5-Substituted 3-chlorokenpaullone derivatives are potent inhibitors of Trypanosoma brucei bloodstream forms

Autor: Andrea Medeiros, Laurent Meijer, Nadège Loaëc, Oliver Koch, Ricarda S. Korn, Lutz Preu, Conrad Kunick, Marcelo A. Comini, Diego Benítez, Oliver C.F. Orban
Přispěvatelé: Technische Universität Braunschweig = Technical University of Braunschweig [Braunschweig], Institut Pasteur de Montevideo, Réseau International des Instituts Pasteur (RIIP), Departamento de Bioquímica, Facultad de Medicina, Universidad de la República [Montevideo] (UCUR), ManRos Therapeutics, Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Straße 6, 44227 Dortmund, Germany., Faculty of Chemistry and Chemical Biology, Technische Universität Dortmund [Dortmund] (TU), This project was funded by the German Federal Ministry of Education and Research (BMBF, program KMU-innovativ 5, grant project code 0315814, to R. S. K., O. K., and C. K.) and supported by the COST action CM1307 (to O. C. F. O. and C. K.). The support of FOCEM (MERCOSUR Structural Convergence Fund, COF 03/11), Institut Pasteur ACIP call 2015 (project ACIP 17-2015) and ANII – Uruguay (POS_NAC_2013_1_114477) is acknowledged by M.A.C., D.B. and A.M., L.M. was supported by a grant from the ‘Agence Nationale de la Recherche’ (ANR), Transleish. Molecular graphics were performed with the UCSF Chimera package
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
Indoles
[SDV]Life Sciences [q-bio]
Clinical Biochemistry
MESH: Amide Synthases
Pharmaceutical Science
MESH: Spectrum Analysis
01 natural sciences
Biochemistry
chemistry.chemical_compound
Drug Discovery
Macrophage
Parasite hosting
MESH: Animals
Trypanosoma brucei
Leishmaniasis
Neglected tropical diseases
chemistry.chemical_classification
MESH: Indoles
biology
Orders of magnitude (mass)
3. Good health
[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology
Molecular Medicine
MESH: Benzazepines
Leishmania infantum
Growth inhibition
Trypanosoma brucei brucei
Antiprotozoal Agents
03 medical and health sciences
Amide Synthases
Trypanosomiasis
parasitic diseases
medicine
Animals
Humans
MESH: Antiprotozoal Agents
Molecular Biology
MESH: Humans
010405 organic chemistry
Spectrum Analysis
Organic Chemistry
MESH: Trypanosoma brucei brucei
Benzazepines
biology.organism_classification
medicine.disease
0104 chemical sciences
030104 developmental biology
Enzyme
chemistry
Paullone
Trypanothione synthetase
Zdroj: Bioorganic and Medicinal Chemistry
Bioorganic and Medicinal Chemistry, Elsevier, 2016, 24 (16), pp.3790-800. ⟨10.1016/j.bmc.2016.06.023⟩
ISSN: 0968-0896
1464-3391
DOI: 10.1016/j.bmc.2016.06.023⟩
Popis: International audience; Trypanothione synthetase is an essential enzyme for kinetoplastid parasites which cause highly disabling and fatal diseases in humans and animals. Inspired by the observation that N(5)-substituted paullones inhibit the trypanothione synthetase from the related parasite Leishmania infantum, we designed and synthesized a series of new derivatives. Although none of the new compounds displayed strong inhibition of Trypanosoma brucei trypanothione synthetase, several of them caused a remarkable growth inhibition of cultivated Trypanosoma brucei bloodstream forms. The most potent congener 3a showed antitrypanosomal activity in double digit nanomolar concentrations and a selectivity index of three orders of magnitude versus murine macrophage cells.
Databáze: OpenAIRE
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