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One-pot, multi-component synthesis and structure-activity relationships of peptoid-based histone deacetylase (HDAC) inhibitors targeting malaria parasites.


ABSTRACT: Malaria drug discovery has shifted from a focus on targeting asexual blood stage parasites, to the development of drugs that can also target exo-erythrocytic forms and/or gametocytes in order to prevent malaria and/or parasite transmission. In this work, we aimed to develop parasite-selective histone deacetylase inhibitors (HDACi) with activity against the disease-causing asexual blood stages of Plasmodium malaria parasites as well as with causal prophylactic and/or transmission blocking properties. An optimized one-pot, multi-component protocol via a sequential Ugi four-component reaction and hydroxylaminolysis was used for the preparation of a panel of peptoid-based HDACi. Several compounds displayed potent activity against drug-sensitive and drug-resistant P. falciparum asexual blood stages, high parasite-selectivity and submicromolar activity against exo-erythrocytic forms of P. berghei. Our optimization study resulted in the discovery of the hit compound 1u which combines high activity against asexual blood stage parasites (Pf 3D7 IC50: 4?nM; Pf Dd2 IC50: 1?nM) and P. berghei exo-erythrocytic forms (Pb EEF IC50: 25?nM) with promising parasite-specific activity (SIPf3D7/HepG2: 2496, SIPfDd2/HepG2: 9990, and SIPbEEF/HepG2: 400).

SUBMITTER: Diedrich D 

PROVIDER: S-EPMC6195125 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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One-pot, multi-component synthesis and structure-activity relationships of peptoid-based histone deacetylase (HDAC) inhibitors targeting malaria parasites.

Diedrich Daniela D   Stenzel Katharina K   Hesping Eva E   Antonova-Koch Yevgeniya Y   Gebru Tamirat T   Duffy Sandra S   Fisher Gillian G   Schöler Andrea A   Meister Stephan S   Kurz Thomas T   Avery Vicky M VM   Winzeler Elizabeth A EA   Held Jana J   Andrews Katherine T KT   Hansen Finn K FK  

European journal of medicinal chemistry 20180907


Malaria drug discovery has shifted from a focus on targeting asexual blood stage parasites, to the development of drugs that can also target exo-erythrocytic forms and/or gametocytes in order to prevent malaria and/or parasite transmission. In this work, we aimed to develop parasite-selective histone deacetylase inhibitors (HDACi) with activity against the disease-causing asexual blood stages of Plasmodium malaria parasites as well as with causal prophylactic and/or transmission blocking propert  ...[more]

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2012-05-01 | GSE25642 | GEO