Design of MKC-442 (emivirine) analogues with improved activity against drug-resistant HIV mutants

J Med Chem. 1999 Nov 4;42(22):4500-5. doi: 10.1021/jm990192c.


Two analogues of the nonnucleoside inhibitor of HIV-1 RT, MKC-442 (emivirine), containing different C6 substituents have been designed to be less susceptible to the commonly found drug-resistance mutation of Tyr181Cys. Compound TNK-6123 had a C6 thiocyclohexyl group designed to have more flexibility in adapting to the mutated drug-binding site. GCA-186 had additional 3',5'-dimethyl substituents aimed at forming close contacts with the conserved residue Trp229. Both compounds showed approximately 30-fold greater inhibitory effect than MKC-442 to the Tyr181Cys mutant virus as well as to the clinically important Lys103Asn virus. X-ray crystallographic structure determination of complexes with HIV-1 RT confirmed the predicted binding modes. These strategies might be used to improve the resilience of other NNRTI series against common drug-resistance mutations.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology
  • Cell Line
  • Crystallography, X-Ray
  • Drug Design
  • Drug Resistance, Microbial
  • HIV-1 / drug effects
  • HIV-1 / genetics*
  • Models, Molecular
  • Molecular Conformation
  • Mutation
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology
  • Uracil / analogs & derivatives*
  • Uracil / chemical synthesis
  • Uracil / chemistry
  • Uracil / pharmacology


  • 6-(3,5-dimethylbenzyl)-1-(ethoxymethyl)-5-isopropyluracil
  • Anti-HIV Agents
  • Reverse Transcriptase Inhibitors
  • Uracil
  • emivirine