Chemical Biology & Drug Design

Cover image for Vol. 85 Issue 1

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 - 86
  1. Research Articles

    1. 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.

    2. 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.

    3. 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.

    4. 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.

    5. 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.

    6. 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.

    7. 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.

    8. 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.

    9. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

    2. Roles of Basic Amino Acid Residues in the Activity of μ-Conotoxin GIIIA and GIIIB, Peptide Blockers of Muscle Sodium Channels

      Kazuki Sato, Yoko Yamaguchi, Yukisato Ishida and Yasushi Ohizumi

      Article first published online: 30 SEP 2014 | DOI: 10.1111/cbdd.12433

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      Seven analogs of μ-conotoxin GIIIA and two analogs of μ-conotoxin GIIIB were synthesized. The inhibitory effects on the twitch contractions of the rat diaphragm showed that the side chain guanidino group of Arg13 of μ-conotoxin GIIIA was important for the activity, whereas that of Arg19 has little role in the biological activity. The results on the analogs of μ-conotoxin GIIIB suggested that there was an appropriate molecular basicity for the maximum activity.

    3. In vitro Antiviral Effects and 3D QSAR Study of Resveratrol Derivatives as Potent Inhibitors of Influenza H1N1 Neuraminidase

      Chao Li, Jian-Song Fang, Wen-Wen Lian, Xiao-Cong Pang, Ai-Lin Liu and Guan-Hua Du

      Article first published online: 29 SEP 2014 | DOI: 10.1111/cbdd.12425

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      50 resveratrol derivatives were evaluated neuraminidase (NA) inhibitory activity and 35 of them with quantitative IC50 were used to develop 3D QSAR models for understanding the chemical-biological interactions governing their activities against NA. Molecular docking was performed to study the molecular interactions between the RV derivatives and NA. CPE reduction assay was used to evaluate the anti-viral effects of the RV derivatives in vitro.

    4. Positional Isomerization of A Non-Cleavable Combi-Molecule Dramatically Altered Tumor Cell Response Profile

      Ying Huang, Zakaria Rachid, Lisa Peyrard, Zhor Senhaji Mouhri, Christopher Williams and Bertrand J. Jean-Claude

      Article first published online: 24 SEP 2014 | DOI: 10.1111/cbdd.12402

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      A quinazoline-based inhibitor of EGFR containing a chloroethylamino group at the 6-position exhibited strong DNA-damaging properties, irreversible EGFR inhibition, and apoptosis. Shifting the group to the 7-position led to a significant decrease in DNA-damaging potential and 10-fold weaker EGFR inhibition.

    5. Structure-Based Grafting, Mutation, and Optimization of Peptide Inhibitors to Fit in the Active Pocket of Human Secreted Phospholipase A2: Find New Use of Old Peptide Agents with Anti-Inflammatory Activity

      Chengye Zhan, Shusheng Li, Qiang Zhong and Daixing Zhou

      Article first published online: 24 SEP 2014 | DOI: 10.1111/cbdd.12424

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      A protocol is described to conduct structure-based grafting, mutation, and optimization of peptide ligands from the snake PLA2–peptide complex crystal structures into the active pocket of apo hsPLA2 structure to computationally generate a number of potent peptide inhibitors for hsPLA2. Several designed peptides are determined to have high inhibitory activity against hsPLA2.

    6. Synthesis, Biological Evaluation, and Molecular Docking Studies of Xanthone Sulfonamides as ACAT Inhibitors

      Xiang Li, Yan Zou, Qingjie Zhao, Yan Yang, Maocheng Wu, Ting Huang, Honggang Hu and Qiuye Wu

      Article first published online: 22 SEP 2014 | DOI: 10.1111/cbdd.12419

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      Three series of xanthone sulfonamides were synthesized and their inhibitory activities against ACAT were evaluated. Computational docking experiments indicated that the hydrophilic H-bond interaction, the hydrophobic interaction and the narrow hydrophobic cleft might contribute to the potent inhibitory activities against ACAT.

    7. Structural and Binding Studies of SAP-1 Protein With Heparin

      Vikash K. Yadav, Rahul S. Mandal, Bhanwar L. Puniya, Rahul Kumar, Sharmistha Dey, Sarman Singh and Savita Yadav

      Article first published online: 22 SEP 2014 | DOI: 10.1111/cbdd.12420

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      The work describes heparin interaction with SAP-1 Protein. SAP-1 binds to heparin with a significant affinity and the binding is dependent on chain length of heparin molecule. Further the docking results suggest that positively charged residue Lysine play important role in these interactions. These findings will improve our knowledge about cystatins activities.

    8. PEG Mediated Synthesis and Biological Evaluation of Asymmetrical Pyrazole Curcumin Analogues as Potential Analgesic, Anti-Inflammatory and Antioxidant Agents

      Shravan Y. Jadhav, Raghunath B. Bhosale, Sachin P. Shirame, Sandeep B. Patil and Suresh D. Kulkarni

      Article first published online: 17 SEP 2014 | DOI: 10.1111/cbdd.12416

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      The new series of asymmetrical pyrazole curcumin analogues 4ag were synthesized by using polyethylene glycol (PEG-400) as a green reaction medium. All the newly synthesized compounds were evaluated for their in vivo analgesic and in vitro antioxidant as well as anti-inflammatory activities.

    9. Anticancer Activity and DNA-Binding Investigations of the Cu(II) and Ni(II) Complexes with Coumarin Derivative

      Taofeng Zhu, Yuan Wang, Weiliang Ding, Jun Xu, Ruhua Chen, Jing Xie, Wenjiao Zhu, Lei Jia and Tieliang Ma

      Article first published online: 15 SEP 2014 | DOI: 10.1111/cbdd.12418

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      Two new copper (II) (2) and nickel(II) (3) complexes with a new coumarin derivative have been synthesized and structurally characterized. They complexes show considerable cytotoxic activity against the three human cancers and induce apoptosis of the threes.

    10. Strong Inhibition of Beta-Amyloid Peptide Aggregation Realized by Two-Steps Evolved Peptides

      Sunita Ghimire Gautam, Masayuki Komatsu and Koichi Nishigaki

      Article first published online: 11 SEP 2014 | DOI: 10.1111/cbdd.12400

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      Pair-wise randomly shuffled library was generated from once evolved peptides and subjected to selection providing nano-molar range affinity peptides to Aβ42 with the Aβ42 cytotoxicity inhibition activity.

    11. Hybrid Molecule from Farnesylthiosalicylic Acid-diamine and Phenylpropenoic Acid as Ras-related Signaling Inhibitor with Potent Antitumor Activities

      Yong Ling, Zhiqiang Wang, Xuemin Wang, Xianghua Li, Xinyang Wang, Wei Zhang, Hong Dai, Li Chen and Yihua Zhang

      Article first published online: 8 SEP 2014 | DOI: 10.1111/cbdd.12393

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      Novel series of Farnesylthiosalicylic acid-diamine/phenylpropenoic acid hybrids were synthesized and biologically evaluated. Compound 12f, with the strongest anti-proliferative activity, exerted selectively grow inhibitory activity against tumor cells but not non-tumor liver cell proliferation, and inhibited both Ras related signaling and phosphorylated NF-κB synergetically which may be advantageous to its strong antitumor activities in vitro.

    12. Design, Synthesis, and Preliminary Activity Evaluation of Novel Pyrimidine Derivatives as Acid Pump Antagonists

      Weiguo Song, Xiaopan Zhang, Shutao Li and Wenfang Xu

      Article first published online: 8 SEP 2014 | DOI: 10.1111/cbdd.12390

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      A series of novel pyrimidine derivatives as acid pump antagonists were designed and synthesized. The preliminary gastric antisecretory activities in anesthetized rats were determined. And the results showed that most compounds displayed potent gastric antisecretory activity when gastric secretion was stimulated by histamine. The most potent compound 5g exhibited even similar gastric antisecretory activity compared with the control revaprazan, the relative inhibition rate was 93.0%, which was worthy of further investigation.

    13. Synthesis and Biological Evaluation of Bisphosphonate Compound Labeled with 99mTc(CO)3+

      Kamile Şenocak, Serap Teksöz, Çiğdem İçhedef and Eser Uçar

      Article first published online: 5 SEP 2014 | DOI: 10.1111/cbdd.12401

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      In the present study a new derivative of alendronate was designed and radiolabeled for imaging purposes. The preparation, characterization and biological evaluation of this newly synthesized 99mTc(CO)3-Diethylenetriaminepentaacetic acid-Alendronate (99mTc(CO)3-DTPA-ABP) complex was performed. Biological evaluation of the radiolabelled complex was performed by biodistribution studies on female rats.

  16. Research Letters

    1. Synthesis and Biological Evaluation of 5-Nitropyrimidine-2,4-dione Analogues as Inhibitors of Nitric Oxide and iNOS Activity

      Liang Ma, Linhong He, Lei Lei, Xiaolin Liang, Kai Lei, Ronghong Zhang, Zhuang Yang and Lijuan Chen

      Article first published online: 5 SEP 2014 | DOI: 10.1111/cbdd.12386

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      Fifty two compounds were readily synthesized and evaluated for their inhibition of nitric oxide production. Compound 36 inhibited the production of nitric oxide (IC50: 8.6 μm) on lipopolysaccharide-induced RAW 264.7 cells and inducible nitric oxide synthase activity (IC50: 6.2 μm). Oral administration of 36 possessed protective properties in carrageenan-induced paw edema of male ICR mice.

  17. Research Articles

    1. Synthesis and Evaluation of Salicylanilide Derivatives as Potential Epidermal Growth Factor Receptor Inhibitors

      Minhua Hu, Wenfeng Ye, Jiaming Li, Guochen Zhong, Guangwei He, Qinlong Xu and Yanchun Zhang

      Article first published online: 2 SEP 2014 | DOI: 10.1111/cbdd.12383

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      Two series of novel salicylanilide derivatives were synthesized and their anti-EGFR activity and anti-proliferative were evaluated. Compound 12b was revealed to be a promising antitumor agent.

    2. Molecular Modeling, Synthesis and Biological Evaluation of N-Heteroaryl Compounds as Reverse Transcriptase Inhibitors Against HIV-1

      Anuradha Singh, Dipti Yadav, Madhu Yadav, Ashwini Dhamanage, Smita Kulkarni and Ramendra K. Singh

      Article first published online: 22 AUG 2014 | DOI: 10.1111/cbdd.12397

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      Several pyrimidine and benzimidazole derivatives were found to show anti-HIV activity against HIV-1 IIIB (EC50: 1–28.03 µm; SI value 5.76–28), ADA 5 (EC50: 1.3–63 µm; SI value 4.61–15.08) and against primary isolates, HIV-1 UG070 and HIV-1 VB59 strains (EC50: 2.4–38 µm; SI: 6.28–38.39 and EC50: 2.6–98 µm; SI 4.97–8.06, respectively) under in vitro conditions.

    3. Up Regulation of Liver-enriched Transcription Factors HNF4a and HNF6 and Liver-Specific MicroRNA (miR-122) by Inhibition of Let-7b in Mesenchymal Stem Cells

      Effat Alizadeh, Abolfazl Akbarzadeh, Mohamadreza Baghaban Eslaminejad, Abolfazl Barzegar, Shahryar Hashemzadeh, Kazem Nejati-Koshki and Nosratollah Zarghami

      Article first published online: 21 AUG 2014 | DOI: 10.1111/cbdd.12398

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      Transient inhibition of let-7b activates in-vitro hepatic differentiation of human adipose tissue derived mesenchymal stem cells by up-regulation of Liver enriched transcription factors (HNF4a and HNF6), liver specific miRNA (miR-122), and accumulation of cells in G0/G1 phase of cell cycle.

    4. Highly Stable, Fluorescence-Labeled Heptapeptides Substituted with a D-Amino Acid for the Specific Detection of Oxidized Low-Density Lipoprotein in Plasma

      Akira Sato, Hikaru Yamanaka, Keitaro Oe, Izumi Yokoyama, Yoji Yamazaki and Keiichi Ebina

      Article first published online: 15 AUG 2014 | DOI: 10.1111/cbdd.12399

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      Probes that can detection oxidized low-density lipoprotein (ox-LDL) in plasma and in atherosclerotic plaques can be useful for to the diagnosis, prevention, and treatment of atherosclerosis. We developed two fluorescence-labeled heptapeptides substituted with a D-amino acid— (FITC)dKP6 and (FITC-AC)dKP6— with high plasma stability for specific detection of ox-LDL. These compounds may be useful as fluorescent probes for specific detection of ox-LDL.

    5. Synthesis and Evaluation of Antidepressant-like Activity of Some 4-Substituted 1-(2-methoxyphenyl)Piperazine Derivatives

      Anna M. Waszkielewicz, Karolina Pytka, Anna Rapacz, Elżbieta Wełna, Monika Jarzyna, Grzegorz Satała, Andrzej Bojarski, Jacek Sapa, Paweł Żmudzki, Barbara Filipek and Henryk Marona

      Article first published online: 14 AUG 2014 | DOI: 10.1111/cbdd.12394

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      New N-(2-methoxyphenyl)piperazine derivatives have been synthesized for their affinity towards serotonergic receptors and for their potential antidepressant-like activity(tail suspension, locomotor activity, and motor coordination tests). All the tested compounds proved very good affinities towards 5-HT1A and 5-HT7. The most promising was 1-[(2-chlor-6-methylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazinehydrochloride, exhibiting Ki <1 nM (5-HT1A), and Ki = 34 nM (5-HT7), activity in tail suspension test at 2.5 mg/kg b.w. (mice, i.p.);sedative activity ED50 (locomotor test, mice, i.p.) = 17.5 mg/kg b.w. and neurotoxicity TD50 (rotarod, mice, i.p.) = 53.2 mg/kg b.w.

    6. Feleucin-BO1: A Novel Antimicrobial Non-Apeptide Amide from the Skin Secretion of the Toad, Bombina orientalis, and Design of a Potent Broad-Spectrum Synthetic Analogue, Feleucin-K3

      Xiaojuan Hou, Qiang Du, Renjie Li, Mei Zhou, Hui Wang, Lei Wang, Can Guo, Tianbao Chen and Chris Shaw

      Article first published online: 11 AUG 2014 | DOI: 10.1111/cbdd.12396

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      Feleucin-BO1 is a novel antimicrobial non-apeptide from toad skin secretion. Feleucin-K3 (F-K3) is a cationicity-enhanced analogue designed from this natural peptide. F-K3 exhibited both significantly enhanced potency and spectrum of action. These data indicate the potential of natural peptide templates in the design of analogues with enhanced actions in specific biological end-points.

    7. Structure–activity Relationship Studies of Microbiologically Active Thiosemicarbazides Derived from Hydroxybenzoic Acid Hydrazides

      Tomasz Plech, Agata Paneth, Barbara Kaproń, Urszula Kosikowska, Anna Malm, Aleksandra Strzelczyk and Paweł Stączek

      Article first published online: 30 JUL 2014 | DOI: 10.1111/cbdd.12392

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      Among the described derivatives we managed to identify a large number of compounds endowed with potent antibacterial activity. As it was showed the antibacterial activity of the obtained compounds was limited only towards Gram-positive bacteria. The obtained results may enable designing novel drugs efficient in treating infectious diseases.

  18. Research Letters

    1. Microwave-assisted Synthesis of Cyclic Phosphopeptide on Solid Support

      Nir Qvit

      Article first published online: 24 JUL 2014 | DOI: 10.1111/cbdd.12388

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      A novel synthesis of cyclic phosphopeptides by a fully automated microwave is described. Using automated microwave synthesis duration was reduced and yields increased, compared to manual conventional method. A general, fast and facile way to synthesize cyclic peptides is proposed, demonstrating the synthesis of cyclic phosphorylated peptides which are known to be among the most challenging to produce.

  19. Research Articles

    1. Zebrafish as a New Model for Phenotype-based Screening of Positive Inotropic Agents

      Chunlei Tang, Desheng Xie and Bainian Feng

      Article first published online: 22 JUL 2014 | DOI: 10.1111/cbdd.12389

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      In this study, we investigated the cardiac defects caused by terfenadine and tested the pharmacological response of digoxin to zebrafish with cardiac defects. The study suggested that zebrafish could be a suitable model for phenotype-based screening and evaluation of positive inotropic agents. This phenotype-based, heart failure zebrafish model system was then utilized in in-house library screen. Some positive inotropic compound was discovered, which could attenuate the cardiac defects by increasing the flow velocity of caudal artery blood.

    2. Discovery, Optimization, and Pharmacophore Modeling of Oleanolic Acid and Analogues as Breast Cancer Cell Migration and Invasion Inhibitors Through Targeting Brk/Paxillin/Rac1 Axis

      Heba E. Elsayed, Mohamed R. Akl, Hassan Y. Ebrahim, Asmaa A. Sallam, Eman G. Haggag, Amel M. Kamal and Khalid A. El Sayed

      Article first published online: 15 JUL 2014 | DOI: 10.1111/cbdd.12380

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      Bioassay-guided fractionation of Terminali bentzoe L. leaves extract identified the triterpene oleanolic acid as its major breast cancer cell migration inhibitor. Further chemical modifications afforded more potent semisynthetic analogues. Western blot analysis indicated the anticancer activities to be related to the suppression of Brk/Paxillin/Rac1 axis. Pharmacophore modeling was conducted to better understand structural binding epitopes important for the antimigratory activity.

    3. Evaluation of Anti-inflammatory and Analgesic Effects of Synthesized Derivatives of Ibuprofen

      Jingjie Wang, Dongyan Dai, Qianqian Qiu, Xin Deng, Haiyan Lin, Hai Qian and Wenlong Huang

      Article first published online: 15 JUL 2014 | DOI: 10.1111/cbdd.12316

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      A series of piperazine carboxamide, propanamide, and pyrrolidine carboxamide derivatives of ibuprofen were designed by modifying carboxylic acid group of ibuprofen based on the common structure of transient receptor potential vanilloid type 1 (TRPV1) antagonists and synthesized. They were evaluated for cyclooxygenase inhibition, TRPV1 antagonistic, anti-inflammatory, analgesic, ulcerogenic action, and the effect on body temperature. Compound 17 emerged as a safe alternative analgesic candidate for pain treatment.

  20. Research Letters

    1. The Evaluation of Statins as Potential Inhibitors of the LEDGF/p75–HIV-1 Integrase interaction

      Angela T. Harrison, Frederik H. Kriel, Maria A. Papathanasopoulos, Salerwe Mosebi, Shaakira Abrahams and Raymond Hewer

      Article first published online: 12 JUL 2014 | DOI: 10.1111/cbdd.12384

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      In this study, the known drug lovastatin was identified as an inhibitor of the LEDGF/p75- HIV-1 integrase interaction, atorvastatin was also verified as an inhibitor of the LEDGF/p75-IN interaction and statin lipophilicity was observed to increase cellular toxicity.

  21. Research Articles

    1. Targeting Dormant Tuberculosis Bacilli: Results for Molecules with a Novel Pyrimidone Scaffold

      Rohit R. Joshi, Avinash Barchha, Vijay M. Khedkar, Raghuvir R. S. Pissurlenkar, Sampa Sarkar, Dhiman Sarkar, Rohini R. Joshi, Ramesh A. Joshi, Anamik K. Shah and Evans C. Coutinho

      Article first published online: 12 JUL 2014 | DOI: 10.1111/cbdd.12373

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      This paper reports the second molecule after TMC-207, with the ability to inhibit tuberculosis bacilli in its dormant phase. The paper reports molecules with a novel Pyrimidone Scaffold, the synthesis of which was accomplished with a modified multi-component Biginelli reaction. A classification model was generated using recursive partitioning (RP) technique to identify structural characteristics of the molecules with their varying activities.

    2. Synthesis and Biological Evaluation of 2-oxo-pyrazine-3-carboxamide-yl Nucleoside Analogues and Their Epimers as Inhibitors of Influenza A Viruses

      Jingjing Gao, Xianjin Luo, Yuhuan Li, Rongmei Gao, Haifeng Chen and Dingjue Ji

      Article first published online: 12 JUL 2014 | DOI: 10.1111/cbdd.12382

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      Novel 2-oxo-pyrazine-3-carboxamide-yl nucleoside analogues and their epimers were designed, synthesized, and evaluated for their activities against influenza A viruses H1N1 and H3N2 in MDCK cells. All the compounds showed low cytotoxicities in these anti-influenza tests. One of the epimers 8a shows high antiviral activity (IC50 = 7.41, 5.63 μm for H3N2 and H1N1, respectively) and remarkable low cytotoxicity (TC50 > 200 μm). Molecular docking of compound 8a with RNA-dependent RNA polymerase was performed to understand the binding mode between these inhibitors and the active site of RdRp.

    3. Comparative Analysis of Various Electrostatic Potentials on Docking Precision Against Cyclin-Dependent Kinase 2 Protein: A Multiple Docking Approach

      Sunil K. Tripathi, Rajendran Naga Soundarya, Poonam Singh and Sanjeev K. Singh

      Article first published online: 12 JUL 2014 | DOI: 10.1111/cbdd.12376

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      Different semiempirical (RM1, AM1, PM3, MNDO) and ab intio (HF, DFT) charge models were investigated for their performance in prediction of docking pose against CDK2 proteins. The preliminary results point out that AM1 charge model can provide precious insight into the design of new potent and selective CDK2 inhibitors with enhanced success rate.

    4. Computer-Aided Drug Discovery Approach Finds Calcium Sensitizer of Cardiac Troponin

      Steffen Lindert, Monica X. Li, Brian D. Sykes and J. Andrew McCammon

      Article first published online: 11 JUL 2014 | DOI: 10.1111/cbdd.12381

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      In the fight against heart failure, therapeutics that increase the calcium sensitivity of the thin filament are a promising option to improve heart contractile power. Here, we combined computational drug discovery methods and solution NMR titration assays to identify a novel calcium sensitizer which binds to cTnC and the cTnC-cTnI147–163 complex. Its presence increases the affinity of switch peptide to cTnC by approximately a factor of two, making its action comparable to that of known levosimendan analogues.

    5. Design, Synthesis and Evaluation of Rhodanine Derivatives as Aldose Reductase Inhibitors

      Yogesh P. Agrawal, Mona Y. Agrawal and Arun K. Gupta

      Article first published online: 11 JUL 2014 | DOI: 10.1111/cbdd.12369

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      Series of substituted 5-phenylbenzoate rhodanine analogs were synthesized and evaluated for their ALR inhibitory activity. The docking study of synthesized compounds was carried out, which revealed that the 5-phenylbenzoate moiety deeply influenced the key π-π stacking while 4-oxo-2-thioxothiazolidines contributed in hydrogen bond interactions.

    6. Highly Potential Antiplasmodial Restricted Peptides

      Torres Marcelo Der Torossian, Adriana F. Silva, Flávio L. Alves, Margareth L. Capurro, Antonio Miranda and Oliveira Vani Xavier Jr.

      Article first published online: 11 JUL 2014 | DOI: 10.1111/cbdd.12354

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      Five angiotensin II-restricted analogs that contain disulfide bridges were synthesized to analyze their effect on antiplasmodial activity. The results indicate that two of the analogs had higher antiplasmodium activity (92% and 98% activity) than angiotensin II (88% activity), measured by fluorescence microscopy. The results obtained with the new restricted analogs showed that the insertion position to preserve the hydrophobic interactions among the non-polar residues is important to the antiplasmodial activity.

    7. 2-(Hetero(aryl)methylene)hydrazine-1-carbothioamides as Potent Urease Inhibitors

      Aamer Saeed, Aqeel Imran, Pervaiz A. Channar, Mohammad Shahid, Wajahat Mahmood and Jamshed Iqbal

      Article first published online: 10 JUL 2014 | DOI: 10.1111/cbdd.12379

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      2-(Hetero(aryl)methylene)hydrazine-1- carbothioamides 3-thiazolocoumarinyl derivatives were synthesized and evaluated for anti-urease activity, most of the assayed compounds were potent inhibitors of the enzyme, and their binding modes were studied by molecular docking experiments.

    8. Synthesis and Evaluation of a New Series of 3,5-bis((5-bromo-6-methyl-2-t-aminopyrimidin-4-yl)thio)-4H-1,2,4-triazol-4-amines and their Cyclized Products ‘Pyrimidinylthio Pyrimidotriazolothiadiazines’ as 15- Lipo-Oxygenase Inhibitors

      Tayebe Asghari, Mehdi Bakavoli, Mohammad Rahimizadeh, Hossein Eshghi, Sattar Saberi, Azam Karimian, Farzin Hadizadeh and Moreteza Ghandadi

      Article first published online: 10 JUL 2014 | DOI: 10.1111/cbdd.12375

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      A series of new 3,5-bis(substituted pyrimidinylthio)triazolamines 4ag and their cyclized products ‘pyrimidinylthio pyrimidotriazolothiadiazines’ 5ag were designed, synthesized, and evaluated as potential inhibitors of 15-lipoxygenase (15-LO). The compounds 4ag were also evaluated by docking with 15-lipo-oxygenase enzyme. Compounds 4d (NR2 = 1-methylpiperazine) and 4f (NR2 = 1-ethylpiperazine) showed the best IC50 of 15-LO inhibition (IC50 = 9 and 12 µm, respectively).

    9. Hologram Quantitative Structure Activity Relationship, Docking, and Molecular Dynamics Studies of Inhibitors for CXCR4

      Chongqian Zhang, Chunmiao Du, Zhiwei Feng, Jingyu Zhu and Youyong Li

      Article first published online: 10 JUL 2014 | DOI: 10.1111/cbdd.12377

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      We perform HQSAR, docking, and molecular dynamics studies of inhibitors for CXCR4. We obtain a reliable HQSAR model (q2 = 0.779) and we perform docking and MD study of CXCR4 with inhibitor bound. We find that the binding are affected by two crucial residues Asp97 and Glu288 of CXCR4. And the butyl amine moiety of AMD11070 is critical for its high antiretroviral activity.

    10. The Potential Roles of Cell Surface pHs in Bioactive Peptide Activation

      Long Chen and Jun F. Liang

      Article first published online: 7 JUL 2014 | DOI: 10.1111/cbdd.12374

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      Cells from different tissues and organs have distinguished cell surface pHs. Cell surface pH could greatly affect the interactions of pH sensitive peptides with cells and contributed signifcantly to the biological activity of peptides. A peptide designed based on the surface pH difference between normal and cancer cells showed selective toxicity to cancer cells.

    11. Drug Repurposing Based on Drug–Drug Interaction

      Bin Zhou, Rong Wang, Ping Wu and De-Xin Kong

      Article first published online: 2 JUL 2014 | DOI: 10.1111/cbdd.12378

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      The associations between drugs were established based on drug-drug interaction data and rendered with a drug association network. In the network, drugs with similar anatomical therapeutic chemical (ATC) codes (indicating they have similar functions) gathered together. And it was also demonstrated that this network can be well applied to the prediction of targets for drugs and is complementary to other target prediction methods.

    12. Structural Basis for Low-Affinity Binding of Non-R2 Carboxylate-Substituted Tricyclic Quinoline Analogs to CK2α: Comparative Molecular Dynamics Simulation Studies

      Yue Zhou, Xitao Li, Na Zhang and Rugang Zhong

      Article first published online: 26 JUN 2014 | DOI: 10.1111/cbdd.12372

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      A combination of molecular modeling techniques are applied to gain insight into the structural mechanisms through which the non-R2 carboxylate substituent influence CX-4945 analogs binding affinity. An allosteric pathway between the deviated ligands and the affected regions (G-loop, C-loop and β4/β5 loop) was proposed.

    13. Discovery of Novel 17-Phenylethylaminegeldanamycin Derivatives as Potent Hsp90 Inhibitors

      Zhenyu Li, Lejiao Jia, Jifeng Wang, Xingkang Wu, Guowei Shi, Chunhua Lu and Yuemao Shen

      Article first published online: 26 JUN 2014 | DOI: 10.1111/cbdd.12371

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      Compound 2y was revealed to be a promising antitumor agent through the synthesis, structure-activity relationship analysis and hepatotoxicity evaluation of 26 novel 17-phenylethylaminegeldanamycin derivatives, which showed the most potent antitumor activity against LNCap cells and the least hepatotoxicity. The binding model of compound 2y to Hsp90 was simulated by Amber12 and shown by PyMoL.


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