Diaryl ethers with carboxymethoxyphenacyl motif as potent HIV-1 reverse transcriptase inhibitors with improved solubility

J Enzyme Inhib Med Chem. 2018 Dec;33(1):9-16. doi: 10.1080/14756366.2017.1387542.

Abstract

In search of new non-nucleoside reverse transcriptase inhibitors (NNRTIs) with improved solubility, two series of novel diaryl ethers with phenacyl moiety were designed and evaluated for their HIV-1 reverse transcriptase inhibition potentials. All compounds exhibited good to excellent results with IC50 at low micromolar to submicromolar concentrations. Two most active compounds (7e and 7 g) exhibit inhibitory potency comparable or even better than that of nevirapine and rilpivirine. Furthermore, SupT1 and CD4+ cell infectivity assays for the most promising (7e) have confirmed its strong antiviral potential while docking studies indicate a novel binding interactions responsible for high activity.

Keywords: HIV; NNRTI; drug solubility; reverse transcriptase.

MeSH terms

  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Catechols / chemistry
  • Catechols / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design
  • Ethers / chemistry
  • Ethers / pharmacology*
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects*
  • HIV-1 / enzymology*
  • Humans
  • Microbial Sensitivity Tests
  • Molecular Docking Simulation
  • Molecular Structure
  • Resorcinols / chemistry
  • Resorcinols / pharmacology*
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Solubility
  • Structure-Activity Relationship

Substances

  • Anti-HIV Agents
  • Catechols
  • Ethers
  • Resorcinols
  • Reverse Transcriptase Inhibitors
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase
  • catechol
  • resorcinol

Grants and funding

The reported studies were supported by the grant 2011/02/A/ST4/00246 (2012–2017) from the Polish National Science Centre (NCN) to PP, and by Ghent University grant BOF17/GOA/013, HIVERA IRIFCURE and grants from the Research Foundation Flanders (FWO) to BV. BV is a Senior Clinical Investigator of the FWO.