Design and synthesis of 7-azaindole derivatives with potential trypanocidal activity

• Grant number: 22/00283-1
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• Start date: July 15, 2022
• End date: January 14, 2023
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Elizabeth Igne Ferreira
• Grantee: Filipe Gomes Pernichelle
• Supervisor: Matthias Gehringer
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Eberhard Karls Universität Tübingen, Germany
• Associated to the scholarship: 20/13347-2 - Potentially active anti-chagas disease: design and synthesis of molecular hybrids of enzymes as fe-superoxide dismutase and CYP51 with nitric oxide releasing groups, BP.MS

Abstract

Chagas disease is a common anthropozoonosis in Latin America, and its transmission occurs through the parasite called Trypanosoma cruzi. This neglected disease presents serious public health problems in Latin America, and nowadays an issue also in other countries such as the United States, Canada, Japan, Australia, as well as some regions of Europe. Currently, in the 21 countries considered endemic, approximately 75 million people are exposed to the infection, 6 million are infected, and more than 30,000 new cases arise each year. Even though Chagas disease completes more than a hundred years since its discovery, its chemotherapy remains precarious with only the drugs nifurtimox and benznidazole available on the market, and only the latter available in Brazil. Both have low effectiveness in the chronic phase of the disease, and more than 80% of patients do not obtain a parasitological cure at this stage. With the need for new effective molecules against T. cruzi, the fragment 7-azaindole has emerged as an interesting kinase privileged group for designing new antiparasitic compounds. 7-azaindole derivatives have shown potent inhibitory activity against Plasmodium falciparum in a screening study (unpublished data), and given the fact that protein kinases are also essential signaling molecules in Trypanosoma, the aim of this work is the synthesis and SAR exploration of a new series of compounds containing 7-azaindole rings as possible inhibitors of T. cruzi growth. This is a repurposing process, as 4-azaindole derivatives presented activity in Chagas disease and 7-azaindole, which is bioisostere of the former, shown to be active against Plasmodium sp. (AU)