Synthesis and Anti-HIV Activities of Unsymmetrical Long Chain Dicarboxylate Esters of Dinucleosides Reverse Transcriptase Inhibitors

Authors

Hitesh K. Agarwal, South University
Bhupender S. Chhikara, University of Delhi
Gustavo F. Doncel, Eastern Virginia Medical School
Keykavous Parang, Chapman UniversityFollow

Document Type

Article

Publication Date

3-16-2017

Abstract

A series of 11 unsymmetrical dinucleoside dicarboxylate conjugates of nucleoside 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 compound 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 3,300 nM.

Comments

NOTICE: this is the author’s version of a work that was accepted for publication in Bioorganic & Medicinal Chemistry Letters. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version will be subsequently published in Bioorganic & Medicinal Chemistry Letters in 2017. DOI: 10.1016/j.bmcl.2017.03.031

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Recommended Citation

Agarwal HK, Chhikara BS, Doncel GF, Parang K. Synthesis and anti-HIV activities of unsymmetrical long chain dicarboxylate esters of dinucleosides reverse transcriptase inhibitors, Bioorg Med Chem Lett. 2017. doi: 10.1016/j.bmcl.2017.03.031

Copyright

Elsevier

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