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

• Published in: Journal of medicinal chemistry Vol. 50; no. 16; pp. 3897 - 3905
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.08.2007; Amer Chemical Soc
• Subjects: Alkenes - chemical synthesis; Alkenes - chemistry; Alkenes - pharmacology; Alkynes - chemical synthesis; Alkynes - chemistry; Alkynes - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; Cell Line; Chemistry, Medicinal; Crystallography, X-Ray; Cytomegalovirus - drug effects; Cytomegalovirus - genetics; DNA Viruses - drug effects; Furans - chemical synthesis; Furans - chemistry; Furans - pharmacology; Herpesvirus 3, Human - drug effects; Herpesvirus 3, Human - genetics; Human cytomegalovirus; Humans; Life Sciences & Biomedicine; Medical sciences; Molecular Structure; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pyrimidine Nucleosides - chemical synthesis; Pyrimidine Nucleosides - chemistry; Pyrimidine Nucleosides - pharmacology; RNA Viruses - drug effects; Science & Technology; Solubility; Stereoisomerism; Structure-Activity Relationship; Thymidine Kinase - genetics; Varicella-zoster virus; SELECTIVE-INHIBITION; ACID RELATED-COMPOUNDS; VZV; VARICELLA-ZOSTER-VIRUS; BIOLOGICAL EVALUATION; HIGHLY POTENT; NONAQUEOUS DIAZOTIZATION; POTENT INHIBITORS; Varicella zoster virus; Nitrogen heterocycle; Herpesviridae; Alphaherpesvirinae; Benzene derivatives; Deoxyribonucleoside; Betaherpesvirinae; In vitro; Human cytomegalovirus; Pyridine derivatives; Virus; Structure activity relation; Six membered ring; Bicyclic compound; Nucleoside analog; Antiviral; Pyrimidine derivatives; Chemical synthesis; Oxygen nitrogen heterocycle
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm070210n

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.