Synthesis and biological characterisation of ester and amide derivatives of fusidic acid as antiplasmodial agents

Marlene Espinoza-Moraga; Kawaljit Singh; Mathew Njoroge; Gurminder Kaur; John Okombo; Carmen De Kock; Peter J Smith; Sergio Wittlin; Kelly Chibale

doi:10.1016/j.bmcl.2016.11.077

Synthesis and biological characterisation of ester and amide derivatives of fusidic acid as antiplasmodial agents

Bioorg Med Chem Lett. 2017 Feb 1;27(3):658-661. doi: 10.1016/j.bmcl.2016.11.077. Epub 2016 Nov 25.

Authors

Marlene Espinoza-Moraga¹, Kawaljit Singh¹, Mathew Njoroge¹, Gurminder Kaur¹, John Okombo¹, Carmen De Kock², Peter J Smith², Sergio Wittlin³, Kelly Chibale⁴

Affiliations

¹ Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
² Division of Clinical Pharmacology, Faculty of Health Sciences, University of Cape Town, K45, OMB, Groote Schuur Hospital, Observatory, 7925, South Africa.
³ Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland; University of Basel, 4002 Basel, Switzerland.
⁴ Department of Chemistry, 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 Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa. Electronic address: Kelly.Chibale@uct.ac.za.

PMID: 28012840
DOI: 10.1016/j.bmcl.2016.11.077

Abstract

A series of novel fusidic acid (FA) derivatives was synthesized by replacing the carboxylic acid group with various ester and amide groups and evaluated in vitro for their antiplasmodial activity against the chloroquine-sensitive NF54 and multidrug-resistant K1 strains of the malarial parasite Plasmodium falciparum. Most of these derivatives showed a 4-49 and 5-17-fold increase in activity against NF54 and KI strains, respectively, as compared to FA and had a good selectivity index. These derivatives are stable over the incubation period and do not appear to be prodrugs of fusidic acid.

Keywords: Antiplasmodial; Fusidic acid; Malaria.

Publication types

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

MeSH terms

Amides / chemistry*
Amides / pharmacology
Antimalarials / chemical synthesis
Antimalarials / chemistry
Antimalarials / pharmacology
Chloroquine / pharmacology
Drug Resistance / drug effects
Esters / chemistry*
Esters / pharmacology
Fusidic Acid / chemical synthesis
Fusidic Acid / chemistry*
Fusidic Acid / pharmacology*
Plasmodium falciparum / drug effects*
Structure-Activity Relationship

Substances

Amides
Antimalarials
Esters
Fusidic Acid
Chloroquine