Allosteric inhibitors against HIV-1 reverse transcriptase: design and synthesis of MKC-442 analogues having an omega-functionalized acyclic structure

Antivir Chem Chemother. 1998 Jul;9(4):325-32.

Abstract

Based on X-ray crystallographic analysis of MKC-442/human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) complex, analogues in which the N1-substituent is replaced with omega-functionalized alkyl groups were designed to improve the affinity for the enzyme. Synthesis of these compounds was carried out starting from MKC-442 by a sequence of reactions (N3-protection, removal of N1-ethoxymethyl group, alkylation, and N3-deprotection). The compounds were evaluated for anti-HIV activity. Structure-activity relationships are discussed in terms of the possible interaction with the enzyme.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Site / drug effects*
  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / pharmacology
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / pharmacology
  • Cell Line
  • HIV Reverse Transcriptase / chemistry
  • HIV-1 / enzymology*
  • Hydrogen Bonding
  • Mass Spectrometry
  • Models, Molecular
  • Molecular Structure
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / pharmacology
  • Uracil* / analogs & derivatives*
  • Uracil* / pharmacology
  • Virus Replication / drug effects

Substances

  • Anti-HIV Agents
  • Antiviral Agents
  • Reverse Transcriptase Inhibitors
  • Uracil
  • HIV Reverse Transcriptase
  • emivirine