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

• 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)