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

Author(s)

Mariana Celestina Frojuello Costa Bernstorff Damião

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Química
• Defense date: 2020-07-30

Examining board members

Júlio Cezar Pastre; Kleber Thiago de Oliveira; Giuliano Cesar Clososki; Wanda Pereira Almeida; Daniel Fábio Kawano

• Advisor: Júlio Cezar Pastre

Abstract

In Chapter 1, we cover general aspects of continuous flow reactors, and the application of this technology in medicinal chemistry, and API synthesis. The following chapters describe the work carried out in our research group, particularly the batch and continuous flow synthesis of compounds bearing the 3-thio-1,2,4-triazole heterocycle, and its biological evaluation. An interesting way to modulate nonsense mutations related to genetic disorders involves the chemical induced read-through of premature stop codons. In this context, in Chapter 2, we describe the design and synthesis of GJ072 analogs, and the evaluation of its read-through potential in HEK293 cells transfected with the mutant MECP2 gene. Molecular modifications in different regions were explored, and several analogs were synthesized; however, we did not identify any compound capable to restore the expression of MECP2 protein. In Chapter 3, we discuss the development of a continuous flow platform to deliver 3-thio-1,2,4-triazoles from hydrazides and isothiocyanates. A library of compounds was generated by integration of three reaction steps: condensation, cyclization and alkylation, and the continuous process afforded the desired products in up to 94% yield after only 48 minutes. As an extension of the protocol used for the synthesis of 3-thio-1,2,4-triazoles, in Chapter 4, we developed a continuous flow synthesis of the URAT1 inhibitor Lesinurad. Our approach afforded a key intermediate in only 55 minutes and 88% yield. Bromination and hydrolysis were also performed under continuous flow, and the optimized process involved five steps (in three separate flow operations) and gave Lesinurad in 68% overall yield. Kidney-type glutaminase [KGA/isoenzyme glutaminase C (GAC)] is becoming an important tumor metabolism target in cancer chemotherapy. In this context, some GJ072 analogs previously synthesized were tested for glutaminase inhibition. These analogs were optimized based on known ligands, and the enzyme allosteric binding site. Our best compound presented IC50 of 9 ?M, although molecular modeling studies indicate that these molecules do not interact with the enzyme in the same manner as other glutaminase inhibitors. In Chapter 6, we describe the synthesis of strained alkynes from dibenzocycloheptenone via fragmentation of 5-hydroxy-1H-tetrazoles. The obtained compounds showed high reactivity and were trapped in situ by an organic azide to generate the corresponding 1,2,3-triazole. Using this methodology, different alkynes were obtained under mild reaction conditions in excellent yields (AU)

• FAPESP's process: 15/18572-6 - Continuous flow synthesis of 3-thio-1,2,4-triazoles and biological evaluation
• Grantee: Mariana Celestina Frojuello Costa Bernstorff Damião
• Support Opportunities: Scholarships in Brazil - Doctorate