Synthesis and Biological Evaluation of 6-(Alkyn-1-yl)furo[2,3-d]pyrimidin-2(3H)-one Base and Nucleoside Derivatives

• Published in: Journal of medicinal chemistry Vol. 49; no. 1; pp. 391 - 398
• Main Authors: Robins, Morris J, Miranda, Karl, Rajwanshi, Vivek K, Peterson, Matt A, Andrei, Graciela, Snoeck, Robert, De Clercq, Erik, Balzarini, Jan
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 12.01.2006
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; Cell Line; Cell Proliferation - drug effects; Cytomegalovirus - drug effects; Herpesvirus 3, Human - drug effects; Humans; Medical sciences; Microbial Sensitivity Tests; Molecular Structure; Pharmacology. Drug treatments; Pyrimidine Nucleosides - chemical synthesis; Pyrimidine Nucleosides - chemistry; Pyrimidine Nucleosides - pharmacology; Stereoisomerism; Structure-Activity Relationship; Varicella zoster virus; Acetylenic compound; Herpesviridae; Alphaherpesvirinae; Deoxyribonucleoside; Betaherpesvirinae; In vitro; Human cytomegalovirus; Virus; Structure activity relation; Bicyclic compound; Antiviral; Nucleoside; Ribonucleoside; Chemical synthesis; Oxygen nitrogen heterocycle
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050867d

Derivatives of the 2‘-deoxynucleoside of furo[2,3-d]pyrimidin-2(3H)-one with long-chain alkyl (or 4-alkylphenyl) substituents at C6 exhibit remarkable anti-VZV (varicella-zoster virus) potency and selectivity, and analogous 2‘,3‘-dideoxynucleoside derivatives show anti-HCMV (human cytomegalovirus) activity. We now report a synthetic approach that enables the preparation of long-chain 6-(alkyn-1-yl)furo[2,3-d]pyrimidin-2(3H)-ones in which the rodlike acetylene spacer replaces the 4-substituted-phenyl ring at C6. Analogues with methyl, β-d-ribofuranosyl, β-d-arabinofuranosyl, and 2-deoxy-β-d-erythro-pentofuranosyl substituents at N3 have been prepared. Long-chain derivatives at C6 in the 2‘-deoxynucleoside series showed virus-encoded nucleoside kinase-sensitive anti-VZV activity. Surprisingly, 3-methyl-6-(octyn-1-yl)furo[2,3-d]pyrimidin-2(3H)-one (prepared as a negative anti-VZV test control) exhibited anti-HCMV activity, which supports the possibility of development of non-nucleoside anti-HCMV agents originating from uncomplicated derivatives of such bicyclic ring systems.