Chemical modification of natural products to obtain trypanocidal agents

• Grant number: 19/18069-3
• Support Opportunities: Regular Research Grants
• Start date: September 01, 2020
• End date: February 28, 2023
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Ivone Carvalho
• Grantee: Ivone Carvalho
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Marcelo Dias Baruffi

Abstract

The Chagas Disease is still a global threat, with an estimated 6 to 7 million people infected, mainly in Latin America. Despite the efforts of national and international agencies to develop an innovative strategy against this disease, no drug candidate has met all the necessary requirements for clinical use. In Brazil, the benznidazole drug is the only drug available for the treatment, and requires careful attention to dose adequacy and to the control of adverse effects that appear in about 30 to 40% of the cases. For this reason, the search of natural compounds has intensified and the possibility of finding a molecule with high activity and low toxicity is increasing as more plant species are investigated. Thus, one of the objectives of this project is to perform the chemical modification of natural products, exploring the glycosylation reactions of quercetin (flavonoid) at C-5 and C-3 positions, and juglone (naphthoquinone) with different carbohydrates to increase trypanocidal activity, reduce toxicity and enhance the pharmacokinetic properties of these compounds. In parallel, the project will also be guided towards the preparation of more potent inhibitors of T.cruzi trans-sialidase enzyme (TcTS), by testing the glycosylated quercetin and juglone and developing molecules that partially mimic sialic acid, the donor substrate of the enzyme, starting from quinic acid, a natural product that preserves characteristics of sialic acid, such as hydroxyl groups and carboxylic acid, attached to the cyclohexanol. In this regard, we intend to perform quinic acid modifications, preserving some key group for enzyme interaction, such as carboxy group and some carbon stereochemistry with high affinity to TcTS donor subsite, but altering the hydroxy group at C-4 by the introduction of amide and triazole cores bearing different side chains by varying polarity, volume and shape to extend the binding on the enzyme. The trypanocidal activity (trypomastigote and amastigote forms and invasion processes of T.cruzi) and cytotoxicity in host fibroblasts of all synthesised compounds will be assessed according to the standard procedures and the results will drive the synthesis of novel optimized products. (AU)