High Target Homology Does Not Guarantee Inhibition: Aminothiazoles Emerge as Inhibitors of Plasmodium falciparum
Year: 2024
Type: article
Abstract: High Resolution Image Download MS PowerPoint Slide In this study, we identified three novel compound classes with potent activity against Plasmodium falciparum, the most dangerous human malarial parasite. Resistance of this pathogen to known drugs is increasing, and compounds with different modes of action are urgently needed. One promising drug target is the enzyme 1-deoxy- d -xylulose-5-phosphate synthase (DXPS) of the methylerythritol 4-phosphate (MEP) pathway for which we have previously identified three active compound classes against Mycobacterium tuberculosis . The close structural similarities of the active sites of the DXPS enzymes of P. falciparum and M. tuberculosis prompted investigation of their antiparasitic action, all classes display good cell-based activity. Through structure–activity relationship studies, we increased their antimalarial potency and two classes also show good metabolic stability and low toxicity against human liver cells. The most active compound 1 inhibits the growth of blood-stage P. falciparum with an IC 50 of 600 nM. The results from three different methods for target validation of compound 1 suggest no engagement of DXPS. All inhibitor classes are active against chloroquine-resistant strains, confirming a new mode of action that has to be further investigated.
Source: ACS Infectious Diseases
Authors: Sandra Johannsen, Robin M. Gierse, Arne Krüger, Rachel L. Edwards, Vittoria Nanna, Anna Fontana, Di Zhu, Tiziana Masini, Lais Pessanha de Carvalho, Mael Poizat, Bart Kieftenbelt, Dana M. Hodge, Sophie Alvarez, Daan Bunt, Antoine Lacour, Atanaz Shams, Kamila Anna Meissner, Edmarcia Elisa de Souza, Melloney Dröge, Bernard van Vliet, Jack den Hartog, Michael C. Hutter, Jana Held, Audrey R. Odom John, Carsten Wrenger, Anna K. H. Hirsch
Institutions: Helmholtz Centre for Infection Research, Helmholtz Institute for Pharmaceutical Research Saarland, Saarland University, University of Groningen, Universidade de São Paulo, Washington University in St. Louis, University of Tübingen, Children's Hospital of Philadelphia, University of Pennsylvania, University of Nebraska–Lincoln, Centre de Recherche Médicales de Lambaréné, German Center for Infection Research
Language: English
Topic: Malaria Research and Control
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Funders: Children's Hospital of Philadelphia, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, University of Pennsylvania, University of Nebraska-Lincoln, Deutsches Zentrum für Infektionsforschung, Rijksuniversiteit Groningen, Fundação de Amparo à Pesquisa do Estado de São Paulo, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, China Scholarship Council, Universität des Saarlandes, Helmholtz Association, National Institutes of Health, Perelman School of Medicine, University of Pennsylvania, National Institute of Allergy and Infectious Diseases
Awards: G1322293037, G144224746, G1781501939, G1928113347, G2169560095, G28213103, G31940382, G407114059, Drug discovery against human infectious diseases, G4259249326, G4402799499, G4869135458, G4950536974, G4961111098, SELECTIVE INHIBITION OF THE P. FALCIPARUM GLUCOSE TRANSPORTER PFHT, TARGETING ISPC TO TREAT MALARIA, G5863953618, Targeting lipoic acid salvage and biosynthesis pathways in MRSA, G8846264003, G8911425176, G9000026982, Structure-based microbially targeted prodrugs, G977212982
OpenAlex ID: W4391913643