Antimalarial Imidazopyridines Incorporating an Intramolecular Hydrogen Bonding Motif: Medicinal Chemistry and Mechanistic Studies

  • ACS Infect Dis. 2023 Apr 14;9(4):928-942. doi: 10.1021/acsinfecdis.2c00584.
Henrietta D Attram  1 ,  Constance M Korkor  1 ,  Dale Taylor  1 ,  Mathew Njoroge  1 ,  Kelly Chibale  1  2  3  4
Affiliations
  • 1. Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
  • 2. Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch 7701, South Africa.
  • 3. South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa.
  • 4. Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa.
PMID: 36946433 DOI: 10.1021/acsinfecdis.2c00584
Abstract

We previously identified a novel class of antimalarial benzimidazoles incorporating an intramolecular hydrogen bonding motif. The frontrunner of the series, analogue A, showed nanomolar activity against the chloroquine-sensitive NF54 and multi-drug-resistant K1 strains of Plasmodium falciparum (PfNF54 IC50 = 0.079 μM; PfK1 IC50 = 0.335 μM). Here, we describe a cell-based medicinal chemistry structure-activity relationship study using compound A as a basis. This effort led to the identification of novel antimalarial imidazopyridines with activities of <1 μM, favorable cytotoxicity profiles, and good physicochemical properties. Analogue 14 ( PfNF54 IC50 = 0.08 μM; PfK1 IC50 = 0.10 μM) was identified as the frontrunner of the series. Preliminary mode of action studies employing molecular docking, live-cell confocal microscopy, and a cellular heme fractionation assay revealed that 14 does not directly inhibit the conversion of heme to hemozoin, although it could be involved in Other processes in the parasite's digestive vacuole.

Keywords
Plasmodium falciparum; heme fractionation; imidazopyridines; intramolecular hydrogen bonding; live-cell microscopy.
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