Chemical Biology & Drug Design

Cover image for Vol. 85 Issue 3

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

Edited By: David Selwood

Impact Factor: 2.507

ISI Journal Citation Reports © Ranking: 2013: 28/58 (Chemistry Medicinal); 173/291 (Biochemistry & Molecular Biology)

Online ISSN: 1747-0285


  1. 1 - 100
  2. 101 - 104
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

    4. Antimicrobial Peptides Derived from Fusion Peptides of Influenza A Viruses, a Promising Approach to Designing Potent Antimicrobial Agents

      Jingyu Wang, Wenjing Zhong, Dongguo Lin, Fan Xia, Wenjiao Wu, Heyuan Zhang, Lin Lv, Shuwen Liu and Jian He

      Article first published online: 6 FEB 2015 | DOI: 10.1111/cbdd.12511

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      A strategy for designing new antimicrobial peptides was proposed by replacing the negatively or neutrally charged residues of fusion peptides from influenza A viruses with positively charged lysins. These peptides exhibited broad and potent antibacterial activities, while their toxicities toward mammalian cells were low. In addition, the mode of action and the secondary structure of these peptides were also discussed.

    5. Synthesis and Preliminary Antiviral Activities of Piperidine-substituted Purines against HIV and Influenza A/H1N1 Infections

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

      Article first published online: 6 FEB 2015 | DOI: 10.1111/cbdd.12520

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      Structure–activity relationship of N2-(1-arylpiperidin-4-yl)-N6-(2,4,6-trimethylphenyl)-9H-purine-2,6-diamine and its antiviral activity against HIV and influenza A/H1N1 infections.

    6. Structure-guided Discovery of a Novel Non-peptide Inhibitor of Dengue Virus NS2B–NS3 Protease

      Linfeng Li, Chandrakala Basavannacharya, Kitti Wing Ki Chan, Luqing Shang, Subhash G. Vasudevan and Zheng Yin

      Article first published online: 4 FEB 2015 | DOI: 10.1111/cbdd.12500

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      Based on structural information of DENV NS2B–NS3 protease and previously reported lead compounds, we carried out a hierarchical virtual screening and biological activity measurement. Finally, we obtained several novel compounds that inhibited the protease, and one hit further demonstrated antiviral activity in cell-based assay with the EC50 of 5 μm.

    7. Synthesis and Evaluation of Millepachine Amino Acid Prodrugs With Enhanced Solubility as Antitumor Agents

      Yuzhe Wu, Dong Cao, Fang Wang, Liang Ma, Ge Gao and Lijuan Chen

      Article first published online: 4 FEB 2015 | DOI: 10.1111/cbdd.12507

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      The glycine derivative compound 7a overcame the shortcoming of poor aqueous solubility of compound 6 and exhibited remarkable in vitro and in vivo activity.

    8. Quantitative Relationships Between the Cytotoxicity of Flavonoids on the Human Breast Cancer Stem-Like Cells MCF7-SC and Their Structural Properties

      Hyeryoung Jung, Soon Young Shin, Yearam Jung, Thao Anh Tran, Hye Ok Lee, Kang-Yeoun Jung, Dongsoo Koh, Somi Kim Cho and Yoongho Lim

      Article first published online: 31 JAN 2015 | DOI: 10.1111/cbdd.12512

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      Chemotherapeutic agents targeting breast cancer stem cells are of interest as a potential treatment. The objective of this study was to measure cytotoxic effects of flavonoids on the human breast cancer stem-like cell line. We determined quantitative structure–activity relationships using both comparative molecular field analysis and comparative molecular similarity analysis. Further biological experiments including Western blot analysis, flow cytometry, and immunofluorescence microscopy were also conducted on the most cytotoxic 8-chloroflavanone.

    9. Labeling of Cellular DNA with a Cyclosal Phosphotriester Pronucleotide Analog of 5-ethynyl-2′-deoxyuridine

      Ngoc Huynh, Charlotte Dickson, Dusan Zencak, David H. Hilko, Alan Mackay-Sim and Sally-Ann Poulsen

      Article first published online: 31 JAN 2015 | DOI: 10.1111/cbdd.12506

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      DNA synthesis is a fundamental biological process central to all proliferating cells and the design of small molecule probes that allow detection of this DNA is important for many applications. In this study, we demonstrate that a cyclosal phosphotriester pronucleotide analog of thymidine is suitable for metabolic incorporation into DNA of proliferating cells and subsequent labeling by click chemistry.

  10. Research Letters

    1. The Synthesis and Evaluation of C7-Substituted α-Tetralone Derivatives as Inhibitors of Monoamine Oxidase

      Lesetja J. Legoabe, Anél Petzer and Jacobus P. Petzer

      Article first published online: 31 JAN 2015 | DOI: 10.1111/cbdd.12508

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      C7-Substituted α-tetralones act as high potency reversible inhibitors of human MAO-A and MAO-B. This class of compounds represent promising leads for the development of therapies for Parkinson's disease and depression.

  11. Research Articles

    1. A Novel Protocol to Differentiate Induced Pluripotent Stem Cells by Neuronal microRNAs to Provide a Suitable Cellular Model

      Mehrak Zare, Masoud Soleimani, Abolfazl Akbarzadeh, Behnaz Bakhshandeh, Seyed Hamid Aghaee-Bakhtiari and Nosratollah Zarghami

      Article first published online: 29 JAN 2015 | DOI: 10.1111/cbdd.12485

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      By lentiviral transduction of miR-124 and miR-128 sequentially to iPS cells in the absence of any extrinsic factor, we differentiated them to cells representing transcriptional and translational characteristics of neural cells.

    2. Oral Delivery of Bovine Lactoferrin Using Pectin- and Chitosan-Modified Liposomes and Solid Lipid Particles: Improvement of Stability of Lactoferrin

      Xudong Yao, Craig Bunt, Jillian Cornish, Siew-Young Quek and Jingyuan Wen

      Article first published online: 29 JAN 2015 | DOI: 10.1111/cbdd.12509

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      Liposome or SLP encapsulation may be harnessed to delay bLf digestion to some extent under SIF condition, raising the possibility of intact bLf delivery. However, considering a compromise between essential long term storage stability and destabilization necessary for drug release in a biological environment, solid lipid particles were desirable to modulate bLf stability and offer a great platform to deliver intact bLf to the human gut.

    3. Binding and Anticancer Properties of Plumbagin with Human Serum Albumin

      Yi Gou, Yao Zhang, Jinxu Qi, Linlin Kong, Zuping Zhou, Shichu Liang, Feng Yang and Hong Liang

      Article first published online: 23 JAN 2015 | DOI: 10.1111/cbdd.12501

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      Anticancer activities of plumbagin are enhanced by binding to IIA subdomain of human serum albumin. The studies may guide the rational design and development of plumbagin – based drugs and a drug-human serum albumin delivery system.

    4. Drug Resistance Reversal Potential of Ursolic Acid Derivatives against Nalidixic Acid- and Multidrug-resistant Escherichia coli

      Gaurav Raj Dwivedi, Anupam Maurya, Dharmendra Kumar Yadav, Feroz Khan, Mahendra P. Darokar and Santosh Kumar Srivastava

      Article first published online: 20 JAN 2015 | DOI: 10.1111/cbdd.12491

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      Drug resistance reversal potential and mechanism of natural compound ursolic acid and its derivative UA-4 were deduced through inhibition of ATP-dependent efflux pumps. Inhibition of efflux pumps is useful in (i) lowering the dose of antibiotics; (ii) reducing the drug resistance development frequency; and (iii) increasing the efficacy of antibiotics against multidrug-resistant Escherichia coli strains.

    5. Novel Glycoconjugate of 8-Fluoro Norfloxacin Derivatives as Gentamicin-resistant Staphylococcus aureus Inhibitors: Synthesis and Molecular Modelling Studies

      Chandra S. Azad, Shome S. Bhunia, Atul Krishna, Praveen K. Shukla and Anil K. Saxena

      Article first published online: 20 JAN 2015 | DOI: 10.1111/cbdd.12503

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      In order to combat gentamicin resistance caused by reduced cell wall permeability, the glycoconjugates of norfloxacin have been synthesized that displayed excellent antibacterial activity as compared to gentamicin.

    6. Synthesis and Antibacterial Activity of Alkylated Diamines and Amphiphilic Amides of Quinic Acid Derivatives

      Celso O. Rezende Jr, Larissa A. Oliveira, Bruno A. Oliveira, Camila G. Almeida, Bianca S. Ferreira, Mireille Le Hyaric, Guilherme S. L. Carvalho, Maria Cristina S. Lourenço, Michel Batista, Fabricio K. Marchini, Vânia L. Silva, Claudio G. Diniz and Mauro V. Almeida

      Article first published online: 20 JAN 2015 | DOI: 10.1111/cbdd.12498

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      Synthesis of amphiphilic amides of quinic acid derivatives. Evaluation of antibacterial properties against Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa and Mycobacterium tuberculosis. Structure activity relationship of the synthesized compounds.

    7. Synthesis and Structure–Activity Relationships of Triazaspirodecanone Derivatives as Nociceptin/Orphanin FQ Receptor Ligands

      Sandra Corrado, Umberto M. Battisti, Claudia Sorbi, Annalisa Tait, Davide Malfacini, Valeria Camarda, Girolamo Calò and Livio Brasili

      Article first published online: 20 JAN 2015 | DOI: 10.1111/cbdd.12505

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      Substitution of the 1,4-benzodioxane moiety of spiroxatrine with a 4-hydroxy-chromane portion gives compound cis-4, a good candidate to generate a new class of NOP agonists.

    8. Synthesis, Docking, In Vitro and In Vivo Antimalarial Activity of Hybrid 4-aminoquinoline–1,3,5-triazine Derivatives Against Wild and Mutant Malaria Parasites

      Hans Raj Bhat, Udaya Pratap Singh, Prashant Gahtori, Surajit Kumar Ghosh, Kabita Gogoi, Anil Prakash and Ramendra K. Singh

      Article first published online: 16 JAN 2015 | DOI: 10.1111/cbdd.12490

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      A series of hybrid 4-aminoquinoline was synthesized and evaluated for antimalarial activity against chloroquine-sensitive (3D-7) and chloroquine-resistant (RKL-2) strains of P. falciparum.

    9. A Conformational Analysis Study on the Melanocortin 4 Receptor Using Multiple Molecular Dynamics Simulations

      Mohsen Shahlaei and Atefeh Mousavi

      Article first published online: 16 JAN 2015 | DOI: 10.1111/cbdd.12495

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      A computational work was presented to study the structure of Melanocortin 4 receptor integrating molecular docking and multiple molecular dynamics simulations to opportunely validate the initial 3D model obtained from homology modeling.

    10. 3-Keto-1,5-bisphosphonates Alleviate Serum-Oxidative Stress in the High-fat Diet Induced Obesity in Rats

      Karima Lahbib, Iyadh Aouani, Jean-François Cavalier and Soufiane Touil

      Article first published online: 13 JAN 2015 | DOI: 10.1111/cbdd.12493

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      A series of 3-keto-1,5-bisphosphonates were prepared and evaluated for their antioxidant activity in vitro and in vivo in an experimental model of fat-induced obesity in rats with a special emphasis on lipotoxicity-induced oxidative stress.

    11. Identification of Nucleoside Analogs as Inducers of Neuronal Differentiation in a Human Reporter Cell Line and Adult Stem Cells

      Katharina Raasch, Edith Malecki, Maria Siemann, Malayko M. Martinez, Jürgen J. Heinisch, Janine Müller, Lidia Bakota, Christian Kaltschmidt, Barbara Kaltschmidt, Helmut Rosemeyer and Roland Brandt

      Article first published online: 12 JAN 2015 | DOI: 10.1111/cbdd.12488

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      Nucleoside analogues (NSAs) were among the first chemotherapeutic agents and could also be useful for manipulation of cell fate. For screening of NSAs that influence neuronal differentiation, we developed a novel phenotypic assay based on a human neuron-committed teratocarcinoma cell line (NT2) as a model for neuronal progenitors. In a small scale screen we tested a panel of structurally related NSAs and report that NSAs with highest activity carried a halogen substituent at their pyrimidine nucleobase and an unmodified or 2′-O-methyl substituted 2-deoxy-β-D-ribofuranosyl residue as glyconic moiety.

    12. Design, Synthesis, and Biological Evaluation of Novel Benzoyl Diarylamine/ether Derivatives as Potential Anti-HIV-1 Agents

      Lingzi Zhang, Jian Guo, Xin Liu, Huiqing Liu, Erik De Clercq, Christophe Pannecouque and Xinyong Liu

      Article first published online: 12 JAN 2015 | DOI: 10.1111/cbdd.12497

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      A novel series of benzoyl diarylamine/ether derivatives were synthesized and evaluated for their anti-HIV-1 activity. Compound 5a exhibited moderate activity against wt HIV-1 with an EC50 value of 10.94 ± 2.72 μm. Further docking study defined compound 5a as an inhibitor with novel chemical skeleton and mode of action with HIV-1 RT.

    13. Synthesis and Bio-Evaluation of New 18F-Labeled Pyridaben Analogs with Improved Stability for Myocardial Perfusion Imaging in Mice

      Tiantian Mou, Zuoquan Zhao, Pu Zhang, Wei Fang, Cheng Peng, Jie Lu, Qian Wang, Yunchuan Ma and Xianzhong Zhang

      Article first published online: 12 JAN 2015 | DOI: 10.1111/cbdd.12499

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      To improve the stability of 18F-labeled pyridaben analogs for myocardial perfusion imaging, three new analogs of pyridaben ([18F]FPTP2, [18F]FPTP-P2 and [18F]FPTP-P3) were synthesized with ‘sidechain’ modifications. [18F]FPTP2 showed favorable myocardial targeting property and remarkable improvement of stability, suggesting that the substitution of the phenyl ‘sidechain’ with other non-phenyl rings has no effect on the myocardial targeting property of 18F-labeled pyridaben analogs. The feasibility of [18F]FPTP2 for MPI with PET should be evaluated in the future.

    14. Identification of Novel Proteasome Inhibitors from an Enaminone Library

      Megan L. Elliott, Kevin Thomas, Steven Kennedy, Naga D. Koduri, R. Syed Hussaini and Robert J. Sheaff

      Article first published online: 9 JAN 2015 | DOI: 10.1111/cbdd.12496

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      A library of structurally distinct enaminones was synthesized and screened for proteasome inhibitors. Results indicate a subset of enaminones and precursor molecules identified in this study are good candidates for further development into novel proteasome inhibitors with potential therapeutic value.

    15. Structural Basis of Why Nelfinavir-Resistant D30N Mutant of HIV-1 Protease Remains Susceptible to Saquinavir

      Vishal Prashar, Subhash C. Bihani, Jean-Luc Ferrer and Madhusoodan V. Hosur

      Article first published online: 9 JAN 2015 | DOI: 10.1111/cbdd.12494

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      D30N mutant-tethered HIV-1 protease–saquinavir complex crystal structure is reported and reasons for why nelfinavir-resistant D30N mutant of HIV-1 protease remains susceptible to saquinavir explored. Saquinavir forms two direct hydrogen bonds with the main chain atoms of the protein. Saquinavir also forms an additional hydrogen bond to the mutated side chain. Maximization of interactions with the protein backbone as drug design principle suggested in conformity with the previous studies.

    16. Design, Synthesis, and Biological Evaluation of 1,4-dihydropyridine Derivatives as Potent Antitubercular Agents

      Nisheeth C. Desai, Amit R. Trivedi, Hardik C. Somani and Kandarp A. Bhatt

      Article first published online: 9 JAN 2015 | DOI: 10.1111/cbdd.12502

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      A series of novel 1,4-dihydropyridine-3,5-dicarbamoyl derivatives bearing an imidazole nucleus at C-4 position were synthesized and evaluated for their antimycobacterial activity. Compounds 3j and 3m showed most prominent activity against Mycobacterium tuberculosis (Mtb) with minimum inhibitory concentration (MIC) of 0.02 μg/mL and SI > 500, making it more potent than first-line antitubercular drug isoniazid.

    17. Synthesis of Novel Hybrids Inspired from Bromopyrrole Alkaloids Inhibiting MMP-2 and -12 as Antineoplastic Agents

      Rajesh A. Rane, Shital S. Naphade, Pavan Kumar Bangalore, Mahesh B. Palkar, Harun M. Patel, Mahamadhanif S. Shaikh, Wesam S. Alwan and Rajshekhar Karpoormath

      Article first published online: 30 DEC 2014 | DOI: 10.1111/cbdd.12481

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      A series of forty novel semicarbazide/thiosemicarbazide hybrids inspired by marine bromopyrrole alkaloid were synthesized and evaluated for in vitro anticancer activity against five human cancer cell lines MCF7, PA1, WRL68, CaCO2, and KB403 followed by MMP inhibition.

    18. You have full text access to this OnlineOpen article
      Evaluation of Novel N-(piperidine-4-yl)benzamide Derivatives as Potential Cell Cycle Inhibitors in HepG2 Cells

      Jin Hou, Wei Zhao, Zhi-Ning Huang, Shao-Mei Yang, Li-Juan Wang, Yu Jiang, Zhong-Shi Zhou, Man-Yi Zheng, Ji-Li Jiang, Shan-Hua Li and Fu-Nan Li

      Article first published online: 28 DEC 2014 | DOI: 10.1111/cbdd.12484

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      A series of N-(piperidine-4-yl)benzamide derivatives were prepared and evaluated for their antitumor activity. The derivatives were proved to have potent antitumor activity. Compound 47 was performed to inhibit cell cycle by p53/p21-dependent pathway.

    19. In Silico Design of Beta-Secretase Inhibitors in Alzheimer's Disease

      Evandro Pizeta Semighini

      Article first published online: 28 DEC 2014 | DOI: 10.1111/cbdd.12492

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      Use of structure-based and pharmacophore-based virtual screening to find 3 new BACE-1 inhibitors at the 1 μm range.

    20. Design, Synthesis, Biological Evaluation, and Molecular Docking of Novel Benzopyran and Phenylpyrazole Derivatives as Akt Inhibitors

      Wenhu Zhan, Sendong Lin, Jing Chen, Xiaowu Dong, Jianbo Chu and Wenting Du

      Article first published online: 28 DEC 2014 | DOI: 10.1111/cbdd.12489

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      A series of novel benzopyran and phenylpyrazole derivatives were designed, synthesized, and biologically evaluated as Akt inhibitors.

    21. Identification of Novel Selective Lysine-Specific Demethylase 1 (LSD1) Inhibitors Using a Pharmacophore-Based Virtual Screening Combined with Docking

      Chen Zhou, Di Kang, Yungen Xu, Luyong Zhang and Xiaoming Zha

      Article first published online: 22 DEC 2014 | DOI: 10.1111/cbdd.12461

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      A pharmacophore of LSD1 inhibitors was constructed and validated in different ways, and then used to screen the compound library combined with three molecular docking tools followed by biochemical assays.

    22. Searching for Dual Inhibitors of the MDM2-p53 and MDMX-p53 Protein–Protein Interaction by a Scaffold-Hopping Approach

      Andrey Zaytsev, Barry Dodd, Matteo Magnani, Chiara Ghiron, Bernard T. Golding, Roger J. Griffin, Junfeng Liu, Xiaohong Lu, Iolanda Micco, David R. Newell, Alessandro Padova, Graeme Robertson, John Lunec and Ian R. Hardcastle

      Article first published online: 19 DEC 2014 | DOI: 10.1111/cbdd.12474

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      Two libraries of substituted benzimidazoles were designed using a ‘scaffold-hopping’ approach based on reported MDM2-p53 inhibitors. Substituents were chosen following library enumeration and docking into an MDM2 X-ray structure. Benzimidazole libraries were prepared using an efficient solution-phase approach, and screened for inhibition of the MDM2-p53 and MDMX-p53 protein-protein interactions. Key examples showed inhibitory activity against both targets.

    23. Synthesis and Antimicrobial Activity of the Hybrid Molecules between Sulfonamides and Active Antimicrobial Pleuromutilin Derivative

      Liangzhu Chen, Dexue Yang, Zhikun Pan, Lihong Lai, Jianhua Liu, Binghu Fang and Shuning Shi

      Article first published online: 18 DEC 2014 | DOI: 10.1111/cbdd.12486

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      A series of novel pleuromutilin-sulfonamide hybrids were synthesized and evaluated. These compounds displayed potent antimicrobial activities in vitro against various drug-susceptible and drug-resistant Gram- positive bacteria.

    24. C-Aryl Glucosides with Substituents at the Distal Aryl Ring as Sodium-Dependent Glucose Cotransporter Inhibitors for the Treatment of Diabetes Mellitus

      Xuekun Wang, Ying Li, Baowei Yang, Zheng Li, Wenlong Huang and Hai Qian

      Article first published online: 18 DEC 2014 | DOI: 10.1111/cbdd.12487

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      Novel C-aryl glucosides were designed, synthesized, and evaluated for hypoglycemic effects in normal and diabetic mice and in type 2 diabetic rats. Once-daily 13c treatment over 2 weeks significantly lowered fasting and fed glucose levels and restored the function of islet.

    25. A High-Sensitivity Coumarin-Based Fluorescent Probe for Monitoring Hydrogen Sulfide in Living Cells

      Qianqian Qiu, Xin Deng, Lei Jiao, Tianxiao Zhao, Fanfei Meng, Wenlong Huang and Hai Qian

      Article first published online: 15 DEC 2014 | DOI: 10.1111/cbdd.12483

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      A novel coumarin-based fluorescence probe displays high sensitivity to H2S and excellent linearity between the fluorescence intensity and the concentrations of H2S in degassed PBS buffers (R2 = 0.9947) and fetal bovine serum (R2 = 0.9931). And it reacts with H2S with high selectivity over Cys, GSH, and other anions. Meanwhile, successful detection of H2S in living cells was also demonstrated, which means this probe can be for further exploration of H2S in physiological and pathological processes.

    26. Ranking the Binding Energies of p53 Mutant Activators and Their ADMET Properties

      Sara Ibrahim Omar and Jack Tuszynski

      Article first published online: 11 DEC 2014 | DOI: 10.1111/cbdd.12480

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      Restoration of wild-type activity to mutant p53 offers promise to eradicate cancer cells using novel pharmacological agents. We docked twelve known activators to p53 into the open pocket to further understand their mechanism and rank the best binders. The alkylating ligands do not all bind at the same position, while the non-alkylating ligands are capable of binding at the same pocket and directly interacting with Cys124. Stictic acid has a great potential as a p53 activator in terms of less adverse effects although it has poorer pharmacokinetic properties. (A) Docked poses showing MQ (green), NB (orange), MIRA-1 (blue) and STIMA-1 (pink) all binding at the same position and showing common interactions with residues Ser116 and Gly117. (B) Docked pose for PRIMA-1 (orange) and APR-246 (green) in mutant p53-R273H.

    27. Structure-Based Design and Synthesis of a Small Molecule that Exhibits Anti-inflammatory Activity by Inhibition of MyD88-mediated Signaling to Bacterial Toxin Exposure

      Shahabuddin Alam, Sacha Javor, Melissa Degardin, Dariush Ajami, Mitra Rebek, Teri L. Kissner, David M. Waag, Julius Rebek Jr and Kamal U. Saikh

      Article first published online: 8 DEC 2014 | DOI: 10.1111/cbdd.12477

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      A synthetic dimeric compound 4210 mimicking BB-loop of MyD88 was evaluated for potential toxin therapeutic in context with the inhibition of MyD88-mediated signaling for pro-inflammatory responses with exposure to bacterial toxins. In a cell based reporter and biochemical assays, the compound 4210 demonstrated anti-inflammatory activity by targeting MyD88, attenuated cytokine production in human primary cultures, and protected mice from lethal toxic shock.

    28. TS-Chemscore, a Target-Specific Scoring Function, Significantly Improves the Performance of Scoring in Virtual Screening

      Wen-Jing Wang, Qi Huang, Jun Zou, Lin-Li Li and Sheng-Yong Yang

      Article first published online: 8 DEC 2014 | DOI: 10.1111/cbdd.12470

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      A simple strategy to construct target-specific scoring functions based on known ‘universal’ scoring functions is proposed. This strategy was applied to Chemscore, leading to a new scoring function, termed TS-Chemscore. TS-Chemscore was validated and showed significantly improved performance compared with the original Chemscore.

    29. Design, Synthesis and Biological Evaluation of Two Opioid Agonist and Cav2.2 Blocker Multitarget Ligands

      Adriano Mollica, Roberto Costante, Ettore Novellino, Azzurra Stefanucci, Stefano Pieretti, Ferenc Zador, Reza Samavati, Anna Borsodi, Sándor Benyhe, Irina Vetter and Richard J. Lewis

      Article first published online: 8 DEC 2014 | DOI: 10.1111/cbdd.12479

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      Two mixed opioid agonist/Cav2.2 blocker peptides have been synthetized and evaluated in vitro and in vivo. Compounds 1 and 2 posses both opioid and Cav2.2 blocking activity in nanomolar and micromolar range, respectively.

    30. Design, Synthesis, and Anti-HIV Evaluation of Novel Triazine Derivatives Targeting the Entrance Channel of the NNRTI Binding Pocket

      Xuwang Chen, Qing Meng, Liyun Qiu, Peng Zhan, Huiqing Liu, Erik De Clercq, Christophe Pannecouque and Xinyong Liu

      Article first published online: 5 DEC 2014 | DOI: 10.1111/cbdd.12471

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      A novel series of triazine derivatives targeting the entrance channel of NNRTI were designed by combining the pharmacophoric groups of the drug etravirine and the pDAPY derivatives, which showed promising activity against HIV-1 in MT-4 cell line.

    31. Design, Synthesis, and Biological Evaluation of Novel 4-Aminopiperidinyl-linked 3,5-Disubstituted-1,2,6-thiadiazine-1,1-dione Derivatives as HIV-1 NNRTIs

      Tao Liu, Boshi Huang, Ye Tian, Xin Liang, Hong Liu, Huiqing Liu, Peng Zhan, Erik De Clercq, Christophe Pannecouque and Xinyong Liu

      Article first published online: 5 DEC 2014 | DOI: 10.1111/cbdd.12468

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      Based on the hybridization of the privileged fragments in DABO and DAPY-typed HIV-1 NNRTIs, a novel series of 4-aminopiperidinyl-linked 3,5-disubstituted-1,2,6-thiadiazine-1,1-dione derivatives were designed, synthesized, and evaluated for their in vitro anti-HIV activities in MT-4 cells.

  12. Reviews

    1. Comprehensive Review in Current Developments of Benzimidazole-Based Medicinal Chemistry

      Rangappa S. Keri, Asha Hiremathad, Srinivasa Budagumpi and Bhari Mallanna Nagaraja

      Article first published online: 28 NOV 2014 | DOI: 10.1111/cbdd.12462

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      Benzimidazoles are important pharmacophores and privileged structures in medicinal chemistry. This article focuses on the various pharmacological profiles of benzimidazoles and development of novel derivatives with their potential activity.

  13. Research Articles

    1. The Unique Binding Mode of Laulimalide to Two Tubulin Protofilaments

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

      Article first published online: 28 NOV 2014 | DOI: 10.1111/cbdd.12475

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      New insight is gained into the binding of laulimalide to microtubules using an extended tubulin model. Contacts between laulimalide and two β-tubulin units reveal the binding-site residues that contribute to laulimalide binding, including the nature and magnitude of these interactions. Laulimalide was also found to cause structural changes to tubulin, which may play a role in microtubule dynamics and explain the mechanism of action of this potential cancer therapeutic.

    2. Selectivity Mechanism of ATP-Competitive Inhibitors for PKB and PKA

      Ke Wu, Jingzhi Pang, Dong Song, Ying Zhu, Congwen Wu, Tianqu Shao and Haifeng Chen

      Article first published online: 28 NOV 2014 | DOI: 10.1111/cbdd.12472

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      Specific targeting on PKB is crucial in drug design and development for antitumor. Here, we had revealed the selectivity mechanism for PKB inhibitors with molecular dynamics simulation and 3D-QSAR methods.

    3. Enzymatic Studies of Isoflavonoids as Selective and Potent Inhibitors of Human Leukocyte 5-Lipo-Oxygenase

      Carolina Mascayano, Victoria Espinosa, Silvia Sepúlveda-Boza, Eric K. Hoobler, Steve Perry, Giovanni Diaz and Theodore R. Holman

      Article first published online: 28 NOV 2014 | DOI: 10.1111/cbdd.12469

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      Of the 26 compounds tested, 10 isoflavones and 9 isoflavans possessed micromolar potency, but only three were selective against 5-LOX (IR-2, HIR-303, and HIR-309), with IC50 values at least 10 times lower than those of 12-LOX, 15-LOX-1, and 15-LOX-2. Docking and steered molecular dynamics were performed to determinate the structure–activity relationship.

    4. A Discovery Strategy for Selective Inhibitors of c-Src in Complex with the Focal Adhesion Kinase SH3/SH2-binding Region

      Jamie A. Moroco, Matthew P. Baumgartner, Heather L. Rust, Hwan Geun Choi, Wooyoung Hur, Nathanael S. Gray, Carlos J. Camacho and Thomas E. Smithgall

      Article first published online: 28 NOV 2014 | DOI: 10.1111/cbdd.12473

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      Our study describes an approach for discovery of inhibitors with selectivity for c-Src when bound to focal adhesion kinase, an interaction relevant to tumor cell invasion. Using assay conditions where c-Src activity is dependent upon interaction with a focal adhesion kinase phosphopeptide, we identified inhibitors selective for the peptide-bound complex. Docking studies show that one compound (WH-4-124-2) may preferentially bind to the DFG-out conformation of the c-Src active site, implying that binding of c-Src to focal adhesion kinase may induce a unique kinase conformation favoring compound binding.

    5. The Use of Cellulose Nanocrystals for Potential Application in Topical Delivery of Hydroquinone

      Azade Taheri and Mina Mohammadi

      Article first published online: 26 NOV 2014 | DOI: 10.1111/cbdd.12466

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      The current study is aimed at introducing cellulose nanocrystals as suitable carriers for drug delivery to skin. The hydroquinone-cellulose nanocrystal complexes showed an approximately sustained release profile of hydroquinone. Approximately 80% of bound hydroquinone released in 4 h.

    6. A Molecular Dynamics Investigation of Mycobacterium tuberculosis Prenyl Synthases: Conformational Flexibility and Implications for Computer-aided Drug Discovery

      Meekyum Olivia Kim, Xinxin Feng, Ferran Feixas, Wei Zhu, Steffen Lindert, Shannon Bogue, William Sinko, César de Oliveira, Guodong Rao, Eric Oldfield and James Andrew McCammon

      Article first published online: 25 NOV 2014 | DOI: 10.1111/cbdd.12463

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      The dynamics of three isoprenoid biosynthesis enzymes from Mycobacterium tuberculosis were investigated using molecular dynamics (MD) methods with a view to discovering new drug leads. Flexible conformations sampled in the MD simulations were used to examine the enzymatic mechanisms and incorporated to our computer-aided drug discovery protocol. Experimental syntheses and assays of compound libraries led to a finding of a compound with multi-target inhibition.

    7. Newly Designed and Synthesized Curcumin Analogs with in vitro Cytotoxicity and Tubulin Polymerization Activity

      Iten M. Fawzy, Khairia M. Youssef, Nasser S. M. Ismail, Joachim Gullbo and Khaled A. M. Abouzid

      Article first published online: 25 NOV 2014 | DOI: 10.1111/cbdd.12464

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      We report the synthesis of novel curcumin analogs as potential cytotoxic agents through disrupting microtubules polymerization cycle; Compound XIIe displayed the highest cytotoxic activity against five different cancer cell lines with IC50 range of 1–2.5 µm and 60.6% microtubules stabilization in the tubulin polymerization assay.

    8. Key Structures and Interactions for Binding of Mycobacterium tuberculosis Protein Kinase B Inhibitors from Molecular Dynamics Simulation

      Auradee Punkvang, Pharit Kamsri, Patchreenart Saparpakorn, Supa Hannongbua, Peter Wolschann, Stephan Irle and Pornpan Pungpo

      Article first published online: 24 NOV 2014 | DOI: 10.1111/cbdd.12465

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      Molecular dynamics (MD) simulations, in conjunction with MM-PBSA binding free energy analysis, were employed to gain insight into the complex structures of the PknB inhibitors and their binding energetics. The detailed analysis of MD results shows that Glu93, Val95, and Leu17 are key residues responsible to the binding of the PknB inhibitors. Our results provide a structural concept that can be used as a guide for the future design of PknB inhibitors with highly increased antagonistic activity.

    9. Repurposing Human PDE4 Inhibitors for Neglected Tropical Diseases. Evaluation of Analogs of the Human PDE4 Inhibitor GSK-256066 as Inhibitors of PDEB1 of Trypanosoma brucei

      Stefan O. Ochiana, Nicholas D. Bland, Luca Settimo, Robert K. Campbell and Michael P. Pollastri

      Article first published online: 18 NOV 2014 | DOI: 10.1111/cbdd.12443

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      This paper describes the exploration of structure-activity relationships of analogs of the human PDE4 inhibitor GSK-256066 as inhibitors of PDEB1 of Trypanosoma brucei. Compounds with improved biochemical and cellular potency were discovered, and molecular modeling was used to qualitatively explain the observed structure-activity relationships.

    10. Derivatives Form Better Lipoxygenase Inhibitors than Piperine: In Vitro and In Silico Study

      Muringayil J. Tomy, Chelankara S. Sharanya, Kalarickal V. Dileep, Shankar Prasanth, Abudulhameed Sabu, Chittalakkottu Sadasivan and Madathilkovilakathu Haridas

      Article first published online: 17 NOV 2014 | DOI: 10.1111/cbdd.12455

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      Piperine is a secondary metabolite of black pepper. In the present study, the lipoxygenase (LOX) inhibitory activity of piperine and its derivatives, piperonylic acid, piperic acid, and piperonal have been assessed and compared by enzyme kinetics, ITC and molecular modeling experiments. The expressed study shows that derivatives form better LOX inhibitors than piperine.

    11. Synthesis, Biological Evaluation, and Molecular Simulation of Chalcones and Aurones as Selective MAO-B Inhibitors

      Nicole Morales-Camilo, Cristian O. Salas, Claudia Sanhueza, Christian Espinosa-Bustos, Silvia Sepúlveda-Boza, Miguel Reyes-Parada, Fernando Gonzalez-Nilo, Marcos Caroli-Rezende and Angélica Fierro

      Article first published online: 15 NOV 2014 | DOI: 10.1111/cbdd.12458

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      A novel series of chalcones and aurones were synthesized and evaluated as MAO inhibitors. Aurones exhibit MAO-B activity in μm range. Computational results, QSAR and docking, indicates the main pharmacophoric features of chalcones and aurones.

    12. Preparation and Evaluation of 99mTc-labeled anti-CD11b Antibody Targeting Inflammatory Microenvironment for Colon Cancer Imaging

      Dengfeng Cheng, Weihong Zou, Xiao Li, Yan Xiu, Hui Tan, Hongcheng Shi and Xiangdong Yang

      Article first published online: 15 NOV 2014 | DOI: 10.1111/cbdd.12459

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      As an active constituent of the innate immune response predominately expressed in myeloid derived suppressor cells (MDSCs) or immature myeloid cells (IMCs), CD11b with high abundance is a special marker of tumor inflammatory microenvironment. In this study, migration of CD11b+-IMCs and localization of small orthotopic colonic neoplasm (<3 mm in diameter) was displayed clearly by non-invasive Micro-SPECT/CT imaging via 99mTc-MAG3-anti-CD11b as a specific probe to CD11b+-MDSCs. Preliminary results indicated that 99mTc-MAG3-anti-CD11b could be used for early diagnosis of colon cancer.

    13. Synthesis, Molecular Modeling, and Biological Evaluation of Novel 1, 3-Diphenyl-2-propen-1-one Based Pyrazolines as Anti-inflammatory Agents

      Syed Nasir Abbas Bukhari, Xin Zhang, Ibrahim Jantan, Hai-Liang Zhu, Muhammad Wahab Amjad and Vijay H. Masand

      Article first published online: 15 NOV 2014 | DOI: 10.1111/cbdd.12457

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      Six novel chalcones have been synthesized. Based on synthesized chalcones, twelve novel pyrazolines have been synthesized. All newly synthesized compounds are characterized and evaluated for their anti-inflammatory properties.

    14. Design, Synthesis, and Biological Activity of Oxime Ether Strobilurin Derivatives Containing Indole Moiety as Novel Fungicide

      Ya-Qiang Xie, Zi-Long Huang, Hui-Dong Yan, Jun Li, Li-Yi Ye, Li-Ming Che and Song Tu

      Article first published online: 15 NOV 2014 | DOI: 10.1111/cbdd.12460

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      A series of novel oxime ether strobilurins containing indole moiety, which employed an indole group to stabilize the E-styryl group in Enoxastrobin, were designed and synthesized. The biological assay indicated that most compounds exhibited potent fungicidal activities.

    15. 4-Substituted-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine Derivatives: Design, Synthesis, Antitumor and EGFR Tyrosine Kinase Inhibitory Activity

      Safinaz E.-S. Abbas, Enayat I. Aly, Fadi M. Awadallah and Walaa R. Mahmoud

      Article first published online: 14 NOV 2014 | DOI: 10.1111/cbdd.12451

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      Four series of compounds comprising the pyrazolo[3,4-d]pyrimidine core substituted at position 4 with various heterocyclic substitutions were synthesized. Antitumor activity and EGFR-TK inhibition were evaluated.

    16. Novel Peptidomimetics for Inhibition of HER2:HER3 Heterodimerization in HER2-Positive Breast Cancer

      Shanthi Kanthala, Sashikanth Banappagari, Ameya Gokhale, Yong-Yu Liu, Gu Xin, Yunfeng Zhao and Seetharama Jois

      Article first published online: 6 NOV 2014 | DOI: 10.1111/cbdd.12453

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      Peptidomimetics that bind to HER2 protein domain IV, were shown to inhibit protein-protein interactions of EGFR, and decrease cell viability in breast cancer cells with HER2 over expression and suppress the tumor growth in a xenograft model of breast cancer.

    17. Design, Synthesis, and Biological Evaluation of Novel Quinazoline Derivatives as Anti-inflammatory Agents against Lipopolysaccharide-induced Acute Lung Injury in Rats

      Jie Hu, Yali Zhang, Lili Dong, Zhe Wang, Lingfeng Chen, Dandan Liang, Dengjian Shi, Xiaoou Shan and Guang Liang

      Article first published online: 6 NOV 2014 | DOI: 10.1111/cbdd.12454

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      Synthesis and anti-inflammatory evaluation of quinazolin derivatives was presented. Compounds 6h, 6m, 6p, and 6q dose dependently inhibited TNF-α and IL-6 release. Compounds 6m and 6q attenuate lipopolysaccharide-induced acute lung injury in rats.

  14. Research Letters

    1. Functional Non-Nucleoside Adenylyl Cyclase Inhibitors

      Marco Lelle, Abdul Hameed, Lisa-Maria Ackermann, Stefka Kaloyanova, Manfred Wagner, Filip Berisha, Viacheslav O. Nikolaev and Kalina Peneva

      Article first published online: 6 NOV 2014 | DOI: 10.1111/cbdd.12452

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      The synthesis of novel functional non-nucleoside adenylyl cyclase inhibitors, which can be easily modified with thiol containing biomolecules such as tumour targeting structures, is reported. The linkage between inhibitor and biomolecule contains cleavable bonds for efficient intracellular delivery in the cytosol as well as in the acidic environment within endosomes and lysosomes. Live-cell Förster resonance energy transfer-based assay in human embryonic kidney cells demonstrated the excellent inhibitory effect of the compounds presented in this study.

  15. Research Articles

    1. Design, Synthesis, and Biological Evaluation of 1-(thiophen-2-yl)-9H-pyrido[3,4-b]indole Derivatives as Anti-HIV-1 Agents

      Penta Ashok, Cui-Lin Lu, Subhash Chander, Yong-Tang Zheng and Sankarnarayanan Murugesan

      Article first published online: 6 NOV 2014 | DOI: 10.1111/cbdd.12456

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      A novel series of 1-(thiophen-2-yl)-9H-pyrido[3,4-b]indole derivatives were evaluated for anti-HIV and p24 antigen production inhibition activity. Among the reported analogues, compounds 7g, 7e, 7i, and 7o exhibited significant to moderate anti-HIV-1 activity with EC50 values 0.53, 3.8, 3.8, and 2.8 µm with good selectivity index 483, >105, >105, and 3.85, respectively. Interestingly, compound 7g inhibited p24 antigen expression in acute HIV-1IIIB infected cell line C8166 with EC50 1.1 µm.

  16. Research Letters

    1. Synthesis and Antitumor Activity of Natural Compound Aloe Emodin Derivatives

      Naraganahalli R. Thimmegowda, Chanmi Park, Bettaswamigowda Shwetha, Krisada Sakchaisri, Kangdong Liu, Joonsung Hwang, Sangku Lee, Sook J. Jeong, Nak K. Soung, Jae H. Jang, In-Ja Ryoo, Jong S. Ahn, Raymond L. Erikson and Bo Y. Kim

      Article first published online: 5 NOV 2014 | DOI: 10.1111/cbdd.12448

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      In the present study we have synthesized natural compound aloe emodin derivatives 4(a – j) to improve the anticancer activity and to explore the structure-activity relationships. Cell growth inhibition assays revealed that the aloe emodin derivatives 4d, 4f and 4i effectively decreased the growth ofHepG2 (human liver cancer cells), NCI-H460 (human lung cancer cells) and some of the derivatives exhibited comparable antitumor activity against HeLa (Human epithelial carcinoma cells) and PC3 (prostate cancer cells) cell lines compared to that of the parent aloe emodin at low micro molar concentrations.

  17. Research Articles

    1. Targeting Receptor Tyrosine Kinases and Their Downstream Signaling with Cell-Penetrating Peptides in Human Pulmonary Artery Smooth Muscle and Endothelial Cells

      Jun Yu, Chamila Rupasinghe, Jamie L. Wilson, Linda Taylor, Nader Rahimi, Dale Mierke and Peter Polgar

      Article first published online: 5 NOV 2014 | DOI: 10.1111/cbdd.12446

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      Cell penetrating peptides (CPP) targeting the tyrosine motifs of PDGFRβ and VEGFR2 were examined to regulate ligand induced signaling transduction in pulmonary artery smooth muscle and endothelial cells. We found specific blockage of tyrosine kinase receptor signaling can be very effective and that the design of specific receptor tyrosine kinase regulators requires a unique approach. This CPP-based strategy could be useful for blockage of specific signal transmission of the receptors and ultimately may be applicable towards the treatment of disease.

    2. A Cisplatin Derivative that Inhibits Collagen Fibril-Formation in vitro

      Miyu Zenda, Hiroyuki Yasui, Shinya Oishi, Ryo Masuda, Nobutaka Fujii and Takaki Koide

      Article first published online: 5 NOV 2014 | DOI: 10.1111/cbdd.12450

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      cis-Diamminedichloroplatinum(II) (cisplatin) dissolved in dimethylsulfoxide (DMSO) was discovered as a potential inhibitor of collagen fibril-formation. This platinum complex exhibited inhibitory effects on in vitro collagen fibril-formation and in situ collagen-deposition in a cell culture system, whereas its cytotoxicity was hardly observed. The active species was suggested to be [Pt(NH3)2(Cl)(DMSO)]+, which targeted His and/or Met residues on the collagen triple-helix.

  18. Research Letters

    1. Carboxylated Hydroxyethyl Starch: A novel Polysaccharide for the Delivery of Doxorubicin

      Constantinos M. Paleos, Zili Sideratou, Theodossis A. Theodossiou and Dimitris Tsiourvas

      Article first published online: 4 NOV 2014 | DOI: 10.1111/cbdd.12447

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      Carboxylated hydroxyethyl starch was prepared and investigated as a potential drug delivery system of doxorubicin, DOX. Employing DU145 human prostate cancer cells, the well-established localization of free DOX inside nuclei was not observed. On the contrary, when the drug was encapsulated in this carrier, it was preferentially localized in the cytosol, as shown in the figure. Significant cytotoxicity was only observed after ~48 h due to slow controlled release of DOX which is electrostatically attached to the polysaccharide scaffold.

  19. Research Articles

    1. Production of an Antimicrobial Peptide AN5-1 in Escherichia coli and its Dual Mechanisms Against Bacteria

      Tonghui Yi, Yibing Huang and Yuxin Chen

      Article first published online: 4 NOV 2014 | DOI: 10.1111/cbdd.12449

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      An antimicrobial peptide, AN5-1, was expressed with the ubiquitin-tag fusion technology. Bacterial membrane permeabilization and genomic DNA interaction assays revealed AN5-1 has multiple intracellular targets in bacteria. AN5-1 was demonstrated as an antimicrobial peptide with great potentials due to the dual mechanisms of AN5-1 against bacteria.

    2. Plant-Derived Flavones as Inhibitors of Aurora B Kinase and Their Quantitative Structure–Activity Relationships

      Yearam Jung, Soon Young Shin, Yeonjoong Yong, Hyeryoung Jung, Seunghyun Ahn, Young Han Lee and Yoongho Lim

      Article first published online: 28 OCT 2014 | DOI: 10.1111/cbdd.12445

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      Quantitative relationships between the structural properties of plant-derived flavones and their inhibitory effects on aurB were obtained. In vitro cellular experiments for quercetagetin showing the best IC50 value demonstrated that it inhibits aurB, and the molecular binding mode between quercetagetin and aurB was elucidated using in silico docking. Quercetagetin binds to aurB and prevents the active phosphorylation of all three aurora kinases. These observations suggest that quercetagetin is a selective aurora kinase inhibitor.

    3. Design, Synthesis and Pharmacological Evaluation of Novel NO-Releasing Benzimidazole Hybrids as Potential Antihypertensive Candidate

      Yanchun Zhang, Jinyi Xu, Yunman Li, Hequan Yao and Xiaoming Wu

      Article first published online: 28 OCT 2014 | DOI: 10.1111/cbdd.12442

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      By coupling NO-donor with compound 6, two series of benzimidazole derivatives (8ae, 9ag) were obtained. Among them, compound 8e was found to release the maximum amount of NO. Furthermore, compound 8e displayed the longest and better Ang II antagonist ability, comparable to that of the positive control Losartan.

    4. Development of Peptidyl Lysine Dendrons: 1,3-Dipolar Cycloaddition for Peptide Coupling and Antibody Recognition

      Christine Hüttl, Cornelia Hettrich, Melanie Riedel, Petra Henklein, Harshadrai Rawel and Frank F. Bier

      Article first published online: 28 OCT 2014 | DOI: 10.1111/cbdd.12444

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      A straightforward synthesis strategy to multimerize peptide mimotopes is described based on lysine dendrons as multivalent scaffolds. The presented peptide dendron is a promising candidate as multivalent ligand and was used for antibody B13-DE1 recognition. The binding affinity, which is characterized by SPR measurements, increases with higher dendron generation without loss of specificity.

  20. Reviews

    1. Histamine H4 Receptor Ligands: Future Applications and State of Art

      Michelle Fidelis Corrêa and João Paulo dos Santos Fernandes

      Article first published online: 27 OCT 2014 | DOI: 10.1111/cbdd.12431

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      H4 receptors ligands can have applications in the treatment of chronic inflammatory and immune diseases. Several H4 receptor ligands have been described from early 2000's till nowadays, being imidazole, indolecarboxamide, 2-aminopyrimidine, quinazoline and quinoxaline scaffolds the most explored and discussed in this review, as well as possible pharmacophores to H4 receptor binding.

  21. Research Articles

    1. Synthesis and Evaluation of Technetium-99m-Labeled Bioreductive Pharmacophores Conjugated with Amino Acids and Peptides for Tumor Imaging

      Rinku Baishya, Dipak K. Nayak, Sanmoy Karmakar, Sankha Chattopadhyay, Satbir S. Sachdeva, Bharat R. Sarkar, Shantanu Ganguly and Mita C. Debnath

      Article first published online: 24 OCT 2014 | DOI: 10.1111/cbdd.12437

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      Technetium-99m-labeled 5-nitroimidazolyl amino acids and RGD-coupled 2-nitroimidazoles have been synthesized and reported for molecular imaging agent in cancer diagnosis. Cell binding studies in EAC and B16F10 cell lines also revealed rapid and comparatively high cellular internalization. Scintigraphy and fluorescent microscopy suggest the great potentiality of the pharmacophore as tumor imaging agent.

    2. Synthesis, Antidepressant Activity, and Toxicity of the Erythro/Threo Racemates and Optical Isomers of 2-(4-benzylpiperazin-1-yl)-1-(5-chloro-6-methoxynaphthalen-2-yl)hexan-1-ol

      Zhijie Weng, Yongyong Zheng and Jianqi Li

      Article first published online: 24 OCT 2014 | DOI: 10.1111/cbdd.12438

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      The erythro/threo racemates and their four optical isomers of 2-(4-benzylpiperazin-1-yl)-1-(5-chloro-6-methoxynaphthalen-2-yl)hexan-1-ol were synthesized and evaluated for their antidepressant activity, toxicity, and pharmacokinetics as novel triple multiple reuptake inhibitors of monoamine transmitters. Pharmacological data indicate that the erythro racemate (SIPI5357) that has better inhibitory activity and lower toxicity than the other racemate and optical isomers is worthy of further evaluation.

  22. Research Letters

    1. Biofilm Eradication Kinetics of the Ultrashort Lipopeptide C12-OOWW-NH2 Utilizing a Modified MBEC Assay

      Garry Laverty, Sean P. Gorman and Brendan F. Gilmore

      Article first published online: 23 OCT 2014 | DOI: 10.1111/cbdd.12441

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      Comparing the biofilm eradication kinetics for potent ultrashort antimicrobial cationic lipopeptides via a modified MBEC Assay.

  23. Research Articles

    1. si-RNA-Mediated Knockdown of PDLIM5 Suppresses Gastric Cancer Cell Proliferation in Vitro

      Yanliang Li, Yongsheng Gao, Yue Xu, Xianjun Sun, Xilin Song, Heng Ma and Mingshan Yang

      Article first published online: 23 OCT 2014 | DOI: 10.1111/cbdd.12428

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      PDLIM5 is widely expressed in human gastric cancer cell lines. Knockdown of PDLIM5 significantly inhibited gastric cancer cell proliferation via cell cycle arrest and apoptosis. si-RNA-mediated silencing of PDLIM5 might serve as a potential therapeutic approach for the treatment of gastric cancer.

    2. Hydrogen-Bonded His93 As a Sensitive Probe for Identifying Inhibitors of the Endocannabinoid Transport Protein FABP7

      Sergiy Tyukhtenko, Karrie Chan, Rubin Jiang, Han Zhou, Richard W. Mercier, De-Ping Yang, Alexandros Makriyannis and Jason J. Guo

      Article first published online: 15 OCT 2014 | DOI: 10.1111/cbdd.12440

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      The human brain FABP (FABP7) has been identified as an anandamide carrier protein which may provide an excellent pharmacological target for treating pain, inflammation, and drug abuse. We found that a well-separated downfield 1H-NMR resonance arising from the hydrogen-bonded His93 side chain is very sensitive to ligand binding. Our data demonstrated that this unique spectral marker can be used for rapidly and unambiguously identifying novel high-affinity FABP7 inhibitors as potential drug leads for the modulation of endocannabinoid transport.

    3. Design, Synthesis, Biological Screening, and Molecular Docking Studies of Piperazine-Derived Constrained Inhibitors of DPP-IV for the Treatment of Type 2 Diabetes

      Ram N. Kushwaha, Rohit Srivastava, Akansha Mishra, Arun K. Rawat, Arvind K. Srivastava, Wahajul Haq and Seturam B. Katti

      Article first published online: 15 OCT 2014 | DOI: 10.1111/cbdd.12426

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      The piperazine-derived constrained compound, 2g was identified as a potent DPP-IV inhibitor having good antidiabetic, antidyslipidemic and insulin resistance reversal properties. Molecular docking is in favor of observed biological activity.

    4. Design, Synthesis, and Cercaricidal Activity of Novel High-efficient, Low-toxic Self-spreading PEG-N-salicylanilide Derivatives Against Cercariae Larvae of Schistosome Japonicum Floating on the Water Surface

      Wei Guo, Lv-Yin Zheng, Ren-Miao Wu and Xiao-Lin Fan

      Article first published online: 12 OCT 2014 | DOI: 10.1111/cbdd.12439

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      Novel self-spreading PEG-N-salicylanilide derivatives were designed and synthesized according to the particular floating habit of cercariae larvae of Schistosome japonicum. These cercaricides could float on the water surface and showed strong cercaricidal activities and low toxicities.

    5. 1,2-Diaryl-2-hydroxyiminoethanones as Dual COX-1 and β-Amyloid Aggregation Inhibitors: Biological Evaluation and In Silico Study

      Hamid Irannejad, Oya Unsal Tan, Keriman Ozadali, Sakineh Dadashpour, Tuba Tuylu Kucukkilinc, Nematollah Ahangar, Mahsa Ahmadnejad and Saeed Emami

      Article first published online: 11 OCT 2014 | DOI: 10.1111/cbdd.12435

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      A series of 1,2-diaryl-2-hydroxyiminoethanones containing vicinal diaryl pharmacophore of COX inhibitors were tested by a set of in vitro, in vivo and computational studies. Compounds 3 (R= MeO) and 5 (R= F) were highly selective COX-1 inhibitors along with the ability to prevent β-amyloid fibril formation.

  24. Research Letters

    1. Discovery of New Non-Steroidal Farnesoid X Receptor Modulators Through 3D Shape Similarity Search and Structure-Based Virtual Screening

      Lei Wang, Pei Si, Yayun Sheng, Yingjie Chen, Ping Wan, Xu Shen, Yun Tang, Lili Chen and Weihua Li

      Article first published online: 10 OCT 2014 | DOI: 10.1111/cbdd.12432

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      The results of transient transfection experiments showed that two compounds can inhibit farnesoid X receptor (FXR) functions in a concentration-dependent manner with IC50 of 8.39 and 6.53 μm, respectively. Both of them can comfortably fit in the FXR binding pocket.

  25. Research Articles

    1. A Fluorescent Probe for Imaging p53–MDM2 Protein–Protein Interaction

      Zhenzhen Liu, Zhenyuan Miao, Jin Li, Kun Fang, Chunlin Zhuang, Lupei Du, Chunquan Sheng and Minyong Li

      Article first published online: 10 OCT 2014 | DOI: 10.1111/cbdd.12434

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      A novel small-molecule fluorescent probe was developed to detect and image the p53–MDM2 interaction based on an environment-sensitive fluorophore, N,N-dimethyl-1,8-naphthalimide. After extensive biological examination, this probe L1 exhibited practical activity and selectivity in vitro and in cellulo.


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