Antitrypanosomal, antileishmanial, and antimalarial activities of quaternary arylalkylammonium 2-amino-4-chlorophenyl phenyl sulfides, a new class of trypanothione reductase inhibitor, and of N-acyl derivatives of 2-amino-4-chlorophenyl phenyl sulfide

J Med Chem. 2005 Dec 15;48(25):8087-97. doi: 10.1021/jm050819t.

Abstract

Quaternization of the nitrogen atom of 2-amino-4-chlorophenyl phenyl sulfide analogues of chlorpromazine improved inhibition approximately 40-fold (3',4'-dichlorobenzyl-[5-chloro-2-phenylsulfanyl-phenylamino)-propyl]-dimethylammonium chloride inhibited trypanothione reductase from Trypanosoma cruzi with a linear competitive Ki value of 1.7 +/- 0.2 microM). Molecular modelling explained docking orientations and energies by: (i) involvement of the Z-site hydrophobic pocket (roughly bounded by F396', P398', and L399'), (ii) ionic interactions for the cationic nitrogen with Glu-466' or -467'. A series of N-acyl-2-amino-4-chlorophenyl sulfides showed mixed inhibition (Ki, Ki' = 11.3-42.8 microM). The quaternized analogues of the 2-chlorophenyl phenyl sulfides had strong antitrypanosomal and antileishmanial activity in vitro against T. brucei rhodesiense STIB900, T. cruzi Tulahuan, and Leishmania donovani HU3. The N-acyl-2-amino-4-chlorophenyl sulfides were active against Plasmodium falciparum. The phenothiazine and diaryl sulfide quaternary compounds were also powerful antimalarials, providing a new structural framework for antimalarial design.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimalarials / chemical synthesis*
  • Antimalarials / chemistry
  • Antimalarials / pharmacology
  • Benzene Derivatives / chemical synthesis*
  • Benzene Derivatives / chemistry
  • Benzene Derivatives / pharmacology
  • Chlorpromazine / analogs & derivatives
  • Chlorpromazine / chemical synthesis
  • Chlorpromazine / chemistry
  • Chlorpromazine / pharmacology
  • Leishmania donovani / drug effects
  • Models, Molecular
  • NADH, NADPH Oxidoreductases / antagonists & inhibitors*
  • NADH, NADPH Oxidoreductases / chemistry
  • Plasmodium falciparum / drug effects
  • Quaternary Ammonium Compounds / chemical synthesis*
  • Quaternary Ammonium Compounds / chemistry
  • Quaternary Ammonium Compounds / pharmacology
  • Structure-Activity Relationship
  • Sulfides / chemical synthesis*
  • Sulfides / chemistry
  • Sulfides / pharmacology
  • Trypanocidal Agents / chemical synthesis*
  • Trypanocidal Agents / chemistry
  • Trypanocidal Agents / pharmacology
  • Trypanosoma brucei rhodesiense / drug effects
  • Trypanosoma cruzi / drug effects

Substances

  • Antimalarials
  • Benzene Derivatives
  • Quaternary Ammonium Compounds
  • Sulfides
  • Trypanocidal Agents
  • NADH, NADPH Oxidoreductases
  • trypanothione reductase
  • Chlorpromazine