- Design, synthesis and biological evaluation of “Multi-Site”-binding influenza virus neuraminidase inhibitors
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Encouraged by our earlier discovery of neuraminidase inhibitors targeting 150-cavity or 430-cavity, herein, to yield more potent inhibitors, we designed, synthesized, and biologically evaluated a series of novel oseltamivir derivatives via modification of C-1 and C5–NH2 of oseltamivir by exploiting 150-cavity and/or 430-cavity. Among the synthesized compounds, compound 15e, the most potent N1-selective inhibitor targeting 150-cavity, showed 1.5 and 1.8 times greater activity than oseltamivir carboxylate (OSC) against N1 (H5N1) and N1 (H5N1–H274Y). In cellular assays, 15e also exhibited greater potency than OSC against H5N1 with EC50 of 0.66 μM. In addition, 15e demonstrated low cytotoxicity in vitro and low acute toxicity in mice. Molecular docking studies provided insights into the high potency of 15e against N1 and N1–H274Y mutant NA. Overall, we envisioned that the significant breakthrough in the discovery of potent group-1-specific neuraminidase inhibitors may lead to further investigation of more potent anti-influenza agents.
- Jia, Ruifang,Zhang, Jian,Ai, Wei,Ding, Xiao,Desta, Samuel,Sun, Lin,Sun, Zhuosen,Ma, Xiuli,Li, Zhong,Wang, Defeng,Huang, Bing,Zhan, Peng,Liu, Xinyong
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Read Online
- Discovery of novel 1,2,3-triazole oseltamivir derivatives as potent influenza neuraminidase inhibitors targeting the 430-cavity
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A novel series of 1,2,3-triazole oseltamivir derivatives, which could simultaneously occupy the classical NA catalytic site and the newly reported 430-cavity, were designed, synthesized, and evaluated for their anti-influenza activities. The results demonstrated that four compounds (6g, 6l, 6y and 8c) showed robust anti-influenza potencies against H5N1, H5N2 and H5N6 strains in both enzymatic assay and cellular assay. Especially, 6l was proved to possess the most potent and broad-spectrum anti-influenza activity, with IC50 values of 0.12 μM, 0.049 μM and 0.16 μM and EC50 values of 2.45 μM, 0.43 μM and 2.8 μM against H5N1, H5N2 and H5N6 strains, respectively, which were slightly weaker than oseltamivir carboxylate. In addition, in the embryonated egg model, 6l achieved the similar protective effect against H9N2 strain with oseltamivir carboxylate in the tested concentrations. Preliminary structure-activity relationships (SARs), molecular modeling, and calculated physicochemical properties of selected compounds were also discussed.
- Ju, Han,Xiu, Siyu,Ding, Xiao,Shang, Min,Jia, RuiFang,Huang, Bing,Zhan, Peng,Liu, Xinyong
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- Novel anti-influenza virus oseltamivir derivative as well as preparation method and application thereof
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The invention belongs to the field of medicinal chemistry and chemical synthesis, and particularly relates to an oseltamivir derivative and a preparation method and application thereof, and the oseltamivir derivative has a structure as shown in a general
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Paragraph 0038-0039; 0041
(2020/12/30)
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- Divalent oseltamivir analogues as potent influenza neuraminidase inhibitors
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A panel of divalent oseltamivir and guanidino oseltamivir analogues with esterification on the carboxyl acid group as potent inhibitors of influenza virus neuraminidase was prepared via click reaction. The primary structure activity relationship study demonstrated that appropriate distance between two oseltamivir monomers around 30 ? can crosslink two adjacent neuraminidase tetramers on the virion surface and result in highly effective NA inhibitors against three strains of influenza virus and H7N9 virus like particle. This strategy also provides a basis for the multivalent modification on oseltamivir.
- Yan, Zhong-Li,Liu, Ao-Yun,Wei, Xia-Xia,Zhang, Zhuang,Qin, Long,Yu, Qun,Yu, Peng,Lu, Kui,Yang, Yang
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- Boronate, trifluoroborate, sulfone, sulfinate and sulfonate congeners of oseltamivir carboxylic acid: Synthesis and anti-influenza activity
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Tamiflu readily undergoes endogenous hydrolysis to give oseltamivir carboxylic acid (OC) as the active anti-influenza agent to inhibit the viral neuraminidase (NA). GOC is derived from OC by replacing the 5-amino group with a guanidino group. In this study, OC and GOC congeners with the carboxylic acid bioisosteres of boronic acid, trifluoroborate, sulfone, sulfinic acid, sulfonic acid and sulfonate ester were first synthesized, starting with conversion of OC to a Barton ester, followed by halodecarboxylation to give the iodocyclohexene, which served as a pivotal intermediate for palladium-catalyzed coupling reactions with appropriate diboron and thiol reagents. The enzymatic and cell-based assays indicated that the GOC congeners consistently displayed better NA inhibition and anti-influenza activity than the corresponding OC congeners. The GOC sulfonic acid congener (7a) was the most potent anti-influenza agent, showing EC50 = 2.2 nM against the wild-type H1N1 virus, presumably because the sulfonic acid 7a was more lipophilic than GOC and exerted stronger interactions on the three arginine residues (R118, R292 and R371) in the NA active site. Although the trifluoroborates, sulfones and sulfonate esters did not have acidic proton, they still exhibited appreciable NA inhibitory activity, indicating that the polarized B?F and S→O bonds still made sufficient interactions with the tri-arginine motif.
- Hong, Bei-Tao,Cheng, Yih-Shyun E.,Cheng, Ting-Jen,Fang, Jim-Min
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p. 710 - 721
(2019/01/04)
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- DNA-linked inhibitor antibody assay (DIANA) as a new method for screening influenza neuraminidase inhibitors
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Influenza neuraminidase is responsible for the escape of new viral particles from the infected cell surface. Several neuraminidase inhibitors are used clinically to treat patients or stockpiled for emergencies. However, the increasing development of viral resistance against approved inhibitors has underscored the need for the development of new antivirals effective against resistant influenza strains. A facile, sensitive, and inexpensive screening method would help achieve this goal. Recently, we described a multiwell plate-based DNA-linked inhibitor antibody assay (DIANA). This highly sensitive method can quantify femtomolar concentrations of enzymes. DIANA also has been applied to high-throughput enzyme inhibitor screening, allowing the evaluation of inhibition constants from a single inhibitor concentration. Here, we report the design, synthesis, and structural characterization of a tamiphosphor derivative linked to a reporter DNA oligonucleotide for the development of a DIANA-type assay to screen potential influenza neuraminidase inhibitors. The neuraminidase is first captured by an immobilized antibody, and the test compound competes for binding to the enzyme with the oligo-linked detection probe, which is then quantified by qPCR. We validated this novel assay by comparing it with the standard fluorometric assay and demonstrated its usefulness for sensitive neuraminidase detection as well as high-throughput screening of potential new neuraminidase inhibitors.
- Ko?í?ek, Milan,Navrátil, Václav,Rojíková, Katerina,Pokorná, Jana,Albi?ana, Carlos Berenguer,Pachl, Petr,Zemanová, Jitka,Machara, Ale?,?ácha, Pavel,Hudlicky, Jason,Císarǒvá, Ivana,Rězácǒvá, Pavlína,Konvalinka, Jan
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p. 3847 - 3860
(2019/01/03)
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- Discovery of C-1 modified oseltamivir derivatives as potent influenza neuraminidase inhibitors
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Inspired by our initial discovery about a series of neuraminidase (NA) inhibitors targeting the 150-cavity, in present study, we designed, synthesized, and biologically tested a panel of novel oseltamivir derivatives with C-1 modification, targeting the 430-cavity, an additional binding site which widely and stably existed in both group-1 and group-2 NAs. Some of the synthesized compounds displayed robust anti-influenza potencies against H5N1 and H5N6 viruses. Among them, compound 8b exerted the greatest inhibition, with IC50 values of 0.088 and 0.097 μM and EC50 values of 4.26 and 1.31 μM against H5N1 and H5N6 strains, respectively, which are similar to those of oseltamivir carboxylate (OSC). And its potency against mutant H5N1-H274Y NA was just 7-fold weaker than OSC. Molecular modeling revealed the elongated group at C-1 position being projected toward the 430-cavity. Notably, although compound 8b was not sensitive toward H5N1 strain relative to OSC in the embryonated egg model, it displayed greater anti-influenza virus effect against H5N6 strain than OSC at the concentration of 10 mmol/L. Overall, this work provided unique insights in the discovery of potent inhibitors against both group-1 and group-2 NAs.
- Ju, Han,Zhang, Jian,Sun, Zhuosen,Huang, Zheng,Qi, Wenbao,Huang, Bing,Zhan, Peng,Liu, Xinyong
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p. 220 - 231
(2018/02/10)
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- Oseltamivir derivative as well as preparation method and application thereof
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The invention discloses an oseltamivir derivative, which is a brand-new oseltamivir derivative targeting a 430-cavity and modified by a carbon 1-position carboxyl group. An anti-influenza activity result of the oseltamivir derivative shows the first appli
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Paragraph 0038; 0039
(2018/05/16)
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- Design, synthesis, and evaluation of carboxyl-modified oseltamivir derivatives with improved lipophilicity as neuraminidase inhibitors
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In this study, a series of carboxyl-modified oseltamivir analogs with improved lipophilicity were designed and synthesized, and their inhibitory activities against neuraminidase from influenza A virus H5N1 subtype were evaluated. The results demonstrated that compound 5m exhibited potent inhibitory activity (IC50 = 1.30 ± 0.23 μM), and it targeted the recently discovered 430-cavity. Compound 5m (Log D = ?0.12) is more lipophilic than oseltamivir carboxylate (Log D = ?1.69) at pH 7.4, which is potentially propitious to improved membrane permeability and oral drug absorption. Meanwhile, 5m showed high stability in human liver microsomes. The findings of this study can be valuable in identifying neuraminidase inhibitors with optimal lipophilicity and in the exploration of 430-cavity.
- Wang, Boyu,Wang, Kuanglei,Meng, Peipei,Hu, Yaping,Yang, Fei,Liu, Kemin,Lei, Zaiqiang,Chen, Binfeng,Tian, Yongshou
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supporting information
p. 3477 - 3482
(2018/10/02)
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- ANTIVIRAL-AGENT RESISTANT VIRUS DETECTION SYSTEM
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An oseltamivir analogue and nanoparticles having the analogue bound thereto, of the present invention, strongly bind to oseltamivir-resistant influenza virus, and thus, the use of the same can allow detection of oseltamivir-resistant influenza viruses qui
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Paragraph 0057; 0060
(2019/01/04)
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- Oseltamivir derivative modified by carboxyl group as well as medicinal application of same
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The invention belongs to the field of medicine chemistry, and relates to oseltamivir derivative modified by carboxyl group as well as a medicinal application of same, and particularly relates to a derivative of a neuraminidase inhibitor oseltamivir, a pre
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Paragraph 0039-0041
(2018/06/26)
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- Design, in silico studies, synthesis and in?vitro evaluation of oseltamivir derivatives as inhibitors of neuraminidase from influenza A virus H1N1
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Since the neuraminidase (NA) enzyme of the influenza A virus plays a key role in the process of release of new viral particles from a host cell, it is often a target for new drug design. The emergence of NA mutations, such as H275Y, has led to great resis
- Neri-Bazán, Rocío M.,García-Machorro, Jazmín,Méndez-Luna, David,Tolentino-López, Luis E.,Martínez-Ramos, Federico,Padilla-Martínez, Itzia I.,Aguilar-Faisal, Leopoldo,Soriano-Ursúa, Marvin A.,Trujillo-Ferrara, José G.,Fragoso-Vázquez, M. Jonathan,Barrón, Blanca L.,Correa-Basurto, José
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p. 154 - 167
(2017/02/10)
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- Kinetic, thermodynamic and structural analysis of tamiphosphor binding to neuraminidase of H1N1 (2009) pandemic influenza
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Influenza virus causes severe respiratory infections that are responsible for up to half a million deaths worldwide each year. Two inhibitors targeting viral neuraminidase have been approved to date (oseltamivir, zanamivir). However, the rapid development of antiviral drug resistance and the efficient transmission of resistant viruses among humans represent serious threats to public health. The approved influenza neuraminidase inhibitors have (oxa)cyclohexene scaffolds designed to mimic the oxonium transition state during enzymatic cleavage of sialic acid. Their active forms contain a carboxylate that interacts with three arginine residues in the enzyme active site. Recently, the phosphonate group was successfully used as an isostere of the carboxylate in oseltamivir, and the resulting compound, tamiphosphor, was identified as a highly active neuraminidase inhibitor. However, the structure of the complex of this promising inhibitor with neuraminidase has not yet been reported. Here, we analyzed the interaction of a set of oseltamivir and tamiphosphor derivatives with neuraminidase from the A/California/07/2009 (H1N1) influenza virus. We thermodynamically characterized the binding of oseltamivir carboxylate or tamiphosphor to the neuraminidase catalytic domain by protein microcalorimetry, and we determined crystal structure of the catalytic domain in complex with tamiphosphor at 1.8 ? resolution. This structural information should aid rational design of the next generation of neuraminidase inhibitors.
- Albina?a, Carlos Berenguer,MacHara, Ale?,Rezacov, Pavlína,Pachl, Petr,Konvalinka, Jan,Kozísek, Milan
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p. 100 - 109
(2016/06/09)
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- FATTY ACID ANTIVIRAL CONJUGATES AND THEIR USES
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The invention relates to fatty acid antiviral conjugates; compositions comprising an effective amount of a fatty acid antiviral conjugate; and methods for treating or preventing a viral infection comprising the administration of an effective amount of a fatty acid antiviral conjugate.
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Paragraph 0733; 0734
(2016/06/01)
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- FATTY ACID ANTIVIRAL CONJUGATES AND THEIR USES
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The invention relates to fatty acid antiviral conjugates; compositions comprising an effective amount of a fatty acid antiviral conjugate; and methods for treating or preventing a viral infection comprising the administration of an effective amount of a fatty acid antiviral conjugate.
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Paragraph 0858; 0859
(2014/09/30)
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- Tamiphosphor monoesters as effective anti-influenza agents
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Oseltamivir is a potent neuraminidase inhibitor for influenza treatment. By replacing the carboxylate group in oseltamivir with phosphonate monoalkyl ester, a series of tamiphosphor derivatives were synthesized and shown to exhibit high inhibitory activities against influenza viruses. Our molecular modeling experiments revealed that influenza virus neuraminidase contains a 371-cavity near the S1-site to accommodate the alkyl substituents of tamiphosphor monoesters to render appreciable hydrophobic interactions for enhanced affinity. Furthermore, guanidino-tamiphosphor (TPG) monoesters are active to the oseltamivir-resistant mutant. TPG monohexyl ester 4e having a more lipophilic alkyl substituent showed better cell permeability and intestinal absorption than the corresponding monoethyl ester 4c, but both compounds showed similar bioavailability. Intranasal administration of TPG monoesters at low dose greatly improved the survival rate of mice infected with lethal dose of H1N1 influenza virus, whereas 4c provided better protection of the infected mice than oseltamivir and other phosphonate congeners by oral administration.
- Chen, Chun-Lin,Lin, Tzu-Chen,Wang, Shi-Yun,Shie, Jiun-Jie,Tsai, Keng-Chang,Cheng, Yih-Shyun E.,Jan, Jia-Tsrong,Lin, Chun-Jung,Fang, Jim-Min,Wong, Chi-Huey
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p. 106 - 118
(2014/06/09)
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- ANTI-INFLUENZA COMPOSITIONS AND METHODS
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Disclosed are novel compounds comprising an imino-ribose derivative covalently linked to a carbocycle or heterocycle. Pharmaceutical compositions comprising the compounds of the invention are also described. Methods of inhibition, treatment and/or suppres
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Paragraph 00339; 00342; 00343; 00344
(2014/12/12)
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- FATTY ACID ANTIVIRAL CONJUGATES AND THEIR USES
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The invention relates to fatty acid antiviral conjugates; compositions comprising an effective amount of a fatty acid antiviral conjugate; and methods for treating or preventing a a viral infection comprising the administration of an effective amount of a fatty acid antiviral conjugate.
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Paragraph 00171
(2013/07/05)
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- Discovery of a series of novel compounds with moderate anti-avian H5N1 influenza virus activity in chick embryo
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Enlightened by some flavonoid compounds, which had been found as influenza neuraminidase inhibitors, we designed and synthesized a series of novel compounds containing different amino acid fragments. We also reported a simple synthetic route from oseltamivir to prepare its active form which was used as the positive control. The result of enzyme inhibition assay indicated that all the designed compounds displayed weak inhibitory activity against neuraminidase. However, they showed moderate anti-avian H5N1 influenza virus activity in chick embryo. Besides interfering with the function of neuraminidase, these compounds seemed to inhibit the replication of influenza virus by some other mechanism which deserved deep study.
- Xie, Yuanchao,Huang, Bing,Yu, Kexiang,Shi, Fangyuan,Xu, Wenfang
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p. 3485 - 3496
(2013/07/19)
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- Formal synthesis of tamiflu: Conversion of tamiflu into tamiphosphor
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A short, enantiomeric, synthesis of Shibasakis 3rd generation intermediate to form (-)-oseltamivir phosphate (Tamiflu) has been achieved in eight steps with the use of inexpensive starting materials. A formal synthetic route to convert tamiflu into tamiphosphor via Fangs tamiphosphor intermediate has been accomplished. Georg Thieme Verlag Stuttgart · New York.
- Gunasekera, Dinara S.
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experimental part
p. 573 - 576
(2012/04/17)
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