Pre-clinical evaluation of quinoxaline-derived chalcones in tuberculosis

Abstract

New effective compounds for tuberculosis treatment are needed. This study evaluated the effects of a series of quinoxaline-derived chalcones against laboratorial strains and clinical isolates of M. tuberculosis. Six molecules, namely N5, N9, N10, N15, N16, and N23 inhibited the growth of the M. tuberculosis H37Rv laboratorial strain. The three compounds (N9, N15 and N23) with the lowest MIC values were further tested against clinical isolates and laboratory strains with mutations in katG or inhA genes. From these data, N9 was selected as the lead compound for further investigation. Importantly, this chalcone displayed a synergistic effect when combined with moxifloxacin. Noteworthy, the anti-tubercular effects of N9 did not rely on inhibition of mycolic acids synthesis, circumventing important mechanisms of resistance. Interactions with cytochrome P450 isoforms and toxic effects were assessed in silico and in vitro. The chalcone N9 was not predicted to elicit any mutagenic, genotoxic, irritant, or reproductive effects, according to in silico analysis. Additionally, N9 did not cause mutagenicity or genotoxicity, as revealed by Salmonella/microsome and alkaline comet assays, respectively. Moreover, N9 did not inhibit the cytochrome P450 isoforms CYP3A4/5, CYP2C9, and CYP2C19. N9 can be considered a potential lead molecule for development of a new anti-tubercular therapeutic agent.

Quinoxaline Moiety: A Potential Scaffold against Mycobacterium tuberculosis

“…The efficacy of quinoxaline-derived chalcones has recently been confirmed by the preclinical evaluation of a new series of derivatives. Of the synthesized compounds, six molecules inhibited Mycobacterium tuberculosis growth, with the MIC ranging from 3.13 to 12.5 µg/mL [ 47 ]. Further investigations on the lead compound ( 20 ) also demonstrated that this derivative exhibited synergistic effect with moxifloxacin and did not cause mutagenicity or genotoxicity ( Table 6 ).…”

“…In addition, the modification of nalidixic acid, a representative of the quinolone and fluoroquinolone antibiotics which are an essential component of treatment strategies for drug-resistant TB [1], on its -COOH group led to the formation of original quinoxaline The efficacy of quinoxaline-derived chalcones has recently been confirmed by the preclinical evaluation of a new series of derivatives. Of the synthesized compounds, six molecules inhibited Mycobacterium tuberculosis growth, with the MIC ranging from 3.13 to 12.5 µg/mL [47]. Further investigations on the lead compound (20) also demonstrated that this derivative exhibited synergistic effect with moxifloxacin and did not cause mutagenicity or genotoxicity (Table 6).…”

Chalcone: A Promising Bioactive Scaffold in Medicinal Chemistry

“…Streptomycin, pyrazinamide, and rifampicin are just a few of the medications created to treat TB [ 95 ]. Many chalcone analogs have been tested for anti-tubercular activity, and there have been reports of chalcones with intense anti-tubercular activity [ 96 , 97 , 98 ] ( Figure 3 ). Quinoline-based chalcone 51 showed anti-tubercular activity against the M. tuberculosis H37Rv strain, with better MIC values (10–80 µM) than the standard drug rifampicin [ 99 ].…”

Effects of tafenoquine against active, dormant and resistant Mycobacterium tuberculosis

“…Mycobacterial suspensions were cultivated and diluted in 7H9 medium at an optical density (OD 595nm ) of 0.001 for M. smegmatis and 0.006 for M. tuberculosis, and 100 μL were added to each well. Following incubation at 37 • C for 24 h for M. smegmatis, or 7 days for M. tuberculosis, 30 μL of a sterile resazurin solution (0.02%) were added to the plates and the results were evaluated after 24 h for M. smegmatis, or 48 h for M. tuberculosis [10,11]. MICs were considered as the lowest drug concentration that prevented a color change from blue (resazurin) to pink (resorufin).…”

“…Combinations of tafenoquine with isoniazid, rifampicin, ethambutol, moxifloxacin, streptomycin and mefloquine were performed by a checkerboard assay in a two-drug association scheme, by using the REMA colorimetric method as a growth indicator, as previously reported [11]. Briefly, drugs were diluted in 7H9 + ADC to obtain concentration ranges in microplates of 30-0.47 μM for isoniazid, 0.25-0.004 μM for rifampicin, 60-0.94 μM for ethambutol, 1.5-0.023 μM for moxifloxacin, 8-0.125 μM for streptomycin, 160-2.5 μM for mefloquine, and 80-1.25 μM for tafenoquine.…”