DESIGN AND SYNTHESIS OF 4-(HYDROXY-(1H-1,2,3-TRIAZOL-4-YL))METHYL PHENOL DERIVATIVES AS ANTITUBERCULOSIS AGENTS

Abstract

The design and synthesis of 4-(hydroxy-(1H-1,2,3-triazol-4-yl))methyl phenol derivatives (compounds 7a-m, 8) were developed and evaluated for their antituberculosis activities. The design strategy was based on combination of scaffold structures of the chemical compound from Alpinia galangal rhizome possessed anti-tubercular activity, 1ʹ-Acetoxychavicol acetate (ACA) and 1,2,3-triazole derivatives to get the target compounds. Compounds 7a-m, 8 were synthesized in 4 steps i.e. (1) The protection of hydroxyl group of 4-hydroxybenzaldehyde with t-butyldimethylsilyl group, (2) Grignard reaction between protected hydroxybenzaldehyde and ethynyl magnesium bromide to get protected hydroxypropynyl phenol, (3) click reactions between the alkynes and various aryl, aralkyl, and alkyl azides in mild condition with the aid of copper (I) catalyst, and (4) deprotections of the hydroxyl groups. The click reactions were performed not only under conventional way at room temperature but also the microwave irradiation condition to accelerate the chemical reactions. A one-pot two-step synthesis of these compounds under microwave irradiation has also performed by (1) microwave-assisted synthesis involved in situ generating of corresponding azides without purification to avoid explosive nature of azide extraction procedure, and (2) coupling reactions with terminal alkyne to generate 1,2,3-triazole derivatives, 6g-m. In the one-pot two-step procedure, the percent yields from microwave-assisted reactions of all azides, 5g-m were ranged from 82.54% to 96.18%. This method provided the comparable percent yields with conventional method. In addition to one-pot two-step, all microwave-assisted reactions offered better yields of the desired products 6a-m within short period of time (5 to 15 min) than conventional method at room temperature for overnight. Therefore, it was concluded that microwave-assisted click reaction synthesis strategy is simple, practical, efficient, safe, eco-friendly, and provided the newly synthesized compounds in a short reaction time with good yields when compared with conventional one. The overall yields of compounds 7a-m ranged from 25.99% to 48.73% and compound 8 was obtained as 27.33% overall yield. The structures of desired compounds were elucidated by FT IR, 1H NMR, 13C NMR and mass spectroscopic methods. Those synthesized compounds 7a-m and 8 were evaluated for antituberculosis activities by agar-dilution method and it was found that they possessed lower activities than control drug kanamycin. The MIC values of compounds 7a-m displayed 80 µg/mL when compared with kanamycin with MIC value 10 µg/mL on 20 clinical isolates and MTB H37Rv reference strains (ATCC 27294).

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