Synthesis and in vitro anti-HIV activities of didanosine prodrugs

Abstract

A series of prodrugs of didanosine were synthesized in an effort to enhance the anti-HIV activity. The 5′-OH function of didanosine was esterified with different aryl piperazine acetic acid derivatives and evaluated for anti-HIV-1 activity in MT-4 cell line using the MTT assay method. Among the synthesized compounds, (tetrahydro-5-(1,6-dihydro-6-oxopurin-9-yl)furan-2-yl)methyl 2-(4-(4-chlorophenyl)piperazin-1-yl)acetate (4b) was found to be the most potent compound with EC₅₀ of 0.64 μM and was not toxic to the MT-4 cells up to 1000 μM with a selectivity index of >1562. Compound 4b was found to be seven times more potent than the parent drug didanosine (EC₅₀ of 4.8 μM) in vitro. In vitro hydrolysis of the various esters in human plasma indicated that these agents were relatively stable toward plasma esterases with t_1/2 ranging from 20–60 min.

Keywords::

• Didanosine
• prodrugs
• anti-HIV activity