Synthesis, activity, and structural analysis of novel α-hydroxytropolone inhibitors of human immunodeficiency virus reverse transcriptase-associated ribonuclease H

J Med Chem. 2011 Jul 14;54(13):4462-73. doi: 10.1021/jm2000757. Epub 2011 Jun 2.

Abstract

The α-hydroxytroplone, manicol (5,7-dihydroxy-2-isopropenyl-9-methyl-1,2,3,4-tetrahydro-benzocyclohepten-6-one), potently and specifically inhibits ribonuclease H (RNase H) activity of human immunodeficiency virus reverse transcriptase (HIV RT) in vitro. However, manicol was ineffective in reducing virus replication in culture. Ongoing efforts to improve the potency and specificity over the lead compound led us to synthesize 14 manicol derivatives that retain the divalent metal-chelating α-hydroxytropolone pharmacophore. These efforts were augmented by a high resolution structure of p66/p51 HIV-1 RT containing the nonnucleoside reverse transcriptase inhibitor (NNRTI), TMC278 and manicol in the DNA polymerase and RNase H active sites, respectively. We demonstrate here that several modified α-hydroxytropolones exhibit antiviral activity at noncytotoxic concentrations. Inclusion of RNase H active site mutants indicated that manicol analogues can occupy an additional site in or around the DNA polymerase catalytic center. Collectively, our studies will promote future structure-based design of improved α-hydroxytropolones to complement the NRTI and NNRTI currently in clinical use.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / pharmacology
  • Benzocycloheptenes / chemistry
  • Catalytic Domain
  • Cations, Divalent
  • Cell Line
  • Coordination Complexes / chemistry
  • Crystallography, X-Ray
  • DNA-Directed DNA Polymerase / chemistry
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / chemistry
  • HIV-1 / drug effects*
  • HIV-1 / physiology
  • Humans
  • Manganese / chemistry
  • Models, Molecular
  • Molecular Structure
  • Mutation
  • Nitriles / chemistry
  • Protein Conformation
  • Pyrimidines / chemistry
  • Ribonuclease H, Human Immunodeficiency Virus / antagonists & inhibitors*
  • Ribonuclease H, Human Immunodeficiency Virus / chemistry
  • Ribonuclease H, Human Immunodeficiency Virus / genetics
  • Rilpivirine
  • Structure-Activity Relationship
  • Tropolone / analogs & derivatives*
  • Tropolone / chemical synthesis*
  • Tropolone / pharmacology
  • Virus Replication

Substances

  • Anti-HIV Agents
  • Benzocycloheptenes
  • Cations, Divalent
  • Coordination Complexes
  • Nitriles
  • Pyrimidines
  • manicol
  • Manganese
  • Tropolone
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase
  • DNA-Directed DNA Polymerase
  • Ribonuclease H, Human Immunodeficiency Virus
  • Rilpivirine

Associated data

  • PDB/3QLJH