Design and synthesis of hybrids of diarylpyrimidines and diketo acids as HIV-1 inhibitors

Bioorg Med Chem Lett. 2017 Apr 15;27(8):1640-1643. doi: 10.1016/j.bmcl.2017.03.009. Epub 2017 Mar 7.

Abstract

Based on the strategy of molecular hybridization, diketo acid fragment as a classical phamacophore of integrase inhibitors was introduced to reverse transcriptase inhibitors diarylpyrimidines to design a series of diarylpyrimidine-diketo acid hybrids (DAPY-DKAs). The target molecules 10b and 11b showed inhibitory activities against WT HIV-1 with EC50 values of 0.18μM and 0.14μM, respectively. And the results of molecular docking demonstrated the potential binding mode and revealed that the DKA moiety and its ester could both be tolerated in the nonnucleoside binding site (NNBS) of HIV-1 RT.

Keywords: AIDS; Diarylpyrimidines; Diketo acids; HIV-1 inhibitors; Integrase; Molecular hybridization; Reverse transcriptase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacology*
  • Cell Line
  • Drug Design*
  • HIV Infections / drug therapy
  • HIV Infections / virology
  • HIV Integrase / metabolism
  • HIV Integrase Inhibitors / chemical synthesis
  • HIV Integrase Inhibitors / chemistry
  • HIV Integrase Inhibitors / pharmacology
  • HIV-1 / drug effects*
  • HIV-1 / enzymology*
  • Humans
  • Keto Acids / chemical synthesis
  • Keto Acids / chemistry
  • Keto Acids / pharmacology
  • Molecular Docking Simulation
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology*
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology

Substances

  • Anti-HIV Agents
  • HIV Integrase Inhibitors
  • Keto Acids
  • Pyrimidines
  • Reverse Transcriptase Inhibitors
  • HIV Integrase