Abstract
Chagas disease is caused by the etiological agent Trypanosoma cruzi that impacts negatively on society and mainly affects 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 effects and low efficiency 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-flavanone with hydrazine was expected to afford 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 final 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 significant trypanocidal activity. The majority of the chromenepyrazoles satisfied 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-flavanone. 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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Acknowledgements
This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001. Authors gratefully acknowledge the generous financial support from the Universidade Federal de Ouro Preto (UFOP), FAPEMIG and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). The authors thank the Program for Technological Development of Tools for Health-PDTIS-FIOCRUZ for use of its facilities (Chagas Disease Platform PlaBio Tc). The authors thank the Laboratório Multiusuário de Caracterização de Moléculas (UFOP) for Nuclear Magnetic Resonance service. The authors thank the IFSC-USP (E.E. Castellano and J. Honorato) for X-ray crystallography measurements. The authors would also like to thank the Laboratório Multiusuário de Proteômica e Biomoléculas (LMU-ProtBio), from Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, MG, Brazil, for providing the required equipment and technical expertise for sample processing and mass spectrometry analyses. Policarpo Ademar Sales Junior is research fellow supported by CNPq.
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Andrade, J.S., Junior, P.A.S., Pereira, F.J. et al. Trypanocidal activity of chromenepyrazole derivatives. Chem. Pap. 76, 5827–5837 (2022). https://doi.org/10.1007/s11696-022-02283-0
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DOI: https://doi.org/10.1007/s11696-022-02283-0