Chemical Biology & Drug Design

Cover image for Vol. 88 Issue 4

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

Edited By: David Selwood

Impact Factor: 2.802

ISI Journal Citation Reports © Ranking: 2015: 26/59 (Chemistry Medicinal); 137/289 (Biochemistry & Molecular Biology)

Online ISSN: 1747-0285

VIEW

  1. 1 - 46
  1. Research Articles

    1. 1-[(Imidazolidin-2-yl)imino]-1H-indoles as new hypotensive agents: synthesis and in vitro and in vivo biological studies

      Anita Kornicka, Aleksandra Wasilewska, Jarosław Sączewski, Alan L. Hudson, Konrad Boblewski, Artur Lehmann, Karol Gzella, Mariusz Belka, Franciszek Sączewski, Maria Gdaniec, Apolonia Rybczyńska and Tomasz Bączek

      Version of Record online: 26 SEP 2016 | DOI: 10.1111/cbdd.12846

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      1-[(Imidazolidin-2-yl)imino]-1H-indole analogues of a hypotensive α2-AR/imidazoline I1 binding site-selective ligand, 7-fluoro-1-[(imidazolidin-2-yl)imino]-1H-indazole (7-F-marsanidine), were synthesized and tested in vitro for α1- and α2-adrenergic and imidazoline I1 and I2 receptors’ binding affinities as well as in vivo for cardiovascular effects. 7-F-indole 3g, the most potent hypotensive agent in this series, is characterized by higher affinity and selectivity for α2-ARs over I1-IBS than that of 7-F-marsanidine. The newly prepared compounds are found to possess a high metabolic stability in vitro.

    2. Rapid synthesis of flavone-based monoamine oxidase (MAO) inhibitors targeting two active sites using click chemistry

      Wei Zhen Jia, Feng Cheng, Yin Jun Zhang, Jin Yan Ge, Shao Q. Yao and Qing Zhu

      Version of Record online: 26 SEP 2016 | DOI: 10.1111/cbdd.12841

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      A new library of flavone derivatives targeting two active sites of MAOs (“Aromatic Cage” and substrate cavity) were designed and synthesized using click chemistry (CuAAC reaction). The most potent flavone MAO inhibitor studied is Az2k19 (1.6 μm for MAO-A, 2.1 μm for MAO-B), while Az1k15 and Az2k15 displayed better selectivity toward MAO-B (SI > 10). Docking studies are in accordance with our hypothesis that this series inhibitors are most likely located at the substrate cavity and the “aromatic cage”.

    3. Synthesis and biological evaluation of novel flavanone derivatives as potential antipsychotic agents

      Hong-shun Gu, Xi Chen, Jian-wei Zhang, Lan Zhang and Lin Li

      Version of Record online: 26 SEP 2016 | DOI: 10.1111/cbdd.12843

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      A series of novel flavanone derivatives were designed and synthesized, and the antipsychotic activities were evaluated by two models in vitro and two models in vivo. These results suggest that some of the synthesized compounds may have potential antipsychotic effect via inhibiting dopamine activity.

    4. Analysis of residue conformations in peptides in Cambridge structural database and protein-peptide structural complexes

      Upadhyayula Surya Raghavender

      Version of Record online: 26 SEP 2016 | DOI: 10.1111/cbdd.12862

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      A statistical approach to studying peptide residue conformations in the crystal structures of protein-peptide complexes in PDB. A synthetic formulation to integrate structural information from CSD and PDB peptide structures is to derive chemically sensible density distributions for backbone conformations characterizing the flexibility of peptide residues.

    5. Characterization of MymA protein as a flavin-containing monooxygenase and as a target of isoniazid

      Iti Saraav, Kirti Pandey, Richa Misra, Swati Singh, Monika Sharma and Sadhna Sharma

      Version of Record online: 23 SEP 2016 | DOI: 10.1111/cbdd.12840

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      This study characterizes MymA protein as a mycobacterial flavin-containing monooxygenase and a target of isoniazid for the first time. The enzyme follows Michaelis–Menten kinetics to catalyze substrates such as trimethylamine and thiourea. Molecular docking studies revealed that isoniazid targeted NADPH-binding site of the MymA. Further, experimental validation revealed that isoniazid inhibits MymA with the IC50 value of 4.9 μm.

    6. Synthesis and comparative in vivo evaluation of 99mTc(CO)3-labeled PEGylated and non-PEGylated cRGDfK peptide monomers

      Kusum Vats, Drishty Satpati, Rohit Sharma, Haladhar D. Sarma and Sharmila Banerjee

      Version of Record online: 23 SEP 2016 | DOI: 10.1111/cbdd.12844

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      In this work two azide-modified PEGylated and non-PEGylated cRGDfK peptide monomers were clicked with propargyl glycine (Pra) to introduce a tridentate chelator for radiolabeling with [99mTc(CO)3(H2O)3]+ precursor. The non-PEGylated radiotracer, 99mTc(CO)3-Pra-Tz-CH2-cRGDfK showed higher tumor/blood, tumor/liver, tumor/kidney and tumor/lung ratios in comparison to the PEGylated radiotracer, 99mTc(CO)3-Pra-Tz-PEG7-cRGDfK.

    7. In vitro study on potential pharmacological activity of curcumin analogues and their copper complexes

      Erika Ferrari, Rois Benassi, Monica Saladini, Giulia Orteca, Zuzana Gazova and Katarina Siposova

      Version of Record online: 23 SEP 2016 | DOI: 10.1111/cbdd.12847

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      Curcumin analogues K2T demonstrated to inhibit Aβ1–40 fibrillization.

      K2T compounds act as copper(II) chelating agents reducing the free metal damage.

      K2T-Cu(II) complexes behave as DNA groove binders.

    8. Binding free energy calculations on E-selectin complexes with sLex oligosaccharide analogs

      Pabla A. Barra, António J. M. Ribeiro, Maria J. Ramos, Verónica A. Jiménez, Joel B. Alderete and Pedro A. Fernandes

      Version of Record online: 21 SEP 2016 | DOI: 10.1111/cbdd.12837

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      Binding free energy calculations were employed to examine the interaction between E-selectin and six oligosaccharide ligands. The accuracy of TI, BAR, MBAR, MM/PBSA, and MM/GBSA methods was assessed showing that all methods succeeded in accounting for an increased binding affinity for the sLex analogs toward E-selectin compared to the native ligand, being TI the method with the best performance.

    9. ff14IDPs force field improving the conformation sampling of intrinsically disordered proteins

      Dong Song, Wei Wang, Wei Ye, Dingjue Ji, Ray Luo and Hai-Feng Chen

      Version of Record online: 19 SEP 2016 | DOI: 10.1111/cbdd.12832

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      The newly force filed ff14IDPs for IDPs was developed. Multiple tests suggest that ff14IDPs can better reproduce the conformation of IDPs than ff14SB. This force field will be a useful and robust tool for drug design targeting on IDPs.

    10. An enzymatic approach to configurationally rare trans-androsteronyl-α-glucoside and Its potential anticancer application

      Feng-Pai Chou, Chia-Tse Tsai, Ya-Sheng Chiou, Yi-Ju Chen, Meng-Erh Li, Ting-Wei Guo, Jason WenJay Lyu, Sheng-Hao Chou and Tung-Kung Wu

      Version of Record online: 19 SEP 2016 | DOI: 10.1111/cbdd.12830

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      Eleven configurationally rare steryl-α-glycosides were enzymatically produced by the HP0421 protein from Helicobacter pylori. Investigation of the trans-androsteronyl-α-glucoside on tamoxifen-treated MCF-7 breast cancer cells shows dose-dependent depression of cell viability and enhanced drug effectiveness, indicating its potential for anticancer application.

    11. Structure-based virtual screening toward the discovery of novel inhibitors of the DNA repair activity of the human apurinic/apyrimidinic endonuclease 1

      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.

  2. Review Articles

    1. Versatility of peptide nucleic acids (PNAs): role in chemical biology, drug discovery, and origins of life

      Chiranjeev Sharma and Satish Kumar Awasthi

      Version of Record online: 14 SEP 2016 | DOI: 10.1111/cbdd.12833

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      PNA reigns superiority to its natural counterparts and has clear advantages with high binding affinity and strong specificity. Targeted structural modifications have extended the arsenal of various biotechnological and diagnostic tools. Although the primary goal of creating a PNA-based drug is unmet, harnessing its potential to make a new generation of drug provides the challenges and opportunities for the next decade.

  3. Research Articles

    1. New pyrazole derivative 5-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]-2H-tetrazole: synthesis and assessment of some biological activities

      Lanussy Porfiro de Oliveira, Daiany Priscilla Bueno da Silva, Iziara Ferreira Florentino, James Oluwagbamigbe Fajemiroye, Thiago Sardinha de Oliveira, Renato Ivan de Ávila Marcelino, Francine Pazini, Luciano Morais Lião, Paulo César Ghedini, Soraia Santana de Moura, Marize Campos Valadares, Verônica Vale de Carvalho, Boniek Gontijo Vaz, Ricardo Menegatti and Elson Alves Costa

      Version of Record online: 14 SEP 2016 | DOI: 10.1111/cbdd.12838

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      Given pyrazole compounds' antipyretic, analgesic, and anti-inflammatory effects, we describe the synthesis and pharmacotoxicological evaluation of a new pyrazole derivative, 5-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]-2H-tetrazole, as well as the antinociceptive, anti-inflammatory activity and involvement of the NO/cGMP pathway and ionic channels in its vasorelaxant effect. The blockade of voltage-dependent calcium channels could have also contributed to the vasorelaxant effect of the compound, which demonstrated a low toxicological profile promising antinociceptive, anti-inflammatory, and vasorelaxant effects.

    2. Design and synthesis of new 2-anilinoquinolines bearing N-methylpicolinamide moiety as potential antiproliferative agents

      Ashraf Kareem El-Damasy, Seon Hee Seo, Nam-Chul Cho, Ae Nim Pae, Eunice Eunkyeong Kim and Gyochang Keum

      Version of Record online: 9 SEP 2016 | DOI: 10.1111/cbdd.12836

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      A series of new 2-anilinoquinolines possessing N-methylpicolinamide motif has been designed, synthesized, and biologically evaluated as sorafenib analogues. All the tested compounds showed promising selective anticancer activities and the 4-chloro-3-trifluoromethyl aniline derivative 6j manifested superior potency than sorafenib over certain cell lines, with submicromolar GI50 values against four cell lines.

    3. Insight into the mechanism of chemical modification of antibacterial agents by antibiotic resistance enzyme O-phosphotransferase-IIIA

      Blake Hollett Power, Nathan Smith, Brandon Downer and Laleh Alisaraie

      Version of Record online: 9 SEP 2016 | DOI: 10.1111/cbdd.12835

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      Aminoglycoside antibiotics and potential antibacterial inhibitors were studied through computational simulations while in complex with a corresponding aminoglycoside resistance enzyme, APH(3′)-IIIa. Insight into the conformational changes of both enzyme and antibiotic, with ATP, were determined throughout the molecular dynamics simulations. As well, beneficial inhibitory results were shown with the small peptides and the enzyme, helping to further advance the understanding of peptide inhibitory use in the fight against antibiotic resistance.

    4. Discovery of neurotrophic agents based on hydroxycinnamic acid scaffold

      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.

    5. Greener synthesis of indolizine analogues using water as a base and solvent: study for larvicidal activity against Anopheles arabiensis

      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.

    6. AVCpred: an integrated web server for prediction and design of antiviral compounds

      Abid Qureshi, Gazaldeep Kaur and Manoj Kumar

      Version of Record online: 9 SEP 2016 | DOI: 10.1111/cbdd.12834

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      AVCpred is a QSAR approach to predict the antiviral potential of chemical compounds using relationships connecting molecular descriptors and inhibition. Experimentally validated antiviral compounds against important human viruses from ChEMBL database were used to develop the prediction models. The web server with user friendly prediction/design options also has other tools for analysis.

    7. The C-terminal sequences of porcine thrombin are active as antimicrobial peptides

      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.

    8. Design, synthesis, and negative inotropic evaluation of 4-phenyl-1H-1,2,4-triazol-5(4H)-one derivatives containing triazole or piperazine moieties

      Zhi-Yu Wei, Bai-Ri Cui, Xun Cui, Yan-Ling Wu, Yang Fu, Li-Ping Liu and Hu-Ri Piao

      Version of Record online: 6 SEP 2016 | DOI: 10.1111/cbdd.12828

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      Four novel series of 4-phenyl-1H-1,2,4-triazol-5(4H)-one derivatives containing triazole or piperazine moieties were designed, synthesized, and evaluated for negative inotropic activity. The cytotoxicity of these compounds was evaluated, and a preliminary investigation of the mechanism of action of these compounds on the atrial dynamics was also conducted.

    9. In-vitro antileishmanial potential of peptide drug hirudin

      Hanif Khan, Akhtar Nadhman, Syed Sikander Azam, Mariam Anees, Imran Khan, Ikram Ullah, Muhammad Farhan Sohail, Gul Shahnaz and Masoom Yasinzai

      Version of Record online: 31 AUG 2016 | DOI: 10.1111/cbdd.12831

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      Hirudin (an anticoagulant) exhibits higher binding affinity with leishmanolysin, showing promising activity against promastigote and amastigote forms of leishmanial parasites. It causes cell death mainly by apoptosis and membrane permeability.

    10. Design, synthesis, and in vitro antimicrobial activity of hydrazide–hydrazones of 2-substituted acetic acid

      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.

    11. 3-aminopyrazolopyrazine derivatives as spleen tyrosine kinase inhibitors

      Jiayi Shen, Xiaokai Li, Zhang Zhang, Jingfeng Luo, Huoyou Long, Zhengchao Tu, Xiaoping Zhou, Ke Ding and Xiaoyun Lu

      Version of Record online: 27 AUG 2016 | DOI: 10.1111/cbdd.12798

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      A series of pyrazolopyrazine-3-amine and pyrazolopyrimidine-3-amine derivatives were designed and synthesized as new spleen tyrosine kinase inhibitors. The efforts yielded compound 6h with promising spleen tyrosine kinase inhibition in both enzymatic and B-lymphoma cells proliferation assays.

    12. Synthesis, biological evaluation, and molecular docking studies of new pyrazol-3-one derivatives with aromatase inhibition activities

      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.

    13. Synthesis of Met-enkephalin by solution-phase peptide synthesis methodology utilizing para-toluene sulfonic acid as N-terminal masking of l-methionine amino acid

      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.

    14. A small molecule identified through an in silico screen inhibits Aurora B–INCENP interaction

      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.

  4. Research Letters

    1. Design and synthesis of 4′-((5-benzylidene-2,4-dioxothiazolidin-3-yl)methyl)biphenyl-2-carbonitrile analogs as bacterial peptide deformylase inhibitors

      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).

  5. Research Articles

    1. Evaluation of multifunctional synthetic tetralone derivatives for treatment of Alzheimer's disease

      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.

    2. Docetaxel–Chitosan nanoparticles for breast cancer treatment: cell viability and gene expression study

      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.

    3. Anticancer activity of gallic acid template-based benzylidene indanone derivative as microtubule destabilizer

      Aastha Singh, Kaneez Fatima, Ankita Srivastava, Sadiya Khwaja, Dev Priya, Arjun Singh, Girish Mahajan, Sarfaraz Alam, Ajit K. Saxena, D. M. Mondhe, Suaib Luqman, Debabrata Chanda, Feroz Khan and Arvind S. Negi

      Version of Record online: 6 AUG 2016 | DOI: 10.1111/cbdd.12805

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      2-Benzylidene indanones have been synthesized. The detailed pharmacology of the best analogue (Compound 8) of the series has been explored.

    4. Synthesis, structure–activity relationship studies and biological evaluation of novel 2,5-disubstituted indole derivatives as anticancer agents

      Hongyu Hu, Jun Wu, Mingtao Ao, Huiru Wang, Tongtong Zhou, Yuhua Xue, Yingkun Qiu, Meijuan Fang and Zhen Wu

      Version of Record online: 2 AUG 2016 | DOI: 10.1111/cbdd.12808

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      Three novel series of 2,5-disubstituted indole derivatives were synthesized. Among them, 2c and 3b which had a pan anti-proliferative activity against human cancer cells and showed effectively HIV-1 inhibition activity, may induce cancer cells apoptosis through inhibiting the phosphorylation at Ser2 of RNAPII CTD which can be phosphorylated by cyclin-dependent kinase 9.

    5. Predicting subtype selectivity of dopamine receptor ligands with three-dimensional biologically relevant spectrum

      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.

  6. Original Research

    1. Biohydroxylation of 7-oxo-DHEA, a natural metabolite of DHEA, resulting in formation of new metabolites of potential pharmaceutical interest

      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.

  7. Research Articles

    1. Identification of the first in silico-designed TREK1 antagonists that block channel currents dose dependently

      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.

    2. Design, synthesis, biological evaluation, NMR and DFT studies of structurally simplified trimethoxy benzamides as selective P-glycoprotein inhibitors: the role of molecular flatness

      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.

    3. Identification of CYP1B1-specific candidate inhibitors using combination of in silico screening, integrated knowledge-based filtering, and molecular dynamics simulations

      Rakesh Kumar and Dinesh Gupta

      Version of Record online: 21 JUL 2016 | DOI: 10.1111/cbdd.12803

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      The known inhibitors except in polycyclic aromatic hydrocarbons and selected ligands derived from docking of CYP1B1 is found to be at a optimum distance 6 Å of heme (Fe) to nearest non-hydrogen atom. The Cluster 1 was largest one containing 94 compounds using LibMCS classification. ∆Evdw component played dominant role in deciding binding energies of ligands, ∆Eele component supported in some ligands. The residues Ser131, Asp326, Asp333, and Thr510 were frequently involved in hydrogen bond formation in CYP1B1 interactions with ligands.

  8. Review Articles

    1. Multitargeted bioactive ligands for PPARs discovered in the last decade

      Jun Zhang, Xin Liu, Xian-Bin Xie, Xian-Chao Cheng and Run-Ling Wang

      Version of Record online: 21 JUL 2016 | DOI: 10.1111/cbdd.12806

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      In this review, we updated and generalized the recent development of PPARγ partial agonists, PPARγ antagonists, PPARα/γ dual agonists, PPARδ partial agonists, PPARδ antagonists, PPARα/δ dual agonists, PPARγ/δ dual agonists, and PPARα/γ/δ pan-agonists published in recent decade. Most of these molecules were modified from known structures or came from high-throughput screening.

  9. Research Articles

    1. Evaluation of the inhibitory activity of (aza)isoindolinone-type compounds: toward in vitro InhA action, Mycobacterium tuberculosis growth and mycolic acid biosynthesis

      Aurélien Chollet, Jean-Luc Stigliani, Maria Rosalia Pasca, Giorgia Mori, Christian Lherbet, Patricia Constant, Annaïk Quémard, Jean Bernadou, Geneviève Pratviel and Vania Bernardes-Génisson

      Version of Record online: 16 JUL 2016 | DOI: 10.1111/cbdd.12804

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      The pharmacomodulation and the synthesis of 15 new (aza)isoindolinone-type compounds were described. Two of them were more effective InhA inhibitors than the hit molecule. The modes of interaction of the (aza)isoindolinones with this enzyme were predicted based on molecular docking calculations and on the structure–activity relationship analysis. The (aza)isoindolinone exhibited only a discrete inhibitory activity upon M. tuberculosis H37Rv growth. Compounds m-4a and 2a were not able to inhibit the biosynthesis of mycolic acids.

    2. Cardioprotective effect of novel sulphonamides-1,3,5-triazine conjugates against ischaemic–reperfusion injury via selective inhibition of MMP-9

      Xiao-Zhu Zheng, Jia-Li Zhou, Jing Ye, Pei-Pei Guo and Chun-Shui Lin

      Version of Record online: 15 JUL 2016 | DOI: 10.1111/cbdd.12807

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      Novel class of sulphonamides-1,3,5-triazine conjugates have been synthesized and tested for inhibitory activity against MMP-2 and MMP-9.

    3. 4-amino-6-alkyloxy-2-alkylthiopyrimidine derivatives as novel non-nucleoside agonists for the adenosine A1 receptor

      Barbara Cosimelli, Giovanni Greco, Sonia Laneri, Ettore Novellino, Antonia Sacchi, Maria Letizia Trincavelli, Chiara Giacomelli, Sabrina Taliani, Federico Da Settimo and Claudia Martini

      Version of Record online: 11 JUL 2016 | DOI: 10.1111/cbdd.12801

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      We describe the biological characterization of two novel non-nucleoside agonists of the human A1 adenosine receptor. The two compounds are 4-amino-6-alkyloxy-2- alkylthiopyrimidine derivatives provided with submicromolar potency at the target receptor and high selectivity versus A2A, A2B and A3 adenosine receptors.

    4. An antiarrhythmic agent as a promising lead compound for targeting the hEAG1 ion channel in cancer therapy: insights from molecular dynamics simulations

      Daniel Șterbuleac and Călin Lucian Maniu

      Version of Record online: 11 JUL 2016 | DOI: 10.1111/cbdd.12797

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      This study investigates the potential of using clofilium as a lead compound for finding a novel cancer therapy agent which may target the hEAG1 ion channel over hERG. The implied findings from a comparative assessment of literature studies were verified using molecular dynamics simulations. The results indicate a particular structural difference between hEAG1 and hERG channels that could provide a novel and realistic way of using clofilium analogues to target hEAG1 in cancer therapy.

    5. Synthesis and anti-Candida activity of novel benzothiepino[3,2-c]pyridine derivatives

      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.

    6. Structure–activity relationship studies of benzyl-, phenethyl-, and pyridyl-substituted tetrahydroacridin-9-amines as multitargeting agents to treat Alzheimer's disease

      Wesseem Osman, Tarek Mohamed, Victor Munsing Sit, Maryam S. Vasefi, Michael A. Beazely and Praveen P. N. Rao

      Version of Record online: 11 JUL 2016 | DOI: 10.1111/cbdd.12800

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      Anti-Alzheimer's agents with potent cholinesterase and beta-amyloid aggregation inhibition were identified. Tetrahydroacridin-9-amine derivatives with nanomolar-scale inhibition of both acetyl- and butyrylcholinesterase were discovered. A 3,4-dimethoxyphenyl substituent was identified as an antiamyloid pharmacophore.

    7. Design, synthesis, and structure–activity relationship studies of novel pleuromutilin derivatives having a piperazine ring

      Jian Luo, Qiu-E Yang, Yuan-Yuan Yang, You-Zhi Tang and Ya-Hong Liu

      Version of Record online: 9 JUL 2016 | DOI: 10.1111/cbdd.12799

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      Through structure-based bioisosteric replacement, a series of novel piperazinesubstituted pleuromutilin derivatives were designed, synthesized. The antibacterial of these derivatives were evaluated. Three of these derivatives were selected for molecular docking investigations.

    8. Design and synthesis of N-benzoyl amino acid derivatives as DNA methylation inhibitors

      Davide Garella, Sandra Atlante, Emily Borretto, Mattia Cocco, Marta Giorgis, Annalisa Costale, Livio Stevanato, Gianluca Miglio, Chiara Cencioni, Eli Fernández-de Gortari, José L. Medina-Franco, Francesco Spallotta, Carlo Gaetano and Massimo Bertinaria

      Version of Record online: 24 JUN 2016 | DOI: 10.1111/cbdd.12794

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      A series of N-benzoyl amino acid derivatives was synthesized by modulation of three different molecular moieties (A, B, and C). The ability of synthesized compounds to inhibit DNMT-dependent total DNA methylation was evaluated. The most active compound 22 inhibited both DNMT1- and DNMT3A-mediated DNA methylation in a concentration-dependent manner at micromolar concentration. Docking studies suggest putative binding at the substrate site of both DNMT isoforms studied.

    9. Angiotensin II analogues with N-terminal lactam bridge cyclization: an overview on AT1 receptor activation and tachyphylaxis

      Flávio Lopes Alves, Vani Xavier Oliveira Jr and Antonio Miranda

      Version of Record online: 24 JUN 2016 | DOI: 10.1111/cbdd.12795

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      Angiotensin II is the final active product of the renin enzymatic cascade, which is responsible for sustaining blood pressure. Cyclization in the N-terminal portion of the Angiotensin II with an i-(i+1) lactam bridge consisting an Asp-(Xaa)n-Lys scaffold maintains the contractile activity and do not interfere in the tachyphylaxis phenomenon.

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