Hit to lead optimization of heterocycles containing isoindolones as antitrypanosomal agents

• Grant number: 23/07081-8
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: October 01, 2023
• End date: July 31, 2027
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Flavio da Silva Emery
• Grantee: Bruna Fleck Godoi
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Previous studies in our research group have identified a series of isoindolone-containing compounds with selective and potent activity against T. b. rhodesiense, no cytotoxicity, and excellent metabolic stability, but low solubility. This last parameter is one of the limitations of the most potent compounds and needs to be improved. In addition, the molecular target of the phenotypically active compounds is also unknown, which opens an opportunity to explore how they act inside the parasite to further medicinal chemistry optimization. Based on our previous SAR (structure-activity relationship) knowledge and with an attempt to obtain improved candidates to reach clinical trials for these parasitic infections, this proposal aims to design, synthesize and identify new heterocyclic compounds with antitrypanosomal activity; to employ and modify synthetic routes to obtain greater chemical diversity in this series of compounds; to carry out the and T. brucei growth inhibition assays, cytotoxicity, evaluate the stability of selected compounds to mouse microsomes/ hepatocytes, solubility, protein binding, and in vivo efficacy studies against T. brucei rhodesiense infections and to study the new candidates with improved bioavailability profile for Drug Metabolism and PharmacoKinetics (DMPK) and their putative mode of action (MoA) analysis, understanding the selectivity only for the rhodesiense subspecies. These studies will be done through a partnership with the researchers at the University of Antwerp (Belgium) and University of Dundee (Scotland, UK). Based on all these results, we will be able toselect the best compound that can be transitioned into clinical trials. (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)

GOMES, RENAN A.; POLETO, MARCELO D.; VERLI, HUGO; ALMEIDA, VITOR M.; MARANA, SANDRO R.; BENDER, ANDREAS; GODOI, BRUNA F.; RODRIGUES, VINICIUS T. L.; EMERY, FLAVIO DE S.; TROSSINI, GUSTAVO H. G.. Fragment Screening Reveals Novel Scaffolds against Sirtuin-2-Related Protein 1 from Trypanosoma brucei. ACS OMEGA, v. 10, n. 4, p. 12-pg., 2024-12-27. (23/07081-8, 17/25543-8, 13/50677-7)