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

Hitesh K. Agarwal, Bhupender S. Chhikara, Gustavo F. Doncel, Keykavous Parang

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish (US)
Pages (from-to)1934-1937
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume27
Issue number9
DOIs
StatePublished - May 1 2017

Keywords

  • Anti-HIV
  • Dicarboxylic acid
  • Ester
  • Fatty acid
  • Nucleosides

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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