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

Abstract

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

(8)

(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)

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, DEC 2021. (18/03918-2, 19/24028-8, 16/25028-3)

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, JAN 15 2021. (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, NOV 2018. (16/01917-3, 18/03918-2, 16/25028-3)

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. (18/03918-2, 16/25028-3, 18/07885-1, 15/23403-9)

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., 2022-04-01. (21/04464-8, 19/14167-0, 18/03918-2, 20/03637-3, 19/24028-8)

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, OCT 1 2020. (18/10279-6, 18/03918-2, 15/04400-9, 16/25028-3, 16/14542-8)

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, AUG 2020. (16/25028-3, 18/03918-2)

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, DEC 2019. (17/05441-6, 18/03918-2, 18/04488-1, 16/25028-3)