Trypanocidal activity of chromenepyrazole derivatives.
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2022
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Resumo
Chagas disease is caused by the etiological agent Trypanosoma cruzi that impacts negatively on society and mainly afects
the poorest populations of the community. The treatment is restricted to two drugs that have been on the market since the
1960s: nifurtimox and benznidazole. However, both have a high incidence of unwanted side efects and low efciency in
the chronic phase of the disease. Therefore, in this context, the objective of this work was to synthesize chromenopyrazole
derivatives and to evaluate their antiparasitic activity in vitro against the intracellular forms of T. Cruzi. Chromenopyrazoles
are heterocyclic compounds having as a basic core a benzene ring fused to a pyran ring and a pyrazole ring, thus forming a
tricyclic compound with a 6, 6, 5 arrangement. Reaction of 3-benzoyl-favanone with hydrazine was expected to aford the
target compounds, but for a similar synthetic route described in the literature, the proposed product was a pyrazole derivative
in an open form that had not undergone the fnal conjugate addition step. Based on NMR and X-ray crystallography analysis,
it has been demonstrated that a tricyclic chromenopyrazole is the correct structural representation for the product of this
reaction. This study resulted in the synthesis of 15 novel chromenopyrazoles compounds displaying signifcant trypanocidal
activity. The majority of the chromenepyrazoles satisfed Lipinski rules, without any violations, whilst only two compounds
showed at least one violation of the rule, due to the log P being greater than 5.6. All chromenepyrazoles exhibited anti-T.
cruzi activity, and improved potency was observed when comparing them to the precursor 3-benzoyl-favanone. The introduction of an anisole moiety at the pyrazole ring and the inclusion of 3,4,5-trimethoxybenzene at the pyranone resulted in a
doubling of potency and improvement in selectivity. The lead compound bearing methoxyl groups was the most active and
displayed comparable anti-T. Cruzi activity to the control drug benznidazole. This result, once again, reinforces the same
observations reported in the literature in which the introduction of the methoxy groups favoured either more active or more
selective trypanocidal compounds.
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Chromenopyrazole, Trypanosoma cruzi, In vitro, Synthesis, Tricyclic
Citação
ANDRADE, J. S. et al. Trypanocidal activity of chromenepyrazole derivatives. Chemical Papers, v. 76, p. 5827-5837, 2022. Disponível em: <https://link.springer.com/article/10.1007/s11696-022-02283-0>. Acesso em: 01 ago. 2023.