Abstract
Tuberculosis continues to be a public health problem in the world, and drug resistance has been a major obstacle in its treatment. Quinoxaline 1,4-di-N-oxide has been proposed as a scaffold to design new drugs to combat this disease. To examine the efficacy of this compound, this study evaluates methyl, ethyl, isopropyl, and n-propyl esters of quinoxaline 1,4-di-N-oxide derivatives in vitro against Mycobacterium tuberculosis (pansusceptible and monoresistant strains). Additionally, the inhibitory effect of esters of quinoxaline 1,4-di-N-oxide on M. tuberculosis gyrase supercoiling was examined, and a stability analysis by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS) was also carried out. Results showed that eight compounds (T-007, T-018, T-011, T-069, T-070, T-072, T-085 and T-088) had an activity similar to that of the reference drug isoniazid (minimum inhibitory concentration (MIC) = 0.12 µg/mL) with an effect on nonreplicative cells and drug monoresistant strains. Structural activity relationship analysis showed that the steric effect of an ester group at 7-position is key to enhancing its biological effects. Additionally, T-069 showed a high stability after 24 h in human plasma at 37 °C.
Highlights
According to the World Health Organization (WHO), tuberculosis (TB) continues to be one of the leading infectious diseases in the world [1]
Tuberculosis compounds of methyl and ethyl ester derivatives were evaluated on M. tuberculosis strain H37Rv
1 -position reduced the activity with a methyl group at R2 -position on the we proposed obtaining two newan series with group an aliphatic substituent
Summary
According to the World Health Organization (WHO), tuberculosis (TB) continues to be one of the leading infectious diseases in the world [1]. First- and second-line drugs are available for the treatment of the disease. Molecules 2018, 23, 1453 and the increasing incidence of resistant strains, the development of new drugs for the treatment of TB is urgently needed. Quinoxalines are a series of compounds with diverse biological activities that have what is considered a privileged structure [3]. Carta and collaborators proposed quinoxaline 1,4-di-N-oxide as a scaffold for the development of new antituberculosis drugs [4]. Monge’s research group reported a series of quinoxaline 1,4-di-N-oxide derivatives with excellent antituberculosis activity in resistant and multiresistant strains of Mycobacterium tuberculosis (M. tuberculosis) as well as nonreplicative cells in in vitro and in vivo models [5,6]. The change of the 2-carbonitrile by the 2-carboxylate group increased the solubility of the compounds and their biological activity [7]
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