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Evaluation of the antiparasitic activity and cytotoxicity of natural products derivatives in Trypanosoma cruzi: design and synthesis of analogues potentially superior

Grant number: 18/03918-2
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): July 01, 2018
Effective date (End): June 30, 2021
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:João Paulo dos Santos Fernandes
Grantee:Marina Themoteo Varela
Home Institution: Instituto de Ciências Ambientais, Químicas e Farmacêuticas (ICAQF). Universidade Federal de São Paulo (UNIFESP). Campus Diadema. Diadema , SP, Brazil
Associated scholarship(s):19/14167-0 - Assessment of pharmacokinetic properties in early drug discovery: evaluation of promising antitrypanosoma compounds and hit-to-lead optimization, BE.EP.DR


American Trypanosomiasis, also known as Chagas' Disease (CD), is one of the parasitosis present in the World Health Organization's (WHO) list of Neglected Tropical Diseases (NTD). Data from WHO estimates that approximately 8 million people are infected with the parasite, especially in Latin America where it prevails. There is no vaccine to prevent the infection and the treatment of CD has only two options of drugs, the nitroheterocycles nifurtimox and benznidazole, which usually do not cure chronic patients. The search for new biologically active compounds in nature has led to the market several drugs and many natural products possess a promising antiparastic activity. Natural product derivatives have been chosen by our group as prototypes for the development of new analogues, since the group has already synthetized and evaluated the biological activity of 24 analogues and has been studying the structure-activity relationship in this set, leading to increased potency and selectivity. In continuation to this objective, the present project presents novel compounds, designed on the structure of the most active and selective analogues from the previous set and other natural products, looking for improved biological activity, reduced cytotoxicity and better hydrosolubility, maintaining the natural product scaffold in the structure (substituted aromatic ring and functionalized side chain). Moreover, it is intended to evaluate the membrane disruption activity, since the analogues obtained so far do not have this capacity, suggesting a different mechanism of action from the natural prototypes. With the obtained data it is intended to elucidate the structure-activity relationships of these molecules in a qualitative or quantitative manner, and maybe find a promising new drug candidate for the treatment of Chagas' Disease. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
VARELA, MARINA T.; COSTA-SILVA, THAIS A.; LAGO, JOAO HENRIQUE G.; TEMPONE, ANDRE G.; FERNANDES, JOAO PAULO S. Evaluation of the antitrypanosoma activity and SAR study of novel LINS03 derivatives. BIOORGANIC CHEMISTRY, v. 89, AUG 2019. Web of Science Citations: 0.
VASCONCELOS, CAMILLA I.; VARELA, MARINA T.; TORRECILHAS, ANA C.; FERNANDES, JOAO P. S. Pyrazinoates as antiparasitic agents against Trypanosoma cruzi. ARCHIV DER PHARMAZIE, v. 351, n. 11 NOV 2018. Web of Science Citations: 0.

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