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Bioorganic & Medicinal Chemistry Letters

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https://www.readbyqxmd.com/read/28739043/pocket-detection-and-interaction-weighted-ligand-similarity-search-yields-novel-high-affinity-binders-for-myocilin-olf-a-protein-implicated-in-glaucoma
#1
Bharath Srinivasan, Sam Tonddast-Navaei, Jeffrey Skolnick
Traditional structure and ligand based virtual screening approaches rely on the availability of structural and ligand binding information. To overcome this limitation, hybrid approaches were developed that relied on extraction of ligand binding information from proteins sharing similar folds and hence, evolutionarily relationship. However, they cannot target a chosen pocket in a protein. To address this, a pocket centric virtual ligand screening approach is required. Here, we employ a new, iterative implementation of a pocket and ligand-similarity based approach to virtual ligand screening to predict small molecule binders for the olfactomedin domain of human myocilin implicated in glaucoma...
July 12, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28733083/design-synthesis-and-in-vitro-anticancer-activity-of-novel-quinoline-and-oxadiazole-derivatives-of-ursolic-acid
#2
Wen Gu, Xiao-Yan Jin, Dong-Dong Li, Shi-Fa Wang, Xu-Bing Tao, Hao Chen
A series of new quinoline derivatives of ursolic acid were designed and synthesized in an attempt to develop potential anticancer agents. The structures of these compounds were identified by (1)H NMR, (13)C NMR, IR and ESI-MS spectra analysis. The target compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines (MDA-MB-231, Hela and SMMC-7721). From the results, compounds 3a-d displayed significant antitumor activity against three cancer cell lines. Especially, compound 3b was found to be the most potent derivative with IC50 values of 0...
July 12, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28729057/neuropathic-pain-alleviating-effects-of-pyrazole-conjugated-arylsulfonamides-as-5-ht6-receptor-antagonists
#3
Jin Ri Hong, Hyunah Choo, Ghilsoo Nam
A novel series of arylsulfonylaminomethyl-3-(1-phenyl-5-isopropyl)pyrazoles was evaluated for serotonin receptor subtype 6 (5-HT6R) antagonistic effects in vitro. We also investigated their neuropathic pain-alleviating effects in vivo using a rat spinal nerve ligation (SNL) model. Bicyclic aromatic sulfonamino groups, such as naphthalene and quinolin-substituted derivatives, showed good 5-HT6 inhibitory activity in vitro. Among them, selected compounds, 12 and 13, having 8-quinoylsulfonamino groups, showed potent neuropathic pain-alleviating effects in the rat model...
July 11, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28729055/novel-1-2-dihydroquinazolin-2-ones-design-synthesis-and-biological-evaluation-against-trypanosoma-brucei
#4
ThanhTruc Pham, Madeline Walden, Christopher Butler, Rosario Diaz-Gonzalez, Guiomar Pérez-Moreno, Gloria Ceballos-Pérez, Veronica Gomez-Pérez, Raquel García-Hernández, Henry Zecca, Emma Krakoff, Brian Kopec, Ogar Ichire, Caden Mackenzie, Marika Pitot, Luis Miguel Ruiz, Francisco Gamarro, Dolores González-Pacanowska, Miguel Navarro, Amy B Dounay
In 2014, a published report of the high-throughput screen of>42,000 kinase inhibitors from GlaxoSmithKline against T. brucei identified 797 potent and selective hits. From this rich data set, we selected NEU-0001101 (1) for hit-to-lead optimization. Through our preliminary compound synthesis and SAR studies, we have confirmed the previously reported activity of 1 in a T. brucei cell proliferation assay and have identified alternative groups to replace the pyridyl ring in 1. Pyrazole 24 achieves improvements in both potency and lipophilicity relative to 1, while also showing good in vitro metabolic stability...
July 11, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28729056/discovery-and-structure-activity-relationship-of-auriculatone-a-potent-hepatoprotective-agent-against-acetaminophen-induced-liver-injury
#5
Meng Zhou, Min Wang, Rui-Feng Zhong, Xiang-Ming Liao, Lian-Li Deng, Guo-Bo Xu, Xun He, Jing Li, Yong-Jun Li, Ting Liu, Yong-Lin Wang, Shang-Gao Liao
Acetaminophen (APAP, paracetamol) overdose has been the most frequent cause of drug-induced liver failure. APAP-induced liver toxicity can be fatal in many cases even with treatment of the clinically used N-acetylcysteine (NAC), and the need for novel therapeutic agents is apparent. Through evaluating the hepatoprotective effects of the co-occurring substances present in oleanolic acid tablets which have been used in China for decades as an adjuvant therapy for acute and chronic hepatitis, auriculatone was found to protect HL-7702 cells from APAP-induced liver injury comparable to NAC at the concentration of 10μM...
July 10, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28705642/corrigendum-to-synthesis-and-carbonic-anhydrase-inhibitory-properties-of-novel-chalcone-substituted-benzenesulfonamides-bioorg-med-chem-lett-26-2016-5867-5870
#6
Tayfun Arslan, Emir Alper Türkoğlu, Murat Şentürk, Claudiu T Supuran
No abstract text is available yet for this article.
July 10, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28734582/the-hydrolytic-susceptibility-of-prochelator-bsih-in-aqueous-solutions
#7
Qin Wang, Katherine J Franz
The prochelator BSIH ((E)-N'-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)isonicotinohydrazide) contains a boronate group that prevents metal coordination until reaction with peroxide releases the iron chelator SIH ((E)-N'-(2-hydroxybenzylidene)isonicotinohydrazide). BSIH exists in aqueous buffer and cell culture media in equilibrium with its hydrolysis products isoniazid and (2-formylphenyl)boronic acid (FBA). The relative concentrations of these species limit the yield of intact SIH available for targeted iron chelation...
July 8, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28729054/isosorbide-based-peptidomimetics-as-inhibitors-of-hepatitis-c-virus-serine-protease
#8
Aline C Portela, Thalita G Barros, Camilo H da S Lima, Luiza R S Dias, Pedro H R de A Azevedo, Anna Sophia C L Dantas, Ronaldo Mohana-Borges, Gustavo T Ventura, Sergio Pinheiro, Estela M F Muri
Hepatitis C infection is a cause of chronic liver diseases such as cirrhosis and carcinoma. The current therapy for hepatitis C has limited efficacy and low tolerance. The HCV encodes a serine protease which is critical for viral replication, and few protease inhibitors are currently on the market. In this paper, we describe the synthesis and screening of novel isosorbide-based peptidomimetic inhibitors, in which the compounds 1d, 1e, and 1i showed significant inhibition of the protease activity in vitro at 100µM...
July 8, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28720505/chemically-generated-igg2-bispecific-antibodies-through-disulfide-bridging
#9
James T Patterson, Edwige Gros, Heyue Zhou, Ghazi Atassi, Lisa Kerwin, Lisa Carmody, Tong Zhu, Bryan Jones, Yanwen Fu, Gunnar F Kaufmann
Bispecific antibodies (BsAbs) are designed to engage two antigens simultaneously, thus, effectively expanding the ability of antibody-based therapeutics to target multiple pathways within the same cell, engage two separate soluble antigens, bind the same antigen with distinct paratopes, or crosslink two different cell types. Many recombinant BsAb formats have emerged, however, expression and purification of such constructs can often be challenging. To this end, we have developed a chemical strategy for generating BsAbs using native IgG2 architecture...
July 8, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28720504/synthesis-of-novel-hybrids-of-pyrazole-and-coumarin-as-dual-inhibitors-of-cox-2-and-5-lox
#10
Fa-Qian Shen, Zhong-Chang Wang, Song-Yu Wu, Shen-Zhen Ren, Ruo-Jun Man, Bao-Zhong Wang, Hai-Liang Zhu
In our previous study, we designed a series of pyrazole derivatives as novel COX-2 inhibitors. In order to obtain novel dual inhibitors of COX-2 and 5-LOX, herein we designed and synthesized 20 compounds by hybridizing pyrazole with substituted coumarin who was reported to exhibit 5-LOX inhibition to select potent compounds using adequate biological trials sequentially including selective inhibition of COX-2 and 5-LOX, anti-proliferation in vitro, cells apoptosis and cell cycle. Among them, the most potent compound 11g (IC50=0...
July 8, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28720502/design-synthesis-and-in-vitro-anti-mycobacterial-evaluation-of-gatifloxacin-1h-1-2-3-triazole-isatin-hybrids
#11
Zhi Xu, Shu Zhang, Xufeng Song, Min Qiang, Zaosheng Lv
A set of novel gatifloxacin-1H-1,2,3-triazole-isatin hybrids 6a-l was designed, synthesized and evaluated for their in vitro anti-mycobacterial activities against M. tuberculosis (MTB) H37Rv and MDR-TB as well as cytotoxicity. The results showed that all the targets (MIC: 0.025-3.12μg/mL) exhibited excellent inhibitory activity against MTB H37Rv and MDR-TB, but were much more toxic (CC50: 7.8-62.5μg/mL) than the parent gatifloxacin (GTFX) (CC50: 125μg/mL). Among them, 61 (MIC: 0.025μg/mL) was 2-32 times more potent in vitro than the references INH (MIC: 0...
July 8, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28716495/3-5-bis-3-dimethylaminomethyl-4-hydroxybenzylidene-4-piperidone-and-related-compounds-induce-glutathione-oxidation-and-mitochondria-mediated-cell-death-in-hct-116-colon-cancer-cells
#12
Eshwari Addala, Hossein Rafiei, Swagatika Das, Brian Bandy, Umashankar Das, Subhas S Karki, Jonathan R Dimmock
This study aims at investigating the cytotoxicity and some of the modes of action of 3,5-bis(3-dimethylamino-4-hydroxybenzylidene)-4-piperidone trihydrochloride 3 and two related compounds 2 (which lacks the dimethylaminomethyl groups) and 4 (which has an additional dimethylaminoethyl substituent in both aryl rings) in order to ascertain the contribution of dimethylaminoethyl substituent to bioactivity. The bioactivities of 2-4 were compared with curcumin 5. Both 2 and 3 displayed submicromolar GI50 values towards HCT-116 cells and were significantly more potent than 4, 5 and 5-fluorouracil (5-FU)...
July 5, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28716494/synthesis-and-in-vitro-antiproliferative-activities-of-5-aryl-1-2-4-oxadiazole-3-yl-methyl-d-ribofuranosides
#13
Romina E Avanzo, José M Padrón, Norma B D'Accorso, Mirta L Fascio
The emergence of multidrug resistance cell lines is one of the major obstacles in the success of cancer chemotherapeutic treatment. Therefore, it remains a big challenge the development of new and effective drugs to defeat cancer. The presence of nitrogen heterocycles in the architectural design of drugs has led to the discovery of new leading compounds. Herein, we report the synthesis, characterization and in vitro antiproliferative activity against six cancer cell lines of d-ribofuranoside derivatives bearing a 1,2,4-oxadiazolic ring, with the aim of developing new active compounds...
July 5, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28712709/synthesis-and-biological-evaluation-of-novel-1-2-3-triazole-derivatives-as-anti-tubercular-agents
#14
Abdul Aziz Ali, Dhrubajyoti Gogoi, Amrita K Chaliha, Alak K Buragohain, Priyanka Trivedi, Prakash J Saikia, Praveen S Gehlot, Arvind Kumar, Vinita Chaturvedi, Diganta Sarma
A library of seventeen novel 1,2,3-triazole derivatives were efficiently synthesized in excellent yields by the popular 'click chemistry' approach and evaluated in vitro for their anti-tubercular activity against Mycobacterium tuberculosis H37Ra (ATCC 25177 strain). Among the series, six compounds exhibited significant activity with minimum inhibitory concentration (MIC) values ranging from 3.12 to 0.78μg/mL and along with no significant cytotoxicity against MBMDMQs (mouse bone marrow derived macrophages)...
July 5, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28712708/discovery-of-novel-2-3-phenylpiperazin-1-yl-pyrimidin-4-ones-as-glycogen-synthase-kinase-3%C3%AE-inhibitors
#15
Yoshihiro Usui, Fumiaki Uehara, Shinsuke Hiki, Kazutoshi Watanabe, Hiroshi Tanaka, Aya Shouda, Satoshi Yokoshima, Keiichi Aritomo, Takashi Adachi, Kenji Fukunaga, Shinji Sunada, Mika Nabeno, Ken-Ichi Saito, Jun-Ichi Eguchi, Keiji Yamagami, Shouichi Asano, Shinji Tanaka, Satoshi Yuki, Narihiko Yoshii, Masatake Fujimura, Takashi Horikawa
We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3β inhibitors from our promising compounds containing a 2-phenylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3β inhibitors. SAR studies focused on the phenyl moiety revealed that a 4-fluoro-2-methoxy group afforded potent inhibitory activity toward GSK-3β. Based on docking studies, new hydrogen bonding between the nitrogen atom of the piperazine moiety and the oxygen atom of the main chain of Gln185 has been indicated, which may contribute to increased activity compared with that of the corresponding phenylmorpholine analogues...
July 5, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28712707/discovery-of-a-potent-angiotensin-converting-enzyme-inhibitor-via-virtual-screening
#16
Zhipeng Ke, Zhenzhen Su, Xinzhuang Zhang, Zeyu Cao, Yue Ding, Liang Cao, Gang Ding, Zhenzhong Wang, Haichun Liu, Wei Xiao
Prompted by the prominent role of angiotensin converting enzyme (ACE) in hypertension, heart failures, myocardial infarction and diabetic nephropathy, we have attempted to discover novel ACE inhibitors through ligand-based virtual screening. Molecular docking method and rigorously validated model was utilized to search a natural compounds database. Finally, 36 compounds were randomly selected and subjected to in vitro ACE kinase inhibitory assay using fluorescence assays method. The results showed that three compounds (Licochalcone A, Echinatin and EGCG) have strong potential to be developed as a new class of ACE inhibitors...
July 5, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28712706/discovery-of-novel-2-4-aryl-2-methylpiperazin-1-yl-pyrimidin-4-ones-as-glycogen-synthase-kinase-3%C3%AE-inhibitors
#17
Toshiyuki Kohara, Kazuki Nakayama, Kazutoshi Watanabe, Shin-Ichi Kusaka, Daiki Sakai, Hiroshi Tanaka, Kenji Fukunaga, Shinji Sunada, Mika Nabeno, Ken-Ichi Saito, Jun-Ichi Eguchi, Akiko Mori, Shinji Tanaka, Tomoko Bessho, Keiko Takiguchi-Hayashi, Takashi Horikawa
We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3β inhibitors from our promising compounds containing a 3-methylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3β inhibitors. SAR studies focused on the nitrogen atom of the piperazine moiety revealed that a phenyl group afforded potent inhibitory activity toward GSK-3β. Docking studies indicated that the phenyl group on the piperazine nitrogen atom and the methyl group on the piperazine make cation-π and CH-π interactions with GSK-3β respectively...
July 5, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28711353/synthesis-and-antibacterial-evaluation-of-novel-11-o-carbamoyl-clarithromycin-ketolides
#18
Li Jia, Mi Yan, Yan Shen, Yinhui Qin, Shengsheng Qiang, Shutao Ma
A series of novel 11-O-carbamoyl clarithromycin ketolides were designed, synthesized and evaluated for their in vitro antibacterial activity. The results showed that the majority of the target compounds displayed improved activity compared with references against erythromycin-resistant S. pneumoniae A22072 expressing the mef gene, S. pneumoniae B1 expressing the erm gene and S. pneumoniae AB11 expressing the mef and erm genes. In particular, compounds 9, 18, 19 and 22 showed the most potent activity against erythromycin-resistant S...
July 5, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28709828/augmenting-the-efficacy-of-anti-cocaine-catalytic-antibodies-through-chimeric-hapten-design-and-combinatorial-vaccination
#19
Cody J Wenthur, Xiaoqing Cai, Beverly A Ellis, Kim D Janda
Given the need for further improvements in anti-cocaine vaccination strategies, a chimeric hapten (GNET) was developed that combines chemically-stable structural features from steady-state haptens with the hydrolytic functionality present in transition-state mimetic haptens. Additionally, as a further investigation into the generation of an improved bifunctional antibody pool, sequential vaccination with steady-state and transition-state mimetic haptens was undertaken. While GNET induced the formation of catalytically-active antibodies, it did not improve overall behavioral efficacy...
July 5, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28739044/essential-structure-of-orexin-1-receptor-antagonist-ynt-707-part-i-role-of-the-4-5-epoxy-ring-for-binding-with-orexin-1-receptor
#20
Naoshi Yamamoto, Sayaka Ohrui, Takahiro Okada, Masahiro Yata, Tsuyoshi Saitoh, Noriki Kutsumura, Yasuyuki Nagumo, Yoko Irukayama-Tomobe, Yasuhiro Ogawa, Yukiko Ishikawa, Yurie Watanabe, Daichi Hayakawa, Hiroaki Gouda, Masashi Yanagisawa, Hiroshi Nagase
The essential structure of the orexin 1 receptor (OX1R) antagonist YNT-707 (2) was clarified, particularly the roles to OX1R antagonist activities of the 3-OMe, the 4,5-epoxy ring, the 14-hydroxy group, and the orientation of the 6-amide side chain. The 3-OMe and 17-sulfonamide group were shown to be essential for the OX1R antagonistic activity. The 4,5-epoxy ring plays an important role for the active orientation of the 6-amide group. The 14-hydroxy group could lower the activity of the 6β-amide isomer by the interaction of the 14-hydroxy group with the 6-amide group, which could orient the 6-amide group toward the upper side of the C-ring...
July 4, 2017: Bioorganic & Medicinal Chemistry Letters
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