Synthesis and Biological Evaluation of Aurachin D Analogues as Inhibitors of Mycobacterium tuberculosis Cytochrome bd Oxidase.

A revised total synthesis of aurachin D ( 1a ), an isoprenoid quinolone alkaloid that targets Mycobacterium tuberculosis ( Mtb ) cytochrome bd (cyt- bd ) 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 Mtb cyt- bd oxidase and growth inhibition of Mtb . Nanomolar inhibition of Mtb cyt- bd oxidase was observed for the shorter-chain analogue 1d (citronellyl side chain) and the aryl-substituted analogues 1g / 1k (fluoro substituent at C6/C7), 1t / 1v (hydroxy substituent at C5/C6) and 1u / 1w / 1x (methoxy substituent at C5/C6/C7). Aurachin D and the analogues did not inhibit growth of nonpathogenic Mycobacterium smegmatis , but the citronellyl ( 1d ) and 6-fluoro-substituted ( 1g ) inhibitors from the Mtb cyt- bd oxidase assay displayed moderate growth inhibition against pathogenic Mtb (MIC = 4-8 μM).