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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:27

Article

Agarwal, Hitesh K.¹  Chhikara, Bhupender S.²  Doncel, Gustavo F.³  Parang, Keykavous⁴ 

[1] South Univ, Sch Pharm, 10 Sci Court, Columbia, SC 29203 USA

[2] Univ Delhi, Dept Chem, Delhi 110039, India

[3] Eastern Virginia Med Sch, CONRAD, 601 Colley Ave, Norfolk, VA 23507 USA

[4] Chapman Univ Sch Pharm, Ctr Targeted Drug Delivery, Irvine, CA 92618 USA

关键词: Anti-HIV;    Dicarboxylic acid;    Ester;    Fatty acid;    Nucleosides;   

DOI  :  10.1016/j.bmcl.2017.03.031

来源: Elsevier

【 摘 要 】

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. (C) 2017 Elsevier Ltd. All rights reserved.

【 授权许可】

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