Synthesis and evaluation of 7-chloro-4-(piperazin-1-yl)quinoline-sulfonamide as hybrid antiprotozoal agents

Bioorg Med Chem. 2013 Jun 1;21(11):3080-9. doi: 10.1016/j.bmc.2013.03.052. Epub 2013 Apr 2.

Abstract

A new series of 4-aminochloroquinoline based sulfonamides were synthesized and evaluated for antiamoebic and antimalarial activities. Out of the eleven compounds evaluated (F1-F11), two of them (F3 and F10) showed good activity against Entamoeba histolytica (IC50 <5 μM). Three of the compounds (F5, F7 and F8) also displayed antimalarial activity against the chloroquine-resistant (FCR-3) strain of Plasmodium falciparum with IC50 values of 2 μM. Compound F7, whose crystal structure was also determined, inhibited β-haematin formation more potently than quinine. To further understand the action of hybrid molecules F7 and F8, molecular docking was carried out against the homology model of P. falciparum enzyme dihydropteroate synthase (PfDHPS). The complexes showed that the inhibitors place themselves nicely into the active site of the enzyme and exhibit interaction energy which is in accordance with our activity profile data. Application of Lipinski 'rule of five' on all the compounds (F1-F11) suggested high drug likeness of F7 and F8, similar to quinine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antiprotozoal Agents / chemical synthesis*
  • Antiprotozoal Agents / pharmacology
  • Cell Survival / drug effects
  • Chloroquine / pharmacology
  • Crystallography, X-Ray
  • Dihydropteroate Synthase / antagonists & inhibitors*
  • Dihydropteroate Synthase / chemistry
  • Drug Resistance
  • Entamoeba histolytica / drug effects*
  • Entamoeba histolytica / enzymology
  • Entamoeba histolytica / growth & development
  • Erythrocytes / drug effects
  • Erythrocytes / parasitology
  • Hemeproteins / antagonists & inhibitors
  • Hemeproteins / chemistry
  • Hemolysis / drug effects
  • Humans
  • Molecular Docking Simulation
  • Molecular Sequence Data
  • Piperazines / chemical synthesis*
  • Piperazines / pharmacology
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / enzymology
  • Plasmodium falciparum / growth & development
  • Protozoan Proteins / antagonists & inhibitors*
  • Protozoan Proteins / chemistry
  • Quinine / pharmacology
  • Quinolines / chemical synthesis*
  • Quinolines / pharmacology
  • Structure-Activity Relationship

Substances

  • Antiprotozoal Agents
  • Hemeproteins
  • Piperazines
  • Protozoan Proteins
  • Quinolines
  • hemozoin
  • Chloroquine
  • Quinine
  • Dihydropteroate Synthase