- Synthesis and antiviral evaluation of 6-(alkyl-heteroaryl)furo[2,3-d] pyrimidin-2(3H)-one nucleosides and analogues with ethynyl, ethenyl, and ethyl spacers at C6 of the furopyrimidine core
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Sonogashira coupling strategies were employed to synthesize new furo[2,3-d]pyrimidin-2(3H)-one (FuPyrm) 2′-deoxynucleoside analogues. Partial or complete reduction of ethyne-linked compounds afforded ethenyl-and ethyl-linked derivatives. Levels of inhibition of varicella-zoster virus (VZV), human cytomegalovirus (HCMV), a broad range of other DNA and RNA viruses, and several cancer cell lines were evaluated in cell cultures. The anti-VZV potency decreased with increasing rigidity of the side chain at C6 of the FuPyrm ring in the order dec-1-yn-1-yl dec-1-en-1-yl decan-1-yl. In contrast, compounds with a rigid ethynyl spacer between C6 of the FuPyrm ring and a 4-alkylphenyl moiety were more potent inhibitors of VZV than the corresponding derivatives with an ethyl spacer. Replacement of the phenyl moiety in 6-(4-alkylphenyl) derivatives with a pyridine ring (in either regioisomeric orientation) gave analogues with increased solubility in methanol but reduced anti-VZV potency, and replacement with a pyrimidine ring reduced the anti-VZV activity even further. The pyridine-ring-containing analogues were ~20-fold more potent inhibitors of VZV than acyclovir but were ~6-fold less potent than BVDU and ~60-fold weaker than the most active 6-(4-pentylphenyl)- substituted prototype.
- Robins, Morris J.,Nowak, Ireneusz,Rajwanshi, Vivek K.,Miranda, Karl,Cannon, John F.,Peterson, Matt A.,Andrei, Graciela,Snoeck, Robert,De Clercq, Erik,Balzarini, Jan
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p. 3897 - 3905
(2008/02/10)
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