Usnic Acid Enaminone-Coupled 1,2,3-Triazoles as Antibacterial and Antitubercular Agents.
Bangalore PK, Vagolu SK, Bollikanda RK, Veeragoni DK, Choudante PC, Misra S, Sriram D, Sridhar B, Kantevari S.
(+)-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 <b>10</b>-<b>44</b> as antimycobacterial agents. (+)-Usnic acid was condensed with propargyl amine to give usnic acid enaminone <b>8</b> with a terminal ethynyl moiety. It was further reacted with various azides <b>A1</b>-<b>A35</b> under copper catalysis to give triazoles <b>10</b>-<b>44</b> in good yields. Among the synthesized compounds, saccharin derivative <b>36</b> proved to be the most active analogue, inhibiting <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) at an MIC value of 2.5 μM. Analogues <b>16</b> and <b>27</b>, with 3,4-difluorophenacyl and 2-acylnaphthalene units, respectively, inhibited <i>Mtb</i> at MIC values of 5.4 and 5.3 μM, respectively. Among the tested Gram-positive and Gram-negative bacteria, the new derivatives were active on <i>Bacillus subtilis</i>, with compounds <b>18</b> [3-(trifluoromethyl)phenacyl] and <b>29</b> (N-acylmorpholinyl) showing inhibitory concentrations of 41 and 90.7 μM, 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.