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Bioorganic & Medicinal Chemistry Letters

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https://www.readbyqxmd.com/read/28526368/synthesis-and-molecular-docking-study-of-some-5-6-dichloro-2-cyclopropyl-1h-benzimidazole-derivatives-bearing-triazole-oxadiazole-and-imine-functionalities-as-potent-inhibitors-of-urease
#1
Emre Menteşe, Hakan Bektaş, Bahar Bilgin Sokmen, Mustafa Emirik, Demet Çakır, Bahittin Kahveci
A new series of benzimidazole compounds including hydrazinecarbothioamide, 1,2,4-triazole, 1,3,4-oxadiazole and imine function were synthesized starting from 5,6-dichloro-2-cyclopropyl-1H-benzimidazole. All of the benzimidazole derivatives exhibited good urease inhibitor activity. Compound 6a proved to be the most potent showing an enzyme inhibitory activity with an IC50=0.06µM. Molecular docking studies were also conducted on enzyme extracted from Jack bean urease to identify the binding mode of the newly synthesized compounds...
May 10, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28526367/discovery-of-a-novel-aminopyrazine-series-as-selective-pi3k%C3%AE-inhibitors
#2
Bernard Barlaam, Sabina Cosulich, Martina Fitzek, Hervé Germain, Stephen Green, Lyndsey L Hanson, Craig S Harris, Urs Hancox, Kevin Hudson, Christine Lambert-van der Brempt, Maryannick Lamorlette, Françoise Magnien, Gilles Ouvry, Ken Page, Linette Ruston, Lara Ward, Bénédicte Delouvrié
We report the discovery of a novel aminopyrazine series of PI3Kα inhibitors, designed by hybridizing two known scaffolds of PI3K inhibitors. We describe the progress achieved from the first compounds plagued with poor general kinase selectivity to compounds showing high selectivity for PI3Kα over PI3Kβ and excellent general kinase selectivity. This effort culminated with the identification of compound 5 displaying high potency and selectivity, and suitable physiochemical and pharmacokinetic properties for oral administration...
May 10, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28526370/synthesis-and-biological-evaluation-of-kresoxim-methyl-analogues-as-novel-inhibitors-of-hypoxia-inducible-factor-hif-1-accumulation-in-cancer-cells
#3
Sanghyuck Lee, Oh Seok Kwon, Chang-Soo Lee, Misun Won, Hyun Seung Ban, Choon Sup Ra
We designed and synthesized strobilurin analogues as hypoxia-inducible factor (HIF) inhibitors based on the molecular structure of kresoxim-methyl. Biological evaluation in human colorectal cancer HCT116 cells showed that most of the synthesized kresoxim-methyl analogues possessed moderate to potent inhibitory activity against hypoxia-induced HIF-1 transcriptional activation. Three candidates, compounds 11b, 11c, and 11d were identified as potent inhibitors against HIF-1 activation with IC50 values of 0.60-0...
May 9, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28499732/activity-of-resveratrol-triesters-against-primary-acute-lymphoblastic-leukemia-cells
#4
Alicja Urbaniak, Magdalena Delgado, Karol Kacprzak, Timothy C Chambers
Resveratrol is a common polyphenol of plant origin known for its cancer prevention and other properties. Its wider application is limited due to poor water solubility, low stability, and weak bioavailability. To overcome these limitations, a series of 13 novel resveratrol triesters were synthesized previously. In this paper, we describe the synthesis of 3 additional derivatives and the activity of all 16 against primary acute lymphoblastic leukemia cells. Of these, 3 compounds were more potent than resveratrol (IC50=10...
May 9, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28527823/antiviral-escin-derivatives-from-the-seeds-of-aesculus-turbinata-blume-japanese-horse-chestnut
#5
Ji Won Kim, Thi-Kim-Quy Ha, Hyomoon Cho, Eunhee Kim, Sang Hee Shim, Jun-Li Yang, Won Keun Oh
Porcine epidemic diarrhea virus (PEDV) causes severe diarrhea and high fatality of piglets, influencing the swine industry. Japanese horse chestnut (seed of Aesculus turbinata) contains many saponin mixtures, called escins, and has been used for a long time as a traditional medicinal plant. Structure-activity relationship (SAR) studies on escins have revealed that acylations at C-21 and C-22 with angeloyl or tigloyl groups were important for their cytotoxic effects. However, the strong cytotoxicity of escins makes them hard to utilize for other diseases and to develop as nutraceuticals...
May 8, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28526369/quorum-sensing-modulators-exhibit-cytotoxicity-in-hodgkin-s-lymphoma-cells-and-interfere-with-nf-%C3%AE%C2%BAb-signaling
#6
Natarajan Nandakumar, Rambabu Dandela, Jacob Gopas, Michael M Meijler
In recent years it has become evident that bacteria can modulate signaling pathways in host cells through the secretion of small signaling molecules. We have evaluated the cytotoxic effects and NF-κB inhibitory activities of a panel of quorum sensing molecules and their reactive analogs on Hodgkin's lymphoma cells (L428). We found that several molecules inhibited NF-κB signaling in a dose dependent manner. Three inhibitors (ITC-12, ITC-Cl and Br-Furanone) showed 50% NF-κB inhibition at concentrations less than 10µM (4...
May 6, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28522253/challenges-in-the-development-of-an-m4-pam-preclinical-candidate-the-discovery-sar-and-in-vivo-characterization-of-a-series-of-3-aminoazetidine-derived-amides
#7
James C Tarr, Michael R Wood, Meredith J Noetzel, Jeanette L Bertron, Rebecca L Weiner, Alice L Rodriguez, Atin Lamsal, Frank W Byers, Sichen Chang, Hyekyung P Cho, Carrie K Jones, Colleen M Niswender, Michael W Wood, Nicholas J Brandon, Mark E Duggan, P Jeffrey Conn, Thomas M Bridges, Craig W Lindsley
This letter details the continued chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core by incorporating a 3-amino azetidine amide moiety. The analogs described within this work represent the most potent M4 PAMs reported for this series to date. The SAR to address potency, clearance, subtype selectivity, CNS exposure, and P-gp efflux are described. This work culminated in the discovery of VU6000918, which demonstrated robust efficacy in a rat amphetamine-induced hyperlocomotion reversal model at a minimum efficacious dose of 0...
May 6, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28512032/cytotoxic-triterpene-diglycosides-from-the-sea-cucumber-stichopus-horrens
#8
Nguyen Xuan Cuong, Le Thi Vien, Le Hoang, Tran Thi Hong Hanh, Do Thi Thao, Nguyen Van Thanh, Nguyen Hoai Nam, Do Cong Thung, Phan Van Kiem, Chau Van Minh
Using various chromatographic separation techniques, eight triterpene diglycosides (1-8), including four new compounds namely stichorrenosides A-D (1-4), were isolated from a methanol extract of the Vietnamese sea cucumber S. horrens. Their structures were elucidated based on spectroscopic analyses, including HR ESI MS, 1D and 2D NMR. Their in vitro cytotoxic activity against five human cancer cell lines, Hep-G2 (hepatoma cancer), KB (epidermoid carcinoma), LNCaP (prostate cancer), MCF7 (breast cancer), and SK-Mel2 (melanoma), was evaluated using SRB methods...
May 6, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28512025/synthesis-of-methanesulphonamido-benzimidazole-derivatives-as-gastro-sparing-antiinflammatory-agents-with-antioxidant-effect
#9
Ratika Sharma, Alka Bali, Bhim Bahadur Chaudhari
A series of 5-methanesulphonamido benzimidazole derivatives were designed by combining the structural features of clinically useful anti-inflammatory drugs (nimesulide and rofecoxib) and antiulcer drugs (lansoprazole, omeprazole, etc.) based on physicochemical and 3D similarity studies. The compounds were evaluated for their anti-inflammatory activity in carrageenan induced rat paw edema model taking rofecoxib and indomethacin as standard drugs. In vitro antioxidant activity of the compounds was assessed by potassium ferricyanide reducing power (PFRAP) assay...
May 6, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28512023/synthesis-and-biological-evaluation-of-novel-5-aryl-4-5-nitrofuran-2-yl-pyrimidines-as-potential-anti-bacterial-agents
#10
Egor V Verbitskiy, Svetlana A Baskakova, Natal'ya A Gerasimova, Natal'ya P Evstigneeva, Natal'ya V Zil'berberg, Nikolay V Kungurov, Marionella A Kravchenko, Sergey N Skornyakov, Marina G Pervova, Gennady L Rusinov, Oleg N Chupakhin, Valery N Charushin
A facile two-step synthetic approach to fluorinated and non-fluorinated 5-aryl-4-(5-nitrofuran-2-yl)-pyrimidines from readily available 5-bromo-4-(furan-2-yl)pyrimidine has been developed. All synthesized compounds were screened in vitro for their antibacterial activities against twelve various bacterial strains. It is demonstrated that some of these compounds exhibited significant antibacterial activities against strains Neisseria gonorrhoeae and Staphylococcus aureus, comparable and even higher with that commercial drug Spectinomycin...
May 6, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28512031/from-a-novel-hts-hit-to-potent-selective-and-orally-bioavailable-kdm5-inhibitors
#11
Jun Liang, Sharada Labadie, Birong Zhang, Daniel F Ortwine, Snahel Patel, Maia Vinogradova, James R Kiefer, Till Mauer, Victor S Gehling, Jean-Christophe Harmange, Richard Cummings, Tommy Lai, Jiangpeng Liao, Xiaoping Zheng, Yichin Liu, Amy Gustafson, Erica Van der Porten, Weifeng Mao, Bianca M Liederer, Gauri Deshmukh, Le An, Yingqing Ran, Marie Classon, Patrick Trojer, Peter S Dragovich, Lesley Murray
A high-throughput screening (HTS) of the Genentech/Roche library identified a novel, uncharged scaffold as a KDM5A inhibitor. Lacking insight into the binding mode, initial attempts to improve inhibitor potency failed to improve potency, and synthesis of analogs was further hampered by the presence of a C-C bond between the pyrrolidine and pyridine. Replacing this with a C-N bond significantly simplified synthesis, yielding pyrazole analog 35, of which we obtained a co-crystal structure with KDM5A. Using structure-based design approach, we identified 50 with improved biochemical, cell potency and reduced MW and lower lipophilicity (LogD) compared with the original hit...
May 5, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28512029/calixarene-mediated-liquid-membrane-transport-of-choline-conjugates-3-the-effect-of-handle-variation-on-neurotransmitter-transport
#12
James L Collins, Ayu Fujii, Sahar Roshandel, Cuong-Alexander To, Michael P Schramm
Upper rim phosphonic acid functionalized calix[4]arene affects selective transport of multiple molecular payloads through a liquid membrane. The secret is in the attachment of a receptor-complementary handle to the payload. We find that the trimethylammonium ethylene group present in choline is one of several general handles for the transport of drug and drug-like species. Herein we compare the effect of handle variation against the transport of serotonin and dopamine. We find that several ionizable amine termini handles are sufficient for transport and identify two ideal candidates...
May 5, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28512024/repurposing-of-proton-pump-inhibitors-as-first-identified-small-molecule-inhibitors-of-endo-%C3%AE-n-acetylglucosaminidase-engase-for-the-treatment-of-ngly1-deficiency-a-rare-genetic-disease
#13
Yiling Bi, Matthew Might, Hariprasad Vankayalapati, Balagurunathan Kuberan
N-Glycanase deficiency, or NGLY1 deficiency, is an extremely rare human genetic disease. N-Glycanase, encoded by the gene NGLY1, is an important enzyme involved in protein deglycosylation of misfolded proteins. Deglycosylation of misfolded proteins precedes the endoplasmic reticulum (ER)-associated degradation (ERAD) process. NGLY1 patients produce little or no N-glycanase (Ngly1), and the symptoms include global developmental delay, frequent seizures, complex hyperkinetic movement disorder, difficulty in swallowing/aspiration, liver dysfunction, and a lack of tears...
May 5, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28512022/synthesis-antimycobacterial-activity-and-docking-study-of-2-aroyl-1-benzopyrano-4-3-c-pyrazol-4-1h-one-derivatives-and-related-hydrazide-hydrazones
#14
Violina T Angelova, Violeta Valcheva, Tania Pencheva, Yulian Voynikov, Nikolay Vassilev, Rositsa Mihaylova, Georgi Momekov, Boris Shivachev
A new convenient method for preparation of 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives 5b-g and coumarin containing hydrazide-hydrazone analogues 4a-e was presented. The antimycobacterial activity against reference strain Mycobacterium tuberculosis H37Rv and cytotoxicity against the human embryonic kidney cell line HEK-293 were tested in vitro. All compounds demonstrated significant minimum inhibitory concentrations (MIC) ranging 0.28-1.69μM, which were comparable to those of isoniazid. The cytotoxicity (IC50>200µM) to the "normal cell" model HEK-293T exhibited by 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives 5b-e, was noticeably milder compared to that of their hydrazone analogues 4a-e (IC50 33-403µM)...
May 5, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28506754/synthesis-biological-evaluation-and-molecular-docking-studies-of-chromone-hydrazone-derivatives-as-%C3%AE-glucosidase-inhibitors
#15
Guangcheng Wang, Ming Chen, Jing Wang, Yaping Peng, Luyao Li, ZhenZhen Xie, Bing Deng, Shan Chen, Wenbiao Li
A series of chromone hydrazone derivatives 4a-4p have been synthesized, characterized by (1)H NMR and (13)C NMR and evaluated for theirinvitro α-glucosidase inhibitory activity. Out of these tested compounds, six (4a, 4b, 4d, 4j, 4o and 4p) displayed potent α-glucosidase inhibitory activity with IC50 values in the range of 20.1±0.19μM to 45.7±0.23μM, as compared to the standard drug acarbose (IC50=817.38±6.27μM). Among this series, compound 4d (IC50=20.1±0.19μM) with 4-sulfonamide substitution at phenyl part of hydrazide was found to be the most active compound...
May 5, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28512027/insights-into-the-myosin-ii-inhibitory-potency-of-a-ring-modified-s-blebbistatin-analogs
#16
Sigrid Verhasselt, Christian V Stevens, Tom Van den Broecke, Marc E Bracke, Bart I Roman
Myosin II is an interesting target for therapeutic intervention, as it is involved in a large number of motility-based diseases. (S)-Blebbistatin is a known micromolar inhibitor of this protein. A new series of (S)-blebbistatin derivatives with a modified A-ring was synthesized and the myosin II inhibitory properties were evaluated in vitro. In this way, we gained insight into the influence of structural modifications in this part of the scaffold on myosin II inhibitory potency. Our results indicate there are few possibilities for potency enhancement via ring A modification of the blebbistatin scaffold...
May 4, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28506753/phenylbenzenesulfonates-and-sulfonamides-as-17%C3%AE-hydroxysteroid-dehydrogenase-type-2-inhibitors-synthesis-and-sar-analysis
#17
Anna Vuorinen, Roger T Engeli, Susanne Leugger, Christoph R Kreutz, Daniela Schuster, Alex Odermatt, Barbara Matuszczak
17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) converts the potent estrogen estradiol into the weakly active keto form estrone. Because of its expression in bone, inhibition of 17β-HSD2 provides an attractive strategy for the treatment of osteoporosis, a condition that is often caused by a decrease of the active sex steroids. Currently, there are no drugs on the market targeting 17β-HSD2, but in multiple studies, synthesis and biological evaluation of promising 17β-HSD2 inhibitors have been reported...
May 4, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28506750/cytotoxic-and-apoptosis-inducing-activities-against-human-lung-cancer-cell-lines-of-cassaine-diterpenoids-from-the-bark-of-erythrophleum-fordii
#18
Manh Tuan Ha, Manh Hung Tran, Thien Thuong Phuong, Jeong Ah Kim, Mi Hee Woo, Jae Sue Choi, Suhyun Lee, Jeong Hyung Lee, Hyeong Kyu Lee, Byung Sun Min
A phytochemical investigation into the bark of Erythrophleum fordii yielded four new compounds, two new cassaine diterpenoids (erythrofordin T and U, 1 and 2) and two new cassaine diterpenoid amines (erythroformine A and B, 6 and 7), as well as nine known compounds. We report for the first time the isolation of erythrofordin V (3) from a natural source and that of the remaining eight known diterpenoids (4-5, 8-13) from E. fordii. All structures were elucidated using spectroscopic analysis. Cytotoxic activity of the isolated compounds (1-13) was examined in vitro against three non-small cell lung cancer cell lines (A549, NCI-H1975, and NCI-H1229) using the MTT assay...
May 4, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28501514/stabilizing-hdac11-with-saha-to-assay-slow-binding-benzamide-inhibitors
#19
Yinping Tian, Wenhui Lv, Xuewei Li, Congying Wang, Dayuan Wang, Peng G Wang, Jin Jin, Jie Shen
Among 18 human histone deacetylases (HDAC), HDAC11 is least studied. MS275, a benzamide HDAC inhibitor (HDACi), was stereotypically considered to selectively target Class I HDACs. We verified this slow-binding inhibitor also targeted HDAC11. In a traditional enzyme based assay, MS275 at low concentrations surprisingly behaved as an agonist. This was attributed to the poor stability of HDAC11 which lost 40% activity in 3h at 37°C. By adding 0.2μM SAHA, HDAC11 activity was stabilized during the 3-h assay period...
May 4, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28501513/qsar-studies-of-the-bioactivity-of-hepatitis-c-virus-hcv-ns3-4a-protease-inhibitors-by-multiple-linear-regression-mlr-and-support-vector-machine-svm
#20
Zijian Qin, Maolin Wang, Aixia Yan
In this study, quantitative structure-activity relationship (QSAR) models using various descriptor sets and training/test set selection methods were explored to predict the bioactivity of hepatitis C virus (HCV) NS3/4A protease inhibitors by using a multiple linear regression (MLR) and a support vector machine (SVM) method. 512 HCV NS3/4A protease inhibitors and their IC50 values which were determined by the same FRET assay were collected from the reported literature to build a dataset. All the inhibitors were represented with selected nine global and 12 2D property-weighted autocorrelation descriptors calculated from the program CORINA Symphony...
May 3, 2017: Bioorganic & Medicinal Chemistry Letters
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