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

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 histon...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2018-10, Vol.158, p.801-813
Main Authors: Diedrich, Daniela, Stenzel, Katharina, Hesping, Eva, Antonova-Koch, Yevgeniya, Gebru, Tamirat, Duffy, Sandra, Fisher, Gillian, Schöler, Andrea, Meister, Stephan, Kurz, Thomas, Avery, Vicky M., Winzeler, Elizabeth A., Held, Jana, Andrews, Katherine T., Hansen, Finn K.
Format: Article
Language:English
Subjects:
Acetylation - drug effects
Antimalarials - chemical synthesis
Antimalarials - chemistry
Antimalarials - pharmacology
HDAC inhibitor
Hep G2 Cells
Histone deacetylase
Histone Deacetylase Inhibitors - chemical synthesis
Histone Deacetylase Inhibitors - chemistry
Histone Deacetylase Inhibitors - pharmacology
Histones - metabolism
Humans
Malaria
Malaria, Falciparum - drug therapy
Malaria, Falciparum - metabolism
Peptoid
Peptoids - chemical synthesis
Peptoids - chemistry
Peptoids - pharmacology
Plasmodium falciparum
Plasmodium falciparum - drug effects
Plasmodium falciparum - metabolism
Protozoan Proteins - metabolism
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Summary: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). [Display omitted] •Novel HDACi were synthesized using a one-pot multi-component protocol.•All compounds showed nanomolar activity against asexual blood stage parasites.•Selected compounds were shown to hyperacetylate P. falciparum histones.•Compound 1u revealed potent and selective activity against exo-erythrocytic forms.•This series of HDACi represents a valuable starting point for further optimization.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2018.09.018