Identification of novel class of falcipain-2 inhibitors as potential antimalarial agents

Bioorg Med Chem. 2015 May 1;23(9):2221-40. doi: 10.1016/j.bmc.2015.02.062. Epub 2015 Mar 18.

Abstract

Falcipain-2 is a papain family cysteine protease and an emerging antimalarial drug target. A pseudo-tripeptide scaffold I was designed using in silico screening tools and the three dimensional structures of falcipain-2, falcipain-3, and papain. This scaffold was investigated at four positions, T1, T2, T3, and T3', with various targeted substitutions to understand the structure-activity relationships. Inhibitor synthesis was accomplished by first obtaining the appropriate dipeptide precursors with common structural components. The pyrrolidine moiety introduced interesting rotamers in a number of synthesized molecules, which was confirmed using high-temperature (1)H NMR spectroscopy. Among the synthesized compounds, 61, 62, and 66 inhibited falcipain-2 activity with inhibition constants (Ki) of 1.8 ± 1.1, 0.2 ± 0.1 and 7.0 ± 2.3 μM, respectively. A group of molecules with a pyrrolidine moiety at the T2 position (68, 70, 71, 72, and 73) also potently inhibited falcipain-2 activity (Ki=0.4 ± 0.1, 2.5 ± 0.5, 3.3 ± 1.1, 7.5 ± 1.9, and 4.6 ± 0.7 μM, respectively). Overall, compound 74 exhibited potent anti-parasitic activity (IC₅₀=0.9 ± 0.1 μM), corresponding with its inhibitory activity against falcipain-2, with a Ki of 1.1 ± 0.1 μM. Compounds 62 and 67 inhibited the growth of the drug resistant parasite Dd2 with better efficacy, and compound 74 exhibited a 7- to 12-fold higher potency against Dd2 and MCamp isolates, than the laboratory strain (3D7). These data suggest that this novel series of compounds should be further investigated as potential antimalarial agents.

Keywords: Anti-parasitic agents; Antimalarial agents; Cysteine proteases; Docking; Falcipain-2 inhibitors; Malaria; Structure–activity relationship.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimalarials / chemical synthesis
  • Antimalarials / chemistry
  • Antimalarials / pharmacology*
  • CHO Cells
  • Cell Proliferation / drug effects
  • Cricetulus
  • Cysteine Endopeptidases / metabolism*
  • Cysteine Proteinase Inhibitors / chemical synthesis
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / classification*
  • Cysteine Proteinase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design
  • Drug Resistance / drug effects
  • Models, Molecular
  • Molecular Structure
  • Parasitic Sensitivity Tests
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / enzymology*
  • Plasmodium falciparum / growth & development
  • Structure-Activity Relationship

Substances

  • Antimalarials
  • Cysteine Proteinase Inhibitors
  • Cysteine Endopeptidases
  • falcipain 2