Abstract
A series of novel 7-oxo-7H-thiazolo[3,2-b]-1,2,4-triazine-2-carboxylic acid derivatives was synthesized in good yields by a multi-step procedure that included the generation of the S-alkylated derivatives from 6-substituted arylmethyl-3-mercapto-1,2,4-triazin-5-ones with ethyl 2-chloroacetoacetate, intramolecular cyclization with microwave irradiation, hydrolysis and amidation. All of the target compounds were fully characterized through 1H-NMR, 13C-NMR and HRMS spectra. The intramolecular cyclization occurred regioselectively at the N2-position of 1,2,4-triazine ring, which was confirmed by compound 3e using single-crystal X-ray diffraction analysis. The antibacterial and antitubercular activities of the target compounds were evaluated. Compared with Ciprofloxacin and Rifampicin, compounds 5d, 5f and 5g containing the terminal amide fragment exhibited broad spectrum antibacterial activity, and carboxylic acid derivatives or its corresponding ethyl esters had less effect on antibacterial properties. The most potent compound 5f also displayed excellent in vitro antitubercular activity against Mycobacterium smegmatis (minimum inhibitory concentration (MIC) = 50 μg/mL) and better growth inhibition activity of leucyl-tRNA synthetase (78.24 ± 4.05% at 15 μg/mL).
Highlights
Since the first discovery of penicillin by Alexander Fleming in 1928, many new antibacterial drugs have been used clinically to treat bacterial pathogen infection
A series of new 7-oxo-7H-thiazolo[3,2-b]-1,2,4-triazine-2-carboxylic acid derivatives was synthesized starting from the 6-substituted arylmethyl-3-mercapto-1,2,4-triazin-5-ones and ethyl
The higher nucleophilicity at the N2 position of 1,2,4-triazine ring led to the regioselectivity of the cyclization step, and the selective annulation was confirmed by the single-crystal X-ray crystallographic structure of compound
Summary
Since the first discovery of penicillin by Alexander Fleming in 1928, many new antibacterial drugs have been used clinically to treat bacterial pathogen infection. Heterocycle-fused thiazole derivatives have been synthesized and investigated with the aim of finding effective antimicrobial agents [6]. In this respect, many thieno[2,3-d]pyrimidinones have been reported as potent antibacterial and antitubercular agents [7,8], Molecules 2020, 25, 1307; doi:10.3390/molecules25061307 www.mdpi.com/journal/molecules structure–activity relationships of this series of compounds reported in the literature demonstrated that the presence of a flexible side chain containing a phenyl ring was critical for activity
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