Development of peptoid-based heteroaryl-decorated histone deacetylase (HDAC) inhibitors with dual-stage antiplasmodial activity

• Published in: European journal of medicinal chemistry 2024-11, Vol.277, p.116782, Article 116782
• Main Authors: Stopper, Daniel, de Carvalho, Lais Pessanha, de Souza, Mariana Laureano, Kponomaizoun, Cindy-Esther, Winzeler, Elizabeth A., Held, Jana, Hansen, Finn K.
• Format: Article
• Language: English
• Subjects: Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Dose-Response Relationship, Drug; HDAC inhibitors; HEK293 Cells; Histone deacetylase; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - metabolism; Humans; Malaria; Molecular Structure; Multicomponent reaction; Parasitic Sensitivity Tests; Peptoid; Peptoids - chemical synthesis; Peptoids - chemistry; Peptoids - pharmacology; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116782

Dynamics of epigenetic modifications such as acetylation and deacetylation of histone proteins have been shown to be crucial for the life cycle development and survival of Plasmodium falciparum, the deadliest malaria parasite. In this study, we present a novel series of peptoid-based histone deacetylase (HDAC) inhibitors incorporating nitrogen-containing bicyclic heteroaryl residues as a new generation of antiplasmodial peptoid-based HDAC inhibitors. We synthesized the HDAC inhibitors by an efficient multicomponent protocol based on the Ugi four-component reaction. 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 (IC50Pf3D7 = 30 nM; IC50PfDd2 = 98 nM), low submicromolar activity against liver-stage parasites (IC50PbEEF = 0.25 μM), excellent microsomal stability (t1/2 > 60 min), and low cytotoxicity to HEK293 cells (IC50 = 136 μM). [Display omitted] •Synthesis of heteroaryl-decorated HDAC inhibitors 6a-6pvia a multicomponent protocol.•Several compounds displayed high potency against asexual blood-stage parasites.•6i and 6j showed additional submicromolar activity against liver stage parasites.•Most compounds exhibited low cytotoxicity.•Several compounds demonstrated metabolic stability in human liver microsomes.