Chemical Biology & Drug Design

Cover image for Vol. 84 Issue 4

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 - 63
  1. Research Articles

    1. 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.

    2. 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.

    3. 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.

    4. 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.

    5. 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.

    6. 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.

    7. 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.

    8. 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.

    9. 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.

    10. 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.

    11. 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.

    12. 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.

  2. 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.

  3. 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. Design, Synthesis, Antibacterial Evaluation and Docking Study of Novel 2-Hydroxy-3-(nitroimidazolyl)-propyl-derived Quinolone

      Qing Li, Junhao Xing, Haibo Cheng, Hui Wang, Jing Wang, Shuai Wang, Jinpei Zhou and Huibin Zhang

      Article first published online: 15 AUG 2014 | DOI: 10.1111/cbdd.12395

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      A novel series of 2-hydroxy-3-(nitroimidazolyl)-propyl derived quinolones 6ao were synthesized and tested for their antibacterial activity. Moxifloxacin analog 6n showed potent activity against all tested strains (MIC = 0.03–2 μg/mL).

    6. Structure-based Design, Synthesis, and Biological Evaluation of Isatin Derivatives as Potential Glycosyltransferase Inhibitors

      Yong Wang, Fung-Yi Chan, Ning Sun, Hok-Kiu Lui, Pui-Kin So, Siu-Cheong Yan, Kin-Fai Chan, Jiachi Chiou, Sheng Chen, Ruben Abagyan, Yun-Chung Leung and Kwok-Yin Wong

      Article first published online: 14 AUG 2014 | DOI: 10.1111/cbdd.12361

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      Virtual screening against the glycosyltransferase (GT) domain of S. aureus PBP2 resulted in the discovery of an isatin derivative as a potential inhibitor. A series of isatin analogs were synthesized and some compounds showed improved antibacterial activity, which could possibly be further optimized to become potent antibacterial agents.

    7. 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.

    8. 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.

    9. 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.

  4. 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.

  5. 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. Synthesis and Evaluation of Novel Marine Bromopyrrole Alkaloid-Based Derivatives as Potential Antidepressant Agents

      Rajesh A. Rane, Shital Napahde, Pavan Kumar Bangalore, Niteshkumar U. Sahu, Nishant Shah, Yogesh A. Kulkarni, Kalyani Barve, Leena Lokare and Rajshekhar Karpoormath

      Article first published online: 15 JUL 2014 | DOI: 10.1111/cbdd.12352

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      We report here synthesis and evaluation of a series of twenty aroyl hydrazones with bromopyrrole feature for their antidepressant activity by FST, TST, actophotometer methods. The molecules were further tested for in vitro human MAOs inhibitory activities.

    4. 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.

  6. 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.

  7. 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. Down-Regulation of Asparagine Synthetase Induces Cell Cycle Arrest and Inhibits Cell Proliferation of Breast Cancer

      Hongjian Yang, Xiangming He, Yabing Zheng, Weiliang Feng, Xianghou Xia, Xingfei Yu and Zhiqiang Lin

      Article first published online: 12 JUL 2014 | DOI: 10.1111/cbdd.12348

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      We employed RNA interference as an efficient tool to silence endogenous ASNS expression in breast cancer cell lines. Depletion of ASNS remarkably inhibited the proliferation and colony formation capacity of breast cancer cells and arrested cell cycle in the S phase. Our findings suggest that ASNS may contribute to breast cancer tumorigenesis and could be a potential therapeutic target in human breast cancer.

    5. 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.

    6. 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.

    7. 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.

    8. 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.

    9. 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).

    10. Specific Interaction between Mycobacterium tuberculosis Lipoprotein-derived Peptides and Target Cells Inhibits Mycobacterial Entry In Vitro

      Marisol Ocampo, Hernando Curtidor, Magnolia Vanegas, Manuel A. Patarroyo and Manuel E. Patarroyo

      Article first published online: 10 JUL 2014 | DOI: 10.1111/cbdd.12365

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      This article presents results obtained with peptides from four lipoproteins : LprG, LpqH, LppC and LppN. Using a robust, highly specific and sensitive methodology was possible to identifying selected M. tuberculosis H37Rv protein sequences having high specific target cell binding ability, named high activity binding peptides (HABPs). HABPs which inhibited mycobacteria entry to U937 monocyte and A549 epithelial cells were taken into account for further studies concerning their immunogenic properties to consider whether to include them in our vaccine approach.

    11. 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.

    12. 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.

    13. Bis(Methylpyridine)-EDTA Derivative as a Potential Ligand for PET Imaging: Synthesis, Complexation, and Biological Evaluation

      Pooja Singh, Swati Aggarwal, Anjani K. Tiwari, Vikas Kumar, Ramendra Pratap, Krishna Chuttani and Anil K. Mishra

      Article first published online: 3 JUL 2014 | DOI: 10.1111/cbdd.12366

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      A novel transitional metal ligand EDTA-Mepy2 was designed and synthesized for PET imaging with radionuclide 68Ga. Molecular modeling and fluorescence binding study (Ksv = 4.9 × 103 m−1) with HSA shows drug likeliness of the ligand. The pharmacokinetics of 68Ga-EDTA-Mepy2 revealed rapid blood clearance (t1/2 slow: 3 h 56 min) via the renal route. EDTA-Mepy2 also proves its efficacy as an optical agent with emission in visible region (λex = 380 nm, RFU = 8000; 710 nm, RFU = 1000 units) of electromagnetic radiations.

    14. Novel Shikonin Derivatives Targeting Tubulin as Anticancer Agents

      Jing Guo, Xiao-Feng Chen, Jing Liu, Hong-Yan Lin, Hong-Wei Han, Hong-Chang Liu, Shou-Cheng Huang, Baloch K. Shahla, Andrew Kulek, Jin-Liang Qi, Xiao-Ming Wang, Li-Jun Ling and Yong-Hua Yang

      Article first published online: 3 JUL 2014 | DOI: 10.1111/cbdd.12353

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      A series of shikonin-phenoxyacetic acid derivative were prepared; among them, compound 16 potently inhibited the function of microtubules, inducing cell growth inhibition and apoptosis of HepG2 cells. Analysis of microtubules with confocal microscopy demonstrated that 16 altered the microtubule architecture and exhibited a significant reduction in microtubule density.

    15. 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.

  8. Research Letters

    1. A PER2-Derived Mechanism-Based Bisubstrate Analog for Casein Kinase 1ε

      Nicholas A. Zeringo and John J. Bellizzi III

      Article first published online: 2 JUL 2014 | DOI: 10.1111/cbdd.12363

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      A transition state-based bisubstrate analog for casein kinase 1ε consisting of an ATP–PER2 phosphopeptide conjugate has been synthesized and assayed to provide insight into the effects of the tau mutation (Arg178Cys) on substrate binding and catalysis. Kinase activity assays determined that the tau mutant has 80% reduced activity and a fourfold decrease in sensitivity to the bisubstrate analog compared to wild-type CK1ε. The results provide evidence for the involvement of Arg178 in phosphate recognition.

  9. Research Articles

    1. Stability of Bovine Lactoferrin in Luminal Extracts and Mucosal Homogenates from Rat Intestine: A Prelude to Oral Absorption

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

      Article first published online: 1 JUL 2014 | DOI: 10.1111/cbdd.12360

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      Bovine lactoferrin was susceptible to both partial and complete degradation by components of the rat intestinal tract which existed trypsin-like and aminopeptidase-like proteases. The kinetics of bovine lactoferrin degradation in the digestion models followed a pseudo-first-order rate. Enzymatic inhibitors and particles encapsulation were successfully able to overcome enzymatic degradation by different mechanisms.

    2. Detailed SAR and PCA of the Tyrocidines and Analogues Towards Leucocin A-Sensitive and Leucocin A-Resistant Listeria monocytogenes

      Adrienne Nyango-Nkeh Leussa and Marina Rautenbach

      Article first published online: 30 JUN 2014 | DOI: 10.1111/cbdd.12344

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      The tyrocidines, cyclic decapeptides from Bacillus aneurinolyticus, have potent activity with drug/disinfectant potential against Listeria monocytogenes. Detailed SAR studies showed that antilisterial activity is dictated by interplay between aromatic residues in the variable pentapeptide and the cationic residue with a prerequisite for a Trp3 and Tyr7 or Phe7 in the variable pentapeptide and ornithine as cationic residue. Any residue change resulting in tighter membrane/cell wall interaction is likely to trap tyrocidines and impede their mechanism of action.

    3. A Re-examination of the MDM2/p53 Interaction Leads to Revised Design Criteria for Novel Inhibitors

      Natalya I. Vasilevich, Ilya I. Afanasyev, Dmitry A. Kovalskiy, Dmitry V. Genis and Valery S. Kochubey

      Article first published online: 30 JUN 2014 | DOI: 10.1111/cbdd.12351

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      The general model of epitope-type MDM2 inhibitor was developed based on the structural information on the complexes between MDM2 and various low molecular weight ligands found in the PDB database. Application of this model to our in-house library has led us to a new scaffold capable of PPIs. A synthetic library based on this and related scaffolds resulted in new classes of compounds that possess biochemical and cellular activity and good pharmacokinetic properties.

    4. Further Insights Into the Pharmacology of the Human Trace Amine-Associated Receptors: Discovery of Novel Ligands for TAAR1 by a Virtual Screening Approach

      Elena Cichero, Stefano Espinoza, Silvia Franchini, Sara Guariento, Livio Brasili, Raul R. Gainetdinov and Paola Fossa

      Article first published online: 29 JUN 2014 | DOI: 10.1111/cbdd.12367

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      In this study, using our TAAR1 receptor homology model, we performed a virtual screening on an in-house database of 240 molecules and among them we identified six biologically active ligands, with a new chemical scaffold.

    5. 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.

    6. 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.

    7. Design, Synthesis, and Pharmacological Evaluation of Novel 2-(4-substituted piperazin-1-yl)1, 8 Naphthyridine 3-Carboxylic Acids as 5-HT3 Receptor Antagonists for the Management of Depression

      Arghya K. Dhar, Radhakrishnan Mahesh, Ankur Jindal, Thangaraj Devadoss and Shvetank Bhatt

      Article first published online: 26 JUN 2014 | DOI: 10.1111/cbdd.12370

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      The carboxylic acid-based 1,8 naphthyridines were designed using ligand-based approach. 5-HT3 receptor antagonism (denoted as pA2 value) of all the compounds was evaluated. Some compounds showed promising antidepressant-like activity in mice model of FST and TST.

    8. Design, Synthesis, and Antimicrobial Evaluation of Hexadentate Hydroxypyridinones with High Iron(III) Affinity

      Ming-Xia Zhang, Chun-Feng Zhu, Ying-Jun Zhou, Xiao- Le Kong, Robert C Hider and Tao Zhou

      Article first published online: 26 JUN 2014 | DOI: 10.1111/cbdd.12358

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      A range of hexadentate 3-hydroxypyridin-4-ones with high affinity for iron(III) has been synthesized. Antimicrobial assay showed that they are able to markedly inhibit the growth of both Gram-positive and Gram-negative bacteria, indicating that hexadentate 3-hydroxypyridin-4-ones have potential application as antimicrobial agents.

    9. Influence of Amodiaquine on the Antimalarial Activity of Ellagic Acid: Crystallographic and Biological Studies

      Ewa Żesławska, Barbara Oleksyn, Aude Fabre and Françoise Benoit-Vical

      Article first published online: 25 JUN 2014 | DOI: 10.1111/cbdd.12359

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      A new hybrid complex of antimalarial amodiaquine and ellagic acid was obtained and its crystal structure was determined. The antiplasmodial activity of the complex was also examined and compared with the values of IC50 for the components separately. The hybrid complex showed improved antiplasmodial activity in comparison with ellagic acid alone.

    10. Enzyme Kinetics Studies on 29-kDa Human Liver Cathepsin L

      Daniele Pietra, Alice Borghini, Claudio Ricci and Anna M. Bianucci

      Article first published online: 21 JUN 2014 | DOI: 10.1111/cbdd.12357

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      The effects of different experimental conditions simulating the lysosomal compartment, the nucleus and the extracellular compartment on the progress curve of the enzymatic reaction catalysed by human liver Cathepsin L were studied. The resulted potential role of Cathepsin L within the extracellular compartment makes it worthy of being investigated as an extracellular target for diagnosis and/or therapy in several pathologies.

    11. Identification of 1, 4-Dihydrothieno[3′, 2′:5, 6]thiopyrano[4, 3-c]pyrazole Derivatives as Human 5-Lipo-oxygenase Inhibitors

      Jianshu Hu, Wei Zhu, Hu Meng, Ying Liu, Xin Wang and Chun Hu

      Article first published online: 21 JUN 2014 | DOI: 10.1111/cbdd.12356

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      A series of novel 1,4-dihydrothieno[3′,2′:5,6]thiopyrano[4,3-c]pyrazole-3-carboxamide derivatives were synthesized and evaluated for their inhibitory activity of human 5-lipo-oxygenase (5-LOX). Compound 7c was found to exhibit significant inhibition to human 5-LOX with IC50 value of 5.7 ± 0.9 μm. Compound 7c was further studied using molecular docking in order to delineate its structure–activity relationship and to gain insight into the design of effective 5-LOX inhibitors.

    12. 19F NMR as a Probe of Ligand Interactions with the iNOS Binding site of SPRY Domain-Containing SOCS Box Protein 2

      Eleanor W. W. Leung, Hiromasa Yagi, Jitendra R. Harjani, Mark D. Mulcair, Martin J. Scanlon, Jonathan B. Baell and Raymond S. Norton

      Article first published online: 5 JUN 2014 | DOI: 10.1111/cbdd.12355

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      19F NMR was utilized as a means of probing ligand binding to 5-F-Trp-labeled SPSB2. Of the six well-resolved 5-F-Trp resonances in the 19F NMR spectrum, that of W207 was significantly perturbed upon binding to DINNN-containing peptides. Analogues of compounds identified in a fragment screen also perturbed the W207 resonance, confirming their binding to the iNOS peptide-binding site on SPSB2. 19F NMR will be a valuable tool in developing inhibitors that bind to the DINNN binding site.

    13. Design, Synthesis and Biological Evaluation of Peptidyl Epoxyketone Proteasome Inhibitors Composed of β-amino Acids

      Jiankang Zhang, Mengmeng Han, Xiaodong Ma, Lei Xu, Jiayi Cao, Yubo Zhou, Jia Li, Tao Liu and Yongzhou Hu

      Article first published online: 3 JUN 2014 | DOI: 10.1111/cbdd.12342

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      A series of novel di- and tripeptidyl epoxyketone derivatives, as exemplified by compounds 21d and 21e, were designed, synthesized and evaluated as proteasome inhibitors. The experimental results validated that the β-amino acid building block is potential for the development of proteasome inhibitors.

    14. Design, Synthesis, Anti-Tobacco Mosaic Virus (TMV) Activity, and SARs of 7-Methoxycryptopleurine Derivatives

      Ziwen Wang, Anzheng Feng, Mingbo Cui, Yuxiu Liu, Lizhong Wang and Qingmin Wang

      Article first published online: 3 JUN 2014 | DOI: 10.1111/cbdd.12340

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      A series of 7-methoxycryptopleurine derivatives 223 were prepared and first evaluated for their antiviral activity. Most of these compounds exhibited excellent anti-TMV activity, especially for 16, 19, and 23.

    15. Combined 1H-NMR and Molecular Dynamics Studies on Conformational Behavior of a Model Heptapeptide, GRGDSPC

      Ashok K. Kulkarni and Rajendra P. Ojha

      Article first published online: 3 JUN 2014 | DOI: 10.1111/cbdd.12346

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      The conformational flexibility, due to the key roles played by the residues Asp4, Ser5, and Cys7, with two-folded states—between Gly1 and Asp4, and between Asp4 and Cys7—within the heptapeptide sequence of GRGDSPC may provide the structural rationale for antagonistic properties of this heptapeptide toward the treatment of integrin-mediated cellular behaviors such as thrombosis and metastasis.

  10. Research Letters

    1. Aporphinoid Antagonists of 5-HT2A Receptors: Further Evaluation of Ring A Substituents and the Size of Ring C

      Shashikanth Ponnala, Nirav Kapadia, Hernán A. Navarro and Wayne W. Harding

      Article first published online: 3 JUN 2014 | DOI: 10.1111/cbdd.12345

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      C3 halogenation improves 5-HT2A antagonist potency in molecules containing a C1 methoxyl/C2 methoxyl or C1 methoxyl/C2 hydroxyl moiety. Molecular docking studies suggest that this improved antagonist activity is attributable to favorable interactions with the C3 halogen and F339 and/or F340.

  11. Research Articles

    1. Synthesis and Antitubercular Screening of [(2-Chloroquinolin-3-yl)methyl] Thiocarbamide Derivatives

      Suresh Kumar, Neeraj Upmanyu, Obaid Afzal and Sandhya Bawa

      Article first published online: 3 JUN 2014 | DOI: 10.1111/cbdd.12339

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      A series of quinoline thiocarbamide derivatives as structural analogues of ethionamide were synthesized and screened against Mycobacterium tuberculosis (ATCC-25177). Compound having two halogens in the phenyl rings viz. 3g, 3h, 4g, and 4h exhibited MIC of 50 μg/mL.

    2. Structure-Activity Relationships for a Series of Compounds that Inhibit Aggregation of the Alzheimer's Peptide, Aβ42

      Angela F. McKoy, Jermont Chen, Trudi Schupbach and Michael H. Hecht

      Article first published online: 21 MAY 2014 | DOI: 10.1111/cbdd.12341

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      Eleven analogues of a novel inhibitor of Aβ42 aggregation (D737) were tested. Overall, the ability of a compound to inhibit Aβ aggregation was a good predictor of its ability to reduce Aβ-induced cell toxicity and prolong the life span and locomotive ability of the transgenic fly model for Alzheimer's disease.

    3. Multiobjective Optimization on Antiplatelet Effects of Three Components Combination by Quantitative Composition–activity Relationship Modeling and Weighted-Sum Method

      Yi Huang, Wei Jiang, Yang Xiao, Yi Wang and Yi Wang

      Article first published online: 19 MAY 2014 | DOI: 10.1111/cbdd.12338

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      We proposed a multiobjective optimization approach by QCAR modeling coupled with weighted-sum method to search the optimal combination between three components on antiplatelet effect assay in three aggregation agents. The combination set was evaluated and validated to prove the rationality of this approach.


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