2. Academic Validation
  3. Novel 3-Trifluoromethyl-1,2,4-oxadiazole Analogues of Astemizole with Multi-stage Antiplasmodium Activity and In Vivo Efficacy in a Plasmodium berghei Mouse Malaria Infection Model

Novel 3-Trifluoromethyl-1,2,4-oxadiazole Analogues of Astemizole with Multi-stage Antiplasmodium Activity and In Vivo Efficacy in a Plasmodium berghei Mouse Malaria Infection Model

  • J Med Chem. 2022 Dec 22;65(24):16695-16715. doi: 10.1021/acs.jmedchem.2c01516.
Dickson Mambwe 1,  Constance M Korkor 1,  Amanda Mabhula 2,  Zama Ngqumba 2,  Cleavon Cloete 2,  Malkeet Kumar 1,  Paula Ladeia Barros 3,  Meta Leshabane 4,  Dina Coertzen 4,  Dale Taylor 2,  Liezl Gibhard 2,  Mathew Njoroge 2,  Nina Lawrence 2,  Janette Reader 4,  Diogo Rodrigo Moreira 3,  Lyn-Marie Birkholtz 4,  Sergio Wittlin 5 6,  Timothy J Egan 1 7,  Kelly Chibale 1 2 8 7
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
  • 2 Drug Discovery and Development Centre (H3D), DMPK & Pharmacology, University of Cape Town, Observatory 7925, South Africa.
  • 3 Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz (Fiocruz), Instituto Gonçalo Moniz, CEP 40296-710 Salvador, Brazil.
  • 4 Department of Biochemistry, Genetics & Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Private Bag X20, Hatfield, 0028 Pretoria, South Africa.
  • 5 Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland.
  • 6 University of Basel, 4003 Basel, Switzerland.
  • 7 Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa.
  • 8 South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa.
PMID: 36507890 DOI: 10.1021/acs.jmedchem.2c01516
Abstract

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 μM; PfK1 IC50 = 0.040 μM) displaying high microsomal metabolic stability (HLM CLint < 11.6 μL·min-1·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 × 50 mg·kg-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.

Figures
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z