Identification of Phenylpyrazolone Dimers as a New Class of Anti-Trypanosoma cruzi Agents

Autor: Louis Maes, Maria de Nazaré Correia Soeiro, Rob Leurs, Alba Ramos Llorca, Geert Jan Sterk, Lydia Stiny, Iwan J. P. de Esch, An Matheeussen, Maarten Sijm, Julianna Siciliano de Araújo, Kristina M. Orrling
Přispěvatelé: Medicinal chemistry, Chemistry and Pharmaceutical Sciences, AIMMS
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Chagas disease
Dimer
Phenotypic screening
Trypanosoma cruzi
nifurtimox
01 natural sciences
Biochemistry
Mice
Structure-Activity Relationship
chemistry.chemical_compound
Parasitic Sensitivity Tests
SDG 3 - Good Health and Well-being
Drug Discovery
medicine
Animals
Humans
Pyrazolones
General Pharmacology
Toxicology and Pharmaceutics
Nifurtimox
Amastigote
Cells
Cultured
Pharmacology
benznidazole
Dose-Response Relationship
Drug
Molecular Structure
Full Paper
biology
010405 organic chemistry
Pharmacology. Therapy
Organic Chemistry
phenotypic screening
Full Papers
biology.organism_classification
medicine.disease
Trypanocidal Agents
Virology
3. Good health
0104 chemical sciences
Chemistry
010404 medicinal & biomolecular chemistry
chemistry
Benznidazole
Toxicity
Molecular Medicine
Dimerization
medicine.drug
Zdroj: ChemMedChem, 14(18), 1662-1668. John Wiley and Sons Ltd
Sijm, M, Siciliano de Araújo, J, Ramos Llorca, A, Orrling, K, Stiny, L, Matheeussen, A, Maes, L, de Esch, I J P, de Nazaré Correia Soeiro, M, Sterk, G J & Leurs, R 2019, ' Identification of Phenylpyrazolone Dimers as a New Class of Anti-Trypanosoma cruzi Agents ', ChemMedChem, vol. 14, no. 18, pp. 1662-1668 . https://doi.org/10.1002/cmdc.201900370
ChemMedChem
Chemmedchem
ISSN: 1860-7179
DOI: 10.1002/cmdc.201900370
Popis: Chagas disease is becoming a worldwide problem; it is currently estimated that over six million people are infected. The two drugs in current use, benznidazole and nifurtimox, require long treatment regimens, show limited efficacy in the chronic phase of infection, and are known to cause adverse effects. Phenotypic screening of an in-house library led to the identification of 2,2′-methylenebis(5-(4-bromophenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one), a phenyldihydropyrazolone dimer, which shows an in vitro pIC50 value of 5.4 against Trypanosoma cruzi. Initial optimization was done by varying substituents of the phenyl ring, after which attempts were made to replace the phenyl ring. Finally, the linker between the dimer units was varied, ultimately leading to 2,2′-methylenebis(5-(3-bromo-4-methoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (NPD-0228) as the most potent analogue. NPD-0228 has an in vitro pIC50 value of 6.4 against intracellular amastigotes of T. cruzi and no apparent toxicity against the human MRC-5 cell line and murine cardiac cells.
Databáze: OpenAIRE
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