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

  • ACS Med Chem Lett. 2022 Sep 26;13(10):1663-1669. doi: 10.1021/acsmedchemlett.2c00401.
Aggie Lawer  1 ,  Chelsea Tyler  1 ,  Kiel Hards  2 ,  Laura M Keighley  2 ,  Chen-Yi Cheung  2 ,  Fabian Kierek  1 ,  Simon Su  1 ,  Siddharth S Matikonda  1 ,  Tyler McInnes  3 ,  Joel D A Tyndall  1 ,  Kurt L Krause  3 ,  Gregory M Cook  2  4 ,  Allan B Gamble  1
Affiliations
  • 1. School of Pharmacy, University of Otago, Dunedin 9054, New Zealand.
  • 2. Department of Microbiology and Immunology, University of Otago, Dunedin 9054, New Zealand.
  • 3. Department of Biochemistry, University of Otago, Dunedin 9054, New Zealand.
  • 4. Maurice Wilkins Centre for Molecular Biodiscovery, University of Otago, Dunedin 9054, New Zealand.
PMID: 36262396 DOI: 10.1021/acsmedchemlett.2c00401
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).

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