Chemical Biology & Drug Design

Cover image for Vol. 87 Issue 2

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

Edited By: David Selwood

Impact Factor: 2.485

ISI Journal Citation Reports © Ranking: 2014: 28/59 (Chemistry Medicinal); 164/290 (Biochemistry & Molecular Biology)

Online ISSN: 1747-0285

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  1. 1 - 52
  1. Research Articles

    1. Synthesis of Novel Pyrimidin-4-One Bearing Piperazine Ring-Based Amides as Glycogen Synthase Kinase-3β Inhibitors with Antidepressant Activity

      Imran Khan, Mushtaq A. Tantray, Hinna Hamid, Mohammad Sarwar Alam, Abul Kalam, Faraz Shaikh, Anamik Shah and Firasat Hussain

      Article first published online: 5 FEB 2016 | DOI: 10.1111/cbdd.12710

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      Novel pyrimidin-4-one derivatives were synthesized and evaluated as GSK-3β inhibitors. Compounds 5, 6f, 6j, 6c, 6b exhibiting significant GSK-3β inhibition were examined for in vivo antidepressant activity. Compound 5 significantly reduced the immobility period. The molecular docking studies were performed to elucidate the binding modes of the compounds with the target. The results of our study suggest that compound 5 may serve as a valuable template for the design and development of GSK-3β inhibitors with antidepressant activity.

    2. Mechanism of Mcl-1 Conformational Regulation Upon Small Molecule Binding Revealed by Molecular Dynamic Simulation

      Anhui Wang, Ting Song, Ziqian Wang, Yubo Liu, Yudan Fan, Yahui Zhang and Zhichao Zhang

      Article first published online: 1 FEB 2016 | DOI: 10.1111/cbdd.12679

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      Molecular dynamics (MD) simulations, together with MM-PB/SA binding free energy analysis, were performed to gain insight into the complex structures of three Mcl-1 inhibitors and their binding energetics. In addition to the excellent agreement with previous experimentally determined affinities, the detailed analysis of MD results shows a bend of helix 4 in Mcl-1 whose biological effects are further identified by ITC experiments. Our study provides a new strategy to improve inhibitory activity on Mcl-1 based on the conformational dynamic change.

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      Systematic Comparisons of Formulations of Linear Oligolysine Peptides with siRNA and Plasmid DNA

      Albert Kwok, David McCarthy, Stephen L. Hart and Aristides D. Tagalakis

      Article first published online: 1 FEB 2016 | DOI: 10.1111/cbdd.12709

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      Linear oligolysine peptides with 16 or more lysines can effectively encapsulate plasmid DNA (pDNA) into monodisperse nanoparticles for gene transfer into the cells. However, the linear oligolysine peptides are not capable of forming monodisperse complexes with siRNA, and hence, they are ineffective in siRNA delivery into cells. Because the linear peptides have limited rotation freedom, they are more suitable for cellular delivery of pDNA which has higher rotation freedom than the more physically rigid siRNA.

    4. Synthesis and Evaluation of Biological and Antitumor Activities of Tetrahydrobenzothieno[2,3-d]Pyrimidine Derivatives as Novel Inhibitors of FGFR1

      Xuebao Wang, Di Chen, Shufang Yu, Zaikui Zhang, Yu Wang, Xiaolu Qi, Weitao Fu, Zixin Xie and Faqing Ye

      Article first published online: 1 FEB 2016 | DOI: 10.1111/cbdd.12687

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      A series of tetrahydrobenzothieno[2,3-d]pyrimidine derivatives were designed, synthesized, and evaluated as inhibitors of FGFR1.

    5. Binding Free Energy Calculations of Nine FDA-approved Protease Inhibitors Against HIV-1 Subtype C I36T[UPWARDS ARROW]T Containing 100 Amino Acids Per Monomer

      Husain A. Lockhat, José R. A. Silva, Cláudio N. Alves, Thavendran Govender, Jerônimo Lameira, Glenn E. M. Maguire, Yasien Sayed and Hendrik G. Kruger

      Article first published online: 29 JAN 2016 | DOI: 10.1111/cbdd.12690

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      This new C-SA PR-mutated strain (I36T[UPWARDS ARROW]T) involves mutations and an insertion to produce 100 amino acids in the PR enzyme. The patient from which this PR was isolated was completely drug naïve with respect to protease inhibitors. We have extended an existing computational model to provide a molecular understanding of the reduced inhibition characteristics of existing HIV PR drugs towards the new I36T[UPWARDS ARROW]T-mutated PR.

    6. Substituent Effects on Cytotoxic Activity, Spectroscopic Property, and DNA Binding Property of Naphthalimide Derivatives

      Ke-Rang Wang, Feng Qian, Qian Sun, Cui-Lan Ma, Rui-Xue Rong, Zhi-Ran Cao, Xiao-Man Wang and Xiao-Liu Li

      Article first published online: 29 JAN 2016 | DOI: 10.1111/cbdd.12698

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      Novel piperazine moieties and piperidine moieties-modified naphthalimide derivatives NI1-5 were synthesized, which showed potent cytotoxic activities against Hela, MCF-7, SGC-7901, and A549 cells, especially for NI3-5 with piperidine moieties functionalization. Compounds NI3-5 exhibited strong fluorescence enhancement on binding with Ct-DNA. Compound NI4 showed very good fluorescence imaging with A549 cells.

    7. Identifying New Drug Targets for Potent Phospholipase D Inhibitors: Combining Sequence Alignment, Molecular Docking, and Enzyme Activity/Binding Assays

      Helene Djakpa, Aditya Kulkarni, Scheneque Barrows-Murphy, Greg Miller, Weihong Zhou, Hyejin Cho, Béla Török and Kimberly Stieglitz

      Article first published online: 29 JAN 2016 | DOI: 10.1111/cbdd.12705

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      Phospholipase D inhibitors based on 1,3-disubstituted-4-amino-pyrazolopyrimidine core structure were utilized to evaluate inhibition of purified S.chromofuscus phospholipase D. Phospholipase D inhibition (IC50) was in the nanomolar range. Sequence searches/alignments with S.chromofuscus phospholipase D identified potential new drug targets. Inhibitors were docked into the selected enzymes and results analyzed to develop next generation inhibitors for several human phosphatases. In vitro assays demonstrated that the predictive protocol was accurate. The strategy of combining sequence comparison, docking, and high through-put screening assays identified new drug targets.

    8. Design, Synthesis of Novel Platinum(II) Glycoconjugates, and Evaluation of Their Antitumor Effects

      Jianbin Han, Xiangqian Gao, Ran Liu, Jinna Yang, Menghua Zhang, Yi Mi, Ying Shi and Qingzhi Gao

      Article first published online: 29 JAN 2016 | DOI: 10.1111/cbdd.12718

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      Highly water-soluble platinum(II) – monosaccharide conjugates were designed and synthesized for GLUT-mediated tumor targeting. Despite their significantly increased water solubility, the conjugates exhibited superior or equal antitumor activity against six different human cancer cell lines compared to oxaliplatin.

    9. Synthesis and Protective Effects of Kaempferol-3′-sulfonate on Hydrogen Peroxide-induced injury in Vascular Smooth Muscle Cells

      Xinbin Yang, Qin Wang, Chunmei Wang, Xiaolin Qin, Yu Huang and Renquan Zeng

      Article first published online: 26 JAN 2016 | DOI: 10.1111/cbdd.12715

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      A novel water-soluble sulfated derivative, kaempferol-3-sulfonate acid sodium (KS), was synthesized and characterized. The protective effects of the KS on human vascular smooth muscle cells injury induced by H2O2 were evaluated. The experimental results indicated that the KS can significantly increase cell viability and reduce apoptosis on H2O2-injured VSMCs, as well as reverse the effects of H2O2 on Bcl-2, Bad, and caspase-3 expressions. Moreover, the KS acted as antioxidant preventing LDH leakage and MDA production, while increasing intracellular SOD and GSH activity in H2O2-injured VSMCs.

    10. Synthesis, Characterization, and Preclinical Evaluation of 99mTc-Labeled Macrobicyclic and Tricyclic Chelators as Single Photon Emission Computed Tomography Tracer

      Neelam Yadav, Krishna Chuttani, Anil K. Mishra and Bachcha Singh

      Article first published online: 26 JAN 2016 | DOI: 10.1111/cbdd.12707

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      The novel tetraaza macrobicyclic chelator 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-2,10-dione (TBPD) and pentaaza-macrotricyclic-chelator 9-oxa-3,6,12,15,21-pentaazatricyclo[15,3,2,1]trieicos-1(21),17,19-triene-2,7,11,16-tetradione (OPTT) have been synthesized, characterized, and preclinically evaluated by in vitro, in vivo serum stability (94.2%–95.2%), in vivo biodistribution, blood kinetics (blood clearance >99% up to 24 h), and tumour scintigraphy after radiolabeling with 99mTc.

    11. Steroidal Ammonium Compounds as New Neuromuscular Blocking Agents

      Zhigang Rao, Hao Hu, Jiazhi Tang, Zhiying Liu, Yue Yang, Guofu Qiu, Yuling Xiao, Peng Liu, Xianming Hu, Xiaoju Zhou and Xuechuan Hong

      Article first published online: 26 JAN 2016 | DOI: 10.1111/cbdd.12711

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      Two compounds exhibited excellent in vitro neuromuscular blocking activities. In vitro IC50: 3g (0.36 μm) and 4g (0.37 μm). A continuous structure–activity relationship (SAR) of 3,16-mono/bis-ammonium steroidal compounds as neuromuscular blocking agents were elucidated based on previous work. Facile thin-layer chromatography (TLC) and column chromatography (CC) method were established for purification of steroidal ammonium compounds.

    12. Preparation and Pharmacological Evaluation of Novel Orally Active Ester Prodrugs of Ketoprofen with Non-Ulcerogenic Property

      Valmik D. Dhakane, Vishnu N. Thakare, Sakharam B. Dongare, Pravin S. Bhale, Yoginath B. Mule, Babasaheb P. Bandgar and Hemant V. Chavan

      Article first published online: 26 JAN 2016 | DOI: 10.1111/cbdd.12719

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      A series of ester prodrugs of ketoprofen were synthesized and evaluated as novel anti-inflammatory agents. Prodrugs 3a, 3f, and 3k were found to possess significant anti-inflammatory activity with almost non-ulcerogenic potential than ketoprofen (1).

    13. Design, Synthesis, and Potential Antidepressant-like Activity of 7-prenyloxy-2,3-dihydroflavanone Derivatives

      Xing-Hua Zhen, Ying-Chun Quan, Zhou Peng, Yan Han, Zhou-Jun Zheng and Li-Ping Guan

      Article first published online: 26 JAN 2016 | DOI: 10.1111/cbdd.12717

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      A series of 7-prenyloxy-2,3- dihydroflavanone derivatives were synthesized and screened for their antidepressant-like activity. Compounds 5j and 5k were found to be the most antidepressant activity. The results suggested that compounds 5j and 5k possessed potent antidepressant-like properties that were mediated via neurochemical systems.

    14. Knockdown of GPR137,G Protein-coupled receptor 137, Inhibits the Proliferation and Migration of Human Prostate Cancer Cells

      Jizhong Ren, Xiuwu Pan, Lin Li, Yi Huang, Hai Huang, Yi Gao, Hong Xu, Fajun Qu, Lu Chen, Linhui Wang, Yi Hong, Xingang Cui and Danfeng Xu

      Article first published online: 17 JAN 2016 | DOI: 10.1111/cbdd.12704

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      GPR137 belongs to the G protein-coupled receptor family involving regulation of important cellular functions. Silencing of GPR137 gene suppressed the proliferation and colony formation of prostate cancer cell lines PC-3 and DU145 via G0/G1 cell cycle arrest. Furthermore, silencing of GPR137 repressed cell migration ability of PC-3 and DU145 by downregulating snail1 and slug and up-regulating E-cadherin. So GPR137 plays an important role in the occurrence and progression of prostate cancer and acts as a potential therapeutic target for advanced PCa.

  2. Reviews

    1. A Note on Derivatives of Isoniazid, Rifampicin, and Pyrazinamide Showing Activity Against Resistant Mycobacterium tuberculosis

      Ameeruddin Nusrath Unissa, Luke Elizabeth Hanna and Soumya Swaminathan

      Article first published online: 17 JAN 2016 | DOI: 10.1111/cbdd.12684

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      One of the possible strategies to overcome the threatening drug resistance problem in an economic manner would be the modification of existing anti-tuberculosis (TB) drugs to obtain derivatives demonstrating activity against resistant TB bacilli. These may have improved half-life and increased bioavailability, more efficacious, and serve as a cost effective alternative than the design and development of a new drug. This article focuses on derivatives of first-line anti-TB agents [Isoniazid (INH), Rifampicin (RIF) and Pyrazinamide (PZA)] showing activity against resistant TB bacilli.

  3. Research Articles

    1. Rapid Identification of Novel Inhibitors of the Human Aquaporin-1 Water Channel

      Rajkumar V. Patil, Shouxi Xu, Alfred N. van Hoek, Andrew Rusinko, Zixia Feng, Jesse May, Mark Hellberg, Najam A. Sharif, Martin B. Wax, Macarena Irigoyen, Grant Carr, Tom Brittain, Peter Brown, Damon Colbert, Sindhu Kumari, Kulandaiappan Varadaraj and Alok K. Mitra

      Article first published online: 17 JAN 2016 | DOI: 10.1111/cbdd.12713

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      Aquaporin (AQP) channels play critical roles in several normal physiological and pathological states involving rapid water transport and are therefore drug targets. A high-throughput cell-based screening on >6000 small molecular weight compounds identified several AQP1 blockers. Compared to canonical mercurial compounds, water transport assay in vesicles (Figure) identified two groups of most active novel AQP1 inhibitors, for example, a sulfonamide (compound 2), which constitute attractive leads for developing small-molecule functional modulators for human AQP1.

    2. Synthesis of Novel Substituted Thiourea and Benzimidazole Derivatives Containing a Pyrazolone Ring as Anti-Inflammatory Agents

      Ashraf A. Moneer, Khaled O. Mohammed and Hala B. El-Nassan

      Article first published online: 17 JAN 2016 | DOI: 10.1111/cbdd.12712

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      Compounds 2c and 3b showed potent anti-inflammatory activity comparable to that of diclofenac. Both compounds act by non-selective inhibition of COX-1 and COX-2.

  4. Reviews

    1. Is miR-34a a Well-equipped Swordsman to Conquer Temple of Molecular Oncology?

      Ammad Ahmad Farooqi, Sundas Fayyaz, Iryna Shatynska-Mytsyk, Zeeshan Javed, Saima Jabeen, Ilhan Yaylim, Maria Luisa Gasparri and Pierluigi Benedetti Panici

      Article first published online: 13 JAN 2016 | DOI: 10.1111/cbdd.12634

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      MRX34, a liposome-formulated mimic of miR-34 for the treatment of metastatic cancer with liver involvement and unresectable primary liver cancer, has entered in clinical trial. There is a successive increase in the research work related to miR-34 biology and miRNA regulation of modulators of intracellular signaling cascades. Clinical trial of miR-34 is indicative of its tremendous potential, and continuous cutting research will prove to be effective in efficiently translating laboratory findings into clinically effective therapeutics.

  5. Research Articles

    1. A New, High Yield, Rapid, and Cost-Effective Protocol to Deprotection of Cysteine-Rich Conopeptide, Omega-Conotoxin MVIIA

      Seyed Sahand Eisapoor, Shahla Jamili, Delavar Shahbazzadeh, Pargol Ghavam Mostafavi and Kamran Pooshang Bagheri

      Article first published online: 13 JAN 2016 | DOI: 10.1111/cbdd.12702

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      Among conopeptides, omega-conotoxin MVIIA, selected as a cysteine-rich peptide model. Protection of cysteine residue from oxidation is critical during solid phase synthesis for its antipain activity. Deprotection of protecting groups from cysteines is a crucial step. Current protocol was performed based on the best ratio of peptide/mercury/2-ME that adjusted to 50 μg/1 mg/10 μL. The results showed 93% yield and 95% purity for omega-conotoxin MVIIA. This protocol would be suggested to deprotection of cysteine-rich conopeptides in laboratory and industrial scales.

    2. Evaluation of Natural and Synthetic 1,4-naphthoquinones as Inhibitors of Monoamine Oxidase

      Samantha Mostert, Anél Petzer and Jacobus P. Petzer

      Article first published online: 12 JAN 2016 | DOI: 10.1111/cbdd.12708

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      The current study expands on the structure–activity relationships (SARs) of MAO inhibition by the 1,4-naphthoquinone class of compounds. Noteworthy inhibitors included juglone, plumbagin, 5,8-dihydroxy-1,4-naphthoquinone and shikonin. Interestingly, most 2-hydroxy-containing compounds evaluated do not inhibit the MAOs.

    3. Design, Synthesis, and Biological Evaluation of Pyrazole Derivatives

      Chunqi Hu, Yali Gao and Wenting Du

      Article first published online: 11 JAN 2016 | DOI: 10.1111/cbdd.12699

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      A series of novel pyrazole derivatives were designed, synthesized, and evaluated for their p53-MDM2 binding inhibitory activities and antiproliferation activities in vitro against five humor cancer cell lines (PC3, A549, HL60, HCT116, and SW620). Although these compounds exhibited weak p53-MDM2 inhibitory activities (29.22 ~ NA μm), most of them displayed a moderate to potent anti-proliferative activities against the tested cells lines. One of them even showed an enhanced antiproliferative activity than Nutlin-1 to p53 mutated or p53 deficient cell lines (SW620, HL60, and PC3).

    4. Discovery of 1,3-Diaryl-pyridones as Potent VEGFR-2 Inhibitors: Design, Synthesis, and Biological Evaluation

      Wei Yan, Zhaoru Huang, Zhengyu Wang, Sufen Cao, Linjiang Tong, Tao Zhang, Chen Wang, Lin Zhou, Jian Ding, Cheng Luo, Jinpei Zhou, Hua Xie and Wenhu Duan

      Article first published online: 11 JAN 2016 | DOI: 10.1111/cbdd.12703

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      Synthesis and biological evaluation of a novel series of 1,3-diaryl-pyridone derivatives as VEGFR-2 inhibitors were described. Two representative compounds, 17 and 35h, exhibited excellent in vitro antiangiogenic activities. Docking simulation showed that compound 17 bound well into the active site of VEGFR-2 with two hydrogen bonds and hydrophobic interactions.

    5. Molecular Modeling on Berberine Derivatives toward BuChE: An Integrated Study with Quantitative Structure–Activity Relationships Models, Molecular Docking, and Molecular Dynamics Simulations

      Jiansong Fang, Xiaocong Pang, Ping Wu, Rong Yan, Li Gao, Chao Li, Wenwen Lian, Qi Wang, Ai-lin Liu and Guan-hua Du

      Article first published online: 11 JAN 2016 | DOI: 10.1111/cbdd.12700

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      The inhibitory activities of 17 berberine derivatives toward BuChE were evaluated. 67 berberine derivatives were studied by quantitative structure–activity relationships models with multilinear regression, partial least-square, and support vector regression methods. Molecular dynamics simulation and binding free energy calculation were performed to elucidate the inhibitory mechanism of three typical berberine derivatives (berberine, C2, and C55) toward BuChE. 2D- quantitative structure–activity relationships results were in good accordance with the molecular dynamics results.

    6. Synthesis, Antifolate and Anticancer Activities of N5-Substituted 8,10-Dideazatetrahydrofolate Analogues

      Chao Tian, Zhili Zhang, Shouxin Zhou, Mengmeng Yuan, Xiaowei Wang and Junyi Liu

      Article first published online: 29 DEC 2015 | DOI: 10.1111/cbdd.12681

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      Seven N5-substituted 8,10-dideazatetrahydrofolate analogues and one 8-deazatetrahydrofolate analogue were synthesized as DHFR inhibitors. The biological assay indicated that replacing N10 with carbon would significantly increase inhibitory activities against DHFR and cytotoxicities against cancer cell lines. Compound 19a with 4-amino and N5-formyl showed great antitumor activities against HL-60, Bel-7402 and BGC823 which were much better than MTX.

  6. Reviews

    1. Betulinic Acid: Recent Advances in Chemical Modifications, Effective Delivery, and Molecular Mechanisms of a Promising Anticancer Therapy

      Mohamed Ali-Seyed, Ibrahim Jantan, Kavitha Vijayaraghavan and Syed Nasir Abbas Bukhari

      Article first published online: 29 DEC 2015 | DOI: 10.1111/cbdd.12682

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      Betulinic acid (BetA) is a naturally occurring pentacyclic triterpene with a wide variety of biological activities and proven as promising agent for cancer therapy and have shown selectivity for cancer cells and a remarkable lack of toxicity for human cells. It targets mitochondria, may be particularly useful in therapy-resistant cancer cells and refractory tumors.

  7. Research Articles

    1. Synthesis of New Congeners of 1-methyl-3-aminoisoquinolines, Evaluation of Their Cytotoxic Activity, In Silico and In Vitro Study of Their Molecular Targets as PDE4B

      Gennady B. Lapa, Toshiyuki Tsunoda, Senji Shirasawa, Maria A. Baryshnikova, Gregory G. Evseev, Daria A. Afanasyeva and Elena A. Chigorina

      Article first published online: 29 DEC 2015 | DOI: 10.1111/cbdd.12691

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      It was found by the phenotypic screening that congeners of 3-amino-isoquinoline possessed cytotoxic activity in the HCT116, HKe3, K562 cell lines. Primary hit (N-(6,7-dimethoxy-1-methylisoquinolin-3-yl)-4-{[(1-ethyl-4-methyl-1H-pyrazol-3-yl)methyl]amino}benzamide (4d)) from small combinatorial library had IC50 18 μm for HCT116 and GI50 1.9 μm for T-47D cell line. Compounds 4c and 4d decreased the area of HKe3-mtKRAS spheroids in the 3D floating (3DF) culture at 50 μm; thus, 4c and 4d selectively inhibited the growth of spheroids dependent on the mtKRAS in the 3DF culture and targeted PDE4B in HKe3-mt-KRAS spheroids.

  8. Research Letters

    1. Novel Quinazoline Derivatives Bearing Various 4-Aniline Moieties as Potent EGFR Inhibitors with Enhanced Activity Against NSCLC Cell Lines

      Changyan Wang, Yajun Sun, Xingqi Zhu, Bin Wu, Qiao Wang, Yuhong Zhen, Xiaohong Shu, Kexin Liu, Youwen Zhou and Xiaodong Ma

      Article first published online: 29 DEC 2015 | DOI: 10.1111/cbdd.12692

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      A class of quinazoline derivatives bearing various C-4 aniline moieties was identified as potent as gefitinib in inhibiting the NSCLC cell lines, and several of them even displayed improved activity against the gefitinib-resistant cells.

  9. Research Articles

    1. Synthesis, in Vitro, and in Vivo Biological Evaluation and Molecular Docking Analysis of Novel 3-(3-oxo-substitutedphenyl-3-)4-(2-(piperidinyl)ethoxy)phenyl)propyl)-2H-chromen-2-one Derivatives as Anti-breast Cancer Agents

      Pritam N. Dube, Madhuri N. Waghmare and Santosh N. Mokale

      Article first published online: 29 DEC 2015 | DOI: 10.1111/cbdd.12696

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      Substituted coumarin–chalcones derivatives were synthesized and evaluated for anti-breast cancer activity using MCF-7 and Zr-75-1 cell lines. In vivo study was performed by MNU-induced mammary carcinoma in virgin female Sprague Dawley rats. Molecular docking was performed to predict their binding orientation to estrogen receptor-alpha.

    2. Chemical RNA Editing for Genetic Restoration: The Relationship between the Structure and Deamination Efficiency of Carboxyvinyldeoxyuridine Oligodeoxynucleotides

      Luyen Thi Vu, Thanh Thi Kim Nguyen, Azad Anam Md Thoufic, Hitoshi Suzuki and Toshifumi Tsukahara

      Article first published online: 29 DEC 2015 | DOI: 10.1111/cbdd.12693

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      To optimize the CVU-containing-ODN structures, we investigated the dependence of the deamination efficiency on the effector CVU-containing ODN's complementary sequence length and hairpin loop length. We found that the deamination efficiency reached its maximum values with a complementary sequence length slightly more than 14 nt and hairpin loop length of 9 nt.

    3. Synthesis of 4-[2-(3,4-dimethoxybenzyl)cyclopentyl]-1,2-dimethoxybenzene Derivatives and Evaluations of Their Carbonic Anhydrase Isoenzymes Inhibitory Effects

      Tekin Artunç, Yasin Çetinkaya, Hülya Göçer, İlhami Gülçin, Abdullah Menzek, Ertan Şahin and Claudiu T. Supuran

      Article first published online: 29 DEC 2015 | DOI: 10.1111/cbdd.12695

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      Eleven new and three known compounds were obtained from 1,6-bis(3,4-dimethoxyphenyl)hexane-1,6-dione. The inhibition of these compounds was investigated against hCA I and II with Ki values in the range of 52.98–1927.31 nm.

    4. A New, Improved Hybrid Scoring Function for Molecular Docking and Scoring Based on AutoDock and AutoDock Vina

      Vsevolod Yu Tanchuk, Volodymyr O. Tanin, Andriy I. Vovk and Gennady Poda

      Article first published online: 29 DEC 2015 | DOI: 10.1111/cbdd.12697

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      A new scoring function was built on a training set of 2412 protein–ligand complexes from the pdbbind database. A test set of 313 complexes that appeared in the 2013 version of the database was used for validation purposes. The new hybrid scoring function performed better than the original functions and gave one of the best results among more than 20 scoring functions tested on the core set of the pdbbind database.

    5. 68Ga-labeled Ciprofloxacin Conjugates as Radiotracers for Targeting Bacterial Infection

      Drishty Satpati, Chanda Arjun, Repaka Krishnamohan, Grace Samuel and Sharmila Banerjee

      Article first published online: 29 DEC 2015 | DOI: 10.1111/cbdd.12701

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      In this study, two ciprofloxacin analogues have been synthesized, linked with propylamine spacer to bifunctional chelating agents, DOTA and NOTA, and radiolabeled with 68Ga. The two radiotracers were tested in vitro in Staphylococcus aureus cells and in vivo in rats induced with infection and inflammation. The radiotracers showed T/NT ratios higher than unity which improved with time and indicated the possible potential for further investigation as infection-specific agents.

    6. Design, Synthesis, and Biological Evaluation of 1-Benzyl-1H-pyrazole Derivatives as Receptor Interacting Protein 1 Kinase Inhibitors

      Chan Zou, Yu Xiong, Lu-Yi Huang, Chun-Li Song, Xiao-Ai Wu, Lin-Li Li and Sheng-Yong Yang

      Article first published online: 19 DEC 2015 | DOI: 10.1111/cbdd.12689

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      Herein, we report the structural optimization of a RIP1 kinase inhibitor, 1-(2,4-dichlorobenzyl)-3-nitro-1H-pyrazole (1a). A number of 1-benzyl-1H-pyrazole derivatives were synthesized and structure-activity relationship (SAR) analysis led to the discovery of a potent compound, 4b, which showed a Kd value of 0.078 μm against the RIP1 kinase and an EC50 value of 0.160 μm in a cell necroptosis inhibitory assay. Compound 4b also displayed considerable ability to protect the pancreas in an l-arginine-induced pancreatitis mouse model.

    7. QSAR Models Guided by Molecular Dynamics Applied to Human Glucokinase Activators

      Tamiris Maria de Assis, Giovanna Cardoso Gajo, Letícia Cristina de Assis, Letícia Santos Garcia, Daniela Rodrigues Silva, Teodorico Castro Ramalho and Elaine Fontes Ferreira da Cunha

      Article first published online: 16 DEC 2015 | DOI: 10.1111/cbdd.12683

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      4D-QSAR studies were performed on a set of 54 glucokinase protein activators. The models were generated by the technique that combines genetic algorithms optimization and partial least squares regression. The 4D-QSAR models developed in this study suggest novel molecular regions to be explored in the search for better glucokinase activators.

    8. Development of 2-(Substituted Benzylamino)-4-Methyl-1, 3-Thiazole-5-Carboxylic Acid Derivatives as Xanthine Oxidase Inhibitors and Free Radical Scavengers

      Md Rahmat Ali, Suresh Kumar, Obaid Afzal, Nishtha Shalmali, Manju Sharma and Sandhya Bawa

      Article first published online: 16 DEC 2015 | DOI: 10.1111/cbdd.12686

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      A series of 2-(substituted benzylamino)-4-methylthiazole-5-carboxylic acid derivatives as structural analogues of febuxostat was synthesized and screened in vitro for their ability to inhibit the enzyme xanthine oxidase along with DPPH free radical scavenging assay. Compound 5k having methyl group at ortho in the phenyl rings exhibited potent xanthine oxidase inhibitory activity along with antioxidant activity with IC50 3.6 and 15.3 μm, respectively.

  10. Research Letters

    1. Synthesis of New ‘Hybrid’ Compounds Based on Benzofuroxans and Aminoalkylnaphthalimides

      Elena Chugunova, Rezeda Mukhamatdinova, Marina Sazykina, Alexey Dobrynin, Ivan Sazykin, Alexander Karpenko, Elena Mirina, Maria Zhuravleva, Nikolai Gavrilov, Shorena Karchava and Alexander Burilov

      Article first published online: 14 DEC 2015 | DOI: 10.1111/cbdd.12685

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      Pathogenic bacteria and fungi eventually develop resistance to existing drugs, and therefore, we need constant development of new drugs. The research is aimed at addressing fundamental scientific problems—the search for new biologically active compounds among several benzofuroxan-containing ‘hybrid’ products. N-substituted naphthalimides were chosen as a second pharmacophore. Biological effects were studied by means of bacterial lux-biosensors. Products displayed more expressed bacteriotoxic action in comparison with the initial substances and represent a certain interest for using as antibacterial substances.

  11. Research Articles

    1. In Vitro Evaluation of the Allergic Potential of Antibacterial Peptides: Camel and Citropin

      Michał Pikuła, Maciej Zieliński, Krzysztof Specjalski, Wioletta Barańska-Rybak, Małgorzata Dawgul, Paulina Langa, Ewa Jassem, Wojciech Kamysz and Piotr Trzonkowski

      Article first published online: 14 DEC 2015 | DOI: 10.1111/cbdd.12688

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      Peptide-based drugs are promising group of compounds; however, they involve a relatively high risk of allergic reactions that are not predictable on the basis of their sequence and chemical properties. Our study proved that basophil activation test (BAT) together with other biological tests and specific databases of allergenic compounds may serve as an initial selection of new active peptides. Our work indicates that in the screening and assessment of allergic potential of new drugs especially hypersensitive patients must be taken into consideration.

  12. Research Letters

    1. Synthesis and Evaluation of 2-Alkylthio-4-(N-substituted sulfonamide)pyrimidine Hydroxamic Acids as Anti-myeloma Agents

      Jinbao Xiang, Crystal Leung, Zhuoqi Zhang, Cassie Hu, Chao Geng, Lili Liu, Lang Yi, Zhiwei Li, James Berenson and Xu Bai

      Article first published online: 10 DEC 2015 | DOI: 10.1111/cbdd.12678

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      A series of pyrimidine hydroxamic acids with a sulfide substituent at the 2-position and a sulfonamide substituent at the 4-position have been synthesized and evaluated for their activity against human myeloma cell line RPMI 8226. It was found that representative compound 6a selectively killed cancerous but not normal cells. Moreover, compound 6a was effective in causing apoptosis in RPMI 8226 cells and exhibited promising HDAC-inhibitory activities.

  13. Research Articles

    1. Iminothiazoline-Sulfonamide Hybrids as Jack Bean Urease Inhibitors; Synthesis, Kinetic Mechanism and Computational Molecular Modeling

      Aamer Saeed, Shams-ul Mahmood, Muhammad Rafiq, Zaman Ashraf, Farukh Jabeen and Sung-Yum Seo

      Article first published online: 26 NOV 2015 | DOI: 10.1111/cbdd.12675

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      2-iminothiazoline-sulfonamide hybrids (3aj) were synthesized by the heterocyclization of sulfanilamide thioureas with propragyl bromide. The compounds (3h) and (3i) exhibited excellent activity with IC50 0.064 and 0.058 µm respectively while IC50 of thiourea is 20.9 µm. Docking score (−10.6466 to −8.7215 Kcal/mol) and binding energy (London dG ranging from −14.4825 to −10.4087 Kcal/mol) are good.

  14. Research Letters

    1. Sirtuins are Unaffected by PARP Inhibitors Containing Planar Nicotinamide Bioisosteres

      Torun Ekblad and Herwig Schüler

      Article first published online: 26 NOV 2015 | DOI: 10.1111/cbdd.12680

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      We show that the activities of the four human sirtuin isoforms SIRT1, SIRT2, SIRT3 and SIRT6 are unaffected by the clinical PARP inhibitors, niraparib, olaparib, rucaparib, talazoparib, and veliparib, and the widely used research tools, PJ34 and XAV939.

  15. Research Articles

    1. Design, Synthesis, and Antimycobacterial Activity of Novel Theophylline-7-Acetic Acid Derivatives With Amino Acid Moieties

      Georgi Stavrakov, Violeta Valcheva, Yulian Voynikov, Irena Philipova, Mariyana Atanasova, Spiro Konstantinov, Plamen Peikov and Irini Doytchinova

      Article first published online: 23 NOV 2015 | DOI: 10.1111/cbdd.12676

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      A model for antitubercular activity prediction was developed and applied to a combinatorial library of 40 theophylline-7-acetic acid derivatives. The best predicted compounds were synthesized and tested against Mycobacterium tuberculosis H37Rv. All of them showed antimycobacterial activity in the nanomolar range and were 60 times more active than ethambutol.

    2. Ternary Dinuclear Copper(II) Complexes of a Reduced Schiff Base Ligand with Diimine Coligands: DNA Binding, Cytotoxic Cell Apoptosis, and Apoptotic Mechanism

      Hao Yu, Yong Yang, Qiaoyu Li, Tieliang Ma, Jun Xu, Taofeng Zhu, Jing Xie, Wenjiao Zhu, Zhihong Cao, Kun Dong, Jiancui Huang and Lei Jia

      Article first published online: 20 NOV 2015 | DOI: 10.1111/cbdd.12669

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      A serial of mixed ligand Cu(II) complexes have been isolated and characterized. The interaction of the complexes with calf thymus DNA has been explored by using physical methods to propose modes of DNA binding of the complexes, which indicate that 4 interacts with DNA more strongly than all of the other complexes through intercalation interaction.

    3. Effects of N-Methylated Amyloid-β30–40 Peptides on the Fibrillation of Amyloid-β1–40

      Hirotsugu Hiramatsu, Hironori Ochiai and Tomoyuki Komuro

      Article first published online: 20 NOV 2015 | DOI: 10.1111/cbdd.12674

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      Inhibitory effect of N-Me Aβ30–40 peptides on Aβ1–40 fibrillation was dependent on the concentration of N-Me peptide and the number and position of N-Me groups. Monomer–dimer equilibrium of N-Me peptides was (partly) responsible for the observed dependence. Monomeric N-Me peptides decreased ThT fluorescence count during Aβ1–40 fibrillation by co-aggregating and disrupting the regular β-sheet structure of Aβ1–40 fibrils.

  16. Research Letters

    1. Synthesis of Naphthyl-, Quinolin- and Anthracenyl Analogues of Clofibric Acid as PPARα Agonists

      Letizia Giampietro, Alessandra Ammazzalorso, Isabella Bruno, Simone Carradori, Barbara De Filippis, Marialuigia Fantacuzzi, Antonella Giancristofaro, Cristina Maccallini and Rosa Amoroso

      Article first published online: 20 NOV 2015 | DOI: 10.1111/cbdd.12677

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      New analogues of clofibric acid analogues conjugated with naphthyl, quinolin, chloroquinolin and anthracenyl scaffolds were synthesized and evaluated for PPARα transactivation activity. Naphthyl and quinolin derivatives showed a good activation of PPARα.

  17. Research Articles

    1. Novel Peptides from Skins of Amphibians Showed Broad-Spectrum Antimicrobial Activities

      Ying Wang, Yue Zhang, Wen-Hui Lee, Xinwang Yang and Yun Zhang

      Article first published online: 13 NOV 2015 | DOI: 10.1111/cbdd.12672

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      12 novel peptides with broad-spectrum antimicrobial activities were identified from the skin of three frogs. A novel antimicrobial peptide family, named as Limnochariin, were characterized for the first time. Amphibian skin peptides provide novel templates for developing new drugs that can overcome the rising resistance of pathogenic microorganisms to classic antibiotic treatments.

    2. Synthesis, In vitro and Docking Studies of New Flavone Ethers as α-Glucosidase Inhibitors

      Syahrul Imran, Muhammad Taha, Nor Hadiani Ismail, Syed Muhammad Kashif, Fazal Rahim, Waqas Jamil, Habibah Wahab and Khalid Mohammed Khan

      Article first published online: 13 NOV 2015 | DOI: 10.1111/cbdd.12666

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      Synthesis and α-glucosidase inhibition activity of new flavone ether derivatives (315).

    3. Geniposide Attenuates the Phosphorylation of Tau Protein in Cellular and Insulin-deficient APP/PS1 Transgenic Mouse Model of Alzheimer's Disease

      Yonglan Zhang, Fei Yin, Jianhui Liu and Zixuan Liu

      Article first published online: 12 NOV 2015 | DOI: 10.1111/cbdd.12673

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      Geniposide attenuates the phosphorylation of tau protein by potentiating the insulin signaling in cellular and APP/PS1 transgenic mouse model of Alzheimer's disease.

    4. Hemisynthesis, Antitumoral Effect, and Molecular Docking Studies of Ferutinin and Its Analogues

      Rémi Safi, Fréderic Rodriguez, Georges Hilal, Mona Diab-Assaf, Youssef Diab, Marwan El-Sabban, Fadia Najjar and Evelyne Delfourne

      Article first published online: 5 NOV 2015 | DOI: 10.1111/cbdd.12670

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      A series of novel ferutinin derivatives were synthesized, biologically evaluated and tested for their in silico targets, the estrogen receptors α and β. Two compounds exhibited improved cytotoxic activities on the proliferation of estrogen-dependent and -independent breast cancer cell lines, as compared to the parent compound. Molecular docking studies and functional assay on ferutinin and its potent analogue showed that the cytotoxic effect in estrogen-dependent cells may be correlated to the antagonist potential of the new compound towards ERα protein.

    5. Bioinformatics Prediction and In Vitro Analysis Revealed That miR-17 Targets Cyclin D1 mRNA in Triple Negative Breast Cancer Cells

      Fariba Karami, Samira Mohammadi-Yeganeh, Nairi Abedi, Ameneh Koochaki, Vahid Kia and Mahdi Paryan

      Article first published online: 2 NOV 2015 | DOI: 10.1111/cbdd.12671

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      miR-17 targets cyclin D1 which is involved in metastatic breast cancer. So, miR-17 is an attractive molecule that after intensive research can probably be used as a biomarker in triple negative breast cancer.

    6. Design, Synthesis, and Biological Evaluation of Novel Cholesteryl Peptides with Anticancer and Multidrug Resistance-Reversing Activities

      Xin Deng, Qianqian Qiu, Xuekun Wang, Wenlong Huang and Hai Qian

      Article first published online: 19 OCT 2015 | DOI: 10.1111/cbdd.12667

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      We designed and synthesized a series of cholesteryl peptides, biological evaluation revealed that these peptides showed improved anti-cancer activity and retained the selectivity to cancer cell lines. In addition, the peptides also presented multidrug resistance-reversing effect on multidrug-resistant cells.

    7. Practical Synthesis, Antidepressant, and Anticonvulsant Activity of 3-Phenyliminoindolin-2-one Derivatives

      Jian-Yin Ma, Ying-Chun Quan, Hong-Guo Jin, Xing-Hua Zhen, Xue-Wu Zhang and Li-Ping Guan

      Article first published online: 19 OCT 2015 | DOI: 10.1111/cbdd.12668

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      A series of 3-phenyliminoindolin-2-one derivatives were synthesized and evaluated for their antidepressant and anticonvulsant activity. Compound 3r was found be to the most antidepressant-like activity. The probable mechanism of action of compound 3r is thought to be related to the increase in 5-HT and NE in the CNS. Fifteen compounds possessed anticonvulsant activity against PTZ-induced seizure.

    8. Novel Inhibitors of Ornithine Decarboxylase of Leishmania Parasite (LdODC): The Parasite Resists LdODC Inhibition by Overexpression of Spermidine Synthase

      Mousumi Das, Shalini Singh and Vikash Kumar Dubey

      Article first published online: 13 OCT 2015 | DOI: 10.1111/cbdd.12665

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      Novel inhibitors of ornithine decarboxylase of Leishmania donovani are identified. Effect of inhibitors on the parasite survival was studied. Leishmania resists these LdODC inhibitors by over-expression of spermidine synthase.

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