2-Aminoquinazolin-4(3H)-one based plasmepsin inhibitors with improved hydrophilicity and selectivity

Bioorg Med Chem. 2018 May 15;26(9):2488-2500. doi: 10.1016/j.bmc.2018.04.012. Epub 2018 Apr 5.

Abstract

2-Aminoquinazolin-4(3H)-ones were previously discovered as perspective leads for antimalarial drug development targeting the plasmepsins. Here we report the lead optimization studies with the aim to reduce inhibitor lipophilicity and increase selectivity versus the human aspartic protease Cathepsin D. Exploiting the solvent exposed area of the enzyme provides an option to install polar groups (R1) the 5-position of 2-aminoquinazolin-4(3H)-one to inhibitors such as carboxylic acid without scarifying enzymatic potency. Moreover, introduction of R1 substituents increased selectivity factors of compounds in this series up to 100-fold for Plm II, IV vs CatD inhibition. The introduction of flap pocket substituent (R2) at 7-postion of 2-aminoquinazolin-4(3H)-one allows to remove Ph group from THF ring without notably impairing Plm inhibitory potency. Based on these findings, inhibitors were developed, which show Plm II and IV inhibitory potency in low nanomolar range and remarkable selectivity against Cathepsin D along with decreased lipophilicity and increased solubility.

Keywords: 2-Aminoquinazolin-4(3H)-ones; Cathepsin D; Inhibitors; Malaria; Plasmepsins; Plasmodium falciparum.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / chemistry
  • Binding Sites
  • Cathepsin D / chemistry
  • Hydrophobic and Hydrophilic Interactions
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Plasmodium falciparum / enzymology
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry*
  • Protozoan Proteins / antagonists & inhibitors*
  • Protozoan Proteins / chemistry
  • Quinazolinones / chemical synthesis
  • Quinazolinones / chemistry*
  • Solubility
  • Structure-Activity Relationship

Substances

  • Protease Inhibitors
  • Protozoan Proteins
  • Quinazolinones
  • Aspartic Acid Endopeptidases
  • plasmepsin
  • plasmepsin II
  • Cathepsin D