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 IC: 4 nM; Pf Dd2 IC: 1 nM) and P. berghei exo-erythrocytic forms (Pb EEF IC: 25 nM) with promising parasite-specific activity (SI: 2496, SI: 9990, and SI: 400).
Malaria, caused by Plasmodium parasites,
results in >400,000 deaths annually. There is no effective vaccine,
and new drugs with novel modes of action are needed because of increasing
parasite resistance to current antimalarials. Histone deacetylases
(HDACs) are epigenetic regulatory enzymes that catalyze post-translational
protein deacetylation and are promising malaria drug targets. Here,
we describe quantitative structure–activity relationship models
to predict the antiplasmodial activity of hydroxamate-based HDAC inhibitors.
The models incorporate P. falciparum in vitro activity data for 385 compounds containing a hydroxamic
acid and were subject to internal and external validation. When used
to screen 22 new hydroxamate-based HDAC inhibitors for antiplasmodial
activity, model A7 (external accuracy 91%) identified
three hits that were subsequently verified as having potent in vitro
activity against P. falciparum parasites
(IC50 = 6, 71, and 84 nM), with 8 to 51-fold selectivity
for P. falciparum versus human cells.
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