嘧啶
胞苷
立体化学
化学
差向异构体
甲型流感病毒
尿苷
性感冒病毒属
衍生工具(金融)
病毒
正粘病毒科
核糖核酸
病毒学
生物
生物化学
酶
基因
金融经济学
经济
作者
Abdalla E. A. Hassan,Hend A. Hegazy,Islam Zaki,M. M. A. Hassan,M. Ramadan,Abdelfattah Haikal,Jia Sheng,Reham A. I. Abou‐Elkhair
标识
DOI:10.1002/ardp.202200382
摘要
Influenza viruses belong to the Orthomyxoviridae family and cause acute respiratory distress in humans. The developed drug resistance toward existing drugs and the emergence of viral mutants that can escape vaccines mandate the search for novel antiviral drugs. Herein, the synthesis of epimeric 4'-methyl-4'-phosphonomethoxy [4'-C-Me-4'-C-(O-CH2 P═O)] pyrimidine ribonucleosides, their phosphonothioate [4'-C-Me-4'-C-(O-CH2 P═S)] derivatives, and their evaluation against an RNA viral panel are described. Selective formation of the α- l-lyxo epimer, [4'-C-(α)-Me-4'-C-(β)-(O-CH2 -P(═O)(OEt)2 )] over the β- d-ribo epimer [4'-C-(β)-Me-4'-C-(α)-(O-CH2 -P(═O)(OEt)2 )] was explained by DFT equilibrium geometry optimizations studies. Pyrimidine nucleosides having the [4'-C-(α)-Me-4'-C-(β)-(O-CH2 -P(═O)(OEt)2 )] framework showed specific activity against influenza A virus. Significant anti-influenza virus A (H1N1 California/07/2009 isolate) was observed with the 4'-C-(α)-Me-4'-C-(β)-O-CH2 -P(═O)(OEt)2 -uridine derivative 1 (EC50 = 4.56 mM, SI50 > 56), 4-ethoxy-2-oxo-1(2H)-pyrimidin-1-yl derivative 3 (EC50 = 5.44 mM, SI50 > 43) and the cytidine derivative 2 (EC50 = 0.81 mM, SI50 > 13), respectively. The corresponding thiophosphonates 4'-C-(α)-Me-4'-C-(β)-(O-CH2 -P( S)(OEt)2 ) and thionopyrimidine nucleosides were devoid of any antiviral activity. This study shows that the 4'-C-(α)-Me-4'-(β)-O-CH2 -P(═O)(OEt)2 ribonucleoside can be further optimized to provide potent antiviral agents.
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