Synthesis and Biological Evaluation of Aurachin D Analogues as Inhibitors of <i>Mycobacterium tuberculosis</i> Cytochrome <i>bd</i> Oxidase

Abstract

A revised total synthesis of aurachin D (<b>1a</b>), an isoprenoid quinolone alkaloid that targets <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) cytochrome <i>bd</i> (cyt-<i>bd</i>) oxidase, was accomplished using an oxazoline ring-opening reaction. The ring opening enabled access to a range of electron-poor analogues, while electron-rich analogues could be prepared using the Conrad-Limpach reaction. The aryl-substituted and side-chain-modified aurachin D analogues were screened for inhibition of <i>Mtb</i> cyt-<i>bd</i> oxidase and growth inhibition of <i>Mtb</i>. Nanomolar inhibition of <i>Mtb</i> cyt-<i>bd</i> oxidase was observed for the shorter-chain analogue <b>1d</b> (citronellyl side chain) and the aryl-substituted analogues <b>1g</b>/<b>1k</b> (fluoro substituent at C6/C7), <b>1t</b>/<b>1v</b> (hydroxy substituent at C5/C6) and <b>1u</b>/<b>1w</b>/<b>1x</b> (methoxy substituent at C5/C6/C7). Aurachin D and the analogues did not inhibit growth of nonpathogenic <i>Mycobacterium smegmatis</i>, but the citronellyl (<b>1d</b>) and 6-fluoro-substituted (<b>1g</b>) inhibitors from the <i>Mtb</i> cyt-<i>bd</i> oxidase assay displayed moderate growth inhibition against pathogenic <i>Mtb</i> (MIC = 4-8 μM).