- 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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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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Read Online
- 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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Read Online
- 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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Read Online
- A dual-functional molecular strategy for in situ suppressing and visualizing of neuraminidase in aqueous solution using iridium(III) complexes
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We have designed for the first time a dual-functional luminescent probe and inhibitor of neuraminidase (NA), a key influenza target. The lead iridium(iii) complex exhibited enhanced inhibition against NA compared to the FDA-approved antiviral drug, oseltamivir, and could detect NA even in the presence of an autofluorescent background.
- Wu, Chun,Wu, Ke-Jia,Liu, Jin-Biao,Zhou, Xiao-Ming,Leung, Chung-Hang,Ma, Dik-Lung
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Read Online
- 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 0038-0040
(2020/12/30)
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- Expedient synthesis of oseltamivir and related compounds via direct olefin diazidation-diamidation reaction
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Disclosed herein are improved methods for the preparation of oseltamivir, and intermediates useful thereto.
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- 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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- 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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- Enantioselective Synthesis of Oseltamivir Phosphate (Tamiflu) via the Iron-Catalyzed Stereoselective Olefin Diazidation
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We herein report a gram-scale, enantioselective synthesis of Tamiflu, in which the key trans-diamino moiety has been efficiently installed via an iron-catalyzed stereoselective olefin diazidation. This significantly improved, iron-catalyzed method is uniquely effective for highly functionalized yet electronically deactivated substrates that have been previously problematic. Preliminary catalyst structure-reactivity-stereoselectivity relationship studies revealed that both the iron catalyst and the complex substrate cooperatively modulate the stereoselectivity for diazidation. Safety assessment using both differential scanning calorimetry (DSC) and the drop weight test (DWT) has also demonstrated the feasibility of carrying out this iron-catalyzed olefin diazidation for large-scale Tamiflu synthesis.
- Li, Hongze,Shen, Shou-Jie,Zhu, Cheng-Liang,Xu, Hao
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p. 10619 - 10626
(2018/08/03)
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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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- 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 0035; 0036
(2018/05/16)
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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; 0059
(2019/01/04)
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- Acylguanidine derivatives of zanamivir and oseltamivir: Potential orally available prodrugs against influenza viruses
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Zanamivir (ZA) and guanidino-oseltamivir carboxylic acid (GOC) are very potent inhibitors against influenza neuraminidase (NA). The guanidinium moiety plays an important role in NA binding; however, its polar cationic nature also hinders the use of ZA and GOC from oral administration. In this study, we investigated the use of ZA and GOC acylguanidine derivatives as possible orally available prodrugs. The acylguanidine derivatives were prepared by coupling with either n-octanoic acid or (S)-naproxen. The lipophilic acyl substituents were verified to improve cell permeability, and may also improve the bioavailability of acylguanidine compounds. In comparison, the acylguanidines bearing linear octanoyl chain showed better NA inhibitory activity and higher hydrolysis rate than the corresponding derivatives having bulky branched naproxen moiety. Our molecular docking experiments revealed that the straight octanoyl chain could extend to the 150-cavity and 430-cavity of NA to gain extra hydrophobic interactions. Mice receiving the ZA octanoylguanidine derivative survived from influenza infection better than those treated with ZA, whereas the GOC octanoylguanidine derivative could be orally administrated to treat mice with efficacy equal to oseltamivir. Our present study demonstrates that incorporation of appropriate lipophilic acyl substituents to the polar guanidine group of ZA and GOC is a feasible approach to develop oral drugs for influenza therapy.
- Hsu, Peng-Hao,Chiu, Din-Chi,Wu, Kuan-Lin,Lee, Pei-Shan,Jan, Jia-Tsrong,Cheng, Yih-Shyun E.,Tsai, Keng-Chang,Cheng, Ting-Jen,Fang, Jim-Min
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p. 314 - 323
(2018/05/29)
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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 0036-0038
(2018/06/26)
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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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- INTERMEDIATE COMPOUNDS OF TAMIFLU, METHODS OF PREPARATION AND USES THEREOF
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Chiral amino compounds, methods of preparation and uses thereof. Tamiflu can be obtained from the said compounds. Multi-substituted chiral tetrahydropyrrolyl amine which can be used as intermediate compounds of medicament can also be produced by the said compounds.
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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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- Discovery of N-substituted oseltamivir derivatives as potent and selective inhibitors of H5N1 influenza neuraminidase
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To discover group-1-specific neuraminidase (NA) inhibitors that are especially involved in combating the H5N1 virus, two series of oseltamivir derivatives were designed and synthesized by targeting the 150-cavity. Among these, compound 20l was the most potent N1-selective inhibitor, with IC50 values of 0.0019, 0.0038, and 0.0067 μM against NAs from three H5N1 viruses. These values are better than those of oseltamivir carboxylate. Compound 32 was another potent N1-selective inhibitor that exhibited a 12-fold increase in activity against the H274Y mutant relative to oseltamivir carboxylate. Molecular docking studies revealed that the 150-cavity was an auxiliary binding site that may contribute to the high selectivity of these compounds. The present work is a significant breakthrough in the discovery of potent group-1-specific neuraminidase inhibitors, which may be further investigated for the treatment of infection by the H5N1 virus.
- Xie, Yuanchao,Xu, Dongqing,Huang, Bing,Ma, Xiuli,Qi, Wenbao,Shi, Fangyuan,Liu, Xinyong,Zhang, Yingjie,Xu, Wenfang
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p. 8445 - 8458
(2014/12/10)
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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; 00340; 00341
(2014/12/12)
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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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- 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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- A concise and practical synthesis of oseltamivir phosphate(Tamiflu) from d-mannose
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A short and practical synthesis of oseltamivir phosphate was accomplished in 11 steps from inexpensive and abundant starting material, d-mannose. This synthetic route featured an intramolecular Horner-Wadsworth-Emmons reaction as the key step to furnish the cyclohexene ring product. The hydroxyl group was converted stereo specifically into an amino group by oxidation to the ketone and reductive amination whereas the second amino group was introduced by azide substitution of a hydroxyl group. This synthesis provided an economical and practical alternative for the synthesis of Tamiflu.
- Chuanopparat, Nutthawat,Kongkathip, Ngampong,Kongkathip, Boonsong
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p. 6803 - 6809
(2012/08/28)
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- Synthesis of a new oseltamivir derivative through late-stage catalytic C-H functionalization
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N-Boc-protected oseltamivir 5 was converted to olefin insertion product 4 via a ruthenium-catalyzed C(sp2)-H functionalization reaction using its ester functionality as a directing group. The addition of a catalytic amount of (p-CF3C
- Saito, Kenta,Kanai, Motomu
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p. 1565 - 1574
(2013/08/23)
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- Several generations of chemoenzymatic synthesis of oseltamivir (Tamiflu): Evolution of strategy, quest for a process-quality synthesis, and evaluation of efficiency metrics
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Four generations of chemoenzymatic approaches to oseltamivir are presented. The first two generations relied on the use of cyclohexadiene-cis-diol derived enzymatically from bromobenzene. The third and fourth generation used the corresponding diol obtaine
- Werner, Lukas,Machara, Ales,Sullivan, Bradford,Carrera, Ignacio,Moser, Michael,Adams, David R.,Hudlicky, Tomas,Andraos, John
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p. 10050 - 10067
(2012/01/15)
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- PROCESS AND COMPOUNDS FOR THE MANUFACTURE OF OSELTAMIVIR AND ANALOGS THEREOF, AND NEW ANTIVIRAL AGENTS
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The present application relates to processes for the preparation of intermediates useful in the manufacture of oseltamivir and the H3PO4 salt of oseltamivir, Tamiflu?. The application further relates to novel intermediate and compoun
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- Enantioselective synthesis of oseltamivir phosphate
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The key steps in the enantioselective synthesis of Tamiflu include an asymmetric Diels-Alder reaction, Mitsunobu inversion using Fukuyama modified Weinreb reagent, carbamate directed epoxidation. Epoxide opening with trimethylsilyl azide furnished a 3:1 mixture of regioisomers that converged to afford the same aziridine. Attempted preparation of the unsaturated ester regioselectively using 2-iodoxybenzoic acid (IBX) following Nicolaou's protocol failed. The unsaturated ester was prepared by phenylselenylation followed by selenoxide elimination.
- Raghavan, Sadagopan,Babu, Vaddela Sudheer
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p. 2044 - 2050
(2011/04/17)
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- An efficient synthesis of oseltamivir phosphate (Tamiflu) via a metal-mediated domino reaction and ring-closing metathesis
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An efficient synthesis of the influenza neuraminidase inhibitor prodrug oseltamivir phosphate (Tamiflu) from cheap, commercially available d-ribose is described. The main features of this approach comprise a metal (Zn, In)-mediated domino reaction and ring-closing olefin metathesis (RCM) of the resultant functionalized dienes to produce the Tamiflu skeleton. The synthesis described in this Letter represents a new and efficient transformation of a shikimic acid derivative into a 1,2-diamino compound which involved oxidation of an alcohol followed by reductive amination, regioselective ring opening of an amino pentylidene ketal and stereospecific nucleophilic replacement of a triflate with an azide.
- Wichienukul, Pawinee,Akkarasamiyo, Sunisa,Kongkathip, Ngampong,Kongkathip, Boonsong
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supporting information; experimental part
p. 3208 - 3210
(2010/08/07)
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- Short chemoenzymatic azide-free synthesis of oseltamivir (tamiflu): Approaching the potential for process efficiency
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A short chemoenzymatic and azide-free synthesis of oseltamivir was attained with the key steps consisting of a one-pot Dauben-Michno oxidative transposition and animation and a reductive transposition of an acrylate.
- Werner, Lukas,Machara, Ales,Hudlicky, Tomas
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scheme or table
p. 195 - 200
(2010/07/03)
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- REDOX DRUG DERIVATIVES
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The present invention provides redox drug derivatives. In particular, 9-fluoro-2,3- dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4- benzoxazine-6-carboxylic acid, 1-ethyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4- oxo-3-quinolinecarboxylic acid, (3R, 4R, 5S)-4-(acetylamino)-5-amino-3-(1- ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester, (3S)-3-(aminomethyl)-5- methylhexanoic acid, (3S)-1 -[2-(2,3-dihydro-5-benzofuranyl)ethyl]-α-α-diphenyl-3- pyrrolidineacetamide, (1S,2S,3S,4R)-3-[(1S)-1 -acetamido-2-ethyl-butyl]-4- (diaminomethylideneamino)-2-hydroxy-cyclopentane-1-carboxylic acid and (2R,3R,4S)- 4-[(diaminomethylidene)amino]-3-acetamido-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4- dihydro-2H-pyran-6-carboxylic acid redox derivatives.
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Page/Page column 52
(2010/12/17)
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- SYNTHESIS OF OSELTAMIVIR CONTAINING PHOSPHONATE CONGENERS WITH ANTI-INFLUENZA ACTIVITY
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Novel phosphonate compounds are described. The compounds have activity as neuraminidase inhibitors against wild-type and H274Y mutant of H1N1 and H5N1 viruses. The present disclosure also provides an enantioselective synthetic route to known neuraminidase inhibitors oseltamivir and the anti-flu drug Tamiflu, as well as novel phosphonate compounds, via D-xylose. Another efficient and flexible synthesis of Tamiflu and the highly potent neuraminidase inhibitor Tamiphosphor was also achieved in 11 steps and > 20% overall yields from the readily available fermentation product (1S-cis)-3-bromo-3,5- cyclohexadiene-1,2-diol. Most of the reaction intermediates were obtained as crystals without tedious purification procedures. The key transformations include an initial regio- and stereoselective bromoamidation of a bromoarene cis- dihydrodiol, as well as the final palladium-catalyzed carbonylation and phosphonylation.
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Page/Page column sheet 5; 77-78
(2009/04/25)
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- The first synthesis of [11C]oseltamivir: A tool for elucidating the relationship between Tamiflu and its adverse effects on the central nervous system
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Oseltamivir phosphate (Tamiflu) is an anti-influenza drug approved in many countries. Recently, in Japan, adverse effects on the central nervous system have been reported in younger patients administrated with Tamiflu. As a tool for elucidating the relationship between Tamiflu and its adverse effects, 11C-labeled oseltamivir was synthesized through a two-step reaction involving [11C]acetylation with [1-11C]acetyl chloride. Starting from approximately 37.0 GBq of [11C]CO2, 1.2-1.8 GBq (n=5) of [11C]oseltamivir was obtained at the end of synthesis (EOS) 36-39 min after the end of bombardment. Radiochemical purity and specific activity were greater than 98% and 2.7-6.3 GBq/μmol at EOS, respectively. Copyright
- Arai, Takuya,Konno, Fujiko,Ogawa, Masanao,Zhang, Ming-Rong,Suzuki, Kazutoshi
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experimental part
p. 350 - 354
(2011/06/25)
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- A synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reaction
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(Chemical Equation Presented) In pursuit of a better route: A new catalytic asymmetric synthesis of Tamiflu was developed. The key transformation was an asymmetric Diels-Alder-type reaction of 1 and 2 catalyzed by a barium/F 2-FujiCAPO complex in the presence of a CsF co-catalyst to construct the core of Tamiflu (see scheme; TMS=trimethylsilyl). The product was converted into Tamiflu in 11 steps on a gram scale.
- Yamatsugu, Kenzo,Yin, Liang,Kamijo, Shin,Kimura, Yasuaki,Kanai, Motomu,Shibasaki, Masakatsu
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supporting information; experimental part
p. 1070 - 1076
(2009/06/20)
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- A concise and flexible synthesis of the potent anti-influenza agents tamiflu and tamiphosphor
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(Chemical Equation Presented) Tamiflu and the highly potent neuraminidase inhibitor tamiphosphor have been synthesized in 11 steps and greater than 20% overall yields from an haloarene (1S,2S)-cis-diol. The key transformations include a regio- and stereoselective bromoamidation, and a palladium-catalyzed carbonylation or phosphonylation reaction (see scheme; tamiflu: A = CO 2Et, B = NH3+H2PO4 -, tamiphosphor: A = PO(ONH4)2, B = NH 2).
- Shie, Jiun-Jie,Fang, Jim-Min,Wong, Chi-Huey
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supporting information; experimental part
p. 5788 - 5791
(2009/03/11)
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- New, efficient synthesis of oseltamivir phosphate (Tamiflu) via enzymatic desymmetrization of a meso-1,3-cyclohexanedicarboxylic acid diester
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(Chemical Equation Presented) A new, enantioselective synthesis of the influenza neuraminidase inhibitor prodrug oseltamivir phosphate 1 (Tamiflu) and its enantiomer ent-1 starting from cheap, commercially available 2,6-dimethoxyphenol 10 is described. The main features of this approach comprise the cis-hydrogenation of 5-(1-ethyl-propoxy)-4,6-dimethoxy-isophthalic acid diethyl ester (6a) and the desymmetrization of the resultant all-cis meso-diesters 7a and 7b, respectively. Enzymatic hydrolysis of the meso-diester 7b with pig liver esterase afforded the (S)-monoacid 8b, which was converted into cyclohexenol 17 via a Curtius degradation and a base-catalyzed decarboxylative elimination of the Boc-protected oxazolidinone 14. Introduction of the second amino function via SN2 substitution of the corresponding triflate 18 with NaN3 followed by azide reduction, N-acetylation, and Boc-deprotection gave oseltamivir phosphate 1 in a total of 10 steps and an overall yield of ~30%. The enantiomer ent-1 was similarly obtained via an enzymatic desymmetrization of meso-diester 7a with Aspergillus oryzae lipase, providing the (R)-monoacid ent-8a.
- Zutter, Ulrich,Iding, Hans,Spurr, Paul,Wirz, Beat
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p. 4895 - 4902
(2008/12/20)
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- Radiosyntheses of two positron emission tomography probes: [11C]Oseltamivir and its active metabolite [11C]Ro 64-0802
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Oseltamivir phosphate (Tamiflu, 1·H3PO4 is an orally active anti-influenza drug, which is hydrolyzed by esterase to its carboxylate metabolite Ro 64-0802 (2) with potent activity inhibiting neuraminidase. In this study, fo
- Konno, Fujiko,Arai, Takuya,Zhang, Ming-Rong,Hatori, Akiko,Yanamoto, Kazuhiko,Ogawa, Masanao,Ito, Gukuto,Odawara, Chika,Yamasaki, Tomoteru,Kato, Koichi,Suzuki, Kazutoshi
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p. 1260 - 1263
(2008/09/18)
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- A method for the synthesis of an oseltamivir PET tracer
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A protocol applicable for the synthesis of an oseltamivir positron emission tomography (PET) tracer was developed. Acetylation of amine 3 with CH3COCl, followed by deprotection and aqueous workup, produced oseltamivir 4 from 3 within 10 min. The obtained 4 was sufficiently pure for PET studies. This method can be extended to PET tracer synthesis using CH311COCl.
- Morita, Masataka,Sone, Toshihiko,Yamatsugu, Kenzo,Sohtome, Yoshihiro,Matsunaga, Shigeki,Kanai, Motomu,Watanabe, Yasuyoshi,Shibasaki, Masakatsu
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p. 600 - 602
(2008/09/17)
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- An iron carbonyl approach to the influenza neuraminidase inhibitor oseltamivir
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A novel synthetic route towards oseltamivir, an influenza neuraminidase inhibitor, has been achieved employing a cationic iron carbonyl complex, providing an alternate pathway with the potential to access diverse analogues. The Royal Society of Chemistry.
- Bromfield, Karen M.,Graden, Henrik,Hagberg, Daniel P.,Olsson, Thomas,Kann, Nina
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p. 3183 - 3185
(2008/02/13)
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- A short enantioselective pathway for the synthesis of the anti-influenza neuramidase inhibitor oseltamivir from 1,3-butadiene and acrylic acid
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A short synthetic pathway has been developed for the synthesis of oseltamivir (1) or the enantiomer (ent-1). The intermediates and conditions for this process are summarized in Scheme 1. The synthesis provides a number of advantages: (1) use of inexpensiv
- Yeung, Ying-Yeung,Hong, Sungwoo,Corey
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p. 6310 - 6311
(2007/10/03)
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- Stereo-specific synthesis of shimikic acid derivatives with improved efficiency
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The invention provides a multistep synthesis for the preparation of 4,5-diamino shikimic acid derivatives of formula 1starting from an isophthalic acid derivative of formula 24,5-Diamino shikimic acid derivatives are potent inhibitors of viral neuraminidase.
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- Structure-activity relationship studies of novel carbocyclic influenza neuraminidase inhibitors
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A series of influenza neuraminidase inhibitors with the cyclohexene scaffold containing lipophilic side chains have been synthesized and evaluated for influenza A and B neuraminidase inhibitory activity. The size and geometry of side chains have been modified systematically in order to investigate structure-activity relationships of this class of compounds. The X-ray crystal structures of several analogues complexed with neuraminidase revealed that the lipophilic side chains bound to the hydrophobic pocket consisted of Glu276, Ala246, Arg224, and Ile222 of the enzyme active site. The structure-activity relationship studies of this series have also demonstrated remarkably different inhibitory potency between influenza A and B neuraminidase. This indicated that the lipophilic side chains had quite different hydrophobic interactions with influenza A and B neuraminidase despite their complete homology in the active site. Influenza B neuraminidase appeared to be much more sensitive toward the increased steric bulkiness of inhibitors compared to influenza A neuraminidase. From the extensive structure-activity relationship investigation reported in this article, GS 4071 emerged as one of the most potent influenza neuraminidase inhibitors against both influenza A and B strains.
- Kim, Choung U.,Lew, Willard,Williams, Matthew A.,Wu, Huiwei,Zhang, Lijun,Chen, Xiaowu,Escarpe, Paul A.,Mendel, Dirk B.,Laver, W. Graeme,Stevens, Raymond C.
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p. 2451 - 2460
(2007/10/03)
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