Homologous acetylenic acetogenins from Porcelia macrocarpa R.E. (Fries) displayed potent activity against amastigotes from Trypanosoma cruzi

Ivanildo A Brito; Erica V Castro Levatti; Luis O Regasini; Edgard A Ferreira; Flavia B Lopes; João Paulo S Fernandes; João M Batista Jr; Andre G Tempone; João Henrique G Lago

doi:10.1016/j.phytochem.2024.114360

Homologous acetylenic acetogenins from Porcelia macrocarpa R.E. (Fries) displayed potent activity against amastigotes from Trypanosoma cruzi

Phytochemistry. 2025 Mar:231:114360. doi: 10.1016/j.phytochem.2024.114360. Epub 2024 Dec 12.

Authors

Ivanildo A Brito¹, Erica V Castro Levatti², Luis O Regasini³, Edgard A Ferreira⁴, Flavia B Lopes⁵, João Paulo S Fernandes⁶, João M Batista Jr⁷, Andre G Tempone⁸, João Henrique G Lago⁹

Affiliations

¹ Centre for Natural and Human Sciences, Federal University of ABC, Santo Andre, SP, 09280-560, Brazil.
² Centre for Pathophysiology, Butantan Institute, São Paulo, SP, 05585-000, Brazil.
³ Institute of Biosciences, Humanities and Exact Sciences, São Paulo State University, São José do Rio Preto, SP, 15054-000, Brazil.
⁴ School of Engineering, Mackenzie Presbyterian University, São Paulo, SP, 01302-907, Brazil.
⁵ Department of Medicine, Federal University of São Paulo, São Paulo, SP, 04023-900, Brazil.
⁶ Department of Pharmaceutical Sciences, Federal University of São Paulo, Diadema, SP, 09913-030, Brazil.
⁷ Institute of Science and Technology, Federal University of São Paulo, São José dos Campos, SP, 12231-280, Brazil.
⁸ Centre for Pathophysiology, Butantan Institute, São Paulo, SP, 05585-000, Brazil. Electronic address: andre.tempone@butantan.gov.br.
⁹ Centre for Natural and Human Sciences, Federal University of ABC, Santo Andre, SP, 09280-560, Brazil. Electronic address: joao.lago@ufabc.edu.br.

PMID: 39672219
DOI: 10.1016/j.phytochem.2024.114360

Abstract

As part of our continuous study on the Annonaceae species Porcelia macrocarpa, in the present work, eight chemically related 2-alkyl-3-hydroxy-4-methyl-γ-lactones (1-8) were isolated. Their structures were characterised by NMR, MS, and VCD. Their antitrypanosomal activity was evaluated in vitro against intracellular amastigotes with EC₅₀ values ranged from 13.9 to 1.1 μM for compounds 1-3 and 6-8, while compounds 4 and 5 were inactive (EC₅₀ > 100 μM). Compounds 1-8 did not exert toxicity against NCTC cells at the highest tested concentration (CC₅₀ > 200 μM). Compared with the standard drug benznidazole (EC₅₀ = 3.6 μM and SI > 54.6), compound 8 proved to be the most potent γ-lactone with an EC₅₀ of 1.1 μM and an SI of >181.8. Finally, the structure-activity relationship analysis suggested that flexibility and length of side chain of the related γ-lactones 1-8 play an important role in the activity against amastigotes. The results contribute to the discovery of new molecular prototypes that can be used as scaffolds for developing drugs to treat Chagas disease.

Keywords: Acetogenins; Annonaceae; Chagas disease; Porcelia macrocarpa; SAR; Trypanosoma cruzi.

MeSH terms

Acetogenins* / chemistry
Acetogenins* / isolation & purification
Acetogenins* / pharmacology
Animals
Annonaceae* / chemistry
Dose-Response Relationship, Drug
Lactones / chemistry
Lactones / isolation & purification
Lactones / pharmacology
Molecular Structure
Parasitic Sensitivity Tests
Structure-Activity Relationship
Trypanocidal Agents* / chemistry
Trypanocidal Agents* / isolation & purification
Trypanocidal Agents* / pharmacology
Trypanosoma cruzi* / drug effects

Substances

Trypanocidal Agents
Acetogenins
Lactones