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Bioorganic & Medicinal Chemistry

Manikandan Alagumuthu, Sivakumar Arumugam
Synthesis and molecular validation of 6-substituted-2-(3-phenoxyphenyl)-4-phenylquinoline derivatives (4a-h) as antibacterial/DNA gyrase inhibitors reported. Primarily, 6-substituted-2-(3-phenoxyphenyl)-4-phenylquinoline derivatives were docked into the active sites of DNA gyrase A&B, to ensure the binding mode of the compounds, and the results were superior on DNA gyrase A over DNA gyrase B. Based on this, S. aureus DNA gyrase A assay was proposed and executed. Most prominent DNA gyrase inhibition showed by 6-fluoro-2-(3-phenoxyphenyl)-4-phenylquinoline (4c), IC50 0...
January 6, 2017: Bioorganic & Medicinal Chemistry
Nikolaus Guttenberger, Wulf Blankenfeldt, Rolf Breinbauer
Phenazines are natural products which are produced by bacteria or by archaeal Methanosarcina species. The tricyclic ring system enables redox processes, which producing organisms use for oxidation of NADH or for the generation of reactive oxygen species (ROS), giving them advantages over other microorganisms. In this review we summarize the progress in the field since 2005 regarding the isolation of new phenazine natural products, new insights in their biological function, and particularly the now almost completely understood biosynthesis...
January 5, 2017: Bioorganic & Medicinal Chemistry
Nirmala S Naik, Lokesh A Shastri, Shrinivas D Joshi, Sheshagiri R Dixit, Bahubali M Chougala, S Samundeeswari, Megharaj Holiyachi, Farzanabi Shaikh, Jyoti Madar, Rashmi Kulkarni, Vinay Sunagar
Bacterial infections are increasingly difficult to combat as bacteria evolve resistance to antibiotic drugs and have severely compromised the arsenal of antibiotic drugs. On the other hand matrix metalloproteinases (MMPs) play a fundamental role in inflammation and extracellular matrix degradation in physiological and pathological conditions. In search of potent antibiotic, taking coumarin and dihydropyrimidinone as lead compound, a green, eco-friendly and efficient protocol has been developed and synthesized the dihydropyrimidin-2(1H)-one/thione derivatives of coumarin 3/4 from substituted 4-formylcoumarins 2 and ethylacetoacetate using urea/thiourea in the presence of catalytic amount of ceric ammonium nitrate is reported...
January 5, 2017: Bioorganic & Medicinal Chemistry
Sarbjit Singh, Ja-Il Goo, Hyojin Noh, Sung Jae Lee, Myoung Woo Kim, Hyejun Park, Hitesh B Jalani, Kyeong Lee, Chunsook Kim, Won-Ki Kim, Chung Ju, Yongseok Choi
Astrocytes play a key role in brain homeostasis, protecting neurons against neurotoxic stimuli such as oxidative stress. Therefore, the neuroprotective therapeutics that enhance astrocytic functionality has been regarded as a promising strategy to reduce brain damage. We previously reported that ciclopirox, a well-known antifungal N-hydroxypyridone compound, protects astrocytes from oxidative stress by enhancing mitochondrial function. Using the N-hydroxypyridone scaffold, we have synthesized a series of cytoprotective derivatives...
January 3, 2017: Bioorganic & Medicinal Chemistry
Hiroyuki Kimura, Hirokazu Matsuda, Yu Ogawa, Hiroyuki Fujimoto, Kentaro Toyoda, Naotaka Fujita, Kenji Arimitsu, Keita Hamamatsu, Yusuke Yagi, Masahiro Ono, Nobuya Inagaki, Hideo Saji
Insulinoma is a tumor derived from pancreatic β-cells, and the resulting hyperinsulinemia leads to characteristic hypoglycemia. Recent studies have reported the frequent overexpression of glucagon-like peptide-1 receptor (GLP-1R) in human insulinomas, suggesting that the binding of a radiolabeled compound to GLP-1R is useful for the imaging of such tumors. Exendin(9-39), a fragment peptide of exendin-3 and -4, binds GLP-1R with high affinity and acts as an antagonist. Accordingly, radiolabeled exendin(9-39) derivatives have also been investigated as insulinoma imaging probes that might be less likely to induce hypoglycemia...
January 3, 2017: Bioorganic & Medicinal Chemistry
Sina Omid Malayeri, Khalil Abnous, Atefeh Arab, Maryam Akaberi, Soghra Mehri, Afshin Zarghi, Razieh Ghodsi
A new series of quinoline analogues was designed and synthesized as Hsp90 inhibitors. The cytotoxic activity of the synthesized compounds was evaluated against three human cancer cell lines including MCF-7 (human breast cancer cells), DU145 (human prostate cancer cell lines), and A549 (adenocarcinomic human alveolar basal epithelial cells). Some of our compounds (13a-13f) showed significant cytotoxic activity on MCF-7 cells. The most potent anti-proliferative compounds were also tested against Her2, a client protein of Hsp90...
January 2, 2017: Bioorganic & Medicinal Chemistry
Hongmao Sun, Kimloan Nguyen, Edward Kerns, Zhengyin Yan, Kyeong Ri Yu, Pranav Shah, Ajit Jadhav, Xin Xu
Cell membrane permeability is an important determinant for oral absorption and bioavailability of a drug molecule. An in silico model predicting drug permeability is described, which is built based on a large permeability dataset of 7488 compound entries or 5435 structurally unique molecules measured by the same lab using parallel artificial membrane permeability assay (PAMPA). On the basis of customized molecular descriptors, the support vector regression (SVR) model trained with 4071 compounds with quantitative data is able to predict the remaining 1364 compounds with the qualitative data with an area under the curve of receiver operating characteristic (AUC-ROC) of 0...
December 31, 2016: Bioorganic & Medicinal Chemistry
Péter Bana, Róbert Örkényi, Klára Lövei, Ágnes Lakó, György István Túrós, János Éles, Ferenc Faigl, István Greiner
Recent advances in the field of continuous flow chemistry allow the multistep preparation of complex molecules such as APIs (Active Pharmaceutical Ingredients) in a telescoped manner. Numerous examples of laboratory-scale applications are described, which are pointing towards novel manufacturing processes of pharmaceutical compounds, in accordance with recent regulatory, economical and quality guidances. The chemical and technical knowledge gained during these studies is considerable; nevertheless, connecting several individual chemical transformations and the attached analytics and purification holds hidden traps...
December 29, 2016: Bioorganic & Medicinal Chemistry
Mai H El-Naggar, Amira Mira, Fatma M Abdel Bar, Kuniyoshi Shimizu, Mohamed M Amer, Farid A Badria
Leukotriene A4 hydrolase (LTA4H) is a proinflammatory enzyme that generates the inflammatory mediator leukotriene which may play an important role in chronic inflammation associated carcinogenesis. [6]-gingerol, the major bioactive compound of Zingiber officinale, is a potential inhibitor of LTA4H, a highly expressed enzyme in colorectal carcinoma. Eighteen compounds; seven of natural origin (including [4]-, [6]-, [8]-, and [10]-gingerol), five new and six known semi-synthesized [6]-gingerol derivatives were examined using docking, in vitro cytotoxicity against human colon cancer cells (HCT-116) and LTA4H aminopeptidase and epoxide hydrolase inhibitory studies...
December 29, 2016: Bioorganic & Medicinal Chemistry
Rajiv Kumar, Silvia Bua, Sita Ram, Sonia Del Prete, Clemente Capasso, Claudiu T Supuran, Pawan K Sharma
Two series of 20 novel heterocyclic compounds, imidazothiadiazoles (3a-3j) and thiazolotriazoles (4a-4j) bearing benzenesulfonamide moiety were synthesized in order to investigate the inhibition potential of both scaffolds against four selected human carbonic anhydrase isoforms (hCA I, II, IX & XII). Against human isoform hCA I, compounds 3j, 4a-4c, and 4j showed better inhibition potential (Ki<100nM) than the standard drug acetazolamide (AZA). Against hCA II, all the compounds showed moderate inhibition with the exception of 3a which showed nearly two fold better profile compared to AZA...
December 29, 2016: Bioorganic & Medicinal Chemistry
Balagani Sathish Kumar, Kusumoori Ravi, Amit Kumar Verma, Kaneez Fatima, Mohammad Hasanain, Arjun Singh, Jayanta Sarkar, Suaib Luqman, Debabrata Chanda, Arvind S Negi
Naphthoquinones are naturally occurring biologically active entities. Practical de novo syntheses of three naphthoquinones i.e. lawsone (1), lapachol (2), and β-lapachone (3b) have been achieved from commercially available starting materials. The conversion of lapachol (2) to β-lapachone (3b) was achieved through p-TSA/Iodine/BF3-etherate mediated regioselective cyclisation. Further, 2-alkyl and 2-benzyllawsone derivatives have been prepared as possible anticancer agents. Four derivatives exhibited significant anticancer activity and the best analogue i...
December 28, 2016: Bioorganic & Medicinal Chemistry
Carsten Börger, Christian Brütting, Konstanze K Julich-Gruner, Ronny Hesse, V Pavan Kumar, Sebastian K Kutz, Marika Rönnefahrt, Claudia Thomas, Baojie Wan, Scott G Franzblau, Hans-Joachim Knölker
A series of 49 oxygenated tricyclic carbazole derivatives has been tested for inhibition of the growth of Mycobacterium tuberculosis and a mammalian cell line (vero cells). From this series, twelve carbazoles showed a significant anti-TB activity. The four most active compounds were the naturally occurring carbazole alkaloids clauszoline-M (45), murrayaline-C (41), carbalexin-C (27), and the synthetic carbazole derivative 22 with MIC90 values ranging from 1.5 to 3.7μM. The active compounds were virtually nontoxic for the mammalian cell line in the concentration range up to 50μM...
December 27, 2016: Bioorganic & Medicinal Chemistry
Lukas Hroch, Patrick Guest, Ondrej Benek, Ondrej Soukup, Jana Janockova, Rafael Dolezal, Kamil Kuca, Laura Aitken, Terry K Smith, Frank Gunn-Moore, Dominykas Zala, Rona R Ramsay, Kamil Musilek
Alzheimer's disease (AD) is a neurodegenerative disorder associated with an excessive accumulation of amyloid-beta peptide (Aβ). Based on the multifactorial nature of AD, preparation of multi-target-directed ligands presents a viable option to address more pathological events at one time. A novel class of asymmetrical disubstituted indolyl thioureas have been designed and synthesized to interact with monoamine oxidase (MAO) and/or amyloid-binding alcohol dehydrogenase (ABAD). The design combines the features of known MAO inhibitors scaffolds (e...
December 27, 2016: Bioorganic & Medicinal Chemistry
Sebastiano Intagliata, Maria N Modica, Valeria Pittalà, Loredana Salerno, Maria A Siracusa, Alfredo Cagnotto, Mario Salmona, Rafał Kurczab, Giuseppe Romeo
Based on our earlier studies of structure activity relationships on 4-substituted piperazine derivatives, in this work we synthesized a novel set of long-chain arylpiperazines with the purpose of elucidating if some structural modifications in the terminal fragment could affect the binding affinity for the 5-HT7 and 5-HT1A receptors. In this new series, the quinazolinone system of the previous derivatives was replaced by a 6-phenylpyrimidine or a 2-methylquinazoline, which were used as versatile building blocks for the preparation of new compounds...
December 27, 2016: Bioorganic & Medicinal Chemistry
Akihito Shimazu, Masashi Kawagoshi, Shoichi Takeda, Haruaki Kurasaki, Asako Kato, Nahoko Morii, Norio Sakai, Takeo Konakahara
The binding modes and binding constants for the complexes of forty types of pyridocarbazole derivatives 1-40 with double stranded DNAs (dsDNAs) were reported. The binding modes were determined by a combination of a deflection spectroscopy and orientation of the corresponding molecule in the DNA-based film with chain alignment. All of the compounds exhibited the intercalation-binding mode. Its binding constants Ka for the complexes, determined by quartz crystal microbalance (QCM), varied from 1.7×10(5) to 4...
December 27, 2016: Bioorganic & Medicinal Chemistry
Riccardo Vago, Arianna Bettiga, Andrea Salonia, Pierangela Ciuffreda, Roberta Ottria
The endocannabinoid system is a signaling system involved in a wide range of biological effects. Literature strongly suggests the endocannabinoid system role in the pathogenesis of cancer and that its pharmacological activation produces therapeutic benefits. Last research promotes the endocannabinoid system modulation by inhibition of endocannabinoids hydrolytic enzymes instead of direct activation of endocannabinoid receptors to avoid detrimental effects on cognition and motor control. Here we report the identification of N-acylethanolamine-hydrolyzing acid amidase (NAAA) inhibitors able to reduce cell proliferation and migration and cause cell death on different bladder cancer cell lines...
December 27, 2016: Bioorganic & Medicinal Chemistry
Irini Abdiaj, Jesús Alcázar
We report herein the transfer of dual photoredox and nickel catalysis for C(sp(2))C(sp(3)) cross coupling form batch to flow. This new procedure clearly improves the scalability of the previous batch reaction by the reactor's size and operating time reduction, and allows the preparation of interesting compounds for drug discovery in multigram amounts.
December 27, 2016: Bioorganic & Medicinal Chemistry
Daniela Vullo, Sonia Del Prete, Alessio Nocentini, Sameh M Osman, Zeid AlOthman, Clemente Capasso, Murat Bozdag, Fabrizio Carta, Paola Gratteri, Claudiu T Supuran
A series of dithiocarbamates (DTCs) was investigated for the inhibition of the β-class carbonic anhydrase (CAs, EC from the fungal parasite Malassezia globosa, MgCA, a validated anti-dandruff drug target. These DTCs incorporate various scaffold, among which those of N,N-dimethylaminoethylenediamine, the aminoalcohols with 3-5 carbon atoms in their molecule, 3-amino-quinuclidine, piperidine, morpholine and piperazine derivatives, as well as phenethylamine and its 4-sulfamoylated derivative. Several DTCs resulted more effective in inhibiting MgCA compared to the standard sulfonamide drug acetazolamide (KI of 74μM), with KIs ranging between 383 and 6235nM...
December 27, 2016: Bioorganic & Medicinal Chemistry
Belma Zengin Kurt, Isil Gazioglu, Aydan Dag, Ramin Ekhteiari Salmas, Gülru Kayık, Serdar Durdagi, Fatih Sonmez
New thymol and carvacrol derivatives with the carbamate moiety were synthesized and their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated. 5-isopropyl-2-methylphenyl(3-fluorophenyl)carbamate (29) was found to be the most potent AChE inhibitor with IC50 values of 2.22μM, and 5-isopropyl-2-methylphenyl (4-fluorophenyl)carbamate (30) exhibited the strongest inhibition against BuChE with IC50 value of 0.02μM. Additionally, the result of H4IIE hepatoma cell toxicity assay for compounds 18, 20, 29, 30 and 35 showed negligible cell death at 0...
December 26, 2016: Bioorganic & Medicinal Chemistry
Carla Grosso, Ana L Cardoso, Maria João Rodrigues, Cátia Marques, Luísa Barreira, Américo Lemos, Teresa M D V Pinho E Melo
A novel synthetic approach to bis(indolyl)methanes has been established. Our one-pot synthetic strategy based on two consecutive hetero-Diels-Alder cycloaddition reactions of electrophilic conjugated nitrosoalkenes with indoles was extended to a range of new 1-hydroxyiminomethyl-bis(indolyl)methanes. Furthermore, a similar and broad range approach was applied to the synthesis of previously unknown 1-hydrazonomethyl-bis(indolyl)methanes. The biological evaluation of the new bis(indolyl)methanes as anti-cancer agents was investigated...
December 26, 2016: Bioorganic & Medicinal Chemistry
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