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High Target Homology Does Not Guarantee Inhibition: Aminothiazoles Emerge as Inhibitors of Plasmodium falciparum.
Johannsen, Sandra; Gierse, Robin M; Krüger, Arne; Edwards, Rachel L; Nanna, Vittoria; Fontana, Anna; Zhu, Di; Masini, Tiziana; de Carvalho, Lais Pessanha; Poizat, Mael; Kieftenbelt, Bart; Hodge, Dana M; Alvarez, Sophie; Bunt, Daan; Lacour, Antoine; Shams, Atanaz; Meissner, Kamila Anna; de Souza, Edmarcia Elisa; Dröge, Melloney; van Vliet, Bernard; den Hartog, Jack; Hutter, Michael C; Held, Jana; Odom John, Audrey R; Wrenger, Carsten; Hirsch, Anna K H.
Afiliação
  • Johannsen S; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), Campus Building E8.1, Saarbrücken 66123, Germany.
  • Gierse RM; Department of Pharmacy, Saarland University, Campus Building E8.1, Saarbrücken 66123, Germany.
  • Krüger A; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), Campus Building E8.1, Saarbrücken 66123, Germany.
  • Edwards RL; Department of Pharmacy, Saarland University, Campus Building E8.1, Saarbrücken 66123, Germany.
  • Nanna V; Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, Groningen 9747 AG, The Netherlands.
  • Fontana A; Unit for Drug Discovery, Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 1374, São Paulo-SP 05508-000, Brazil.
  • Zhu D; Department of Pediatrics, Washington University School of Medicine, Saint Louis, Missouri 63110, United States.
  • Masini T; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), Campus Building E8.1, Saarbrücken 66123, Germany.
  • de Carvalho LP; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), Campus Building E8.1, Saarbrücken 66123, Germany.
  • Poizat M; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), Campus Building E8.1, Saarbrücken 66123, Germany.
  • Kieftenbelt B; Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, Groningen 9747 AG, The Netherlands.
  • Hodge DM; Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, Groningen 9747 AG, The Netherlands.
  • Alvarez S; Institute of Tropical Medicine, University of Tübingen, Wilhelmstraße 27, Tübingen 72074, Germany.
  • Bunt D; Symeres, Kadijk 3, Groningen 9747 AT, The Netherlands.
  • Lacour A; Symeres, Kadijk 3, Groningen 9747 AT, The Netherlands.
  • Shams A; Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
  • Meissner KA; Proteomics & Metabolomics Facility, Center for Biotechnology, Department of Agronomy and Horticulture, University of Nebraska-Lincoln, Lincoln, Nebraska 68588, United States.
  • de Souza EE; Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, Groningen 9747 AG, The Netherlands.
  • Dröge M; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), Campus Building E8.1, Saarbrücken 66123, Germany.
  • van Vliet B; Department of Pharmacy, Saarland University, Campus Building E8.1, Saarbrücken 66123, Germany.
  • den Hartog J; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), Campus Building E8.1, Saarbrücken 66123, Germany.
  • Hutter MC; Department of Pharmacy, Saarland University, Campus Building E8.1, Saarbrücken 66123, Germany.
  • Held J; Unit for Drug Discovery, Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 1374, São Paulo-SP 05508-000, Brazil.
  • Odom John AR; Unit for Drug Discovery, Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 1374, São Paulo-SP 05508-000, Brazil.
  • Wrenger C; Symeres, Kadijk 3, Groningen 9747 AT, The Netherlands.
  • Hirsch AKH; Symeres, Kadijk 3, Groningen 9747 AT, The Netherlands.
ACS Infect Dis ; 10(3): 1000-1022, 2024 03 08.
Article em En | MEDLINE | ID: mdl-38367280
ABSTRACT
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 IC50 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tiazóis / Malária Falciparum / Antimaláricos Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tiazóis / Malária Falciparum / Antimaláricos Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article