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https://www.arca.fiocruz.br/handle/icict/63692
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
Oxadiazol
Astemizol
Antiplasmódio
Plasmódio
Malária
Infecção
Ratos
Author
Mambwe, Dickson
Korkor, Constance M.
Mabhul, Amanda
Ngqumba, Zama
Cloete, Cleavon
Kumar, Malkeet
Barros, Paula Ladeia
Leshabane, Meta
Coertzen, Dina
Taylor, Dale
Gibhard, Liezl
Njoroge, Mathew
Lawrence, Nina
Reader, Janette
Moreira, Diogo Rodrigo
Birkholtz, Lyn-Marie
Wittlin, Sergio
Egan, Timothy J.
Chibale, Kelly
Korkor, Constance M.
Mabhul, Amanda
Ngqumba, Zama
Cloete, Cleavon
Kumar, Malkeet
Barros, Paula Ladeia
Leshabane, Meta
Coertzen, Dina
Taylor, Dale
Gibhard, Liezl
Njoroge, Mathew
Lawrence, Nina
Reader, Janette
Moreira, Diogo Rodrigo
Birkholtz, Lyn-Marie
Wittlin, Sergio
Egan, Timothy J.
Chibale, Kelly
Affilliation
Department of Chemistry. University of Cape Town. Rondebosch, South Africa.
Department of Chemistry. University of Cape Town. Rondebosch, South Africa.
Drug Discovery and Development Centre (H3D). DMPK & Pharmacology. University of Cape Town. Observatory, South Africa.
Drug Discovery and Development Centre (H3D). DMPK & Pharmacology. University of Cape Town. Observatory, South Africa.
Drug Discovery and Development Centre (H3D). DMPK & Pharmacology. University of Cape Town. Observatory, South Africa.
Department of Chemistry. University of Cape Town. Rondebosch, South Africa.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.
Department of Biochemistry, Genetics & Microbiology. Institute for Sustainable Malaria Control. University of Pretoria. Private Bag X20. Hatfield, Pretoria, South Africa.
Department of Biochemistry, Genetics & Microbiology. Institute for Sustainable Malaria Control. University of Pretoria. Private Bag X20. Hatfield, Pretoria, South Africa.
Drug Discovery and Development Centre (H3D). DMPK & Pharmacology. University of Cape Town. Observatory, South Africa.
Drug Discovery and Development Centre (H3D). DMPK & Pharmacology. University of Cape Town. Observatory, South Africa.
Drug Discovery and Development Centre (H3D). DMPK & Pharmacology. University of Cape Town. Observatory, South Africa.
Drug Discovery and Development Centre (H3D). DMPK & Pharmacology. University of Cape Town. Observatory, South Africa.
Department of Biochemistry, Genetics & Microbiology. Institute for Sustainable Malaria Control. University of Pretoria. Private Bag X20. Hatfield, Pretoria, South Africa.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.
Department of Biochemistry, Genetics & Microbiology. Institute for Sustainable Malaria Control. University of Pretoria. Private Bag X20. Hatfield, Pretoria, South Africa.
Swiss Tropical and Public Health Institute. Socinstrasse, Basel, Switzerland / University of Basel. Basel, Switzerland.
Department of Chemistry. University of Cape Town. Rondebosch, South Africa. / Institute of Infectious Disease and Molecular Medicine. University of Cape Town. Rondebosch, South Africa.
Department of Chemistry. University of Cape Town. Rondebosch, South Africa / Drug Discovery and Development Centre (H3D). DMPK & Pharmacology. University of Cape Town. Observatory, South Africa / Institute of Infectious Disease and Molecular Medicine. University of Cape Town. Rondebosch, South Africa / South African Medical Research Council Drug Discovery and Development Research Unit. University of Cape Town. Rondebosch, South Africa.
Department of Chemistry. University of Cape Town. Rondebosch, South Africa.
Drug Discovery and Development Centre (H3D). DMPK & Pharmacology. University of Cape Town. Observatory, South Africa.
Drug Discovery and Development Centre (H3D). DMPK & Pharmacology. University of Cape Town. Observatory, South Africa.
Drug Discovery and Development Centre (H3D). DMPK & Pharmacology. University of Cape Town. Observatory, South Africa.
Department of Chemistry. University of Cape Town. Rondebosch, South Africa.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.
Department of Biochemistry, Genetics & Microbiology. Institute for Sustainable Malaria Control. University of Pretoria. Private Bag X20. Hatfield, Pretoria, South Africa.
Department of Biochemistry, Genetics & Microbiology. Institute for Sustainable Malaria Control. University of Pretoria. Private Bag X20. Hatfield, Pretoria, South Africa.
Drug Discovery and Development Centre (H3D). DMPK & Pharmacology. University of Cape Town. Observatory, South Africa.
Drug Discovery and Development Centre (H3D). DMPK & Pharmacology. University of Cape Town. Observatory, South Africa.
Drug Discovery and Development Centre (H3D). DMPK & Pharmacology. University of Cape Town. Observatory, South Africa.
Drug Discovery and Development Centre (H3D). DMPK & Pharmacology. University of Cape Town. Observatory, South Africa.
Department of Biochemistry, Genetics & Microbiology. Institute for Sustainable Malaria Control. University of Pretoria. Private Bag X20. Hatfield, Pretoria, South Africa.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.
Department of Biochemistry, Genetics & Microbiology. Institute for Sustainable Malaria Control. University of Pretoria. Private Bag X20. Hatfield, Pretoria, South Africa.
Swiss Tropical and Public Health Institute. Socinstrasse, Basel, Switzerland / University of Basel. Basel, Switzerland.
Department of Chemistry. University of Cape Town. Rondebosch, South Africa. / Institute of Infectious Disease and Molecular Medicine. University of Cape Town. Rondebosch, South Africa.
Department of Chemistry. University of Cape Town. Rondebosch, South Africa / Drug Discovery and Development Centre (H3D). DMPK & Pharmacology. University of Cape Town. Observatory, South Africa / Institute of Infectious Disease and Molecular Medicine. University of Cape Town. Rondebosch, South Africa / South African Medical Research Council Drug Discovery and Development Research Unit. University of Cape Town. Rondebosch, South Africa.
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.
Keywords in Portuguese
TrifluorometilOxadiazol
Astemizol
Antiplasmódio
Plasmódio
Malária
Infecção
Ratos
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