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Synthesis and Biological Evaluation of Aurachin D Analogues as Inhibitors of Mycobacterium tuberculosis Cytochrome bd Oxidase.
Lawer, Aggie; Tyler, Chelsea; Hards, Kiel; Keighley, Laura M; Cheung, Chen-Yi; Kierek, Fabian; Su, Simon; Matikonda, Siddharth S; McInnes, Tyler; Tyndall, Joel D A; Krause, Kurt L; Cook, Gregory M; Gamble, Allan B.
Afiliação
  • Lawer A; School of Pharmacy, University of Otago, Dunedin 9054, New Zealand.
  • Tyler C; School of Pharmacy, University of Otago, Dunedin 9054, New Zealand.
  • Hards K; Department of Microbiology and Immunology, University of Otago, Dunedin 9054, New Zealand.
  • Keighley LM; Department of Microbiology and Immunology, University of Otago, Dunedin 9054, New Zealand.
  • Cheung CY; Department of Microbiology and Immunology, University of Otago, Dunedin 9054, New Zealand.
  • Kierek F; School of Pharmacy, University of Otago, Dunedin 9054, New Zealand.
  • Su S; School of Pharmacy, University of Otago, Dunedin 9054, New Zealand.
  • Matikonda SS; School of Pharmacy, University of Otago, Dunedin 9054, New Zealand.
  • McInnes T; Department of Biochemistry, University of Otago, Dunedin 9054, New Zealand.
  • Tyndall JDA; School of Pharmacy, University of Otago, Dunedin 9054, New Zealand.
  • Krause KL; Department of Biochemistry, University of Otago, Dunedin 9054, New Zealand.
  • Cook GM; Department of Microbiology and Immunology, University of Otago, Dunedin 9054, New Zealand.
  • Gamble AB; Maurice Wilkins Centre for Molecular Biodiscovery, University of Otago, Dunedin 9054, New Zealand.
ACS Med Chem Lett ; 13(10): 1663-1669, 2022 Oct 13.
Article em En | MEDLINE | ID: mdl-36262396
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).

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2022 Tipo de documento: Article