Synthesis and Antiviral Evaluation of Novel 2,3-Dihydroxypropyl Nucleosides from 2- and 4-Thiouracils

• Published in: Nucleosides, nucleotides & nucleic acids nucleotides & nucleic acids, 2008-12, Vol.27 (12), p.1257-1271
• Main Authors: Abdel-Rahman, Adel A.-H., El-Etrawy, Abd-Allah SH, Abdel-Megied, Ahmed E.-S., Zeid, Ibrahim F., El Ashry, El Sayed H.
• Format: Article
• Language: English
• Subjects: 2,3-dihydroxypropyl nucleosides; 2-(methylthio) pyrimidin-4(1H)-ones; 4-(methylthio)pyrimidin-2(1H)-ones; Acyclic nucleosides; antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; hepatitis B; Hepatitis B virus; Hepatitis B virus - drug effects; Magnetic Resonance Spectroscopy; Molecular Structure; Nucleosides - chemical synthesis; Nucleosides - chemistry; Nucleosides - pharmacology; Thiouracil - chemistry
• ISSN: 1525-7770; 1532-2335
• DOI: 10.1080/15257770802086898

Regioselective alkylation of 2-thiouracils 1a-c and 4-thiouracils 7a,b with 2,3-O-isopropylidene-2,3-dihydroxypropyl chloride (2) afforded 2-{[(2,2-Dimethyl-1,3-dioxolan-4-yl) methyl]thio}pyrimidin-4(1H)-ones 3a-c and 4-{[(2,2-Dimethyl-1,3-dioxolan-4-yl)methyl]thio} pyrimidin-2(1H)-ones 8a,b, respectively. Further alkylation with 2 and/or 2,3-O-isopropylidine-1-O-(4-toluenesulfonyl)-glycerol (4) gave the acyclo N-nucleosides 5a-c and 9a,b whose deprotection afforded 6a-c and 10a,b. 2-(Methylthio)pyrimidin-4(1H)-ones 11a-c and 4-(methylthio)pyrimidin-2(1H)-ones 14a,b were treated with 2 and/or 4 to give 12a-c and 15a,b which were deprotected to give 13a-c and 16a,b. Pyrimidine-2,4(1H,3H)-dithiones 17a-c were treated with two equivalents of 2 to give 2,4-bis{[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]thio}pyrimidines 18a-c. Deprotection of compounds 18a-c gave 2,4-bis[(2,3-dihydroxypropyl)thio]pyrimidines 19a-c. The activity of the deprotected nucleosides against Hepatitis B virus was evaluated and showed moderate inhibition activity against HBV with mild cytotoxicity.