Development of peptoid-based antimalarial histone deacetylase inhibitors with multi-stage activity
Final Report Abstract
Malaria remains a major global health challenge, with Plasmodium falciparum being the primary cause of the most severe cases and deaths. As resistance to current antimalarial drugs, particularly artemisinin-based combination therapies (ACTs), continues to rise, there is an urgent need for new therapeutic approaches. One promising approach is the use of histone deacetylase inhibitors (HDACi), which were originally developed for cancer treatment, due to their potent antiplasmodial effects. Histone deacetylases (HDACs), which are present in both humans and Plasmodium species, regulate gene expression by modulating the acetylation of histones and other proteins. Previous research identified several HDACi with potent antiplasmodial activity but limited selectivity and poor metabolic stability. This project hypothesized that selective human HDAC6 inhibitors could serve as a promising basis for developing parasite-selective antimalarials. During the first funding period, our peptoid-based HDAC6 inhibitors emerged as potent and selective antplasmosial HDACi with activity against both drug-sensitive and -resistant asexual blood stage parasites. In addition, they showed submicromolar activity against liver stage parasites. During the second funding period, three medicinal chemistry strategies were explored: 1. Zinc-binding group (ZBG) replacement: Ten alternative ZBGs were tested, but most variations reduced the antiplasmodial activity. The hit compound, DS-103, exhibited moderate antiplasmodial activity but emerged as a strong anticancer candidate. 2. Linker and cap group optimization: Modifications yielded compounds such as Cpd. 1h and Cpd. 6i, which demonstrated low nanomolar activity against asexual blood parasites, submicromolar liver stage activity, high metabolic stability, low cytotoxicity, and high parasite selectivity. Scaffold hopping based on quisinostat resulted in a new series of compounds, including Cpd. 18b, which exhibited highly potent and selective antiplasmodial activity. 3. Dihydroartemisinin-HDACi hybrids: These compounds showed strong nanomolar antiplasmodial activity, including against artemisinin-resistant parasites. Notably, hybrid (α)-7c showed enhanced efficacy against artemisinin-resistant parasites compared to dihydroartemisinin alone. In conclusion, this project has generated potent, metabolically stable, and selective antiplasmodial HDACi, making them promising antimalarial candidates. Thus far, the results of the project's two funding periods have been published in 11 articles and one preprint. Another publication, which will summarize the newly developed gametocyte assay and is expected to enhance future screening capabilities, is anticipated for late 2025.
Publications
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Design and Synthesis of Terephthalic Acid‐Based Histone Deacetylase Inhibitors with Dual‐Stage Anti‐Plasmodium Activity. ChemMedChem, 12(19), 1627-1636.
Stenzel, Katharina; Chua, Ming Jang; Duffy, Sandra; Antonova‐Koch, Yevgeniya; Meister, Stephan; Hamacher, Alexandra; Kassack, Matthias U.; Winzeler, Elizabeth; Avery, Vicky M.; Kurz, Thomas; Andrews, Katherine T. & Hansen, Finn K.
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Multicomponent Synthesis and Binding Mode of Imidazo[1,2-a]pyridine-Capped Selective HDAC6 Inhibitors. Organic Letters, 20(11), 3255-3258.
Mackwitz, Marcel K. W.; Hamacher, Alexandra; Osko, Jeremy D.; Held, Jana; Schöler, Andrea; Christianson, David W.; Kassack, Matthias U. & Hansen, Finn K.
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One-pot, multi-component synthesis and structure-activity relationships of peptoid-based histone deacetylase (HDAC) inhibitors targeting malaria parasites. European Journal of Medicinal Chemistry, 158, 801-813.
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.
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Histone deacetylase inhibitors with high in vitro activities against Plasmodium falciparum isolates collected from Gabonese children and adults. Scientific Reports, 9(1).
Koehne, Erik; Kreidenweiss, Andrea; Zoleko Manego, Rella; McCall, Matthew; Mombo-Ngoma, Ghyslain; Mackwitz, Marcel Karl Walter; Hansen, Finn K. & Held, Jana
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Structure–Activity and Structure–Toxicity Relationships of Peptoid‐Based Histone Deacetylase Inhibitors with Dual‐Stage Antiplasmodial Activity. ChemMedChem, 14(9), 912-926.
Mackwitz, Marcel K. W.; Hesping, Eva; Antonova‐Koch, Yevgeniya; Diedrich, Daniela; Woldearegai, Tamirat Gebru; Skinner‐Adams, Tina; Clarke, Mary; Schöler, Andrea; Limbach, Laura; Kurz, Thomas; Winzeler, Elizabeth A.; Held, Jana; Andrews, Katherine T. & Hansen, Finn K.
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Investigation of the in vitro and in vivo efficacy of peptoid-based HDAC inhibitors with dual-stage antiplasmodial activity. European Journal of Medicinal Chemistry, 211, 113065.
Mackwitz, Marcel K.W.; Hesping, Eva; Eribez, Korina; Schöler, Andrea; Antonova-Koch, Yevgeniya; Held, Jana; Winzeler, Elizabeth A.; Andrews, Katherine T. & Hansen, Finn K.
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Synthesis, Antiplasmodial, and Antileukemia Activity of Dihydroartemisinin–HDAC Inhibitor Hybrids as Multitarget Drugs. Pharmaceuticals, 15(3), 333.
von Bredow, Lukas; Schäfer, Thomas Martin; Hogenkamp, Julian; Tretbar, Maik; Stopper, Daniel; Kraft, Fabian B.; Schliehe-Diecks, Julian; Schöler, Andrea; Borkhardt, Arndt; Bhatia, Sanil; Held, Jana & Hansen, Finn K.
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The problem of antimalarial resistance and its implications for drug discovery. Expert Opinion on Drug Discovery, 19(2), 209-224.
Schäfer, Thomas Martin; Pessanha de Carvalho, Lais; Inoue, Juliana; Kreidenweiss, Andrea & Held, Jana
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Development of peptoid-based heteroaryl-decorated histone deacetylase (HDAC) inhibitors with dual-stage antiplasmodial activity. European Journal of Medicinal Chemistry, 277, 116782.
Stopper, Daniel; de Carvalho, Lais Pessanha; de Souza, Mariana Laureano; Kponomaizoun, Cindy-Esther; Winzeler, Elizabeth A.; Held, Jana & Hansen, Finn K.
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Exploration of fluorinated peptoid-based histone deacetylase inhibitors as dual-stage antiplasmodial agents. American Chemical Society (ACS).
Reßing, Nina; Stopper, Daniel; Schäfer, Thomas Martin; de Carvalho, Lais Pessanha; Winzeler, Elizabeth; Held, Jana & Hansen, Finn Kristian
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Exploring Alternative Zinc-Binding Groups in Histone Deacetylase (HDAC) Inhibitors Uncovers DS-103 as a Potent Ethylhydrazide-Based HDAC Inhibitor with Chemosensitizing Properties. Journal of Medicinal Chemistry, 68(4), 4426-4452.
Stopper, Daniel; Biermann, Lukas; Watson, Paris R.; Li, Jingyu; König, Beate; Gaynes, Matthew N.; Pessanha de Carvalho, Lais; Klose, Jana; Hanl, Maria; Hamacher, Alexandra; Schäker-Hübner, Linda; Ramsbeck, Daniel; Held, Jana; Christianson, David W.; Kassack, Matthias U. & Hansen, Finn K.
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Multicomponent syntheses enable the discovery of novel quisinostat-derived chemotypes as histone deacetylase inhibitors. European Journal of Medicinal Chemistry, 281, 117045.
Stopper, Daniel; Buntrock, Susanna; Tan, Kathrin; de Carvalho, Lais Pessanha; Schäker-Hübner, Linda; Held, Jana; Kassack, Matthias U. & Hansen, Finn K.
