Wang, Pádraig D'Arcy, Thomas R. Caulfield, Aneel Paulus, Kasyapa Chitta, Chitralekha Mohanty, Joachim Gullbo, Asher Chanan-Khan and Stig Linder

      Article first published online: 27 MAY 2015 | DOI: 10.1111/cbdd.12571

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      The compound b-AP15 was previously shown to inhibit proteasome DUB (deubiquitinase) activity, leading to proteasome blocking and tumor cell apoptosis. The authors have examined the biological activities of a number of structurally related compounds and describe the analogue VLX1570. This compound is an inhibitor of proteasome DUBs USP14 and UCHL5, whereas other DUBs are not significantly inhibited.

    7. Long Non-coding RNA Linc-ITGB1 Knockdown Inhibits Cell Migration and Invasion in GBC-SD/M and GBC-SD Gallbladder Cancer Cell Lines

      Lei Wang, Yunjiao Zhang, Wenjie Lv, Jianhua Lu, Jiasheng Mu, Yingbin Liu and Ping Dong

      Article first published online: 20 MAY 2015 | DOI: 10.1111/cbdd.12573

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      Long non-coding RNA linc-ITGB1 is differentially expressed in a pair of higher and lower metastatic gallbladder cancer cell sublines. Linc-ITGB1 promoted gallbladder cancer invasion and metastasis by accelerating the process of epithelial-to-mesenchymal transition. Linc-ITGB1 RNA interference might be a potential form of gallbladder cancer treatment in advanced cases.

    8. A Peptide Inhibitor Derived from the Conserved Ectodomain Region of DENV Membrane (M) Protein with Activity Against Dengue Virus Infection

      Aussara Panya, Nunghathai Sawasdee, Mutita Junking, Chatchawan Srisawat, Kiattawee Choowongkomon and Pa-thai Yenchitsomanus

      Article first published online: 20 MAY 2015 | DOI: 10.1111/cbdd.12576

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      The interaction of two dengue virus (DENV) surface proteins, envelope (E) and membrane (M), is important for virus stability and infectivity. We synthesized a peptide inhibitor mimicking DENV M protein (MLH40) to interfere the E-M protein interaction. MLH40 peptide in micromolar ranges inhibited four DENV serotypes in the in vitro experiments. This finding suggested that MLH40 is potential for further development as anti-DENV drug.

    9. Design, Synthesis, and Biological Evaluation of Scutellarein Carbamate Derivatives as Potential Multifunctional Agents for the Treatment of Alzheimer's Disease

      Zhi-pei Sang, Xiao-ming Qiang, Yan Li, Bei Wu, Hui Zhang, Ming-gao Zhao and Yong Deng

      Article first published online: 20 MAY 2015 | DOI: 10.1111/cbdd.12580

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      A series of scutellarein carbamate derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. Among the reported analogues, compound 7b demonstrated potent AChE and BuChE inhibitory activities, antioxidant activities, metals chelation and neuroprotective effects. It could improve memory impairment induced by scopolamine, ethanol and sodium nitrite, and could remarkably decreased the activity of acetylcholinesterase in mice brain.

    10. Identification of Orthologous Target Pairs with Shared Active Compounds and Comparison of Organism-specific Activity Patterns

      Dilyana Dimova, Dagmar Stumpfe and Jürgen Bajorath

      Article first published online: 18 MAY 2015 | DOI: 10.1111/cbdd.12578

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      Compound-based relationships between orthologous targets from many organisms were systematically identified. Orthologous target pairs were generated and classified. Many candidate compounds were identified that were potent against non-human orthologues but had no activity records for corresponding human targets.

    11. Isoenzyme- and Allozyme-Specific Inhibitors: 2,2′-Dihydroxybenzophenones and Their Carbonyl N-Analogues that Discriminate between Human Glutathione Transferase A1-1 and P1-1 Allozymes

      Foteini M. Pouliou, Trias N. Thireou, Elias E. Eliopoulos, Petros G. Tsoungas, Nikolaos E. Labrou and Yannis D. Clonis

      Article first published online: 14 MAY 2015 | DOI: 10.1111/cbdd.12574

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      Structural differences between the active sites of human GST isoenzyme A1-1 and three P1-1 allozymes (left protein models) determine the absolute discriminating ability of certain benzophenones and their carbonyl N-analogues (right; bound models in blue, green and red). Such findings are important for the rational design of inhibitors against MDR-involved human GSTs.

    12. Novel Selective Inhibitor of Leishmania (Leishmania) amazonensis Arginase

      Edson R. da Silva, Nubia Boechat, Luiz C. S. Pinheiro, Monica M. Bastos, Carolina C. P. Costa, Juliana C. Bartholomeu and Talita H. da Costa

      Article first published online: 14 MAY 2015 | DOI: 10.1111/cbdd.12566

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      Three novel triazolopyrimidine have been synthesized and evaluated as arginase inhibitors. Compound 30 has a CF3 group in the 2-position (R1) and a hydrazinecarbothioamide in the 7-position (R3). Compound 30 showed an IC50 of 16.5 ± 0.5 and is a non-competitive inhibitors (Ki = Ki′) with Ki = 17 ± 1 μm.

    13. Synthesis and Biological Evaluation of Kojic Acid Derivatives Containing 1,2,4-triazole as Potent Tyrosinase Inhibitors

      Wenlin Xie, Jingai Zhang, Xiaojing Ma, Wenqian Yang, Ying Zhou, Xufu Tang, Yan Zou, Hui Li, Jingjing He, Shimin Xie, Yunhui Zhao and Fengping Liu

      Article first published online: 14 MAY 2015 | DOI: 10.1111/cbdd.12577

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      A series of novel 5-substituted-3-[5-hydroxy-4-pyrone-2-yl- methymercapto]-4-amino-1,2,4-triazole were synthesized. All newly synthesized compounds were screened for tyrosinase inhibitory activity. Most of the prepared compounds exhibited significant inhibitory activity of tyrosinase in vitro, and the structure-activity relationship was discussed.

    14. Downregulation of TPTE2P1 Inhibits Migration and Invasion of Gallbladder Cancer Cells

      Wenjie Lv, Lei Wang, Jianhua Lu, Jiasheng Mu, Yingbin Liu and Ping Dong

      Article first published online: 11 MAY 2015 | DOI: 10.1111/cbdd.12533

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      Lentivirus-mediated RNAi technique was employed to silence the pseudogene of TPTE2 (TPTE2P1) to enhance the activity of TPTE2. Depletion of TPTE2P1 remarkably inhibited gallbladder cancer cell migration and invasion. TPTE2P1 knockdown could elevate the expression of β-catenin via epithelial-mesenchymal transition signaling.

    15. Re(I) and Tc(I) Complexes for Targeting Nitric Oxide Synthase: Influence of the Chelator in the Affinity for the Enzyme

      Bruno L. Oliveira, Maurício Morais, Filipa Mendes, Irina S. Moreira, Carlos Cordeiro, Pedro A. Fernandes, Maria J. Ramos, Roger Alberto, Isabel Santos and João D. G. Correia

      Article first published online: 7 MAY 2015 | DOI: 10.1111/cbdd.12575

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      Molecular dynamics simulations suggested that the high affinity of L4 and L5 for iNOS is due to strong interactions among the NH3+ and inline image groups of the chelator and the polar residues of the binding cavity, which are hampered by metallation. The higher inhibitory potency of Re5 compared to Re4 was assigned to the increased bulkiness of its organometallic tail and the presence of additional anchoring groups. The organometallic tail of Re6 is not accommodated within the binding pocket of iNOS.

    16. Tubulin Inhibitor Identification by Bioactive Conformation Alignment Pharmacophore-Guided Virtual Screening

      Shanthi Nagarajan, Min Jeong Choi, Yong Seo Cho, Sun-Joon Min, Gyochang Keum, Soo Jin Kim, Chang Sik Lee and Ae Nim Pae

      Article first published online: 5 MAY 2015 | DOI: 10.1111/cbdd.12568

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      Bioactive conformation alignment pharmacophore (BCAP) model generated based on protein ligand interaction represented at the αβ tubulin heterodimers interface in the left panel. The final hit molecule H05 identified from the BCAP and docking screening shown in the right panel.

    17. Synthesis and Evaluation of Trehalose-Based Compounds as Novel Inhibitors of Cancer Cell Migration and Invasion

      Yong-Li Jiang, Shui-Xian Li, Yu-Jing Liu, Lian-Ping Ge, Xiu-Zhen Han and Zhao-Peng Liu

      Article first published online: 30 APR 2015 | DOI: 10.1111/cbdd.12569

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      A convenient synthetic approach for the preparation of 6,6′-dideoxy-6,6′-bis(acylamino)-α,α-D-trehaloses was developed. Compound 8b was discovered as a no cytotoxic anti-invasive agent against murine colon 26-L5 and human breast MDA-MB-231 cancer cells. It can inhibit the activity on MMP-9 and suppress the expression of MMP-9, VEGF and p-Akt in breast cancer cells.

    18. Combination of Pharmacophore Matching, 2D Similarity Search, and In Vitro Biological Assays in the Selection of Potential 5-HT6 Antagonists from Large Commercial Repositories

      Krisztina Dobi, Beáta Flachner, Mária Pukáncsik, Enikő Máthé, Melinda Bognár, Mária Szaszkó, Csaba Magyar, István Hajdú, Zsolt Lőrincz, István Simon, Ferenc Fülöp, Sándor Cseh and György Dormán

      Article first published online: 30 APR 2015 | DOI: 10.1111/cbdd.12563

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      A combination of 2D similarity approach and pharmacophore matching was used in selecting potential 5-HT6 antagonists. Three pharmacophore models were created based on the structure of the reference compounds and the 1st round hit compounds. The pharmacophore search resulted in a high hit rate (40%) and led to novel chemotypes, while 2D similarity search had slightly better hit rate (51%), but lacking novelty.

  12. Research Letters

    1. Synthesis of 5,6-dihydro-4H-benzo[d]isoxazol-7-one and 5,6-dihydro-4H-isoxazolo[5,4-c]pyridin-7-one Derivatives as Potential Hsp90 Inhibitors

      Loana Musso, Raffaella Cincinelli, Giuseppe Giannini, Fabrizio Manetti and Sabrina Dallavalle

      Article first published online: 30 APR 2015 | DOI: 10.1111/cbdd.12570

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      A series of 5,6-dihydro-4H-benzo[d]isoxazol-7-ones and 5,6-dihydro-4H-isoxazolo[5,4-c]pyridin-7-ones was designed, synthesized, and assayed to investigate affinity toward Hsp90 protein. Compounds carrying a resorcinol-like fragment showed a remarkable inhibitory effect on Hsp90. Docking calculations were performed to investigate the orientation of the new compounds within the binding site of the enzyme.

    2. Lazaroids U83836E and U74389G are Potent, Time-Dependent Inhibitors of Caspase-1

      Margaret Kawarski, Thomas K. Hagerman and Caitlin E. Karver

      Article first published online: 30 APR 2015 | DOI: 10.1111/cbdd.12572

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      Caspase-1 undergoes potent and time-dependent inhibition using the antioxidant lazaroids U83836E and U74389G. Both lazaroids inhibited caspase-1 with Ki values near 50 nm and were readily reversed to regenerate active caspase-1. These studies provide a link between antioxidants and caspase-1 inhibition for the potential treatment of inflammatory disorders.

  13. Research Articles

    1. Prediction of Human Clearance Based on Animal Data and Molecular Properties

      Wenkang Huang, Lv Geng, Rong Deng, Shaoyong Lu, Guangli Ma, Jianxiu Yu, Jian Zhang, Wei Liu, Tingjun Hou and Xuefeng Lu

      Article first published online: 28 APR 2015 | DOI: 10.1111/cbdd.12567

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      A SVM model based on molecular descriptors and animal data was built to predict human clearance. Compared with the conventional Mahmood method, the SVM model, constructed on the 122 commercially available drugs, can markedly enhance the prediction performance of CLhuman. This approach should be considered as an improved allometric scaling method in further drug research and development.

    2. Design, Synthesis, and Biological Evaluation of Novel Peptide Gly3-MC62 Analogues as Potential Antidiabetic Agents

      Baowei Yang, Chenyu Zhang, Xue Li, Sijia Yan, Wei Wei, Xuekun Wang, Xin Deng, Wenlong Huang and Hai Qian

      Article first published online: 25 APR 2015 | DOI: 10.1111/cbdd.12564

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      Two series of Gly3-MC62 analogues were synthesized and were evaluated for their antihyperglycemic effects. Antihyperglycemic effect of III-4 was more potent than that of parent peptide Gly3-MC62. III-4 merits further screening for antihyperglycemic/antioxidative effects.

    3. Targeting NAMPT for Therapeutic Intervention in Cancer and Inflammation: Structure-Based Drug Design and Biological Screening

      Venkat K. Pulla, Dinavahi S. Sriram, Vijay Soni, Srikant Viswanadha, Dharmarajan Sriram and Perumal Yogeeswari

      Article first published online: 24 APR 2015 | DOI: 10.1111/cbdd.12562

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      In this study, inhibitors against NAMPT were designed using an energy-based pharmacophore strategy and evaluated for efficacy in cellular assays. Besides reducing cellular pools of NAD and NMN, NAMPT inhibitors decreased concentrations of reactive oxygen species as well as mRNA levels of TNFα and IL6, thereby implicating their potential in alleviating the inflammatory process.

    4. Anticancer Properties of Novel 4-methylene-1,2-diphenylpyrazolidin-3-ones

      Katarzyna Gach, Jacek Szymański, Dorota Pomorska, Angelika Długosz, Jakub Modranka, Marlena Michalak, Tomasz Janecki and Anna Janecka

      Article first published online: 21 APR 2015 | DOI: 10.1111/cbdd.12565

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      Two α-methylene-γ-lactams with an additional nitrogen atom in the lactam ring, 5-vinyl-1,2-diphenyl-4-methylenepyrazolidin-3-one (2a) and 5-phenyl-1,2-diphenyl-4 methylenepyrazolidin-3-one (2b) were synthesized and tested for their anti-cancer activity in MCF-7 cells. Both compounds inhibited cell proliferation and induced DNA damage and apoptosis. Additionally, 2a showed synergistic effect in co-treatment with anti-caner drugs, oxaliplatin and 5-fluorouracil.

  14. Research Letters

    1. A Constrained Helical Peptide Against S100A4 Inhibits Cell Motility in Tumor Cells

      Gitashri Naiya, Stephanie Kaypee, Tapas K. Kundu and Siddhartha Roy

      Article first published online: 15 APR 2015 | DOI: 10.1111/cbdd.12553

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      S100A4 protein plays a determinative role in cell motility and metastasis. A constrained helical peptide was designed and synthesized which binds to the target with high affinity. The peptide inhibits cell motility in two cancer cells in would-healing assays.

  15. Research Articles

    1. Design, Synthesis and Biological Evaluation of Imidazo[1,2-a]pyridine Derivatives as Novel DPP-4 Inhibitors

      Qing Li, Muxing Zhou, Li Han, Qing Cao, Xinning Wang, LeiLei Zhao, Jinpei Zhou and Huibin Zhang

      Article first published online: 12 APR 2015 | DOI: 10.1111/cbdd.12560

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      A new series of DPP-4 inhibitors with imidazo[1,2-a]pyridine scaffold were designed by exploiting scaffold hopping strategy and docking study. Structure modifications led to identification of compound 5d as a potent (IC50 = 0.13 μm), selective (DPP-8/DPP-4 = 215 and DPP-9/DPP-4 = 192) and in vivo efficacious DPP-4 inhibitor.

    2. Improving the Specificity of the Prostate-Specific Antigen Substrate Glutaryl-Hyp-Ala-Ser-Chg-Gln as a Promoiety

      Herve Aloysius and Longqin Hu

      Article first published online: 9 APR 2015 | DOI: 10.1111/cbdd.12559

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      Systematic replacements of the N-terminal segment in the known PSA substrate sequence glutaryl-Hyp-Ala-Ser-Chg-Gln with D-retro-inverso-peptides resulted in PSA peptide substrates with improved specificity and plasma stability. GABA[LEFTWARDS ARROW]D-Ser-ψ[NH-CO-NH]-Ala-Ser-Chg-Gln-AMC (5) and GABA[LEFTWARDS ARROW]mGly-Ala-Ser-Chg-Gln-AMC (6) were most stable to non-PSA-mediated proteolysis while P5 substitution of Hyp with Ser as in 11 showed significant improvements in PSA cleavage rate.

    3. In Vitro and In Vivo Evaluation of Small Cationic Abiotic Lipopeptides as Novel Antifungal Agents

      Sandeep Lohan, Jitender Monga, Chetan Singh Chauhan and Gopal Singh Bisht

      Article first published online: 7 APR 2015 | DOI: 10.1111/cbdd.12558

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      All tested lipopeptides exhibit good antifungal activity with negligible difference between the MICs against susceptible and drug resistant clinical isolates. In particular, LP24 display highest potency against most of the tested fungal isolates with MICs in the range of 1.5–4.5 mg/L. LP24 (5 mg/kg), significantly reduces the A. fumigatus burden among the various organs of infected animals and 70% of infected mice were survived when observed for 28 days.

    4. Some Anti-Inflammatory Agents Inhibit Esterase Activities of Human Carbonic Anhydrase Isoforms I and II: An In Vitro Study

      Zuhal Alım, Namık Kılınç, Mehmet M. İşgör, Bülent Şengül and Şükrü Beydemir

      Article first published online: 7 APR 2015 | DOI: 10.1111/cbdd.12561

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      Carbonic anhydrases (CAs) are known as a drug target enzymes. The inhibitors of the enzyme are important compounds for discovery new therapeutic agents and understanding in detail protein-drug interactions at molecular level. So, the in vitro effects of some anti-inflammatory agents such as tenoxicam, fluorometholone acetate and dexamethasone were investigated on esterase activity of human erythrocyte CA-I and II and these drugs were potent inhibitors against esterase activity of human erythrocyte CA-I and II was shown.

  16. Reviews

    1. Cdc42: Role in Cancer Management

      Muhammad Imran Qadir, Amna Parveen and Muhammad Ali

      Article first published online: 7 APR 2015 | DOI: 10.1111/cbdd.12556

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      Over expression of Cdc42 cause the bind of IQGAP with ß1 integrin whic in turns disrupt the cell adhesion and develop tumor progression.

  17. Research Articles

    1. Screening Feature Genes of Venous Thromboembolism with DNA Microarray

      Tao Zhou, Yudong Zhang, Peng Wu, Qiang Sun and Yanan Guo

      Article first published online: 1 APR 2015 | DOI: 10.1111/cbdd.12557

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      The bioinformatics methods were applied to screen the feature genes and pathways related with venous thromboembolism. The miRNA target gene network and PPI network were constructed and the function of the differentially expressed genes were analyzed. The featured genes may provide the possibility of therapeutic targets for venous thromboembolism.

    2. Synthesis, Biological Evaluation, and Computer-Aided Drug Designing of New Derivatives of Hyperactive Suberoylanilide Hydroxamic Acid Histone Deacetylase Inhibitors

      Song Zhang, Weibin Huang, Xiaonan Li, Zhicheng Yang and Binghong Feng

      Article first published online: 30 MAR 2015 | DOI: 10.1111/cbdd.12554

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      Compared with SAHA, our compounds showed obvious superiority in molecular docking studies and biological test (high efficiency and low toxicity). All of our results indicated that these SAHA cap derivatives could serve as potential lead compounds for further optimization. N3F and N2E both displayed promising profile as antitumor candidates for the treatment of human glioma.

    3. Insights into the Interaction Mechanism of Ligands with Aβ42 Based on Molecular Dynamics Simulations and Mechanics: Implications of Role of Common Binding Site in Drug Design for Alzheimer's Disease

      Harish S. Kundaikar and Mariam S. Degani

      Article first published online: 28 MAR 2015 | DOI: 10.1111/cbdd.12555

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      Our study reveals a single preferential binding site (shown in grey) for all the currently known ligands on the NMR solution structure of Aβ protofibrils, which can be used in rationalizing structure based drug design of diagnostics or therapeutics for Alzheimer's disease. Differences in the interactions of known ligands was observed, correlating to their distinct modes of activity as therapeutics or diagnostics.

    4. Improving the Tuberculosis Drug Development Pipeline

      Dimitrios Evangelopoulos and Timothy D. McHugh

      Article first published online: 28 MAR 2015 | DOI: 10.1111/cbdd.12549

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      The drug development in tuberculosis is a slow process and the biology of its aetiological agent Mycobacterium tuberculosis complements to the complexity of evaluating new drugs and drug combinations. To accelerate the drug development, evaluation of different models is needed from in vitro screens that take into consideration the different physiological states of the bacterium found in human disease to in vivo experiments and integration of clinical data. Furthermore, identification of more sensitive biomarkers for drug efficacy and treatment success monitoring throughout the drug development procedures is required for an improved outcome.

    5. Inhibition of Acetylcholinesterase (AChE): A Potential Therapeutic Target to Treat Alzheimer's Disease

      Yong Li, Xiao-xiao Zhang, Li-juan Jiang, Li Yuan, Ting-ting Cao, Xia Li, Lin Dong, Ying Li and Shu-Fan Yin

      Article first published online: 28 MAR 2015 | DOI: 10.1111/cbdd.12550

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      A new series of icariin derivatives were synthesized and evaluated for their in vitro acetylcholinesterase (AChE) inhibitory activity. Most of the tested compounds exhibited high AChE inhibition and low toxicity, and among which compounds 1, 2, and 10 were the most potent (IC50 = 71.52 ± 22.43, 8.28 ± 1.45, 5.830 ± 1.78 nm, respectively).

    6. Curcumin Binding to Beta Amyloid: A Computational Study

      Praveen P. N. Rao, Tarek Mohamed, Karan Teckwani and Gary Tin

      Article first published online: 24 MAR 2015 | DOI: 10.1111/cbdd.12552

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      Curcumin is a known inhibitor of beta amyloid. This study correlates its binding to the hexapeptide steric zipper assembly and full length peptide. These investigations show that curcumin binding promotes non-toxic forms of amyloid aggregates.

    7. Combined Molecular Docking, 3D-QSAR, and Pharmacophore Model: Design of Novel Tubulin Polymerization Inhibitors by Binding to Colchicine-binding Site

      Dong-Dong Li, Ya-Juan Qin, Xin Zhang, Yong Yin, Hai-Liang Zhu and Lin-Guo Zhao

      Article first published online: 20 MAR 2015 | DOI: 10.1111/cbdd.12545

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      Evaluated by a series of combination of commonly used computer methods such as molecular docking, 3D-QSAR, and pharmacophore model, we can obtain the ultimate 16 tubulin polymerization inhibitors derived from five important basic scaffolds in the field of medicinal chemistry. Among these compounds, compound A-132 with moderate activity in in silico screening was synthesized, and subsequently validated for preliminary inhibition of tubulin polymerization by immunofluorescence assay.

    8. Controlled and Targeted Drug Delivery by a UV-responsive Liposome for Overcoming Chemo-resistance in Non-Hodgkin Lymphoma

      Huafei Li, Kun Guo, Cong Wu, Ling Shu, Shiwei Guo, Jing Hou, Naping Zhao, Lixin Wei, Xiaobo Man and Li Zhang

      Article first published online: 20 MAR 2015 | DOI: 10.1111/cbdd.12551

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      This study describes a novel CD20 targeting liposomal drug delivery system with appropriate size, well-defined regular spherical structure, favorable biocompatibility and high serum stability. The doxorubicin loaded liposomes exhibits exceptionally potent lymphoma suppression abilities in both in and ex vivo experiments, which merits further investigation in the clinic.

    9. Design, Synthesis and in vivo Evaluation of Novel C-Aryl Glucosides as Potent Sodium-Dependent Glucose Cotransporters Inhibitors for the Treatment of Diabetes

      Zheng Li, Xuekun Wang, Xue Xu, Qianqian Qiu, Lei Jiao, Wenlong Huang and Hai Qian

      Article first published online: 20 MAR 2015 | DOI: 10.1111/cbdd.12547

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      A series of novel C-aryl glucosides with substituents at the 3′- position or cyclization at 3′ 4′- positions of the distal aryl ring were designed and synthesized. Once-daily 19a treatment 30 days exhibited sustained antihyperglycemic effect without particular side effects.

    10. Synthesis and Anti-Inflammatory Evaluation of Novel C66 Analogs for the Treatment of LPS-Induced Acute Lung Injury

      Jianpeng Feng, Bing Xiao, Wenbo Chen, Ting Ding, Lingfeng Chen, Pengtian Yu, Fengli Xu, Huajie Zhang, Zhiguo Liu and Guang Liang

      Article first published online: 20 MAR 2015 | DOI: 10.1111/cbdd.12548

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      Novel asymmetric C66 analogs were synthesized and evaluated their anti-inflammation for the treatment of LPS-induced acute lung injury.

    11. Knockdown of Myosin VI Inhibits Proliferation of Hepatocellular Carcinoma Cells In Vitro

      Xiaoming Ma, Jiqi Yan, Wei Chen, Peng Du, Jiaming Xie, Hongpei Yu and Haorong Wu

      Article first published online: 17 MAR 2015 | DOI: 10.1111/cbdd.12544

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      Myosin VI is overexpressed in hepatocellular carcinoma tissues. Knockdown of myosin VI resulted in a significant diminution in hepatocellular carcinoma cell proliferation via cell cycle arrest. Knockdown of myosin VI caused an obvious decrease in PRAS40 phosphorylation and an increase in p38 phosphorylation.

    12. Design, Synthesis, and Antimicrobial Evaluation of Novel Quinolone Imidazoles and Interactions with MRSA DNA

      Ling Zhang, Kannekanti Vijaya Kumar, Syed Rasheed, Rong-Xia Geng and Cheng-He Zhou

      Article first published online: 16 MAR 2015 | DOI: 10.1111/cbdd.12532

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      Some compounds exhibited strong anti-MRSA activity with low cytotoxicity. Inducing bacterial resistance by target compounds was much slower than clinical drugs. Interactions of compound and MRSA DNA indicated a possible interaction mechanism.

    13. Synthesis and Evaluation of 3-(furo[2,3-b]pyridin-3-yl)-4-(1H-indol-3-yl)-maleimides as Novel GSK-3β Inhibitors and Anti-Ischemic Agents

      Qing Ye, Qiu Li, Yubo Zhou, Lei Xu, Weili Mao, Yuanxue Gao, Chenhui Li, Yuan Xu, Yazhou Xu, Hong Liao, Luyong Zhang, Jianrong Gao, Jia Li and Tao Pang

      Article first published online: 16 MAR 2015 | DOI: 10.1111/cbdd.12546

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      A series of novel 3-(furo[2,3-b]pyridin-3-yl)-4-(1H- indol-3- yl)-maleimides were prepared and identified as potent GSK-3β inhibitors and anti-ischemic agents. In the in vivo cerebral ischemia animal model, compound 5o reduced infarct size by 10% and improved the neurological deficit following focal cerebral ischemia.

    14. Discovery of Novel 2-(piperidin-4-yl)-1H-benzo[d]imidazole Derivatives as Potential Anti-Inflammatory Agents

      Qing Li, Qinghua Hu, Xinning Wang, Yang Zong, Leilei Zhao, Junhao Xing, Jinpei Zhou and Huibin Zhang

      Article first published online: 16 MAR 2015 | DOI: 10.1111/cbdd.12513

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      Based on the hit compound 5, two series of 2-(piperidin-4-yl)-1H-benzo[d]imidazole derivative 6ag and 7ah were designed and synthesized as novel anti-inflammatory agents, in which compound 6e showed most potent inhibitory activity on NO (IC50 = 0.86 μm) and TNF-α (IC50 = 1.87 μm) production.

    15. Synthesis and Evaluation of Cleistanthin A Derivatives as Potent Vacuolar H+-ATPase Inhibitors

      Yu Zhao, Yapeng Lu, Jinlong Ma and Li Zhu

      Article first published online: 13 MAR 2015 | DOI: 10.1111/cbdd.12538

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      Glycosides and alkane derivatives of cleistanthin A have been synthesized. Compounds 3e and 4a displayed strong antiproliferative activity and vacuolar H+-ATPase inhibitory activity.

    16. Targeting Influenza A Virus RNA Promoter

      Angel Bottini, Surya K. De, Bainan Wu, Changyan Tang, Gabriele Varani and Maurizio Pellecchia

      Article first published online: 13 MAR 2015 | DOI: 10.1111/cbdd.12534

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      The influenza A RNA promoter is universally conserved among influenza A virus strains, making it potentially an ideal drug target for novel antiviral agents. Using an NMR-based approach, we report on the characterization and initial SAR studies of RNA binding compounds, including ex vivo anti-influenza activity assays.

    17. 4-Aminoquinoline Derivatives as Potential Antileishmanial Agents

      Luciana M. R. Antinarelli, Rafael M. P. Dias, Isabela O. Souza, Wallace P. Lima, Jacy Gameiro, Adilson D. da Silva and Elaine S. Coimbra

      Article first published online: 11 MAR 2015 | DOI: 10.1111/cbdd.12540

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      The leishmanicidal activity of a series of 4-aminoquinoline (AMQ) derivatives was assayed against Leishmania amazonensis. The compound AMQ-j exhibited a strong leishmanicidal activity its mechanism of action appears to be mediated by mitochondrial dysfunction associated to ROS production.

  18. Research Letters

    1. New Oxidovanadium Complexes Incorporating Thiosemicarbazones and 1, 10-Phenanthroline Derivatives as DNA Cleavage, Potential Anticancer Agents, and Hydroxyl Radical Scavenger

      Peng Ying, Pengfei Zeng, Jiazheng Lu, Hongyuan Chen, Xiangwen Liao and Ning Yang

      Article first published online: 9 MAR 2015 | DOI: 10.1111/cbdd.12535

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      Four oxidovanadium complexes were synthesized. They exhibited high activity against different cancer cells and low IC50 values in the range 0.2–10.0 μm. In addition, they expressed efficient hydroxyl radical scavenging properties.

    2. Probing the Conformational Dynamics of the Bioactive Peptide TLQP-21 in Solution: A Molecular Dynamics Study

      Sandipan Chakraborty, Shamim Akhter, Jesús R. Requena and Soumalee Basu

      Article first published online: 9 MAR 2015 | DOI: 10.1111/cbdd.12541

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      We have explored the folding energy landscape of the peptide TLQP-21 using MD simulation. The peptide is highly flexible in solution and that the region A7-R9 and three C-terminal residues, P19-R21, possess strong helical propensity. The peptide adopts a highly compact globular form stabilized by several hydrogen bonding interactions, π-cationic interactions and strong surface complementarity of hydrophobic residues allows tighter spatial fit of the residues within the core region of the peptide.

  19. Research Articles

    1. Novel Oxazolidinone Antibacterial Analogues with a Substituted Ligustrazine C-ring Unit

      Yan Chen, Zhi-Xiong Ruan, Fang Wang, De-Sheng Huangfu, Ping-Hua Sun, Jing Lin and Wei-Min Chen

      Article first published online: 6 MAR 2015 | DOI: 10.1111/cbdd.12537

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      A series of novel oxazolidinone derivatives with a substituted ligustrazine C-ring unit were designed and synthesized. Meanwhile, their antibacterial and anti-inflammatory activities were evaluated. Compounds 14a and 14b exhibited both antibacterial and anti-inflammatory potential activities.

    2. Synthesis and Antimicrobial Evaluation of 6-Alkylamino-N-phenylpyrazine-2-carboxamides

      Barbora Servusova-Vanaskova, Pavla Paterova, Vladimir Garaj, Jana Mandikova, Jiri Kunes, Lieve Naesens, Petr Jílek, Martin Dolezal and Jan Zitko

      Article first published online: 6 MAR 2015 | DOI: 10.1111/cbdd.12536

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      Tuberculosis (TB) belongs to the most dangerous and frequent infection diseases worldwide. Drug-resistant TB-forms as well as increasing number of patient co-infected with HIV constitute a serious problem and emphasize the need for novel drugs. Pyrazinamide, an essential component of short-course anti-TB chemotherapy, was used as a model compound for substances referred in this project. A series of new pyrazinamide derivatives was designed, synthesized and screened for in vitro antimycobacterial activity.

    3. Synthesis and Biological Evaluation of Oxygen-containing Heterocyclic Ring-fused 23-Hydroxybetulinic Acid Derivatives as Antitumor Agents

      Hengyuan Zhang, Fangzheng Li, Peiqing Zhu, Jie Liu, Hequan Yao, Jieyun Jiang, Wencai Ye, Xiaoming Wu and Jinyi Xu

      Article first published online: 6 MAR 2015 | DOI: 10.1111/cbdd.12543

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      Most of the newly synthesized compounds exhibited more potent antiproliferative activity than patent compound 23-hydroxybetulinic acid (HBA), especially 13e and 14a were about four- to sevenfold more potent against all tested cancer cell lines than HBA. Furthermore, the in vivo antitumor activity of 13e and 14a was validated in H22 liver cancer and B16 melanoma xenograft mouse models.

    4. Solid-Supported Synthesis and 5-HT7/5-HT1A Receptor Affinity of Arylpiperazinylbutyl Derivatives of 4,5-dihydro-1,2,4-triazine-6-(1H)-one

      Katarzyna Grychowska, Nicolas Masurier, Pascal Verdié, Grzegorz Satała, Andrzej J. Bojarski, Jean Martinez, Maciej Pawłowski, Gilles Subra and Paweł Zajdel

      Article first published online: 6 MAR 2015 | DOI: 10.1111/cbdd.12539

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      We have designed and synthesized a novel series of arylpiperazinylbutyl derivatives of 4,5-dihydro-1,2,4-triazine-6(1H)-ones. For this purpose we have developed a new solid-phase methodology enabling construction of the 1,2,4-triazine-6-(1H)-one system from the Fmoc-protected glycine. The study enabled identification of some potent dual 5-HT7/5-HT1A receptor ligands. The structure–affinity relationship analysis revealed that the receptor affinity and selectivity of tested compounds depended on the kind of substituent in position 3 of triazinone fragment as well as substitution pattern of the phenylpiperazine moiety.

    5. Design and Synthesis of Butenolide-based Novel Benzyl Pyrrolones: Their TNF-α based Molecular Docking with In vivo and In vitro Anti-inflammatory Activity

      Yakub Ali, Mohammad Sarwar Alam, Hinna Hamid, Asif Husain, Syed Shafi, Abhijeet Dhulap, Firasat Hussain, Sameena Bano, Chetna Kharbanda, Syed Nazreen and Saqlain Haider

      Article first published online: 1 MAR 2015 | DOI: 10.1111/cbdd.12522

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      Twenty-four benzyl pyrrolones have been synthesized. Compounds 3b and 2b were found to show significant anti-inflammatory and analgesic activity in comparison with standard drug, indomethacin. Both compounds suppressed TNF-α level and protein expression of COX-2 and NF- κB.

    6. Synthesis and Evaluation of a CBZ-AAN-Dox Prodrug and its in vitro Effects on SiHa Cervical Cancer Cells Under Hypoxic Conditions

      Hongyuan Chen, Xiao Liu, Eric S. Clayman, Fangyuan Shao, Manshan Xiao, Xuyan Tian, Wuyu Fu, Caiyun Zhang, Bibo Ruan, Pengjun Zhou, Zhong Liu, Yifei Wang and Wen Rui

      Article first published online: 1 MAR 2015 | DOI: 10.1111/cbdd.12525

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      A novel prodrug, N-benzyloxycarbonyl-Ala-Ala-Asn-Doxorubicin, was synthesized, and its effects on cervical cancer cells were evaluated under hypoxic conditions. The results suggest that the prodrug potentially increases both the safety and efficacy of clinical treatment of tumors by exploiting the tumor's innate expression of legumain.

    7. Novel Diketopiperazine Dihydroorotate Dehydrogenase Inhibitors Purified from Traditional Tibetan Animal Medicine Osteon Myospalacem Baileyi

      Lei Jiang, Huaixiu Wen, Yun Shao, Ruitao Yu, Zenggen Liu, Shuo Wang, Qilan Wang, Xiaohui Zhao, Peng Zhang, Yanduo Tao and Lijuan Mei

      Article first published online: 1 MAR 2015 | DOI: 10.1111/cbdd.12530

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      In this article, we found a natural dihydroorotate dehydrogenase (DHODH) inhibitor by multi-dimensional chromatography and in vitro Homo sapiens recombinant dihydroorotate dehydrogenase inhibition assay. Then, the binding mode of this compound with its receptor DHODH was studied. It is found that the binding mode of this compound was very similar with that of positive control teriflunomide. This compound could serve as a lead compound and more diketopiperazine skeleton DHODH inhibitors could be found.

    8. Design, Synthesis, and In Vitro Evaluation of Novel 3, 7-Disubstituted Coumarin Derivatives as Potent Anticancer Agents

      Yubin Wang, Haitao Liu, Peng Lu, Rui Mao, Xiaojian Xue, Chen Fan and Jinxiong She

      Article first published online: 1 MAR 2015 | DOI: 10.1111/cbdd.12531

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      Twenty-seven 3, 7-dissubstituted coumarin derivatives were designed, synthesized and evaluated in vitro as potent anticancer agents. Methylation of benzimidazole moiety at 3-position of coumarin exhibited significant enhancement of activity.

    9. Role of the Copper(II) Complex Cu[15]pyN5 in Intracellular ROS and Breast Cancer Cell Motility and Invasion

      Ana S. Fernandes, Ana Flórido, Nuno Saraiva, Sara Cerqueira, Sérgio Ramalhete, Madalena Cipriano, Maria Fátima Cabral, Joana P. Miranda, Matilde Castro, Judite Costa and Nuno G. Oliveira

      Article first published online: 27 FEB 2015 | DOI: 10.1111/cbdd.12521

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      Cu[15]pyN5 is a redox-active copper(II) complex developed as a chemotherapy sensitizer for breast cancer. Cu[15]pyN5 decreased MCF7 cell migration, and a cotreatment of the complex with doxorubicin reduced the proteolytic invasion of MDA-MB-231 cells. Cu[15]pyN5 and doxorubicin significantly increased intracellular ROS in both cell lines. Moreover, given the high affinity of the ligand [15]pyN5 for copper(II), it displays potential anti-angiogenic properties. Overall, we present a potential drug that might arrest the progression of breast cancer by complementary mechanisms.

    10. The Pyrazolobenzothiazine Core as a New Chemotype of p38 Alpha Mitogen-Activated Protein Kinase Inhibitors

      Stefano Sabatini, Giuseppe Manfroni, Maria Letizia Barreca, Silke M. Bauer, Marco Gargaro, Rolando Cannalire, Andrea Astolfi, Jose Brea, Carmine Vacca, Matteo Pirro, Serena Massari, Oriana Tabarrini, Maria Isabel Loza, Francesca Fallarino, Stefan A. Laufer and Violetta Cecchetti

      Article first published online: 19 FEB 2015 | DOI: 10.1111/cbdd.12516

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      A series of pyrazolobenzothiazines has been identified as novel p38α MAPK inhibitors. Hit compound 6 turned out to be an effective inhibitor with a reasonable kinase selectivity profile. The obtained results strongly indicate the pyrazolobenzothiazine core as a new p38α inhibitor chemotype worthy of hit-to-lead optimization work.

  20. Research Letters

    1. Design and Biological Evaluation of Furan/Pyrrole/Thiophene-2-carboxamide Derivatives as Efficient DNA GyraseB Inhibitors of Staphylococcus aureus

      Renuka Janupally, Bhramam Medepi, Parthiban Brindha Devi, Priyanka Suryadevara, Variam Ullas Jeankumar, Pushkar Kulkarni, Perumal Yogeeswari and Dharmarajan Sriram

      Article first published online: 19 FEB 2015 | DOI: 10.1111/cbdd.12529

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      Identified a series of furan/pyrrole/thiophene-2-carboxamide derivatives targeting Staphylococcus aureusDNA GyrB domain at a lower micromolar concentration with a better in vitroMIC, least cytotoxicity and no human ether-a-go-go-related gene cardiotoxicity.

  21. Research Articles

    1. Lentivirus-Mediated Silencing of Myosin VI Inhibits Proliferation and Cell Cycle Progression in Human Lung Cancer Cells

      Hui Yu, Zhenghong Zhu, Jianhua Chang, Jialei Wang and Xiaoyong Shen

      Article first published online: 19 FEB 2015 | DOI: 10.1111/cbdd.12528

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      In the present study, we found that MYO6 is over-expressed in lung cancer tissues and associated with lung cancer progression, particularly lymph node metastasis. Lentivirus-mediated silencing of MYO6 significantly decreased the proliferation of lung cancer cells via the inhibition of ERK1/2 activation. Moreover, the cell cycle was stuck at the G0/G1 phase, especially at the sub-G1 phase, which represents apoptotic cells. These results suggest that MYO6 is crucial in maintaining cell cycle and cell growth of lung cancer cells.

  22. Reviews

    1. Triazole: A Promising Antitubercular Agent

      Rangappa S. Keri, Siddappa A. Patil, Srinivasa Budagumpi and Bhari Mallanna Nagaraja

      Article first published online: 19 FEB 2015 | DOI: 10.1111/cbdd.12527

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      Tuberculosis is a contagious disease with comparatively high mortality worldwide. The statistics shows that around three million people throughout the world die annually from tuberculosis and there are around eight million new cases each year, out of which developing countries showed major share. Triazole core is considered as a privileged structure in medicinal chemistry, are widely used as ‘parental’ compounds to synthesize molecules with medical benefits, especially with infection related activities. In the present review, we have collated published reports on this versatile core to provide an insight so that its complete therapeutic potential can be utilized for the treatment of tuberculosis. It is hoped that, this review will be helpful for new thoughts in the quest for rational designs of more active and less toxic triazole-based anti-tuberculosis drugs.

  23. Research Articles

    1. Synthesis and Biological Evaluation of a Series of 2-((1-substituted-1H-1,2,3-triazol-4-yl)methylthio)-6-(naphthalen-1-ylmethyl)pyrimidin-4(3H)-one As Potential HIV-1 Inhibitors

      Zengjun Fang, Dongwei Kang, Lingzi Zhang, Boshi Huang, Huiqing Liu, Christophe Pannecouque, Erik De Clercq, Peng Zhan and Xinyong Liu

      Article first published online: 19 FEB 2015 | DOI: 10.1111/cbdd.12524

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      The 1,2,3-triazole containing S-DABO derivative B5b7 displayed similar HIV-1 inhibitory potency (EC50 = 3.22 μm) compared with 3TC (EC50 = 2.24 μm).

    2. Synthesis and Biological Evaluation of New Eugenol Mannich Bases as Promising Antifungal Agents

      Pedro Henrique O. Abrão, Rafael B. Pizi, Thiago B. de Souza, Naiara C. Silva, Antonio M. Fregnan, Fernanda N. Silva, Luiz Felipe L. Coelho, Luiz Cosme C. Malaquias, Amanda Latercia T. Dias, Danielle F. Dias, Marcia P. Veloso and Diogo T. Carvalho

      Article first published online: 19 FEB 2015 | DOI: 10.1111/cbdd.12504

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      A series of new eugenol derivatives was synthesized and evaluated for its anticandidal activities. The morpholinyl Mannich base 7 (4-allyl-2-methoxy-6-(morpholin-4-ylmethyl) phenyl benzoate) showed high antifungal activity (IC50 0.63 μm) and an expressive selectivity index (600.0) against Candida albicans and Candida krusei.

    3. PAD2 Activity Monitored via a Fluorescent Substrate Analog

      Mary J. Sabulski, Yanming Wang and Marcos M. Pires

      Article first published online: 16 FEB 2015 | DOI: 10.1111/cbdd.12526

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      We describe a facile fluorescence-based assay to detect PAD2 activity. The assay links a profluorescent substrate to PAD2-mediated citrullination and responds to the presence of known inhibitors.

  24. Research Letters

    1. Design, Synthesis, and Biological Evaluation of γ-Aminopropyl Silatrane–Acyclovir Hybrids with Immunomodulatory Effects

      Faqing Ye, Xiaoqin Song, Jianmin Liu, Xuemei Xu, Yuewu Wang, Lichuan Hu, Yi Wang, Guang Liang, Ping Guo and Zixin Xie

      Article first published online: 16 FEB 2015 | DOI: 10.1111/cbdd.12519

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      Acyclovir-containing γ-aminopropyl silatrane derivatives could potentially stimulate immune response and have antiviral activity.

  25. Research Articles

    1. Synthesis and Biological Evaluation of Strictosamide Derivatives with Improved Antiviral and Antiproliferative Activities

      Zan Li, Zhaoliang Li, Yunwei Lin, Zhaoqing Meng, Gang Ding, Liang Cao, Na Li, Wenjun Liu, Wei Xiao, Xiaoming Wu and Jinyi Xu

      Article first published online: 12 FEB 2015 | DOI: 10.1111/cbdd.12515

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      A series of strictosamide derivatives was designed and synthesized. Compounds Ib and If possessed antiviral activities against influenza A virus (A/Jinan/15/90) with IC50 values of 4.12 and 12.35 μg/mL, respectively. Compound Ie possessed antiviral activity against respiratory syncytial virus (RSV) with an IC50 value of 9.58 μg/mL. Both compounds IIc and IId had moderate antiproliferative effects against five human cancer cell lines.

    2. Novel Potent and Selective Acetylcholinesterase Inhibitors as Potential Drugs for the Treatment of Alzheimer's Disease: Synthesis, Pharmacological Evaluation, and Molecular Modeling of Amino-Alkyl-Substituted Fluoro-Chalcones Derivatives

      Hao-ran Liu, Chao Zhou, Hao-qun Fan, Jing-jing Tang, Lin-bo Liu, Xiao-hui Gao, Qiu-an Wang and Wu-kun Liu

      Article first published online: 12 FEB 2015 | DOI: 10.1111/cbdd.12514

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      A new series of fluoro chalcones substituted amino alkyl derivatives (3a˜3l) were designed, synthesized, characterized and evaluated for the inhibition activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The most promising compound 3l had potent inhibitory activity (IC50 = 0.21 ± 0.03 μmol/L) and high selectivity for AChE over BuChE (ratio = 65).The molecular modeling study further indicated that it can bind with both the (CAS) and (PAS) of AChE.

  26. Research Letters

    1. Antiproliferative Activity of Polyether Antibiotic – Cinchona Alkaloid Conjugates Obtained via Click Chemistry

      Iwona Skiera, Michał Antoszczak, Justyna Trynda, Joanna Wietrzyk, Przemysław Boratyński, Karol Kacprzak and Adam Huczyński

      Article first published online: 10 FEB 2015 | DOI: 10.1111/cbdd.12523

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      Cu(I) catalyzed Huisgen 1,3-dipolar cyclo-addition (click chemistry) was used for the first time for the conjugation of natural ionophores – salinomycin and monensin with Cinchona alkaloids. Four of the compounds exhibited high anti-proliferative activity (IC50 below 3.00 μm) in vitro.

  27. Research Articles

    1. N-(2,4)-dinitrophenyl-L-arginine Interacts with EphB4 and Functions as an EphB4 Kinase Modulator

      Rhiannon L. Kamstra, Andrew Freywald and Wely B. Floriano

      Article first published online: 6 FEB 2015 | DOI: 10.1111/cbdd.12510

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      The EphB4 receptor tyrosine kinase is expressed in many types of cancer and often exhibits anti-malignant activity. Modulators of its activity are good candidates for cancer treatment. Through virtual screening, we identified and experimentally confirmed DNP-L-Arg as an EphB4 modulator, with potential activating effect.

    2. Virulence-targeted Antibacterials: Concept, Promise, and Susceptibility to Resistance Mechanisms

      Ségolène Ruer, Nikos Pinotsis, David Steadman, Gabriel Waksman and Han Remaut

      Article first published online: 6 FEB 2015 | DOI: 10.1111/cbdd.12517

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      In this review we discuss the ideas behind antivirulence therapies, the progress in the field, and more particular the anticipated susceptibility of antivirulence therapies to drug resistance mechanisms. For this analysis, we first review mechanisms of antibacterial resistance known from classical, on-the-market antibacterials, and than discuss their relevance with respect to two broad groups of antivirulence therapeutics: quorum sensing inhibitors and bacterial adherence inhibitors in Gram-negative pathogens.

    3. Estimation of the Binding Free Energy of AC1NX476 to HIV-1 Protease Wild Type and Mutations Using Free Energy Perturbation Method

      Son Tung Ngo, Binh Khanh Mai, Dinh Minh Hiep and Mai Suan Li

      Article first published online: 6 FEB 2015 | DOI: 10.1111/cbdd.12518

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      The binding mechanism of AC1NX476 to HIV-1 protease by the docking and molecular dynamics simulations. The binding free energy was calculated using the double-annihilation binding-free energy method. The mutations were found to reduce the receptor-ligand interaction by widening the binding pocket and the binding propensity is mainly driven by the van der Waals interaction.

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