Synthesis and antienteroviral activity of a series of novel, oxime ether-containing pyridyl imidazolidinones.
A series of novel, oxime ether-containing pyridyl imidazolidinones were synthesized and their antiviral activity was evaluated in a plaque reduction assay. It is very interesting that this class of compounds is specific for human enteroviruses, in particular, enterovirus 71 (EV71). Some derivatives strongly inhibited enterovirus replication with activities higher or comparable to those of the reference compounds such as A1 and A2. Preliminary SAR studies revealed that the chain length of the alkyl linker and the alkyl substituent at the oxime ether group largely influenced the in vitro anti-EV71 activity of this new class of potent antiviral agents. Among this series of compounds synthesized, the pyridyl imidazolidinone with an ethyl oxime ether group located at the para position of the phenoxyl ring (8b) was identified as the most potent enterovirus 71 inhibitor (IC50=0.001 microM) with no apparent cytotoxic effect toward RD (rhabdomyosarcoma) cell lines (CC50>25 microM). Furthermore, this compound has been shown broad-spectrum activity against most of the serotypes of enteroviruses tested in the nanomolar range.
Chern
Jyh-Haur
JH
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 9F, 161, Sec. 6, Min-Chiuan East Road, Taipei 114, Taiwan, ROC. jhchen@nhri.org.tw
Lee
Chung-Chi
CC
Chang
Chih-Shiang
CS
Lee
Yen-Chun
YC
Tai
Chia-Liang
CL
Lin
Ying-Ting
YT
Shia
Kak-Shan
KS
Lee
Ching-Yin
CY
Shih
Shin-Ru
SR
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004770:Enterovirus / Q000187:drug effects; D029822:Enterovirus B, Human / Q000187:drug effects; D004987:Ethers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D048289:Imidazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D010948:Viral Plaque Assay
D000998:Antiviral Agents; D004987:Ethers; D048289:Imidazolidines; D010091:Oximes; D011725:Pyridines