title: Synthesis and anti-HIV activities of unsymmetrical long chain dicarboxylate esters of dinucleoside reverse transcriptase inhibitors.
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 EC50values of 47 and 75nM against X4 and R5 HIV-1 strains, respectively, while the EC50values for the parent analogs, FLT and FTC, ranged from 700 to 3300nM.
authors.affiliation: School of Pharmacy, South University, 10 Science Court, Columbia, SC 29203, United States.
authors.forename: Hitesh K
authors.initials: HK
authors.lastname: Agarwal
authors.affiliation: Department of Chemistry, University of Delhi, Aditi Mahavidyalaya, Bawana, Delhi 110039, India.
authors.forename: Bhupender S
authors.initials: BS
authors.lastname: Chhikara
authors.affiliation: CONRAD, Eastern Virginia Medical School, 601 Colley Avenue, Norfolk, VA 23507, United States.
authors.forename: Gustavo F
authors.initials: GF
authors.lastname: Doncel
authors.affiliation: Center for Targeted Drug Delivery, Chapman University School of Pharmacy, Irvine, CA 92618, United States. Electronic address: parang@chapman.edu.
authors.forename: Keykavous
authors.initials: K
authors.lastname: Parang
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D003998:Dicarboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D003998:Dicarboxylic Acids; D004952:Esters; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase
keywords: Anti-HIV; Dicarboxylic acid; Ester; Fatty acid; Nucleosides