In Vitro, In Vivo, and In Silico Studies of Cumanin Diacetate as a Potential Drug against Trypanosoma cruzi Infection

Abstract

The sesquiterpene lactones cumanin, helenalin, and hymenin and their semisynthetic derivatives were evaluated against Trypanosoma cruzi epimastigotes. The cytotoxicity of the compounds was evaluated on murine splenocytes. Cumanin diacetate was one of the most active and selective compounds [IC50 = 3.20 ± 0.52 μg/mL, selectivity index (SI) = 26.0]. This sesquiterpene lactone was selected for its evaluation on trypomastigote and amastigote forms of the parasite. The diacetylated derivative of cumanin showed moderate activity on trypomastigotes (IC50 = 32.4 ± 5.8 μg/mL). However, this compound was able to efficiently inhibit parasite replication with an IC50 value of 2.2 ± 0.05 μg/mL against the amastigote forms. Cumanin diacetate showed selectivity against the intracellular forms of Trypanosoma cruzi with an SI value of 52.7. This cumanin analogue was also active on an in vivo model of Chagas disease, leading to a reduction in the parasitemia levels in comparison with nontreated animals. Histopathological analysis of skeletal muscular tissues from treated mice showed only focal interstitial lymphocyte inflammatory infiltrates with slight myocyte necrosis; in contrast, nontreated animals showed severe lymphocyte inflammatory infiltrates with necrosis of the myocytes. A molecular docking study of cumanin and its derivatives on trypanothione reductase from T. cruzi (TcTR) was performed. The results of ΔG docking achieved let the identification of diacetylated and O-alkylated derivatives of cumanin as good inhibitors of TcTR. Cumanin diacetate could be considered a potential candidate for further studies for the development of new therapies against Chagas disease.

Anti-Trypanosoma cruzi Properties of Sesquiterpene Lactones Isolated from Stevia spp.: In Vitro and In Silico Studies

“…Given the data presented in this paper, santhemoidin C and 2-oxo-8-deoxyligustrin are suitable candidates for the obtention of semisynthetic derivatives in the search for more effective and less cytotoxic trypanocidal compounds. In this sense, the synthesis of ester derivatives of STLs bearing an OH group, such as santhemoidin C, has been an alternative to reduce cytotoxicity and improve the selectivity index [ 6 ].…”

“…The trypanocidal activity of compounds A and B on intracellular forms of T. cruzi was evaluated [ 6 ]. Vero cells (5 × 10 3 /well) were infected with culture-derived trypomastigotes of T. cruzi Tulahuen strain expressing β-galactosidase (MOI: 10).…”

“…STLs have been thoroughly studied for their wide range of biological activities [ 5 ]. Their potential as antiprotozoal agents has been demonstrated in recent years by several authors [ 6 , 7 , 8 , 9 ].…”

Trypanocidal and Anti-Inflammatory Effects of Three ent-Kaurane Diterpenoids from Gymnocoronis spilanthoides var. subcordata (Asteraceae)

“…The activity of compounds 1–3 on the intracellular forms of T. cruzi was evaluated [ 23 ]. Vero cells (5 × 10 3 /well) were infected with culture-derived trypomastigotes of T. cruzi from the Tulahuen strain expressing β-galactosidase (MOI: 10).…”

Structural New Data for Mitochondrial Peroxiredoxin From Trypanosoma cruzi Show High Similarity With Human Peroxiredoxin 3: Repositioning Thiostrepton as Antichagasic Drug

“…Blood trypomastigotes were obtained as described in Section 2.1. Parasites were counted and blood was diluted with DMEM medium to reach 2x10 6 trypomastigotes/ml as described previously ( Sánchez Alberti et al., 2022 ). These parasites were incubated with TS, like cell-derived trypomastigotes.…”