Abstract
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.
Original language | English |
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Pages (from-to) | 1662-1668 |
Number of pages | 7 |
Journal | ChemMedChem |
Volume | 14 |
Issue number | 18 |
DOIs | |
Publication status | Published - 1 Jan 2019 |
Funding
The PDE4NPD project was funded by the European Union under the FP-7-Health program, project ID: 602 666. M.d.N.C.S. is CNE from FAPERJ and a CNPq researcher. Fiocruz, CNPq, and FAPERJ are acknowledged. The authors thank A. van der Stolpe and H. Custers for their technical assistance. The PDE4NPD project was funded by the European Union under the FP‐7‐Health program, project ID: 602 666. M.d.N.C.S. is CNE from FAPERJ and a CNPq researcher. Fiocruz, CNPq, and FAPERJ are acknowledged. The authors thank A. van der Stolpe and H. Custers for their technical assistance.
Funders | Funder number |
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FP-7-Health program | |
Seventh Framework Programme | 602666 |
European Commission | |
Conselho Nacional de Desenvolvimento CientÃfico e Tecnológico | |
Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro |
Keywords
- benznidazole
- Chagas disease
- nifurtimox
- phenotypic screening
- Trypanosoma cruzi