Design, Synthesis and anti Mycobacterium tuberculosis activity of new N-oxides derivatives

Abstract

Mycobacterium tuberculosis ( MTB ), the main agent of tuberculosis ( TB ) , is responsible for the annual death of two to three million people worldwide, and global economic losses of about 12 billion dollars a year . Currently , one of the major global concerns is the increasing number of cases of multi - drug resistant ( MDR - TB ) and extensively drug resistant tuberculosis ( XDR - TB) due to the high mortality rate , difficulty of treatment and the high costs involved. It is estimated that , worldwide, the number of people infected with drug-resistant MTB first and second line people is 50 million. Currently , only the bedaquilina drug is approved by the North American agency - the Food and Drug Administration ( FDA ) - for treatment of MDR - TB and XDR - TB , a fact that justifies the need for the discovery of other agents to the therapeutic arsenal. Compounds containing the N-oxide function as furoxan and quinoxaline has been described as prototypes for discovery of new anti-TB drugs. Our research group previously identified furoxan compounds with activity against strains H37Rv and multi - drug resistant clinical isolates . These compounds showed minimum inhibitory concentration values of between 1.02 e 65.4 ¼M in resistant clinical isolates ( MDR - TB and XDR - TB ) and selectivity index between 10.4 and 105 . In addition, they were able to inhibit the activity of efflux pumps MTB, associated with drug resistance. Another class of compounds containing the N-oxide function is the quinoxaline 1,4- dioxide. These heterocyclic compounds , bioredutíveis in hypoxic conditions , are able to increase oxidative stress by increased levels of reactive oxygen species and nitrogen . This class has been described as useful in the treatment not only of MDR - TB and XDR - TB , but also in latent TB . In this context, we summarize and characterize the chemical structure of two series of compounds: furoxan (Series 1 ) and quinoxaline (Series 2 ) designed by molecular hybridization approach. These novel compounds will be further evaluated against MTB using strains H37Rv and MDR clinical isolates (genotypically and phenotypically characterized by the laboratory of mycobacteria FCF - UNESP Araraquara).