TKK130 is a 3-Hydroxy-Propanamidine (HPA) with Potent Antimalarial <i>In Vivo</i> Activity and a High Barrier to Resistance
Malaria continues to pose a significant burden on populations in endemic areas and requires innovative treatment options. Here, we report the synthesis and preclinical evaluation of the novel 3-hydroxypropanamidine (HPA) <b>2 (TKK130)</b>, which shows excellent antiplasmodial <i>in vitro</i> activity against drug-sensitive and -resistant <i>Plasmodium falciparum</i> strains. Moreover, in various human cell lines, the compound shows no cytotoxicity and excellent parasite selectivity. The compound inhibits synthetic hemozoin (β-hematin) formation, with IC<sub>50</sub> values lower than chloroquine (CQ), and its <i>in vitro</i> rate of activity is comparable with the fast-acting antimalarial drug dihydroartemisinin. Furthermore, selection studies reveal a very low propensity for resistance development. Based on initial <i>in vivo</i> pharmacokinetic snapshot data, <b>2 (TKK130)</b> has a long-lasting, linear pharmacokinetic profile. <i>In vivo</i>, this novel HPA exhibits curative activity in the <i>Plasmodium berghei</i>mouse model and potent activity in the<i>P. falciparum</i> SCID mouse model after oral administration.
Authors
- Jana Held (ORCID: https://orcid.org/0000-0002-7970-1429)
- Thomas Kurz (ORCID: https://orcid.org/0000-0002-9474-4224)
- Bjoern B. Burckhardt (ORCID: https://orcid.org/0000-0002-1782-9937)
- Lars Schack Kruse
- Katherine A. de Villiers (ORCID: https://orcid.org/0000-0002-2932-395X)
- Ghyslain Mombo‐Ngoma (ORCID: https://orcid.org/0000-0003-2658-8706)
- Sergio Wittlin (ORCID: https://orcid.org/0000-0002-0811-0912)
- Beate Lungerich
- Lily Orta
- Alfred Moritz
- Saskia K. Klein (ORCID: https://orcid.org/0000-0001-8847-2704)
- Katharina Lohse
- Laís Pessanha de Carvalho (ORCID: https://orcid.org/0000-0002-3857-5462)
- David A. Fidock (ORCID: https://orcid.org/0000-0001-6753-8938)
- Jean‐Baptiste Thibaud (ORCID: https://orcid.org/0000-0002-0824-6465)
- Tanja C. Knaab
Institutions
- Swiss Tropical and Public Health Institute (CH)
- Universität Hamburg (DE)
- China Pharmaceutical University (CN)
- University of Basel (CH)
- University of Münster (DE)
- Stellenbosch University (ZA)
- Columbia University Irving Medical Center (US)
- Research Institute for Tropical Medicine (PH)
- Centre de Recherche Médicales de Lambaréné (GA)
- University Medical Center Hamburg-Eppendorf (DE)
- German Center for Infection Research (DE)
- CNR de la Résistance aux Antibiotiques (FR)
- Pharmac (NZ)
- Eppendorf (Belgium) (BE)
- Heinrich Heine University Düsseldorf (DE)
- University of Tübingen (DE)
- Bernhard Nocht Institute for Tropical Medicine (DE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-12-26
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01465
- Citations
- 2
- Primary Topic
- Malaria Research and Control
- Type
- article
- Field-Weighted Citation Impact
- 1.09