- Development of coumarine derivatives as potent anti-filovirus entry inhibitors targeting viral glycoprotein
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Filoviruses, including Ebolavirus (EBOV), Marburgvirus (MARV) and Cuevavirus, cause hemorrhagic fevers in humans with up to 90% mortality rates. In the 2014–2016 West Africa Ebola epidemic, there are 15,261 laboratory confirmed cases and 11,325 total deaths. The lack of effective vaccines and medicines for the prevention and treatment of filovirus infection in humans stresses the urgency to develop antiviral therapeutics against filovirus-associated diseases. Our previous study identified a histamine receptor antagonist compound CP19 as an entry inhibitor against both EBOV and MARV. The preliminary structure-activity relationship (SAR) studies of CP19 showed that its piperidine, coumarin and linker were related with its antiviral activities. In this study, we performed detailed SAR studies on these groups with synthesized CP19 derivatives. We discovered that 1) the piperidine group could be optimized with heterocycles, 2) the substitution groups of C3 and C4 of coumarin should be relatively large hydrophobic groups and 3) the linker part should be least substituted. Based on the SAR analysis, we synthesized compound 32 as a potent entry inhibitor of EBOV and MARV (IC50 = 0.5 μM for EBOV and 1.5 μM for MARV). The mutation studies of Ebola glycoprotein and molecular docking studies showed that the coumarin and its substituted groups of compound 32 bind to the pocket of Ebola glycoprotein in a similar way to the published entry inhibitor compound 118a. However, the carboxamide group of compound 32 does not have strong interaction with N61 as compound 118a does. The coumarin skeleton structure and the binding model of compound 32 elucidated by this study could be utilized to guide further design and optimization of entry inhibitors targeting the filovirus glycoproteins.
- Gao, Yinyi,Cheng, Han,Khan, Sameer,Xiao, Gaokeng,Rong, Lijun,Bai, Chuan
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- Novel Nitric Oxide Donors of Phenylsulfonylfuroxan and 3-Benzyl Coumarin Derivatives as Potent Antitumor Agents
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In this work, five new hybrids of phenylsulfonylfuroxan merging 3-benzyl coumarin and their seco-B-ring derivatives 2-6 were designed and synthesized. Among them, compound 3 showed the most potent antiproliferation activities with IC50 values range from 0.5 to 143 nM against nine drug-sensitive and four drug-resistant cancer cell lines. Preliminary pharmacologic studies showed that these compounds displayed lower toxicities than that of lead compound 1. Compound 3 obviously induced the early apoptosis and hardly affected the cell cycle of A2780, which was significantly different from compound 1. Especially, it gave 559- and 294-fold selectivity antiproliferation activity in P-gp overexpressed drug-resistant cancer cell lines MCF-7/ADR and KB-V compared to their drug-sensitive ones MCF-7 and KB, implying that compounds 2-6 might have an extra mechanism of anti-MDR-cancer with P-gp overexpression.
- Guo, Yalan,Wang, Yujie,Li, Haihong,Wang, Ke,Wan, Qi,Li, Jia,Zhou, Yubo,Chen, Ying
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p. 502 - 506
(2018/05/14)
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- Agents and methods for treating ischemic and other diseases
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This invention relates to compounds that modulate TRPM7 protein activity and use of the same for treatment or prophylaxis of ischemia, cancer, pain or glaucoma.
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Page/Page column 139; 140
(2016/06/01)
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- Substituted 3-benzylcoumarins as allosteric MEK1 inhibitors: Design, synthesis and biological evaluation as antiviral agents
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In order to find novel antiviral agents, a series of allosteric MEK1 inhibitors were designed and synthesized. Based on docking results, multiple optimizations were made on the coumarin scaffold. Some of the derivatives showed excellent MEK1 binding affinity in the appropriate enzymatic assays and displayed obvious inhibitory effects on the ERK pathway in a cellular assay. These compounds also significantly inhibited virus (EV71) replication in HEK293 and RD cells. Several compounds showed potential as agents for the treatment of viral infective diseases, with the most potent compound 18 showing an IC 50 value of 54.57 nM in the MEK1 binding assay.
- Wang, Chao,Zhang, Hao,Xu, Fengrong,Niu, Yan,Wu, Yun,Wang, Xin,Peng, Yihong,Sun, Jing,Liang, Lei,Xu, Ping
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p. 6057 - 6091
(2013/06/27)
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- Synthesis of substituted coumarins via Bronsted acid mediated condensation of allenes with substituted phenols or anisoles
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Coumarins were obtained from the condensation of electron-rich arenes with allenes in the presence of TfOH in good yield. Depending on the substituent pattern of allenes employed, the general synthetic method of 4-substituted and 3,4-disubstituted 3-arylc
- Kim, Sundae,Kang, Dongjin,Lee, Chang-Hee,Lee, Phil Ho
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experimental part
p. 6530 - 6537
(2012/10/08)
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- Coumarins as novel 17β-hydroxysteroid dehydrogenase type 3 inhibitors for potential treatment of prostate cancer
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The synthesis and SAR studies of 3- and 4-substituted 7-hydroxycoumarins as novel 17β-HSD3 inhibitors are discussed. The most potent compounds from this series exhibited low nanomolar inhibitory activity with acceptable selectivity versus other 17β-HSD isoenzymes and nuclear receptors.
- Harada, Koichiro,Kubo, Hideki,Tomigahara, Yoshitaka,Nishioka, Kazuhiko,Takahashi, Junya,Momose, Mio,Inoue, Shinichi,Kojima, Atsuyuki
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scheme or table
p. 272 - 275
(2010/04/06)
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- BENZOPYRONE COMPOUNDS, PREPARATION METHOD AND USE THEREOF
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The invention relates to pesticide and bactericide, specifically to the benzopyrone compounds and its preparation method and use thereof. The benzopyrone compounds of the invention having general formula (I): The present invention, having good pesticide activity and broad bactericide activity, applied for controlling various pests in plants such as army worm, diamond backmoth and aphid, carmine spider mite, two-spotted spider mite, ladybeetle, mites and mosquito larvae. Various disease in plants can be controlled by the invention and that of grape downy mildew, rice sheath and culm blight, rice blast, tomato early blight, tomato late blight ,wheat leaf rust, wheat leaf blotch, wheat powdery mildew, cucumber powdery mildew, cucumber downy mildew, cucumber grey mold and so on.
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Page/Page column 19
(2008/06/13)
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- Discovery and structure-activity relationship of coumarin derivatives as TNF-α inhibitors
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The discovery and structure-activity relationship of a novel series of coumarin-based TNF-α inhibitors is described. Starting from the initial lead 1a, various derivatives were prepared surrounding the coumarin core structure to optimize the in vitro inhibitory activity of TNF-α production by human peripheral blood mononuclear cells (hPBMC), stimulated by bacterial lipopolysaccharide (LPS). Selected compounds also demonstrated in vivo inhibition of TNF-α production in rats.
- Cheng, Jie-Fei,Chen, Mi,Wallace, David,Tith, Sovouthy,Arrhenius, Thomas,Kashiwagi, Hirotaka,Ono, Yoshiyuki,Ishikawa, Akira,Sato, Haruhiko,Kozono, Toshiro,Sato, Hediki,Nadzan, Alex M.
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p. 2411 - 2415
(2007/10/03)
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