Design, synthesis and anti-Mycobacterium tuberculosis evaluation of new N-oxides derivatives

Author(s)

Guilherme Felipe dos Santos Fernandes

• Document type: Master's Dissertation
• Press: Araraquara. 2016-07-04.
• Institution: Universidade Estadual Paulista (Unesp). Faculdade de Ciências Farmacêuticas. Araraquara
• Defense date: 2016-06-10
• Advisor: Jean Leandro dos Santos

Abstract

Mycobacterium tuberculosis, the main agent of tuberculosis, is responsible for the annual death of 1.5 million people worldwide. Currently, one of the major global concerns is the increasing number of cases of multi drug-resistant tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB) due to the high mortality rate, difficulty of treatment and the high costs involved. Bedaquiline was the last drug approved by the north american agency - Food and Drug Administration - to treat MDR-TB and XDR-TB after a gap of more 50 years without new drugs. All these facts justify the need for discovery of new drugs for treatment. Isoniazid is one of the main first line drugs used to treat tuberculosis. Compounds containing the N-oxide functions, such as furoxans and quinoxalines, have been described as prototypes for discovery novel anti-TB drugs. The aim of this work was the planning, synthesis and biological evaluation of novel hybrid molecules between furoxan and INH (Series 1) and quinoxaline and INH (Series 2). In this context, we have synthesized and characterized eleven hybrid molecules of series 1 and seven molecules of series 2. Moreover, we have evaluated the anti-TB activity of these molecules against MTB H37Rv strains and multidrug-resistant clinical isolates. The compounds exhibited minimum inhibitory concentration ranging from 1,03 to 101 µM. Four molecules from series 1 have shown promising antitubercular activity and were evaluated regarding their cytotoxicity against J774A.1 and MRC-5 cells. The molecules of series 2 were not considered promising due to their low selectivity index values. The selectivity index of these four molecules ranged from 3.78 to 52.74 in MRC-5 cells and 1,25 - 34,78 in J774A.1 cells. Furthermore, the molecules have shown activity against several multidrug-resistant strains, with MIC values ranging between 1.44 – 23.53 µM. The furoxan derivatives were capable to release nitric oxide at levels ranging from 0,16 - 44,23%. It was observed that the antitubercular activity of these molecules seems to be related in part to the nitric oxide release. The most promising compound of series 1 was stable at different pHs (5.0 and 7.4) evaluated through chemical stability studies. Furthermore, it was characterized that logPo/w values from both series ranged from 0.7 to 2.9. In conclusion, the new furoxan derivatives have shown promising antitubercular activity useful for the treatment of tuberculosis, including MDR-TB. (AU)

• FAPESP's process: 14/02240-1 - Design, Synthesis and anti Mycobacterium tuberculosis activity of new N-oxides derivatives
• Grantee: Guilherme Felipe dos Santos Fernandes
• Support Opportunities: Scholarships in Brazil - Master