Synthesis, in vitro anti-human immunodeficiency virus structure-activity relationships and biological stability of 5'-O-myristoyl analogue derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) as potential prodrugs

K. Parang, L. I. Wiebe, E. E. Knaus

Research output: Contribution to journalArticlepeer-review

Abstract

5'O-Myristoyl analogue derivatives of 3'-azido-2',3'-dideoxythymidine (AZT), designed as potential double-barrelled prodrugs to AZT and the myristic acid analogues, were synthesized. Their ability to protect CEM cells against human immunodeficiency virus (HIV)-induced cytopathogenicity was determined and structure-activity paradigms were developed. 3'-Azido-2',3'- dideoxy-5'-O-(4-oxate-tradecanoyl)thymidine (EC50=1.4 nM) and 3'-azido- 2',3'-deoxy-5'-O-(12-bromododecanoyl)thymidine (EC50=3.2 nM) were the most effective anti-HIV-1 agents, relative to AZT (EC50=10 nM). These myristoyl analogue derivatives were more lipophilic (calculated log P=4.5-8.1 range) than the parent compound AZT (log P=0.06), and a linear correlation between their log P and HPLC log retention times was observed. The ester cleavage half-lives (t(1/2)) for esters upon in vitro incubation with porcine liver esterase, rat plasma or rat brain homogenate was dependent on the steric bulk, and electronegative inductive effect of the α-substituent (H, Br, F), of the 5'-O-myristoyl analogue moiety. 3'-Azido-2',3'-dideoxy-5'-O-(11-(4- iodophenoxy) undecanoyl)-thymidine exhibited t(1/2) values of 80.4, 3.7 and 150.0 min upon incubation with porcine liver esterase, rat plasma and rat brain homogenate, respectively.

Original languageEnglish (US)
Pages (from-to)311-323
Number of pages13
JournalAntiviral Chemistry and Chemotherapy
Volume9
Issue number4
StatePublished - Jul 1998
Externally publishedYes

Keywords

  • 3'-azido-2',3'-dideoxythymidine
  • Anti-HIV activity
  • Enzymic hydrolysis
  • Ester prodrugs
  • Myristic acid analogues
  • Structure-activity relationships

ASJC Scopus subject areas

  • Virology
  • Pharmacology

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