Anti-Mycobacterium tuberculosis Activity of Esters of Quinoxaline 1,4-Di-N-Oxide

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.

N-Pyrazinoyl Substituted Amino Acids as Potential Antimycobacterial Agents—the Synthesis and Biological Evaluation of Enantiomers

“…In fact, the majority of methyl esters (represented by circles) are located below the activity cut-off in Figure 3, with the exception of highly lipophilic compounds, e.g., PC-l-OBn-Ser-Me, PC-d/l-Pgl-Me. The effect of growing activity with the lengthening of the ester carbon chain had previously also been observed in derivatives of POA [21,23] or other antimycobacterial compounds [55] and it has been attributed to the above-mentioned better penetration inside the mycobacteria. However, as discussed later, other effects-as stereochemistry-seem to play an important role in structure-activity relationships in our compounds.…”

Quinoxaline Moiety: A Potential Scaffold against Mycobacterium tuberculosis

“…Additionally, the inhibitory effect of methyl, ethyl, isopropyl, and n -propyl esters of quinoxaline 1,4-di- N -oxide on Mycobacterium tuberculosis was assessed [ 62 ]. Of the 18 original esters of the 1,4-di- N -oxide synthesized, eight derivatives showed similar activity to that of isoniazid taken as reference ( Table 12 ).…”

“…Compounds bearing a thioether linkage and a sterically bulky aromatic group at the terminal side chain on the C2 position are the best representatives of these original series. Additionally, the inhibitory effect of methyl, ethyl, isopropyl, and n-propyl esters of quinoxaline 1,4-di-N-oxide on Mycobacterium tuberculosis was assessed [62]. Of the 18 original esters of the 1,4-di-N-oxide synthesized, eight derivatives showed similar activity to that of isoniazid taken as reference (Table 12).…”

“…Of the 18 original esters of the 1,4-di-N-oxide synthesized, eight derivatives showed similar activity to that of isoniazid taken as reference (Table 12). Additionally, the inhibitory effect of methyl, ethyl, isopropyl, and n-propyl esters of quinoxaline 1,4-di-N-oxide on Mycobacterium tuberculosis was assessed [62]. Of the 18 original esters of the 1,4-di-N-oxide synthesized, eight derivatives showed similar activity to that of isoniazid taken as reference (Table 12).…”

Organic synthesis and anti-influenza A virus activity of cyclobakuchiols A, B, C, and D

“…Sekine et al reported that the presence and difference of the isopropyl group in a ring of p -menthane monoterpenoids affected termite mortality [ 37 ]. Several studies have reported that the isopropyl group in the compound has biological effects, such as anti-mycobacterial [ 38 , 39 ], anti-amoebic [ 40 ], and anticancer [ 39 ] activities. Therefore, the isopropyl group arrangement is important for the pharmacological activity of the compounds.…”