Synthesis and anti-HIV activities of unsymmetrical long chain dicarboxylate esters of dinucleoside reverse transcriptase inhibitors

A series of 11 unsymmetrical dicarboxylate conjugates of dinucleoside reverse transcriptase inhibitors were synthesized. Three dicarboxylic acids, succinic acid, suberic acid and 1,14-tetradecandioc acid, were diesterified with either 3′-azido-2′,3′-dideoxythymidine (AZT), 3′-fluoro-2′,3′-dideoxythymidine (FLT), 2′,3′-dideoxy-3′-thiacytidine (3TC), or 5-fluoro-2′,3′-dideoxy-3′-thiacytidine (FTC). The anti-HIV activity of synthesized compounds was evaluated against HIV-1 X4 (IIIB) and R5 (BaL) viral strains in single-round infection assays. Results indicated that the tetradecandioate esters of nucleosides were more active against HIV than the corresponding parent nucleosides and nucleoside conjugates. The tetradecandioate conjugate of FLT and FTC (5) was found to be the most potent compounds with EC₅₀ values of 47 and 75 nM against X4 and R5 HIV-1 strains, respectively, while the EC₅₀ values for the parent analogs, FLT and FTC, ranged from 700 to 3300 nM.