In vitro and in silico evaluation of the schistosomicidal activity of eugenol derivatives using biochemical, molecular, and morphological tools

• Published in: Journal of Venomous Animals and Toxins including Tropical Diseases
• Main Authors: Isabella Maria Monteiro de Souza, Romulo Dias Novaes, Reggiani Vilela Gonçalves, Felipe Leonardo Bley Fialho, Diogo Teixeira Carvalho, Thiago Belarmino de Souza, Danielle Ferreira Dias, Stefânia Neiva Lavorato, Raquel Lopes Martins Souza, Marcos José Marques, Aline Pereira Castro
• Format: Article in Journal/Newspaper
• Language: English
• Published: SciELO 2022
• Subjects: Schistosoma mansoni; Eugenol; Schistosomiasis; Mechanism of action; Arctic medicine. Tropical medicine; RC955-962; Toxicology. Poisons; RA1190-1270; Zoology; QL1-991; Arctic
• Online Access: https://doi.org/10.1590/1678-9199-jvatitd-2021-0108; https://doaj.org/article/d35e6fcd38cf41d7b58160953deba8f9

Abstract Background Eugenol shows both antibacterial and antiparasitic activities, suggesting that it might be evaluated as an option for the treatment of praziquantel-resistant schistosome. Methods The in vitro activities of three eugenol derivatives (FB1, FB4 and FB9) on adult worms from Schistosoma mansoni were examined by fluorescence and scanning electron microscopy to analyze effects on the excretory system and integument damage, respectively. Biochemical tests with verapamil (a calcium channel antagonist) and ouabain (a Na+/K+-ATPase pump inhibitor) were used to characterize eugenol derivative interactions with calcium channels and the Na+/K+-ATPase, while in silico analysis identified potential Na+/K+-ATPase binding sites. Results The compounds showed effective doses (ED50) of 0.324 mM (FB1), 0.167 mM (FB4), and 0.340 mM (FB9). In addition, FB4 (0.322 mM), which showed the lowest ED50, ED90 and ED100 (p < 0.05), caused the most damage to the excretory system and integument, according to both fluorescence and scanning electron microscopy analysis. The death of adult worms was delayed by ouabain treatment plus FB1 (192 versus 72 hours) and FB9 (192 versus 168 hours), but the response to FB4 was the same in the presence or absence of ouabain. Besides, no changes were noted when all of the eugenol derivatives were combined with verapamil. Moreover, FB1 and FB9 inhibited Na+/K+-ATPase activity according to in silico analysis but FB4 did not show a time-dependent relationship and may act on targets other than the parasite Na+/K+-ATPase. Conclusion Eugenol derivatives, mainly FB4 when compared to FB1 and FB9, seem to act more effectively on the integument of adult S. mansoni worms.