Synthesis, functionalization and bioprospection of heterocyclic fragments based on underexplored heteroaromatic cores

Author(s)

Fernando Fumagalli

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC)
• Defense date: 2019-01-18

Examining board members

Flavio da Silva Emery; Giuliano Cesar Clososki; Daniela Barretto Barbosa Trivella; Paulo Cezar Vieira

• Advisor: Flavio da Silva Emery

Abstract

The increasing knowledge about the macromolecular mechanisms of different diseases allowed the identification of several therapeutic targets over the years. However, the development of drugs to these targets did not follow the same rate. In addition, the introduction of innovative frameworks in new drugs is unsatisfactory. In this scenario, we aim to introduce new useful fragments for application in the development of innovative bioactive compounds, by charting the medicinal chemical space of heteroaromatic compounds. For this purpose, two approaches were evaluated: 1) Develop a feasible synthetic strategy to obtain two new heteroaromatic cores (Cores 20 and 22); 2) Develop a new synthetic route to obtain the furo[2,3-b]pyridine core, chemical elaborate it and screening it against Mycobacterium tuberculosis. For the first approach (Chapter 1), one aromatization step is needed to obtain core 22 (pyridazine-pyridone). On the other hand, after evaluating several synthetic strategies, it was possible to obtain core 20 (pyrido-pyridazinone) in low yields. Therefore, a synthetic route optimization and a complete characterization are still required for 20. An unexpected result in attempt to obtain core 20, resulted in a new synthetic route to furo[2-3-b]pyridine, C-2 and C- 3 substituted, that was explored in the second approach (Chapter 2). Using mild and metal-free conditions, it was possible to obtain various furopyridines with different substitutions patterns at C-2 (aryl or alkyl) using either acyl chlorides or anhydrides. In addition, the furan moiety in this core, showed to be stable under the C-3-ester hydrolysis, however, in solution, hydrazine opens the furan ring to form a new pyrazolone ring. Regarding the chemical reactivity of the pyridine moiety in the furopyridine core, it was possible to perform the C-H borylation followed by Suzuki coupling reaction at the C-5 position. Furthermore, radical arylation at C-4 and direct fluorination at C-6 had not satisfactory yields. Therefore, the reactivity of the furopyridine N-oxide derivative with nucleophiles using different activating agents was studied. Using triflic anhydride, as an activating agent, it was possible to iodinate at C-5, brominated at C-4 and hydroxylated at C-4 and C-6. Using PyBroP, as an activator, it was possible to perform amination reactions at positions C-4, C-5 and C-6. In the end, our in-house library of furopyridines was screened against Mycobacterium tuberculosis and it was found a promising selective bioactive compound against different multidrug-resistant strains of this mycobacteria. Furthermore, this compound is a fragment, which will allow future structural optimization. (AU)

• FAPESP's process: 15/06588-5 - Development of library of heterocyclic fragments based on new heteroaromatic cores
• Grantee: Fernando Fumagalli
• Support Opportunities: Scholarships in Brazil - Doctorate