Dataset Information

Substituted Aminoacetamides as Novel Leads for Malaria Treatment.

ABSTRACT: Herein we describe the optimization of a phenotypic hit against Plasmodium falciparum based on an aminoacetamide scaffold. This led to N-(3-chloro-4-fluorophenyl)-2-methyl-2-{[4-methyl-3-(morpholinosulfonyl)phenyl]amino}propanamide (compound 28) with low-nanomolar activity against the intraerythrocytic stages of the malaria parasite, and which was found to be inactive in a mammalian cell counter-screen up to 25??m. Inhibition of gametes in the dual gamete activation assay suggests that this family of compounds may also have transmission blocking capabilities. Whilst we were unable to optimize the aqueous solubility and microsomal stability to a point at which the aminoacetamides would be suitable for in?vivo pharmacokinetic and efficacy studies, compound 28 displayed excellent antimalarial potency and selectivity; it could therefore serve as a suitable chemical tool for drug target identification.

SUBMITTER: Norcross NR

PROVIDER: S-EPMC6899483 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Substituted Aminoacetamides as Novel Leads for Malaria Treatment.

Norcross Neil R NR Wilson Caroline C Baragaña Beatriz B Hallyburton Irene I Osuna-Cabello Maria M Norval Suzanne S Riley Jennifer J Fletcher Daniel D Sinden Robert R Delves Michael M Ruecker Andrea A Duffy Sandra S Meister Stephan S Antonova-Koch Yevgeniya Y Crespo Benigno B de Cózar Cristina C Sanz Laura M LM Gamo Francisco Javier FJ Avery Vicky M VM Frearson Julie A JA Gray David W DW Fairlamb Alan H AH Winzeler Elizabeth A EA Waterson David D Campbell Simon F SF Willis Paul A PA Read Kevin D KD Gilbert Ian H IH

ChemMedChem 20190703 14

Herein we describe the optimization of a phenotypic hit against Plasmodium falciparum based on an aminoacetamide scaffold. This led to N-(3-chloro-4-fluorophenyl)-2-methyl-2-{[4-methyl-3-(morpholinosulfonyl)phenyl]amino}propanamide (compound 28) with low-nanomolar activity against the intraerythrocytic stages of the malaria parasite, and which was found to be inactive in a mammalian cell counter-screen up to 25 μm. Inhibition of gametes in the dual gamete activation assay suggests that this fami ...[more]

PMID: 31188540

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Project description:Falciparum malaria is clinically heterogeneous and yet in most cases the risk of life-threatening disease dramatically declines after the first few infections of life because children rapidly acquire disease tolerance (resistance to severe malaria without improved control of parasite burden). Identifying the factors that determine clinical outcome in a malaria-naive host is therefore paramount to reduce malaria mortality. However, the relative contribution of disease-causing variants of the Plasmodium var gene family versus pathogenic inflammatory cytokine cascades remains fiercely debated - we sought to reconcile these conflicting arguments by studying their interaction in vivo. To this end, two human challenge models were used to reveal the parasite-host interactions that underpin variation in falciparum malaria. To capture the diversity of human immune responses, each individual was analysed independently by tracking dynamic changes in their whole blood transcriptome through time. And to uncover evidence of preferential expansion of disease-causing variants, var gene expression was tracked in vivo from the start to end of infection. In this way, we could show that group A var genes are always expressed upon liver egress but in a minority population that does not increase over 10-days of blood cycling; there is no selection of disease-causing variants in the naive host. In fact, parasites do not respond in any way to differences or changes in host environment. On the other hand, host-intrinsic variation determines the intensity of inflammation and progression to clinical malaria. And furthermore, regulation of the interferon signaling network controls host fate. These data emphasise the role of human immune decision-making in shaping course & outcome of infection. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

Dataset Information

Substituted Aminoacetamides as Novel Leads for Malaria Treatment.

Publications

Substituted Aminoacetamides as Novel Leads for Malaria Treatment.

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