Synthesis and exploration of multiple synthetic vectors in \future heteroaromatic\ fragments

Author(s)

Paulo Eliandro da Silva Júnior

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC)
• Defense date: 2018-08-21

Examining board members

Flavio da Silva Emery; Giuliano Cesar Clososki; Marcio Vinícius Bertacine Dias; Daniel Fabio Kawano; Kleber Thiago de Oliveira

• Advisor: Flavio da Silva Emery

Abstract

One of the remaining challenges for synthetic chemistry is the regioselective functionalization of structurally complex polar molecules, such as hydroxy-naphthyridine and pyrazole-hydroxypyridine fragments. Thus, in this project synthetic methods were studied to obtain and functionalize fragments based on the structure of \"heterocycles of the future\", for development of a small library of compounds and medicinal chemistry studies. Methods of synthesis on multigrams scale of hydroxy-naphthyridine and pyrazole-hydroxypyridine have been developed, as well as derivatives obtained by modification and substitution of starting materials. A reactivity study was carried out in order to identify synthetically accessible vectors for obtaining of a compounds collection. There were applied two transition metal free methods for arylation of the hydroxypyridine moiety of the fragments. The first method involved aryl hydrazines as the source of the aryl radical which led to the formation of aryl derivatives in moderate yields without the need for polar groups protection. The second method involved a solar flux reactor and arylazo sulfones as source of aryl radicals, from which it was possible to obtain a series of aryl derivatives. Functionalization of the pyrazole moiety of the pyrazole-hydroxypyridine heterocycle involved the base-mediated sulfonyl N-C migration which resulted in the production of a series of biarylsulfone derivatives. The obtained compounds were studied for the development of antiviral and antipsychotic activities. Biarylsulfones were tested against the human T-cell leukemia virus type 1 (HTLV-1), and showed similar activity to standards. In another approach, an analog of aripiprazole was developed by scaffold hopping, which presented promising results in vivo for antipsychotic activity. Finally, combining simple and innovative methods, this project provides tools to practitioners of medicinal chemistry of fragments, as well as proves the usefulness of the studied fragments for application in the process of drug discovery (AU)

• FAPESP's process: 13/26485-0 - Development of new ligands for Peroxisome Proliferator-Activated Receptor by an approach of fragment based drug discovery
• Grantee: Paulo Eliandro da Silva Júnior
• Support Opportunities: Scholarships in Brazil - Doctorate