Derivatives of 3-(1H-1,2,3-triazol-1-yl)quinoline-2,4(1H,3H)-dione unsubstituted on quinolone nitrogen atom, which are available by the previously described four step synthesis starting from aniline, were exploited as intermediates in obtaining the title compounds. The procedure involves the introduction of propargyl group onto the quinolone nitrogen atom of mentioned intermediates by the reaction of them with propargyl bromide in N,N-dimethylformamide (DMF) in presence of a potassium carbonate and the subsequent formation of a second triazole ring by copper catalyzed cyclisation reaction with azido compounds. The products were characterized by ¹H, 13C and 15N NMR spectroscopy. The corresponding resonances were assigned on the basis of the standard 1D and gradient selected 2D NMR experiments (¹H⁻¹H gs-COSY, ¹H⁻13C gs-HSQC, ¹H⁻13C gs-HMBC) with ¹H⁻15N gs-HMBC as a practical tool to determine 15N NMR chemical shifts at the natural abundance level of 15N isotope.
In this study, a 50-membered library of substituted 4-hydroxyquinolin-2(1H)-ones and two closely related analogues was designed, scored in-silico for drug likeness and subsequently synthesized. Thirteen derivatives, all sharing a common 3-phenyl substituent showed minimal inhibitory concentrations against Mycobacterium tuberculosis H37Ra below 10 μM and against Mycobacterium bovis AN5A below 15 μM but were inactive against faster growing mycobacterial species. None of these selected derivatives showed significant acute toxicity against MRC-5 cells or early signs of genotoxicity in the Vitotox™ assay at the active concentration range. The structure activity study relation provided some insight in the further favourable substitution pattern at the 4-hydroxyquinolin-2(1H)-one scaffold and finally 6-fluoro-4-hydroxy-3-phenylquinolin-2(1H)-one (38) was selected as the most promising member of the library with a MIC of 3.2 μM and a CC50 against MRC-5 of 67.4 μM.
- MeSH
- Antitubercular Agents chemical synthesis chemistry pharmacology MeSH
- Quinolones chemical synthesis chemistry pharmacology MeSH
- Humans MeSH
- Microbial Sensitivity Tests MeSH
- Molecular Structure MeSH
- Mycobacterium bovis drug effects growth & development MeSH
- Mycobacterium tuberculosis drug effects growth & development MeSH
- Drug Design * MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
N-(α-ketoacyl)anthranilic acids reacted with phenylhydrazinium chloride in boiling acetic acid to afford 2-(indol-2-carboxamido)benzoic acids in good to excellent yields and 2-indolyl-3,1-benzoxazin-4-ones as by-products. The formation of the latter products could easily be suppressed by a hydrolytic workup. Alternatively, by increasing the reaction temperature and/or time, 2-indolyl-3,1-benzoxazin-4-ones can be obtained exclusively. Optimisations of the reaction conditions as well as the scope and the course of the transformations were investigated. The products were characterized by (1)H, (13)C and (15)N NMR spectroscopy. The corresponding resonances were assigned on the basis of the standard 1D and gradient selected 2D NMR experiments ((1)H-(1)H gs-COSY, (1)H-(13)C gs-HSQC, (1)H-(13)C gs-HMBC) with (1)H-(15)N gs-HMBC as a practical tool to determine (15)N NMR chemical shifts at the natural abundance level of (15)N isotope.
A comparative study for selective glucosylation of N-unsubstituted 4-hydroxyquinolin-2(1H)-ones into 4-(tetra-O-acetyl-beta-D-glucopyranosyloxy)quinolin-2(1H)-ones is reported. Four glycosyl donors including tetra-O-acetyl-alpha-D-glucopyranosyl bromide, beta-D-glucose pentaacetate, glucose tetraacetate and tetra-O-acetyl-alpha-D-glucopyranosyl trichloroacetimidate were tested, along with different promoters and reaction conditions. The best results were obtained with tetra-O-acetyl-alpha-D-glucopyranosyl bromide with Cs(2)CO(3) in CH(3)CN. In some cases the 4-O-glucosylation of the quinolinone ring was accompanied by 2-O-glucosylation yielding the corresponding 2,4-bis(tetra-O-acetyl-beta-D-glucopyranosyloxy)quinoline. Next, 4-(tetra-O-acetyl-beta-D-glucopyranosyloxy)quinolin-2(1H)-ones were deacetylated into 4-(beta-D-glucopyranosyloxy)quinolin-2(1H)-ones with Et(3)N in MeOH. In some instances the deacetylation was accompanied by the sugar-aglycone bond cleavage. Structure elucidation, complete assignment of proton and carbon resonances as well as assignment of anomeric configuration for all the products under investigation were performed by 1D and 2D NMR spectroscopy.
