| Grant number: | 18/10279-6 |
| Support Opportunities: | Regular Research Grants |
| Duration: | October 01, 2018 - September 30, 2020 |
| Field of knowledge: | Biological Sciences - Parasitology - Protozoology of Parasites |
| Principal Investigator: | André Gustavo Tempone Cardoso |
| Grantee: | André Gustavo Tempone Cardoso |
| Host Institution: | Instituto Adolfo Lutz (IAL). Coordenadoria de Controle de Doenças (CCD). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil |
| Associated researchers: | João Henrique Ghilardi Lago ; Juliana Mariotti Guerra ; Samanta Etel Treiger Borborema de Carvalho |
| Associated grant(s): | 18/26655-7 - Natural metabolites for treating antimicrobial resistant gonorrhoea and visceral leishmaniasis, AP.R SPRINT |
Abstract
Considering the morbidity and mortality of visceral leishmaniasis and Chagas' disease, and the therapeutic limitations, these neglected protozoan diseases have been prioritized by WHO. The present proposal aims the search for a new pharmaceutical prototype for each disease, through coordinated activities in Drug Discovery. Based in a multidisciplinary proposal, we propose the continuation of previous project Sprint Fapesp: University of Oxford (2015/50075-2), aligning Synthetic Organic Chemistry, Chemistry of Natural Products, Medicinal Chemistry, Pharmacology and Parasitology, for the selection and optimization of lead compounds against Leishmania (L.) infantum and Trypanosoma cruzi. Acting in two steps of Drug Discovery pipeline, the project has as main focus, the a hit-to-lead stage, through the organic synthesis of synthetic derivatives of natural metabolites, originally isolated from the plant from the genus Nectandra. Additionally, a continuous screening will be performed for the search for new natural secondary metabolites of plants, aiming in vitro potency and selectivity (hit identification). During the optimization stage, one or more hit compounds will be chemically modified based on: i) in vitro studies on intracellular amastigotes (EC50); ii) mammalian cytotoxicity (CC50); iii) mechanism of action (MoA); iv) in silico and in vitro data of absorption, distribution, metabolism, excretion, (ADME); v) in silico physicochemical parameters of solubility, log P, log D and Lipinski's Rule-of-Five; and vi) in silico studies for the elimination of interfering compounds (PAINS). At the end of the project, the synthesis of a lead compound will be scaled-up aiming the efficacy evaluation in a murine model for visceral leishmaniasis and Chagas' disease. Counting on national (UFABC) and international collaborations (University of Oxford, University of Dundee e Oregon State University), the project aims a multidisciplinary approach, taking advantage of different areas for a structure-activity relationship study towards new treatments for neglected protozoan diseases. (AU)
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