ABSTRACT
Alkylation of 2-methylthiopyrimidin-4(1H)-one (1a) and its 5(6)-alkyl derivatives 1b-d as well as theophylline (7) with 2,2-bis(bromomethyl)-1,3-diacetoxypropane (2) under microwave irradiation gave the corresponding acyclonucleosides 1-[(3-acetoxy-2-acetoxymethyl-2-bromomethyl)prop-1-yl]-2-methyl-thio pyrmidin-4(1H)-ones 3a-d and 7-[(3-acetoxy-2-acetoxymethyl-2-bromomethyl)prop-1-yl]theophylline (8), which upon further irradiation gave the double-headed acyclonucleosides 1,1 '-[(2,2-diacetoxymethyl)-1,3-propylidene]-bis[(2-(methylthio)-pyrimidin-4(1H)-ones] 4a-c, and 7,7 '-[(2,2-diacetoxymethyl)-1,3-propylidene]-bis(theophylline) (9). The deacetylated derivatives were obtained by the action of sodium methoxide. The activity of deacetylated nucleosides against Hepatitis B virus was evaluated. Compound 5b showed moderate inhibition activity against HBV with mild cytotoxicity.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Hepatitis B virus/drug effects , Pyrimidine Nucleosides/chemistry , Pyrimidine Nucleosides/pharmacology , Pyrimidinones/chemistry , Theophylline/chemistry , Antiviral Agents/chemical synthesis , Cells, Cultured , Humans , Microwaves , Pyrimidine Nucleosides/chemical synthesis , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacologyABSTRACT
The sodium salts of some hetaryls of the quinoxalin-2-ones 2-4, phthalazine-1,4-dione 5, phthalazin-1-one 6, and pyridazin-6-ones 7 and 8 were alkylated with (+/-) 2,3-O-isopropylidene-1-O-(4-toluenesulfonyl)glycerol (1) to give the respective tetraseco-nucleosides 9-15. Their deisopropylidenation with 70% acetic acid in water gave the corresponding 2,3-dihydroxyprop-1-yl hetaryls 16-22. Compounds 16-22 showed varying inhibition activity against Hepatitis B virus (HBV) with low to moderate cytotoxicity, where 18 and 21 showed the highest replication inhibition and low cytotoxicity.
Subject(s)
Antiviral Agents/chemical synthesis , Hepatitis B virus/drug effects , Propylene Glycols/chemical synthesis , Antiviral Agents/pharmacology , Cells, Cultured , DNA, Viral/biosynthesis , Humans , Polymerase Chain Reaction , Propylene Glycols/pharmacologyABSTRACT
The ambident nucleophilic nature of the sodium salts of 2(1H)-qunioxalinone (2) and the phthalazinedione (3) has been realized from their alkylation with 2-(2-chloroethoxy)ethylacetate (1) to afford 1-[2-(2-acetoxyethoxy)ethyl]-2(1H)-quinoxalinone (8) and 2-[2-(2-acetoxyethoxy)ethoxy]qunioxaline (9) as well as 10 and 11, respectively. The corresponding derivatives 12-15 were similarly prepared by the alkylation of the unnatural bases 4-7 with 1. Treatment of the alkylated derivatives 8-15 with methanolic ammonia solution (1:1) at room temperature gave the corresponding hydroxyalkyl derivatives 16-23. The site of the alkylation was deduced from the spectral characteristics of the products. The activity of compounds 16-22 against Hepatitis B virus (HBV) in HepG2 cell has been tested. Some of the compounds showed high viral replication inhibition with low cytotoxicity.