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

Bioorg Med Chem Lett. 2017 May 1;27(9):1934-1937. doi: 10.1016/j.bmcl.2017.03.031. Epub 2017 Mar 16.

Abstract

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 75nM against X4 and R5 HIV-1 strains, respectively, while the EC50 values for the parent analogs, FLT and FTC, ranged from 700 to 3300nM.

Keywords: Anti-HIV; Dicarboxylic acid; Ester; Fatty acid; Nucleosides.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacology*
  • Dicarboxylic Acids / chemical synthesis
  • Dicarboxylic Acids / chemistry
  • Dicarboxylic Acids / pharmacology
  • Esters / chemical synthesis
  • Esters / chemistry
  • Esters / pharmacology
  • HIV Infections / drug therapy
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV-1 / drug effects
  • Humans
  • Nucleosides / chemical synthesis
  • Nucleosides / chemistry*
  • Nucleosides / pharmacology*
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry*
  • Reverse Transcriptase Inhibitors / pharmacology*

Substances

  • Anti-HIV Agents
  • Dicarboxylic Acids
  • Esters
  • Nucleosides
  • Reverse Transcriptase Inhibitors
  • HIV Reverse Transcriptase