Usnic Acid Enaminone-Coupled 1,2,3-Triazoles as Antibacterial and Antitubercular Agents

(+)-Usnic acid, a product of secondary metabolism in lichens, has displayed a broad range of biological properties such as antitumor, antimicrobial, antiviral, anti-inflammatory, and insecticidal activities. Interested by these pharmacological activities and to tap into its potential, we herein present the synthesis and biological evaluation of new usnic acid enaminone-conjugated 1,2,3-triazoles 10-44 as antimycobacterial agents. (+)-Usnic acid was condensed with propargyl amine to give usnic acid enaminone 8 with a terminal ethynyl moiety. It was further reacted with various azides A1-A35 under copper catalysis to give triazoles 10-44 in good yields. Among the synthesized compounds, saccharin derivative 36 proved to be the most active analogue, inhibiting Mycobacterium tuberculosis (Mtb) at an MIC value of 2.5 mu M. Analogues 16 and 27, with 3,4-difluorophenacyl and 2-acylnaphthalene units, respectively, inhibited Mtb at MIC values of 5.4 and 5.3 mu M, respectively. Among the tested Gram-positive and Gram-negative bacteria, the new derivatives were active on Bacillus subtilis, with compounds 18 [3-(trifluoromethyl)phenacyl] and 29 (N-acylmorpholinyl) showing inhibitory concentrations of 41 and 90.7 mu M, respectively, while they were inactive on the other tested bacterial strains. Overall, the study presented here is useful for converting natural (+)-usnic acid into antitubercular and antibacterial agents via incorporation of enaminone and 1,2,3-triazole functionalities.