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Structure-Based Opt...
Structure-Based Optimization of N-Substituted Oseltamivir Derivatives as Potent Anti-Influenza A Virus Agents with Significantly Improved Potency against Oseltamivir-Resistant N1-H274Y Variant
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Zhang, J. (författare)
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- Natarajan Arul, Murugan (författare)
- KTH,Teoretisk kemi och biologi
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Tian, Y. (författare)
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Bertagnin, C. (författare)
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Fang, Z. (författare)
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Kang, D. (författare)
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Kong, X. (författare)
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Jia, H. (författare)
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Sun, Z. (författare)
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Jia, R. (författare)
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Gao, P. (författare)
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Poongavanam, V. (författare)
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Loregian, A. (författare)
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Xu, W. (författare)
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Ma, X. (författare)
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Ding, X. (författare)
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Huang, B. (författare)
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Zhan, P. (författare)
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Liu, X. (författare)
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(creator_code:org_t)
- 2018-10-26
- 2018
- Engelska.
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society. - 0022-2623 .- 1520-4804. ; 61:22, s. 9976-9999
- Relaterad länk:
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https://findresearch...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Due to the emergence of highly pathogenic and oseltamivir-resistant influenza viruses, there is an urgent need to develop new anti-influenza agents. Herein, five subseries of oseltamivir derivatives were designed and synthesized to improve their activity toward drug-resistant viral strains by further exploiting the 150-cavity in the neuraminidases (NAs). The bioassay results showed that compound 21h exhibited antiviral activities similar to or better than those of oseltamivir carboxylate (OSC) against H5N1, H5N2, H5N6, and H5N8. Besides, 21h was 5- to 86-fold more potent than OSC toward N1, N8, and N1-H274Y mutant NAs in the inhibitory assays. Computational studies provided a plausible rationale for the high potency of 21h against group-1 and N1-H274Y NAs. In addition, 21h demonstrated acceptable oral bioavailability, low acute toxicity, potent antiviral activity in vivo, and high metabolic stability. Overall, the above excellent profiles make 21h a promising drug candidate for the treatment of influenza virus infection.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine (hsv//eng)
Nyckelord
- 4 acetamido 3 (pentan 3 yloxy) 5 [(4 phenoxybenzyl)amino]cyclohex 1 ene 1 carboxylic acid
- 4 acetamido 3 (pentan 3 yloxy) 5 [[4 (pentan 3 yloxy)benzyl]amino]cyclohex 1 ene 1 carboxylic acid
- 4 acetamido 3 (pentan 3 yloxy) 5 [[4 (phenylsulfonyl)benzyl]amino]cyclohex 1 ene 1 carboxylic acid
- 4 acetamido 3 (pentan 3 yloxy) 5 [[4 (phenylthio)benzyl]amino]cyclohex 1 ene 1 carboxylic acid
- 4 acetamido 3 (pentan 3 yloxy) 5 [[4 (thiophen 2 yl thio)benzyl]amino]cyclohex 1 ene 1 carboxylic acid
- 4 acetamido 5 amino 3 (1 ethylpropoxy) 1 cyclohexene 1 carboxylic acid
- 4 acetamido 5 [(4 benzoylbenzyl)amino] 3 (pentan 3 yloxy)cyclohex 1 ene 1 carboxylic acid
- 4 acetamido 5 [(4 benzylbenzyl)amino] 3 (pentan 3 yloxy)cyclohex 1 ene 1 carboxylic acid
- 4 acetamido 5 [(4 ethylbenzyl)amino] 3 (pentan 3 yloxy)cyclohex 1 ene 1 carboxylic acid
- 4 acetamido 5 [(4 isopropylbenzyl)amino] 3 (pentan 3 yloxy)cyclohex 1 ene 1 carboxylic acid
- 4 acetamido 5 [(4 methoxybenzyl)amino] 3 (pentan 3 yloxy)cyclohex 1 ene 1 carboxylic acid
- 4 acetamido 5 [[3 (cyclopentyl)benzyl]amino] 3 (pentan 3 yloxy)cyclohex 1 ene 1 carboxylic acid
- 4 acetamido 5 [[3 (sec butylthio)benzyl]amino] 3 (pentan 3 yloxy)cyclohex 1 ene 1 carboxylic acid
- 4 acetamido 5 [[4 (benzo[b]thiophen 2 yl)benzyl)amino] 3 (pentan 3 yloxy)cyclohex 1 ene 1 carboxylic acid
- 4 acetamido 5 [[4 (cyclohexylthio)benzyl]amino] 3 (pentan 3 yloxy)cyclohex 1 ene 1 carboxylic acid
- 4 acetamido 5 [[4 (cyclopentyl)benzyl]amino] 3 (pentan 3 yloxy)cyclohex 1 ene 1 carboxylic acid
- 4 acetamido 5 [[4 (isobutylthio)benzyl]amino] 3 (pentan 3 yloxy)cyclohex 1 ene 1 carboxylic acid
- 4 acetamido 5 [[4 (sec butylthio)benzyl]amino] 3 (pentan 3 yloxy)cyclohex 1 ene 1 carboxylic acid
- antivirus agent
- diclofenac
- ethyl 4 acetamido 3 (pentan 3 yloxy) 5 [[4 (phenylthio)benzyl]amino]cyclohex 1 ene 1 carboxylate
- ethyl 4 acetamido 5 [[4 (benzo[b]thiophen 5 yl)benzyl]amino] 3 (pentan 3 yloxy) cyclohex 1 ene 1 carboxylate
- oseltamivir
- oseltamivir derivative
- propafenone
- ribavirin
- testosterone
- unclassified drug
- unindexed drug
- virus sialidase
- zanamivir
- animal experiment
- animal model
- antiviral activity
- area under the curve
- Article
- bioassay
- controlled study
- drug clearance
- drug half life
- drug potency
- drug stability
- drug structure
- drug synthesis
- human
- human cell
- Influenza A virus
- Influenza A virus (H3N2)
- Influenza A virus (H5N1)
- Influenza A virus (H5N2)
- Influenza A virus (H5N6)
- Influenza A virus (H5N8)
- maximum concentration
- MDCK cell line
- metabolic stability
- molecular model
- nonhuman
- pharmacokinetic parameters
- plasma concentration-time curve
- rat
- time to maximum plasma concentration
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
Hitta via bibliotek
Till lärosätets databas
- Av författaren/redakt...
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Zhang, J.
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Natarajan Arul, ...
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Tian, Y.
-
Bertagnin, C.
-
Fang, Z.
-
Kang, D.
-
visa fler...
-
Kong, X.
-
Jia, H.
-
Sun, Z.
-
Jia, R.
-
Gao, P.
-
Poongavanam, V.
-
Loregian, A.
-
Xu, W.
-
Ma, X.
-
Ding, X.
-
Huang, B.
-
Zhan, P.
-
Liu, X.
-
visa färre...
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