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Searching for specialized metabolites from Brazilian floristic biodiversity as drug candidates for neglected tropical diseases

Abstract

The neglected diseases caused by parasites affect more than one billion people and represent a negative impact on health, education, productivity and socioeconomic development. Chemotherapy remains the main method of controlling these diseases, but the available drugs are limited in number and effectiveness. Aware of this problem, the World Health Organization (WHO), in its new roadmap with global goals and milestones for the control of neglected diseases by the year 2030, emphasizes the importance of the search for new antiparasitic agents. In this context, considering that Brazilian biodiversity is a promising source of molecules with pharmacological activity, our research group, together with several researchers, has been making efforts in the search for natural bioactive substances with antiparasitic action, mainly those originating from Brazilian plant species. Thus, in this project, continuity will be given to prospecting studies of bioactive molecules, particularly with regard to studies of prospecting bioactive molecules, especially with antiparasitic action (antileishmania, antitrypanosomal and/or anthelmintic), derived from plant species belonging to mainly to Annonaceae, Asteraceae, Lauraceae and Piperaceae that occur in areas of the Atlantic Forest and Cerrado in the State of São Paulo. For this purpose, the 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 aided by the open platform Global Natural Products Social Molecular Networking (GNPS). Once new bioactive chemical entities are recognized, they will be isolated and structurally characterized. After identifying the active substances, they may be subjected to molecular modifications guided by analysis of ADME/Tox in silico properties aimed at optimizing biological activities and/or reducing toxicity. Additionally, this proposal intends to carry out specific tests to define the phenotypic/molecular mode of action of substances with proven activity in relation to the parasite, in particular the evaluation of the membrane pore and ultrastructural studies. Finally, the selected compounds (natural or semi-synthetic) that have high potential in vitro, reduced toxicity and that meet the criteria recommended by the analyzes via ADME/Tox in silico and, in particular, if they prove to be stable through assays using murine hepatocytes (model experimental) will be submitted to experimental studies (in vivo). Thus, this 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)

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