Synthesis of C-4-modified zanamivir analogs as neuraminidase inhibitors and their anti-AIV activities.
With the introduction of bioisosteres of the guanidinium group together with scaffold hopping, 35 zanamivir analogs with C-4-modification were synthesized, and their inhibitory activities against both group-1 and group-2 neuraminidase (H5N1 and H3N2) were determined. Compound D26 exerts the most potency, with IC(50) values of 0.58 and 2.72 μM against N2 and N1, respectively. Further preliminary anti-avian influenza virus (AIV, H5N1) activities against infected MDCK cells were evaluated, and D5 exerts ∼58% protective against AIV infection, which was comparable to zanamivir (∼67%). In a rat pharmacokinetic study, compound D5 showed an increased plasma half-life (t(1/2)) compared to zanamivir following either intravenous or oral administration. This study may represent a new start point for the future development of improved anti-AIV agents.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu chong zhi Road, Shanghai 201203, China.
Deju
D
Ye
Woo-Jin
WJ
Shin
Ning
N
Li
Wei
W
Tang
Enguang
E
Feng
Jian
J
Li
Pei-Lan
PL
He
Jian-Ping
JP
Zuo
Hanjo
H
Kim
Ky-Youb
KY
Nam
Weiliang
W
Zhu
Baik-Lin
BL
Seong
Kyoung Tai
KT
No
Hualiang
H
Jiang
Hong
H
Liu
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D060326:Chemistry Techniques, Synthetic; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects* / Q000201:enzymology*; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects* / Q000201:enzymology*; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D051381:Rats; D053243:Zanamivir / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D009439:Neuraminidase; D053243:Zanamivir