Search for bioactive metabolites with antiparasitic action in plant species from Atlantic Forest and Cerrado regions - a chemical, phenotypical, and metabolomic approach

Abstract

In the present project, the prospective studies of bioactive molecules will be continued, especially with antiparasitic action (antileishmanial, antitrypanosomal and/or anthelmintic), originating from plant species belonging mainly to Annonaceae, Asteraceae, Lauraceae and Piperaceae occurring in Atlantic Forest and "Cerrado" areas of the State of São Paulo. Initially, selected species will be collected, and their extracts prepared, and those with proven antiparasitic action will be subjected to molecular dereplication processes through analysis via HPLC/MS assisted by the open platform Global Natural Products Social Molecular Networking (GNPS). Once new bioactive chemical entities are recognized, they will be isolated by chromatographic fractionation and structurally characterized by spectroscopic/spectrometric techniques (UV, IR, NMR, MS, DC, VCD). After identification of the active substances, they may be subjected to molecular changes guided by analysis of ADME/Tox properties in silico in order to optimize biological activities and/or reduce toxicity. Additionally, it is intended, in this proposal, to carry out specific tests to define the phenotypic mode of action of substances with proven activity in relation to the parasite, especially the evaluation in the membrane pore and ultrastructural studies as well as using metabolomic tools (HPLC/MS and GC/MS in conjunction with chemometric analyzes) to study the effect on the production of metabolites in the parasite, after treatment with the tested substances, in order to corroborate the phenotypic information. Finally, selected compounds (natural or semi-synthetic) that have high in vitro potential, reduced toxicity and that meet the criteria recommended by the analyzes via ADME/Tox in silico, will be subjected to pre-clinical studies. In this way, the present project intends to add new compounds with proven pharmacological activity to the restricted therapeutic arsenal of these neglected diseases, providing tools for the development of new drugs of plant origin. (AU)