ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

Trypanocidal activity of chromenepyrazole derivatives

Josimara Souza Andrade, Policarpo Ademar Sales Junior, Fabio Junio Pereira, Silvane Maria Fonseca Murta, Rodrigo S. Correa, and Jason Guy Taylor

Chemistry Department, ICEB, Universidade Federal de Ouro Preto, Campus Universitário Morro Do Cruzeiro, Ouro Preto, Brazil

E-mail: josimara.souza28@hotmail.com

Received: 8 December 2021  Accepted: 12 May 2022

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.

Keywords: Chromenopyrazole; Trypanosoma cruzi; In vitro; Synthesis; Tricyclic

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-022-02283-0

Chemical Papers 76 (9) 5827–5837 (2022)