Synthesis and Biological Evaluation of Aurachin D Analogues as Inhibitors of <i>Mycobacterium tuberculosis</i> Cytochrome <i>bd</i> Oxidase
Aggie Lawer, Chelsea Tyler, Kiel Hards, Laura M. Keighley, Chen‐Yi Cheung, Fabian Kierek, Simon Su, Siddharth S. Matikonda, Tyler McInnes, Joel D. A. Tyndall, Kurt L. Krause, Gregory M. Cook, Allan B. Gamble
Abstract
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).