Novel antimycobacterial C-21 amide derivatives of the antibiotic fusidic acid: synthesis, pharmacological evaluation and rationalization of media-dependent activity using molecular docking studies in the binding site of human serum albumin

Abstract

Fusidic acid is a natural product antibiotic used clinically, primarily against staphylococcal infections. It has also exhibited antimycobacterial activity against <i>Mycobacterium</i> species, including <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>). Novel C-21 fusidic acid amides were synthesized and evaluated for antimycobacterial activity in a drug repositioning approach for tuberculosis. The synthesized compounds exhibited good potency in MB7H9/CAS medium albeit showing low to no activity in MB7H9/ADC medium. The fusidic acid ethanamides were, generally, the most potent of the analogues evaluated for antimycobacterial activity (MIC₉₀ < 10 μM) in the MB7H9/CAS medium. The lack of activity in the MB7H9/ADC medium was supported by strong binding interactions in the fusidic acid binding site of the human serum albumin (HSA) protein. The most potent antimycobacterial analogue was the <i>N</i>-(4-sulfamoylbenzyl)fusidic acid amide (<b>1.26</b>) with an MIC₉₀ value of 2.71 μM.