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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 Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): July 01, 2018
Effective date (End): September 30, 2022
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:João Paulo dos Santos Fernandes
Grantee:Marina Themoteo Varela
Host 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)

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Scientific publications (12)
(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.; ROMANELLI, MAIARA; AMARAL, MAIARA; TEMPONE, ANDRE G.; FERNANDES, JOAO PAULO S.. Piperazine amides with desirable solubility, physicochemical and drug-like properties: Synthesis and evaluation of the anti-Trypanosoma cruzi activity. SAUDI PHARMACEUTICAL JOURNAL, v. 31, n. 7, p. 9-pg., . (21/04464-8, 19/24028-8, 19/14167-0, 18/03918-2)
VARELA, MARINA T.; AMARAL, MAIARA; ROMANELLI, MAIARA M.; LEVATTI, ERICA V. DE CASTRO; TEMPONE, ANDRE G.; FERNANDES, JOAO PAULO S.. Optimization of physicochemical properties is a strategy to improve drug-likeness associated with activity: Novel active and selective compounds against Trypanosoma cruzi. European Journal of Pharmaceutical Sciences, v. 171, p. 12-pg., . (21/04464-8, 19/14167-0, 18/03918-2, 20/03637-3, 19/24028-8)
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, . (18/03918-2, 16/25028-3, 18/07885-1, 15/23403-9)
WALLER, STEFANIE BRESSAN; CLEFF, MARLETE BRUM; RIPOLL, MARCIA KUTSCHER; ARAUJO MEIRELES, MARIO CARLOS; FERRARINI, MARCIO; VARELA, MARINA THEMOTEO; FERNANDES, JOAO PAULO S.. ioisosteric modification on benzylidene-carbonyl compounds improved the drug-likeness and maintained the antifungal activity against Sporothrix brasiliensi. CHEMICAL BIOLOGY & DRUG DESIGN, v. 99, n. 3, . (18/03918-2, 19/24028-8, 16/25028-3)
OLIVEIRA, LIDIANE; FERRARINI, MARCIO; DOS SANTOS, ALEXANDRE PAES; VARELA, MARINA THEMOTEO; SANTOS CORREA, ISABELA TERESA; TEMPONE, ANDRE GUSTAVO; MELHEM, MARCIA S. C.; VALLIM, MARCELO A.; FERNANDES, JOAO PAULO S.; PASCON, RENATA C.. Coumaric acid analogues inhibit growth and melanin biosynthesis in Cryptococcus neoformans and potentialize amphotericin B antifungal activity. European Journal of Pharmaceutical Sciences, v. 153, . (18/10279-6, 18/03918-2, 15/04400-9, 16/25028-3, 16/14542-8)
AMARAL, MAIARA; VARELA, MARINA T.; KANT, RAVI; CHRISTODOULIDES, MYRON; FERNANDES, JOAO PAULO S.; TEMPONE, ANDRE G.. Synthetic Analogues of Gibbilimbol B Induce Bioenergetic Damage and Calcium Imbalance in Trypanosoma cruzi. LIFE-BASEL, v. 13, n. 3, p. 17-pg., . (21/04464-8, 18/26655-7, 17/50333-7, 18/03918-2, 19/24028-8, 18/25128-3)
CORRE, MICHELLE F.; BALICO-SILVA, ANDRE L.; KISS, DORA J.; FERNANDES, GUSTAVO A. B.; MARASCHIN, JHONATAN C.; PARREIRAS-E-SILVA, LUCAS T.; VARELA, MARINA T.; SIMOES, SARAH C.; BOUVIER, MICHEL; KESERU, GYORGY M.; et al. Novel potent (dihydro)benzofuranyl piperazines as human histamine receptor ligands - Functional characterization and modeling studies on H-3 and H(4 )receptors. Bioorganic & Medicinal Chemistry, v. 30, . (16/24120-3, 17/05441-6, 12/20148-0, 16/25028-3, 18/03918-2, 18/00153-5, 16/08920-0, 16/23139-2)
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, . (16/01917-3, 18/03918-2, 16/25028-3)
CORREA, MICHELLE F.; REINER, DAVID; FERNANDES, GUSTAVO A. B.; VARELA, MARINA T.; ARANHA, CECILIA M. S. Q.; STARK, HOLGER; FERNANDES, JOAO PAULO S.. Profiling of LINS01 compounds at human dopamine D-2 and D-3 receptors. JOURNAL OF CHEMICAL SCIENCES, v. 132, n. 1, . (17/05441-6, 18/03918-2, 18/04488-1, 16/25028-3)
WALLER, STEFANIE BRESSAN; CLEFF, MARLETE BRUM; RIPOLL, MARCIA KUTSCHER; ARAUJO MEIRELES, MARIO CARLOS; VARELA, MARINA THEMOTEO; FERNANDES, JOAO PAULO DOS S.. Benzylidene-carbonyl compounds are active against itraconazole-susceptible and itraconazole-resistantSporothrix brasiliensis. Folia Microbiologica, v. 65, n. 6, . (16/25028-3, 18/03918-2)
CORREA, M. F.; SILVA, A. B.; PENOMIAN, L.; SIMOES, S. C.; FERNANDES, G. A. B.; ARANHA, C. M. S. Q.; VARELA, M. T.; COSTA-NETO, C. M.; FERNANDES, J. P. S.. EVALUATION AND SAR STUDY OF NOVEL SUBSTITUTED (DIHYDRO)BENZOFURANYL-PIPERAZINES AS HISTAMINE H3R AND H4R LIGANDS. Inflammation Research, v. 68, p. 1-pg., . (18/04488-1, 18/03918-2, 16/23139-2, 16/25028-3, 17/05441-6)
VARELA, MARINA THEMOTEO; FERRARINI, MARCIO; MERCALDI, VITORIA GALLO; SUFI, BIANCA DA SILVA; PADOVANI, GIOVANA; SBRUGNERA NAZATO, LUCAS IDACIR; FERNANDES, JOAO PAULO S.. Coumaric acid derivatives as tyrosinase inhibitors: Efficacy studies through in silico, in vitro and ex vivo approaches. BIOORGANIC CHEMISTRY, v. 103, p. 11-pg., . (16/25028-3, 18/03918-2)

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