New alkenyldiarylmethanes with enhanced potencies as anti-HIV agents which act as non-nucleoside reverse transcriptase inhibitors

J Med Chem. 1998 Jun 4;41(12):2076-89. doi: 10.1021/jm9800595.

Abstract

Twenty-two new alkenyldiarylmethanes (ADAMs) were synthesized and evaluated for inhibition of HIV-1 replication. The most potent compound proved to be methyl 3',3"-dichloro-4',4"-dimethoxy-5', 5"-bis(methoxycarbonyl)-6,6-diphenyl-5-hexenoate (ADAM II), which displayed an EC50 of 13 nM for inhibition of the cytopathic effect of HIV-1RF in CEM-SS cells. ADAM II inhibited HIV-1 reverse transcriptase with an IC50 of 0.3 microM but was inactive as an inhibitor of HIV-1 attachment/fusion to cells, protease, integrase, and the nucleocapsid protein. Molecular target-based and cell-based assays revealed that ADAM II acted biologically as a nonnucleoside reverse transcriptase inhibitor (NNRTI). ADAM II inhibited replication of a wide variety of laboratory, clinical, and clade-representative isolates of HIV-1 in T cell lines and cultures of peripheral blood mononuclear cells or monocyte/macrophages. Mutations that conferred resistance to ADAM II clustered at residues 101, 103, 108, 139, 179, 181, and 188, which line the nonnucleoside binding pocket of HIV-1 reverse transcriptase. However, HIV-1 NL4-3 strain expressing a mutation at residue 100 of reverse transcriptase, and an AZT-resistant virus, displayed increased sensitivity to ADAM II. Thus, ADAM II could serve as an adjunct therapy to AZT and NNRTIs that select for L100I resistance mutations.

Publication types

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

MeSH terms

  • Alkanes* / chemical synthesis
  • Alkanes* / chemistry
  • Alkanes* / metabolism
  • Alkanes* / pharmacology
  • Animals
  • Anti-HIV Agents* / chemical synthesis
  • Anti-HIV Agents* / chemistry
  • Anti-HIV Agents* / metabolism
  • Anti-HIV Agents* / pharmacology
  • Binding Sites
  • Caproates* / chemical synthesis
  • Caproates* / chemistry
  • Caproates* / metabolism
  • Caproates* / pharmacology
  • Cell Line
  • Cytopathogenic Effect, Viral / drug effects
  • Drug Evaluation, Preclinical
  • Drug Resistance, Microbial
  • HIV Reverse Transcriptase / genetics
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • HIV-1 / genetics
  • HIV-1 / physiology
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / virology
  • Macrophages / drug effects
  • Macrophages / virology
  • Mice
  • Models, Molecular
  • Mutation
  • Reverse Transcriptase Inhibitors* / chemical synthesis
  • Reverse Transcriptase Inhibitors* / chemistry
  • Reverse Transcriptase Inhibitors* / metabolism
  • Reverse Transcriptase Inhibitors* / pharmacology
  • Structure-Activity Relationship
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / virology
  • Virus Replication / drug effects
  • Zidovudine / pharmacology

Substances

  • ADAM II
  • Alkanes
  • Anti-HIV Agents
  • Caproates
  • Reverse Transcriptase Inhibitors
  • Zidovudine
  • HIV Reverse Transcriptase