Continuous flow synthesis of 3-thio-1,2,4-triazoles and biological evaluation

• Grant number: 15/18572-6
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: January 01, 2016
• End date: May 31, 2020
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Júlio Cezar Pastre
• Grantee: Mariana Celestina Frojuello Costa Bernstorff Damião
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 14/26378-2 - Development of methodologies and synthetic processes employing a new technological platform: micro and meso reactor assisted synthesis of natural products and derivatives with potential pharmacological activity, AP.JP
• Associated scholarship(s): 17/02093-7 - Design and synthesis of readthrough compounds, BE.EP.DR

Abstract

Among the technologies currently available, continuous flow chemistry can aid the synthesis of pharmaceutical actives by integrating multiple steps, and by direct scale up of reactions. In 2017 we developed an integrated flow synthesis for the rapid generation of 3-thio-1,2,4-triazoles from hydrazides and isothiocyanates. Lesinurad is a uric acid transporter protein (URAT1) inhibitor approved for the treatment of gout in 2015 and it presents the 3-thio-1,2,4-triazole core. In this work, we aim to apply the previously published methodology to develop a new synthetic route to generate Lesinurad by integrating batch and continuous flow reactions. In addition, the 3-thio-1,2,4-triazole system will be explored in the development of glutaminase inhibitors. Glutaminases play an essential role in the regulation of glutamine metabolism in tumor cells. The search for glutaminase allosteric inhibitors began in 2002, and efforts of various research groups contributed to the great development in this area. BPTES is an inhibitor extensively explored, however it presents solubility issues and poor metabolic stability. In this project, we envisage to develop and synthesize a new series of 3-thio-1,2,4-triazoles with improved druglike properties and capable of inhibiting glutaminase.

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)

DAMIAO, MARIANA C. F. C. B.; GALAVERNA, RENAN; KOZIKOWSKI, ALAN P.; EUBANKS, JAMES; PASTRE, JULIO C.. Telescoped continuous flow generation of a library of highly substituted 3-thio-1,2,4-triazoles. REACTION CHEMISTRY & ENGINEERING, v. 2, n. 6, p. 896-907, DEC 2017. (15/18572-6, 14/25770-6, 14/26378-2, 13/07607-8)

DAMIAO, MARIANA C. F. C. B.; MARCON, HENRIQUE M.; PASTRE, JULIO CEZAR. Continuous flow synthesis of the URAT1 inhibitor lesinurad. REACTION CHEMISTRY & ENGINEERING, v. 5, n. 5, p. 865-872, MAY 1 2020. (14/25770-6, 14/26378-2, 15/18572-6, 13/07607-8, 18/25233-1)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

DAMIÃO, Mariana Celestina Frojuello Costa Bernstorff. Continuous flow synthesis of 3-thio-1,2,4-triazoles and biological evaluation. 2020. Doctoral Thesis - Universidade Estadual de Campinas (UNICAMP). Instituto de Química Campinas, SP.