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 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).

Structure–Activity and Structure–Toxicity Relationships of Peptoid‐Based Histone Deacetylase Inhibitors with Dual‐Stage Antiplasmodial Activity

“…In this regard, we and others hypothesized that class‐II‐selective hHDACi might be a better starting point for the development of parasite‐selective antiplasmodial HDACi, due to their usually lower toxicity toward mammalian cells . In addition, knock‐out experiments with the class IIb isozyme hHDAC6 in mice led to a viable phenotype with no significant defects .…”

“…In addition, knock‐out experiments with the class IIb isozyme hHDAC6 in mice led to a viable phenotype with no significant defects . In a previous publication, starting from a hHDAC6 preferential scaffold, we reported on the multicomponent synthesis and biological evaluation of novel peptoid‐based antiplasmodial HDACi . Several of these HDACi displayed potent activities against the 3D7 line of P. falciparum , with IC 50 values ranging from 4 to 158 n m and promising parasite selectivity .…”

“…Another interesting finding regarding antiplasmodial HDACi is their activity against several malaria parasite life‐cycle stages. While most antimalarial drugs target just one specific life‐cycle stage (mostly asexual blood stages), several HDACi are also active against liver stages and late‐stage gametocytes . This highlights the potential of HDACi as novel antiplasmodial agents.…”

“…In a previous publication, starting from a hHDAC6 preferential scaffold, we reported on the multicomponent synthesis and biological evaluation of novel peptoid‐based antiplasmodial HDACi . Several of these HDACi displayed potent activities against the 3D7 line of P. falciparum , with IC 50 values ranging from 4 to 158 n m and promising parasite selectivity . Furthermore, several compounds showed sub‐micromolar activity against P. berghei exo‐erythrocytic stages, making this novel type of HDACi an encouraging starting point for the development of antiplasmodial drug leads with dual‐stage activity .…”

“…Several of these HDACi displayed potent activities against the 3D7 line of P. falciparum , with IC 50 values ranging from 4 to 158 n m and promising parasite selectivity . Furthermore, several compounds showed sub‐micromolar activity against P. berghei exo‐erythrocytic stages, making this novel type of HDACi an encouraging starting point for the development of antiplasmodial drug leads with dual‐stage activity . The aim of this study was to gain better insight into the structure–activity and structure–toxicity relationships of this new class of HDACi with antiplasmodial activity and in particular, to explore the structural requirements for potent dual‐stage activity.…”