Potent Plasmodium falciparum gametocytocidal compounds identified by exploring the kinase inhibitor chemical space for dual active antimalarials.

Autor:	van der Watt ME; Department of Biochemistry, Institute for Sustainable Malaria Control and South African Medical Research Council Collaborating Centre for Malaria Research, University of Pretoria, Private Bag x20, Hatfield, Pretoria 0028, South Africa., Reader J; Department of Biochemistry, Institute for Sustainable Malaria Control and South African Medical Research Council Collaborating Centre for Malaria Research, University of Pretoria, Private Bag x20, Hatfield, Pretoria 0028, South Africa., Churchyard A; Plasmodium Molecular Research Unit, Wits Research Institute for Malaria, Department of Molecular Medicine and Haematology, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand and National Health Laboratory Service, Johannesburg 2193, South Africa., Nondaba SH; Department of Biochemistry, Institute for Sustainable Malaria Control and South African Medical Research Council Collaborating Centre for Malaria Research, University of Pretoria, Private Bag x20, Hatfield, Pretoria 0028, South Africa., Lauterbach SB; Plasmodium Molecular Research Unit, Wits Research Institute for Malaria, Department of Molecular Medicine and Haematology, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand and National Health Laboratory Service, Johannesburg 2193, South Africa., Niemand J; Department of Biochemistry, Institute for Sustainable Malaria Control and South African Medical Research Council Collaborating Centre for Malaria Research, University of Pretoria, Private Bag x20, Hatfield, Pretoria 0028, South Africa., Abayomi S; Department of Biochemistry, Institute for Sustainable Malaria Control and South African Medical Research Council Collaborating Centre for Malaria Research, University of Pretoria, Private Bag x20, Hatfield, Pretoria 0028, South Africa., van Biljon RA; Department of Biochemistry, Institute for Sustainable Malaria Control and South African Medical Research Council Collaborating Centre for Malaria Research, University of Pretoria, Private Bag x20, Hatfield, Pretoria 0028, South Africa., Connacher JI; Department of Biochemistry, Institute for Sustainable Malaria Control and South African Medical Research Council Collaborating Centre for Malaria Research, University of Pretoria, Private Bag x20, Hatfield, Pretoria 0028, South Africa., van Wyk RDJ; Department of Biochemistry, Institute for Sustainable Malaria Control and South African Medical Research Council Collaborating Centre for Malaria Research, University of Pretoria, Private Bag x20, Hatfield, Pretoria 0028, South Africa., Le Manach C; Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa., Paquet T; Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa., González Cabrera D; Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa., Brunschwig C; Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa., Theron A; Biosciences, Council for Scientific and Industrial Research, PO Box 395, Pretoria 0001, South Africa., Lozano-Arias S; GlaxoSmithKline, Tres Cantos Medicines Development Campus, Severo Ochoa, 2, 28760 Tres Cantos, Madrid, Spain., Rodrigues JFI; GlaxoSmithKline, Tres Cantos Medicines Development Campus, Severo Ochoa, 2, 28760 Tres Cantos, Madrid, Spain., Herreros E; GlaxoSmithKline, Tres Cantos Medicines Development Campus, Severo Ochoa, 2, 28760 Tres Cantos, Madrid, Spain., Leroy D; Medicines for Malaria Venture, International Center Cointrin, Route de Pré-Bois 20, 1215, Geneva, Switzerland., Duffy J; Medicines for Malaria Venture, International Center Cointrin, Route de Pré-Bois 20, 1215, Geneva, Switzerland., Street LJ; Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa., Chibale K; Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.; South African Medical Research Council, Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa., Mancama D; Biosciences, Council for Scientific and Industrial Research, PO Box 395, Pretoria 0001, South Africa., Coetzer TL; Plasmodium Molecular Research Unit, Wits Research Institute for Malaria, Department of Molecular Medicine and Haematology, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand and National Health Laboratory Service, Johannesburg 2193, South Africa., Birkholtz LM; Department of Biochemistry, Institute for Sustainable Malaria Control and South African Medical Research Council Collaborating Centre for Malaria Research, University of Pretoria, Private Bag x20, Hatfield, Pretoria 0028, South Africa.
Jazyk:	angličtina
Zdroj:	The Journal of antimicrobial chemotherapy [J Antimicrob Chemother] 2018 May 01; Vol. 73 (5), pp. 1279-1290.
DOI:	10.1093/jac/dky008
Abstrakt:	Objectives: Novel chemical tools to eliminate malaria should ideally target both the asexual parasites and transmissible gametocytes. Several imidazopyridazines (IMPs) and 2-aminopyridines (2-APs) have been described as potent antimalarial candidates targeting lipid kinases. However, these have not been extensively explored for stage-specific inhibition of gametocytes in Plasmodium falciparum parasites. Here we provide an in-depth evaluation of the gametocytocidal activity of compounds from these chemotypes and identify novel starting points for dual-acting antimalarials. Methods: We evaluated compounds against P. falciparum gametocytes using several assay platforms for cross-validation and stringently identified hits that were further profiled for stage specificity, speed of action and ex vivo efficacy. Physicochemical feature extraction and chemogenomic fingerprinting were applied to explore the kinase inhibition susceptibility profile. Results: We identified 34 compounds with submicromolar activity against late stage gametocytes, validated across several assay platforms. Of these, 12 were potent at <100 nM (8 were IMPs and 4 were 2-APs) and were also active against early stage gametocytes and asexual parasites, with >1000-fold selectivity towards the parasite over mammalian cells. Front-runner compounds targeted mature gametocytes within 48 h and blocked transmission to mosquitoes. The resultant chemogenomic fingerprint of parasites treated with the lead compounds revealed the importance of targeting kinases in asexual parasites and gametocytes. Conclusions: This study encompasses an in-depth evaluation of the kinase inhibitor space for gametocytocidal activity. Potent lead compounds have enticing dual activities and highlight the importance of targeting the kinase superfamily in malaria elimination strategies.
Databáze:	MEDLINE
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