Discovery and Characterization of Fluorine-Substituted Diarylpyrimidine Derivatives as Novel HIV-1 NNRTIs with Highly Improved Resistance Profiles and Low Activity for the hERG Ion Channel

J Med Chem. 2020 Feb 13;63(3):1298-1312. doi: 10.1021/acs.jmedchem.9b01769. Epub 2020 Jan 24.

Abstract

Our previous efforts have led to the development of two potent NNRTIs, K-5a2 and 25a, exhibiting effective anti-HIV-1 potency and resistance profiles compared with etravirine. However, both inhibitors suffered from potent hERG inhibition and short half-life. In this article, with K-5a2 and etravirine as leads, series of novel fluorine-substituted diarylpyrimidine derivatives were designed via molecular hybridization and bioisosterism strategies. The results indicated 24b was the most active inhibitor, exhibiting broad-spectrum activity (EC50 = 3.60-21.5 nM) against resistant strains, significantly lower cytotoxicity (CC50= 155 μM), and reduced hERG inhibition (IC50 > 30 μM). Crystallographic studies confirmed the binding of 24b and the role of the fluorine atom, as well as optimal contacts of a nitrile group with the main-chain carbonyl group of H235. Furthermore, 24b showed longer half-life and favorable safety properties. All the results demonstrated that 24b has significant promise in circumventing drug resistance as an anti-HIV-1 candidate.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-HIV Agents / metabolism
  • Anti-HIV Agents / pharmacokinetics
  • Anti-HIV Agents / pharmacology*
  • Anti-HIV Agents / toxicity
  • Cell Line
  • Crystallography, X-Ray
  • Drug Discovery
  • ERG1 Potassium Channel / metabolism*
  • Female
  • Fluorine / chemistry
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects*
  • Humans
  • Male
  • Mice
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Protein Binding
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology*
  • Pyrimidines / toxicity
  • Rats, Wistar
  • Reverse Transcriptase Inhibitors / metabolism
  • Reverse Transcriptase Inhibitors / pharmacokinetics
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Reverse Transcriptase Inhibitors / toxicity
  • Structure-Activity Relationship
  • Thiophenes / metabolism
  • Thiophenes / pharmacokinetics
  • Thiophenes / pharmacology*
  • Thiophenes / toxicity

Substances

  • Anti-HIV Agents
  • ERG1 Potassium Channel
  • KCNH2 protein, human
  • Pyrimidines
  • Reverse Transcriptase Inhibitors
  • Thiophenes
  • Fluorine
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase