Design, synthesis and anti-Mycobacterium tuberculosis evaluation of new benzofuroxan and nitroimidazooxazine derivatives useful for the treatment of multiresistant tuberculosis

Author(s)

Guilherme Felipe dos Santos Fernandes

• Document type: Doctoral Thesis
• Press: Araraquara. 2021-02-16.
• Institution: Universidade Estadual Paulista (Unesp). Instituto de Química. Araraquara
• Defense date: 2021-02-01
• Advisor: Jean Leandro dos Santos

Abstract

Although advances have been made in recent years for the treatment of tuberculosis (TB), enormous challenges such as the emergence of resistant strains make it increasingly difficult to meet the goals of eliminating the disease. According to the World Health Organization (WHO), in 2018, about 10 million new cases were reported and 1.2 million deaths were recorded. Of the new cases, 484,000 patients had multidrug-resistant TB (MDR-TB) or extensively drugresistant TB (XDR-TB) making treatment even more time-consuming and challenging. In the past, intense efforts made by our research group have enabled, through a national and international research network, the discovery of prototypes with potent anti-Mycobacterium tuberculosis (Mtb) activity, including against MDR-TB and XDR-TB strains. Of these, the benzofuroxan derivative named BZ8 is highlighted, a protein synthesis inhibitor, which during the treatment of animals infected with Mtb reduced the colony-forming units in the animals' lungs to zero, an effect, not observed for any of the drugs currently available. Since then, structure-activity-relationship studies have allowed the identification of structural patterns necessary to maintain anti-Mtb activity. In this thesis, we carried out the synthesis and biological evaluation of two new series of compounds designed from BZ8. The 1st series included 27 new compounds. Most compounds showed some degree of anti-Mtb activity. The compounds (GF1), (GF3), (GF10), (GF12), (GF14), (GF16) and (GF19) were the most promising in the series, with minimum inhibitory concentration values (MIC90) below 3.0 µM. In addition, the compounds did not show cytotoxicity in the cell lines evaluated. The most promising compounds were selected for evaluation against MDR-TB strains. In general, compounds showed MIC90 values below 5 µM. The compounds (GF3) and (GF16) were particularly the most promising within the series with MIC90 values below 1 µM for most of the MDR-Mtb strains tested. The 2nd series covered 10 new nitroimidazooxazine derivatives. The compounds did not show cytotoxicity in the cell lines evaluated. Biological tests to determine the anti-Mtb activity of 2nd sieres compounds are underway. In conclusion, the new benzofuroxan derivatives identified in this work are presented as a new class of promising compounds useful for the treatment of MDR-TB and XDR-TB. (AU)

• FAPESP's process: 16/09502-7 - Design, synthesis and antitubercular activity of new oxazolidinones useful for the treatment of multidrug-resistant tuberculosis
• Grantee: Guilherme Felipe dos Santos Fernandes
• Support Opportunities: Scholarships in Brazil - Doctorate