Novel giardicidal compounds bearing proton pump inhibitor scaffold proceeding through triosephosphate isomerase inactivation

作者：Hernandez Ochoa B; Navarrete Vazquez G; Nava Zuazo C; Castillo Villanueva A; Mendez S T; Torres Arroyo A; Gomez Manzo S; Marcial Quino J; Ponce Macotela M; Rufino Gonzalez Y; Martinez Gordillo M; Palencia Hernandez G; Esturau Escofet N; Calderon Jaimes E; Oria Hernandez J^*; Reyes Vivas H^*

来源：Scientific Reports, 2017, 7(1): 7810.

DOI：10.1038/s41598-017-07612-y

Giardiasis is a worldwide parasitic disease that affects mainly children and immunosuppressed people. Side effects and the emergence of resistance over current used drugs make imperative looking for new antiparasitics through discovering of new biological targets and designing of novel drugs. Recently, it has determined that gastric proton-pump inhibitors (PPI) have anti-giardiasic activity. The glycolytic enzyme, triosephosphate isomerase (GlTIM), is one of its potential targets. Therefore, we employed the scaffold of PPI to design new compounds aimed to increase their antigiardial capacity by inactivating GlTIM. Here we demonstrated that two novel PPI-derivatives (BHO2 and BHO3), have better antigiardiasic activity than omeprazole in concentrations around 120-130 mu M, without cytotoxic effect on mammal cell cultures. The derivatives inactivated GlTIM through the chemical modification of Cys222 promoting local structural changes in the enzyme. Furthermore, derivatives forms adducts linked to Cys residues through a C-S bond. We demonstrated that PPI can be used as scaffolds to design better antiparasitic molecules; we also are proposing a molecular mechanism of reaction for these novel derivatives.

• 出版日期2017-8-10