In vitro, in vivo and in silico studies of cumanin diacetate as a potential drug against Trypanosoma cruzi infection

ALBERTI, ANDRÉS SÁNCHEZ; EMILIO L. MALCHIODI

American Chemical Society Omega

ACS Publications

Lugar: Washington DC; Año: 2022 vol. 7 p. 968 - 978

2470-1343

The sesquiterpene lactones cumanin, helenalin and hymenin and their semysinthetic 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, 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).This compound was also able to inhibit the 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 T. cruzi with 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 parasitaemia levels in comparison with non-treated animals (area under parasitaemia curves 3.23 vs. 30.47, respectively). Hystopatological analysis of skeletal muscular tissues from treated mice showed only focal interstitial lymphocyte inflammatory infiltrates with slight myocyte necrosis, in contrast, non-treated 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 G docking achieved let the identification of diacetylatedand 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.