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2025-01-01
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- IOC - Artigos de Periódicos [12115]
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IDENTIFICATION OF PHENYLPYRAZOLONE DIMERS AS A NEW CLASS OF ANTI-TRYPANOSOMA CRUZI AGENTS
Trypanosoma cruzi
Dímeros de fenilpirazolona
Identificação
Agentes anti-Trypanosoma cruzi
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Affilliation
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.
Keywords in Portuguese
Doença de ChagasTrypanosoma cruzi
Dímeros de fenilpirazolona
Identificação
Agentes anti-Trypanosoma cruzi
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