Effect of partial O-methylation in dehydrodieugenol on its antitrypanosomal activity-correlation with the toxicity using cell membrane models

Author(s)

Goncalves, Giulia Elisa G. ; Oliveira, Samuel ; Gomes, Kaio de Souza ; Costa-Silva, Thais Alves ; Tempone, Andre Gustavo ; Lago, Joao Henrique Ghilardi ; Caseli, Luciano

• Document type: Journal article
• Source: Biophysical Chemistry; v. 296, p. 11-pg., 2023-02-24.

Abstract

Biseugenol (1), a neolignan with antiprotozoal activity against Trypanosoma cruzi, was partially methylated, and the compound obtained - methyl biseugenol (2) - had its activity evaluated against the extracellular (trypomastigotes) and intracellular (amastigotes) forms of T. cruzi. It was observed that both compounds 1 and 2 exhibited similar effects against trypomastigotes (IC50 of 11.7 and 16.2 mu M, respectively), whereas compound 2 displayed higher activity against amastigotes (IC50 = 8.2 mu M) in comparison with biseugenol (IC50 = 15.4 mu M). Additionally, reduced toxicity against NCTC cells for compound 2 was observed (CC50 > 200 mu M), differently from compound 1 with CC50 = 58.0 mu M. Aiming to understand better the molecular mechanism of the biological action of compound 2, the prodrug was incorporated into cellular membrane models constituted of Langmuir monolayers of the lipids dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylserine (DPPS), and dipalmitoylphosphatidylglycerol (DPPG). The lipid-drug interaction was inferred through tensiometry, surface potential, infrared spectroscopy (PM-IRRAS), and Brewster angle microscopy (BAM). The prodrug expanded DPPC and DPPG monolayers and condensed DPPE ones, as well as presented characteristic behaviors regarding the chemical structure of the lipid considering expansioncompression curves, surface potential-area isotherms, and stability of previously compressed monolayers to relevant-biological surface pressures. PM-IRRAS indicated a molecular disorder for DPPC and DPPS alkyl chains in the presence of the drug. BAM revealed the presence of domains in the DPPG and DPPE monolayers, which was probably induced by the prodrug. These data suggest, in general, that the lipid composition modulates the interaction of compound 2, whose results are expected to correlate to its trypanocidal activity, which involves the plasma membrane of T. cruzi as the primary target, i.e., the first barrier that the compound should encounter to interact with the microorganism. (AU)

• FAPESP's process: 19/03239-0 - Nanostructured interfaces for the investigation of bioactive substances in cell membrane models and for the construction of optoelectronic devices
• Grantee: Luciano Caseli
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/02789-7 - Search for bioactive metabolites with antiparasitic action in plant species from Atlantic Forest and Cerrado regions - a chemical, phenotypical, and metabolomic approach
• Grantee: João Henrique Ghilardi Lago
• Support Opportunities: BIOTA-FAPESP Program - Regular Research Grants
• FAPESP's process: 22/03736-7 - Nanostructured interfaces for the investigation of bioactive substances in cell membrane models and for the construction of optoelectronic devices
• Grantee: Luciano Caseli
• Support Opportunities: Regular Research Grants