2. Academic Validation
  3. Structure-activity relationship analyses of fusidic acid derivatives highlight crucial role of the C-21 carboxylic acid moiety to its anti-mycobacterial activity

Structure-activity relationship analyses of fusidic acid derivatives highlight crucial role of the C-21 carboxylic acid moiety to its anti-mycobacterial activity

  • Bioorg Med Chem. 2020 Jul 1;28(13):115530. doi: 10.1016/j.bmc.2020.115530.
Kawaljit Singh 1,  Gurminder Kaur 2,  Petrus Siningu Shanika 3,  Godwin Akpeko Dziwornu 3,  John Okombo 3,  Kelly Chibale 4
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa; Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch 7701, South Africa; South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa.
  • 2 Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa; Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch 7701, South Africa.
  • 3 Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
  • 4 Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa; Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch 7701, South Africa; South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa; Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa. Electronic address: kelly.chibale@uct.ac.za.
PMID: 32362386 DOI: 10.1016/j.bmc.2020.115530
Abstract

Fusidic acid (FA) is a potent congener of the fusidane triterpenoid class of Antibiotics. Structure-activity relationship (SAR) studies suggest the chemical structure of FA is optimal for its Antibacterial activity. SAR studies from our group within the context of a drug repositioning approach in tuberculosis (TB) suggest that, as with its Antibacterial activity, the C-21 carboxylic acid group is indispensable for its anti-mycobacterial activity. Further studies have led to the identification of 16-deacetoxy-16β-ethoxyfusidic acid (58), an analog which exhibited comparable activity to FA with an in vitro MIC99 value of 0.8 µM. Preliminary SAR studies around the FA scaffold suggested that the hydrophobic side chain at C-20, like the C-11 OH group, was required for activity. The C-3 OH group, however, can be functionalized to obtain more potent compounds.

Keywords

Anti-mycobacterial activity; Bioisosteres; Cytotoxicity; Fusidic acid.

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