Synthesis, biological evaluation, Structure - Activity relationship studies of quinoline-imidazole derivatives as potent antimalarial agents

Bioorg Chem. 2022 Apr:121:105671. doi: 10.1016/j.bioorg.2022.105671. Epub 2022 Feb 11.

Abstract

In our efforts to identify novel chemical scaffolds for the development of antimalarial agents, a series of quinoline - imidazole hybrid compounds were synthesized and their blood-stage antimalarial activity was evaluated in both drug-sensitive and -multi drug-resistant (MDR) P. falciparum strains. The new analogs possess sub-micromolar activities against Plasmodium falciparum. Among all synthesized derivatives, 11(xxxii) exhibited significant antimalarial efficacy in-vitro against both CQ-sensitive (IC50-0.14 μM) and MDR strain (IC50- 0.41 μM) with minimal cytotoxicity and high selectivity. Structure-activity relationships revealed that Br and OMe substitutions on quinoline ring improved the antimalarial activity and selectivity index. The role of stereochemistry in the inhibitory activity was assessed by enantiomeric separation of a racemic mixture of 11(xxxii). The enantiomer (-)-11(xxxii) had potent antimalarial activity over the other isomer, with IC50 of 0.10 µM.

Keywords: Antimalarial agents; Quinoline-imidazole hybrids; Structure−Activity relationship.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-alpha Demethylase Inhibitors / pharmacology
  • Antimalarials* / chemistry
  • Antiprotozoal Agents* / pharmacology
  • Cytochrome P-450 CYP3A Inhibitors
  • Hydroxyquinolines*
  • Imidazoles
  • Nitroimidazoles*
  • Plasmodium falciparum
  • Quinolines* / chemistry
  • Structure-Activity Relationship

Substances

  • 14-alpha Demethylase Inhibitors
  • Antimalarials
  • Antiprotozoal Agents
  • Cytochrome P-450 CYP3A Inhibitors
  • Hydroxyquinolines
  • Imidazoles
  • Nitroimidazoles
  • Quinolines
  • imidazole
  • quinoline