Concerted effort to address rational drug design against Chagas disease
Through a multidisciplinary approach that combine medicinal chemistry, structural bioinformatics, molecular docking and immunobiology of the infectious process, we identified two new inhibitors of an essential enzyme to T. cruzi, the parasite at the origin of Chagas infection and pathology. More than 60 analogues were then designed and synthesized by Medicinal Chemistry according to the most relevant molecular modeling data. Functional analysis ofsome of the new TcPRAC inhibitors showed that they exhibit low toxicity on green monkey kidney cells in culture, decrease in vitro cellular infection and parasite multiplication and fate in a dose-response manner. Continuing pharmacomodulations are in progress to optimize the biodisponibility and the trypanosomicide and/or trypanostatic effect of these new compounds.