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

Kawaljit Singh; Gurminder Kaur; Petrus Siningu Shanika; Godwin Akpeko Dziwornu; John Okombo; Kelly Chibale

doi:10.1016/j.bmc.2020.115530

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. Epub 2020 Apr 25.

Authors

Kawaljit Singh¹, Gurminder Kaur², Petrus Siningu Shanika³, Godwin Akpeko Dziwornu³, John Okombo³, Kelly Chibale⁴

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: [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Bacterial Agents / chemistry*
Anti-Bacterial Agents / pharmacology
Cricetulus
Drug Evaluation, Preclinical
Drug Repositioning
Fusidic Acid / chemistry*
Fusidic Acid / pharmacology
Humans
Microbial Sensitivity Tests
Mycobacterium / drug effects*
Structure-Activity Relationship
Tuberculosis / drug therapy*

Substances

Anti-Bacterial Agents
Fusidic Acid