Selective inactivation of triosephosphate isomerase from Trypanosoma cruzi by brevifolin carboxylate derivatives isolated from Geranium bellum Rose

Design, synthesis, molecular modelling, and in vitro evaluation of tricyclic coumarins against Trypanosoma cruzi

“…The improvement in T. cruzi activity observed for coumarins bearing a methoxy group suggests some important hydrogen bonding interaction with TcTIM. The importance of methoxy substituents was also noted for the trypanocidal activity of coumarin-chalcone hybrid molecules (Gayosso- De-Lucio et al, 2009). The chlorobenzene group present in 3g resulted in compound that was equipotent to benznidazole but four times more toxic than 3a, thus making the presence of a chloro atom undesirable.…”

“…This approach is in accordance with the guidelines proposed by the Fiocruz Program for Research and Technological Development on Chagas Disease and the Drugs for Neglected Diseases Initiative (DNDi) (de Souza et al, 2018;Elias et al, 2016). The importance of methoxy substituents was also noted for the trypanocidal activity of coumarin-chalcone hybrid molecules (Gayosso- De-Lucio et al, 2009). Benznidazole was used as positive control against T. cruzi, and cytotoxicity was determined in mammalian L929 cells (Table 2).…”

“…Through molecular docking, it is possible to predict the most stable structure of the protein-ligand complex and also to calculate the energy of interaction (Menezes et al, 2014) based on preliminary study of Gayosso-De-Lucio et al (2009) that described the inactivation of the T. cruzi triosephosphate isomerase (TIM) enzyme by isocoumarins isolated from hellum rose geranium, and this study was performed with molecular docking in silico of new coumarin compounds. Through molecular docking, it is possible to predict the most stable structure of the protein-ligand complex and also to calculate the energy of interaction (Menezes et al, 2014) based on preliminary study of Gayosso-De-Lucio et al (2009) that described the inactivation of the T. cruzi triosephosphate isomerase (TIM) enzyme by isocoumarins isolated from hellum rose geranium, and this study was performed with molecular docking in silico of new coumarin compounds.…”

“…In the search of molecules that can serve as leads in the design of a new drug for the treatment of Chagas' disease, our attention was drawn to brevifolin carboxylate derivatives ( Figure 1) isolated from Geranium bellum Rose. These compounds were able to inactivate triosephosphate isomerase from T. cruzi (TcTIM) | 339 COELHO Et aL. in a species-specific manner (Gayosso-De-Lucio et al, 2009). In view of the spectrum of biological activity of naturally occurring coumarins (isolated from plants, fungi, and animals), several research groups have searched for new semi-synthetic or synthetic coumarins that contain a spectrum of biological activity better than the natural analog ( Figure 2).…”

An alternative hepatoprotective and antioxidant agent: the <i>Geranium</i>

“…Another geranium studied by our group is Geranium Shiedeanum (Gs). The phytochemical study of Gs led to the isolation of the following hydrolyzable tannins, which are well known as potent antioxidants: gallic acid, geraniin, ellagic acid, and a lesser proportion of the kaempferol glycoside flavonoid, 3-O-α-L-arabinofuranoside-7-O-β-D-rhamnoside of kaempferol (14). Notably, to our knowledge, this is the first time these compounds have been identified in this genus.…”