Chemical Biology & Drug Design

Cover image for Vol. 88 Issue 6

December 2016

Volume 88, Issue 6

Pages 779–944

  1. Issue Information

    1. Top of page
    2. Issue Information
    3. Editor's Choice
    4. Research Articles
    5. Research Letter
    1. Issue Information (pages 779–782)

      Version of Record online: 4 NOV 2016 | DOI: 10.1111/cbdd.12649

  2. Editor's Choice

    1. Top of page
    2. Issue Information
    3. Editor's Choice
    4. Research Articles
    5. Research Letter
    1. A small molecule identified through an in silico screen inhibits Aurora B–INCENP interaction (pages 783–794)

      Esra Unsal, Bahar Degirmenci, Büşra Harmanda, Burak Erman and Nurhan Ozlu

      Version of Record online: 20 AUG 2016 | DOI: 10.1111/cbdd.12816

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      A structure-based virtual screen was performed to target the interaction between Aurora B kinase and its activator INCENP. In silico molecular docking analysis identified five potential candidates of 200 000 compounds, which selectively bind to the Aurora B::INCENP interaction site but not to the ATP-binding site (kinase pocket) of Aurora B and other fourteen related kinases. Further characterization in vivo validated the inhibitory role of one of these five compounds in Aurora B:INCENP complex formation.

  3. Research Articles

    1. Top of page
    2. Issue Information
    3. Editor's Choice
    4. Research Articles
    5. Research Letter
    1. Synthesis and anti-Candida activity of novel benzothiepino[3,2-c]pyridine derivatives (pages 795–806)

      Nina Božinović, Sandra Šegan, Sandra Vojnovic, Aleksandar Pavic, Bogdan A. Šolaja, Jasmina Nikodinovic-Runic and Igor M. Opsenica

      Version of Record online: 11 JUL 2016 | DOI: 10.1111/cbdd.12809

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      A novel series of thiepine derivatives were synthesized and evaluated as potential antimicrobials. Synthesized compounds showed higher antifungal activity than antibacterial activity, indicating that they could be used as selective antimicrobials. Thiepine 8-phenyl[1]benzothiepino[3,2-c]pyridine efficiently killed Candida albicans at 15.6 µg/mL and showed no embryotoxicity at 75 µg/mL. Results obtained from in vivo embryotoxicity on zebrafish (Danio rerio) encourage further structure optimizations.

    2. Identification of the first in silico-designed TREK1 antagonists that block channel currents dose dependently (pages 807–819)

      Ambily Nath Indu Viswanath, Seo Yun Jung, Eun Mi Hwang, Ki Duk Park, Sang Min Lim, Sun-Joon Min, Yong Seo Cho and Ae Nim Pae

      Version of Record online: 27 JUL 2016 | DOI: 10.1111/cbdd.12810

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      This study aimed to find novel chemotypes by pharmacophore and structure-based virtual screening forTREK1 channel blockers. Electrophysiological assay confirmed the TREK1 modulating activities of 11 virtual hit compounds, among these, NC30, significantly reduced the channel current with an IC50 of 4.7 μM.

    3. Design, synthesis, biological evaluation, NMR and DFT studies of structurally simplified trimethoxy benzamides as selective P-glycoprotein inhibitors: the role of molecular flatness (pages 820–831)

      Angela Stefanachi, Giuseppe Felice Mangiatordi, Piero Tardia, Domenico Alberga, Francesco Leonetti, Mauro Niso, Nicola Antonio Colabufo, Carlo Adamo, Orazio Nicolotti and Saverio Cellamare

      Version of Record online: 26 JUL 2016 | DOI: 10.1111/cbdd.12811

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      We designed new structurally simplified trimethoxy benzamides to detect the minimal molecular requirements for P-gp modulation. The proposed ligands were provided with a high efficiency and IC50 values in the low micromolar range. By employing DFT and NMR approaches, we found a clear rationale bridging molecular flatness and P-gp modulation.

    4. Synthesis, biological evaluation, and molecular docking studies of new pyrazol-3-one derivatives with aromatase inhibition activities (pages 832–843)

      Xue-Jing Yi, Tamer T. El-Idreesy, Taha M. A. Eldebss, Ahmad M. Farag, Mohamed M. Abdulla, Shaimaa A. Hassan and Yahia N. Mabkhot

      Version of Record online: 27 AUG 2016 | DOI: 10.1111/cbdd.12812

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      A new series of pyrazol-3-one derivatives was synthesized, characterized and its pharmacological activity towards aromatase enzyme inhibition was screened and compared to the reference native ligand Letrozole. The findings were also supported by molecular docking studies.

    5. Biohydroxylation of 7-oxo-DHEA, a natural metabolite of DHEA, resulting in formation of new metabolites of potential pharmaceutical interest (pages 844–849)

      Alina Świzdor, Anna Panek and Natalia Milecka-Tronina

      Version of Record online: 29 JUL 2016 | DOI: 10.1111/cbdd.12813

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      New oxygenated metabolites of biologically active 7-oxo-DHEA were formed by fungal stereoselective hydroxylations by Syncephalastrum racemosum. The studies demonstrated that the obtained derivatives may be simultaneously the final metabolites of DHEA. The observed reactions suggested that this micro-organism contains enzymes exhibiting similar activity to those present in human cells. The resulting compounds can be considered as potential components of the eukaryotic, including human, metabolome.

    6. Docetaxel–Chitosan nanoparticles for breast cancer treatment: cell viability and gene expression study (pages 850–858)

      Zahra H. Mirzaie, Shiva Irani, Reza Mirfakhraie, Seyed Mohammad Atyabi, Meshkat Dinarvand, Rassoul Dinarvand, Reyhaneh Varshochian and Fatemeh Atyabi

      Version of Record online: 17 AUG 2016 | DOI: 10.1111/cbdd.12814

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      Less toxic effect of DTX-conjugated nanoparticles on normal cells was observed in comparison with cancerous cells. The ratio of BAX/BCL2 was optimized to conduct the fate of cell toward apoptosis. Suitable uptake of DTX-conjugated nanoparticles to the cell was also observed.

    7. Predicting subtype selectivity of dopamine receptor ligands with three-dimensional biologically relevant spectrum (pages 859–872)

      Zheng-Kun Kuang, Shi-Yu Feng, Ben Hu, Dong Wang, Song-Bing He and De-Xin Kong

      Version of Record online: 29 JUL 2016 | DOI: 10.1111/cbdd.12815

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      We applied a novel molecular descriptor, three-dimensional biologically relevant spectrum (BRS-3D), in subtype selectivity prediction of dopamine receptor (DR) ligands. BRS-3D is calculated by superposing the objective compounds against 300 template ligands from sc-PDB; it can encode the ligand's multiple conformations into a similarity array. BRS-3D-based method provided a new strategy for the selectivity prediction of structurally diverse ligands.

    8. Design, synthesis, and in vitro antimicrobial activity of hydrazide–hydrazones of 2-substituted acetic acid (pages 873–883)

      Łukasz Popiołek and Anna Biernasiuk

      Version of Record online: 27 AUG 2016 | DOI: 10.1111/cbdd.12820

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      Synthesis and in vitro antimicrobial activity of hydrazide-hydrazones of 2-substituted acetic acid.

    9. Synthesis of Met-enkephalin by solution-phase peptide synthesis methodology utilizing para-toluene sulfonic acid as N-terminal masking of l-methionine amino acid (pages 884–888)

      Riaz A. Khan

      Version of Record online: 20 AUG 2016 | DOI: 10.1111/cbdd.12821

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      Met-enkephalin, Tyr-Gly-Gly-Phe-Met, was synthesized in solution-phase with a simultaneous a-amino and carboxyl group's protection of the l-Methionine (l-Met) as PTSA.Met-OBzl towards a C-terminal 2 + 2 + 1 fragments condensation convergent approach. The strategy provided a stable, robust, and feasible procedure to carry through the coupling between Boc-Phe-OH and deprotected PTSA-Met-OBzl to produce one of the designated dipeptide fragments, Boc-Phe-Met-OBzl. Devoid of any structural deformities, and near quantitative yields, the cost-effective, single step, orthogonal protection with process's racemization under control made the strategy suitable for scale-up towards feasible synthesis of the pentapeptide.

    10. Evaluation of multifunctional synthetic tetralone derivatives for treatment of Alzheimer's disease (pages 889–898)

      Jing Leng, Hua-Li Qin, Kaicheng Zhu, Ibrahim Jantan, Muhammad Ajaz Hussain, Muhammad Sher, Muhammad Wahab Amjad, Muhammad Naeem-ul-Hassan, Waqas Ahmad and Syed Nasir Abbas Bukhari

      Version of Record online: 17 AUG 2016 | DOI: 10.1111/cbdd.12822

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      Effects of a series of α, β-unsaturated carbonylbased tetralone derivatives against Alzheimer's disease (AD) were investigated. The findings of in vitro experiment revealed that most of these compounds exhibited potent inhibitory activity against MAO-B, AChE and self-induced Aβ1–42 aggregation. Collectively, these findings suggest that some compounds from this series have potential to be promising multifunctional agents for AD treatment.

    11. Greener synthesis of indolizine analogues using water as a base and solvent: study for larvicidal activity against Anopheles arabiensis (pages 899–904)

      Chandrashekharappa Sandeep, Katharigatta N. Venugopala, Raquel M. Gleiser, Abeen Chetram, Basavaraj Padmashali, Rashmi S. Kulkarni, Rashmi Venugopala and Bharti Odhav

      Version of Record online: 9 SEP 2016 | DOI: 10.1111/cbdd.12823

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      The title compounds 2a–j have been synthesized by two-step chemical reaction, purified by recrystallization method at 69%–83% yield. Larvicidal results revealed that title compounds 2e and 2g emerged as promising larvicidal agents compared to standard compound.

    12. The C-terminal sequences of porcine thrombin are active as antimicrobial peptides (pages 905–914)

      Xiting Lv, Qingquan Ma, Dandan Zhu, Changxuan Shao, Yinfeng Lv and Anshan Shan

      Version of Record online: 7 SEP 2016 | DOI: 10.1111/cbdd.12824

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      A series of short antimicrobial peptides were obtained from C-terminus of porcine thrombin to investigate their antimicrobial potency, structure–activity relationship, and mechanism. The 21-residue peptide T-6 exhibited a considerably higher level of cell selectivity with TI of 43.4. T-6 demonstrated a typical α-helix structure in membrane-mimetic environment and rapidly disrupted the microbial membrane, leading to leakage of the intracellular content and eventual cell death at its MIC.

    13. Structure-based virtual screening toward the discovery of novel inhibitors of the DNA repair activity of the human apurinic/apyrimidinic endonuclease 1 (pages 915–925)

      Patrícia S. Guerreiro, Sílvia G. Estácio, Fernando Antunes, Ana S. Fernandes, Pedro F. Pinheiro, João G. Costa, Matilde Castro, Joana P. Miranda, Rita C. Guedes and Nuno G. Oliveira

      Version of Record online: 16 SEP 2016 | DOI: 10.1111/cbdd.12826

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      A structure-based virtual screening (SBVS) study combined with molecular docking analysis was performed on the National Cancer Institute (NCI) database to identify novel inhibitors of the DNA repair activity of human apurinic/apyrimidinic endonuclease 1 (APE1). Compounds 37 and 41 inhibited the enzyme in the micromolar range, while compound 22 showed inhibitory effects at nanomolar concentrations, being non-cytotoxic to human non-tumoral MCF10A cells. These compounds appear to be important scaffolds for the design of novel APE1 inhibitors.

    14. Discovery of neurotrophic agents based on hydroxycinnamic acid scaffold (pages 926–937)

      Razieh Hosseini, Fatemeh Moosavi, Hamid Rajaian, Tiago Silva, Diogo Magalhães e Silva, Pedro Soares, Luciano Saso, Najmeh Edraki, Ramin Miri, Fernanda Borges and Omidreza Firuzi

      Version of Record online: 9 SEP 2016 | DOI: 10.1111/cbdd.12829

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      In this study, the neurotrophic capacity of hydroxycinnamic acids and their alkyl esters was examined. Our findings demonstrate that alkyl esters of caffeic acid possess strong neurotrophic effects, especially decyl and dodecyl caffeate, which significantly promoted neuronal survival. Propyl and butyl caffeate esters could also significantly enhance NGF-induced neurite outgrowth. The findings of the docking study suggested phosphatidylinositol 3-kinase (PI3K) as the potential molecular target. In conclusion, esters of caffeic acid could be potentially useful for discovery of therapeutic agents for neurodegenerative diseases.

  4. Research Letter

    1. Top of page
    2. Issue Information
    3. Editor's Choice
    4. Research Articles
    5. Research Letter
    1. Design and synthesis of 4′-((5-benzylidene-2,4-dioxothiazolidin-3-yl)methyl)biphenyl-2-carbonitrile analogs as bacterial peptide deformylase inhibitors (pages 938–944)

      Firoz A. Kalam Khan, Rajendra H. Patil, Devanand B. Shinde and Jaiprakash N. Sangshetti

      Version of Record online: 17 AUG 2016 | DOI: 10.1111/cbdd.12817

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      Synthesis and evaluation of 4′-((5-benzylidene-2,4-dioxothiazolidin-3-yl)methyl)biphenyl-2-carbonitrile analogs 11(a–j) as bacterial peptide deformylase (PDF) enzyme inhibitors. The compounds 11b (IC50 value = 139.28 μM), 11g (IC50 value = 136.18 μM), and 11h (IC50 value = 131.65 μM) had shown good PDF inhibition activity. The compounds 11b (MIC range = 103.36–167.26 μg/mL), 11g (MIC range = 93.75–145.67 μg/mL), and 11h (MIC range = 63.61–126.63 μg/mL) had also shown potent antibacterial activity when compared with standard ampicillin (MIC range = 100.00–250.00 μg/mL).

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