Design, synthesis, antiviral and cytostatic evaluation of novel isoxazolidine nucleotide analogues with a 1,2,3-triazole linker

Abstract

Azidation (TMSN(3), SnCl(4)) of a 9:1 mixture of trans- and cis-5-acetoxy-2-methylisoxazolidin-3-yl-3-phosphonates at the anomeric carbon atom led to the formation of the equimolar mixture of cis- and trans-5-azido-2-methylisoxazolidin-3-yl-3-phosphonates, which were efficiently separated. The 1,3-dipolar cycloaddition of pure trans- and cis-5-azidoisoxazolidin-3-yl-3-phosphonates with selected alkynes gave the respective nucleoside mimetics containing a 1,2,3-triazole linker. The (1,2,3-triazolyl)isoxazolidine phosphonates obtained herein were evaluated in vitro for activity against a variety of DNA and RNA viruses. None of the compounds were endowed with antiviral activity at subtoxic concentrations. Compounds 15f-j and 16f-j were cytostatic in the higher micromolar range.