Synthesis of aminophenylhydroxamate and aminobenzylhydroxamate derivatives and in vitro screening for antiparasitic and histone deacetylase inhibitory activity

Int J Parasitol Drugs Drug Resist. 2018 Apr;8(1):59-66. doi: 10.1016/j.ijpddr.2018.01.002. Epub 2018 Jan 31.

Abstract

A series of aminophenylhydroxamates and aminobenzylhydroxamates were synthesized and screened for their antiparasitic activity against Leishmania, Trypanosoma, and Toxoplasma. Their anti-histone deacetylase (HDAC) potency was determined. Moderate to no antileishmanial or antitrypanosomal activity was found (IC50 > 10 μM) that contrast with the highly efficient anti-Toxoplasma activity (IC50 < 1.0 μM) of these compounds. The antiparasitic activity of the synthetized compounds correlates well with their HDAC inhibitory activity. The best-performing compound (named 363) express a high anti-HDAC6 inhibitory activity (IC50 of 0.045 ± 0.015 μM) a moderate cytotoxicity and a high anti-Toxoplasma activity in the range of known anti-Toxoplasma compounds (IC50 of 0.35-2.25 μM). The calculated selectivity index (10-300 using different human cell lines) of the compound 363 makes it a lead compound for the future development of anti-Toxoplasma molecules.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiparasitic Agents / chemical synthesis
  • Antiparasitic Agents / pharmacology*
  • Cell Line
  • Dose-Response Relationship, Drug
  • High-Throughput Screening Assays
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / isolation & purification
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / drug effects*
  • Humans
  • Hydroxamic Acids / chemical synthesis*
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / pharmacology*
  • Inhibitory Concentration 50
  • Leishmania / drug effects
  • Molecular Structure
  • Structure-Activity Relationship
  • Toxoplasma / drug effects
  • Trypanosoma / drug effects

Substances

  • Antiparasitic Agents
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Histone Deacetylases