Synthesis and biological evaluation of novel C5 halogen-functionalized S-DABO as potent HIV-1 non-nucleoside reverse transcriptase inhibitors

Bioorg Med Chem. 2010 May 1;18(9):3231-7. doi: 10.1016/j.bmc.2010.03.025. Epub 2010 Mar 15.

Abstract

A series of novel S-DABO analogues (4a1-5a12) have been synthesized by an efficient method and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). The biological testing results clearly indicated that the substitution of halogen at the C5 position of pyrimidine ring could increase the anti-HIV-1 RT activity. The most active compounds showed activity in the low micromole range with IC(50) values (IC(50) 0.18-3.03 microM) comparable to nevirapine (IC(50) 4.12 microM). The docking showed that a new halogen bond was formed between halogen and carbonyl of TYR188 in the HIV-I RT.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Design*
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV-1 / drug effects*
  • Halogens / chemistry
  • Humans
  • Inhibitory Concentration 50
  • Magnetic Resonance Spectroscopy
  • Molecular Structure
  • Nevirapine / chemistry
  • Nevirapine / pharmacology
  • Pyrimidinones / chemical synthesis
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacology
  • Quantitative Structure-Activity Relationship
  • Reverse Transcriptase Inhibitors* / chemical synthesis
  • Reverse Transcriptase Inhibitors* / chemistry
  • Reverse Transcriptase Inhibitors* / pharmacology
  • Sulfur / chemistry

Substances

  • DABO 546
  • Halogens
  • Pyrimidinones
  • Reverse Transcriptase Inhibitors
  • Sulfur
  • Nevirapine
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase