Syntheses and biological evaluation of 5'-O-myristoyl derivatives of thymidine against human immunodeficiency virus

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

Research output: Contribution to journalArticle

Abstract

A series of 5'-O-acyl derivatives of thymidine (dThd) were prepared by direct acylation of thymidine using the Mitsunobu reaction. Further reaction of the bromo analogues with sodium azide gave azido ester analogues. Anti-human immunodeficiency virus type 1 (HIV-1) activities were determined against HIV-infected T4 lymphocytes. 5'-O-(12-Azidododecanoyl)thymidine exhibited moderate activity (EC50 4.6 μM) against HIV-infected T4 lymphocytes. 5'-O-(2-Bromotetradecanoyl)-thymidine was found to be the most stable ester (t( 1/4 ) 15.3 min) to hydrolysis by porcine liver esterase in vitro. Partition coefficients (P) in n-octanol-phosphate buffer were determined (log P range 4.15-6.72) and compared with the theoretical values calculated (log10 P 3.96-6.53) using the PALLAS program. Anti-HIV structure-activity data suggest that the experimental partition coefficient should be in the log10 P 4.6-4.8 range for optimum anti-HIV activity. The structures of these thymidine analogues were optimized using molecular mechanics (MM+ force field) and semi-empirical quantum mechanics PM3 calculations. The moderately active compounds adopted a similar C-2' endo sugar conformation and exhibited similar energies for the lowest conformer. A quaniitative structure-activity relationship (QSAR) regression equation was developed, based on the optimized structures and anti-HIV data using the SciQSAR program, which showed that log P was a determinant of anti-HIV activity.

Original languageEnglish (US)
Pages (from-to)417-427
Number of pages11
JournalAntiviral Chemistry and Chemotherapy
Volume8
Issue number5
StatePublished - Sep 1997
Externally publishedYes

Keywords

  • Anti-HIV activity
  • Enzymic hydrolysis
  • Ester prodrug
  • Quantitative structure-activity relationships
  • Thymidine

ASJC Scopus subject areas

  • Virology
  • Pharmacology

Fingerprint Dive into the research topics of 'Syntheses and biological evaluation of 5'-O-myristoyl derivatives of thymidine against human immunodeficiency virus'. Together they form a unique fingerprint.

  • Cite this