Development of Peptoid-Based Heteroaryl-Decorated Histone Deacetylase (HDAC) Inhibitors with Dual-Stage Antiplasmodial Activity

Malaria remains a significant global health challenge, causing approximately 608,000 deaths and over 249 million infections in 2022. With the rise of resistance to current chemotherapies, including artemisinin-based combination therapies (ACTs), the search for novel antimalarial drugs with new modes of action is of utmost importance. Histone deacetylases (HDACs) have been identified as promising targets for antiplasmodial drug development. In this study, we present a novel series of peptoid-based HDAC inhibitors incorporating heteroaryl residues, synthesized via an efficient multicomponent protocol. The subsequent screening of 16 compounds from our mini-library identified 6i as the most promising candidate, demonstrating potent activity against asexual blood-stage parasites (IC50 Pf3D7 = 30 nM; IC50 PfDd2 = 98 nM), low submicromolar activity against liver-stage parasites (IC50 PbEEF = 0.25 µM), excellent microsomal stability (t1/2 > 60 min), and negligible cytotoxicity to HepG2 cells (IC50 > 10 µM).