Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 65, Issue 24, Pages 16695-16715Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c01516
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- University of Cape Town
- South African Medical Research Council
- South African Research Chairs Initiative of the Department of Science and Innovation
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Iterative medicinal chemistry optimization led to the discovery of a highly potent compound 23 with metabolic stability and selectivity, displaying activity against multiple stages of malaria and showing in vivo efficacy in mice.
Iterative medicinal chemistry optimization of an ester-containing astemizole (AST) analogue 1 with an associated metabolic instability liability led to the identification of a highly potent 3-trifluoromethyl-1,2,4-oxadiazole analogue 23 (PfNF54 IC50 = 0.012 mu M; Pf K1 IC50 = 0.040 mu M) displaying high microsomal metabolic stability (HLM CLint < 11.6 mu Lmiddotmin(-1)middot mg(-1)) and > 1000-fold higher selectivity over hERG compared to AST. In addition to asexual blood stage activity, the compound also shows activity against liver and gametocyte life cycle stages and demonstrates in vivo efficacy in Plasmodium berghei-infected mice at 4 x 50 mgmiddotkg(-1) oral dose. Preliminary interrogation of the mode of action using live-cell microscopy and cellular heme speciation revealed that 23 could be affecting multiple processes in the parasitic digestive vacuole, with the possibility of a novel target at play in the organelles associated with it.
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