A series of benzaldehyde and salicylaldehyde-S-benzylisothiosemicarbazones was synthesized and tested against 12 different strains of mycobacteria, Gram-positive and Gram-negative bacteria, and the significant selectivity toward mycobacteria was proved. Twenty-eight derivatives were evaluated for the inhibition of isocitrate lyase, which is a key enzyme of the glyoxylate cycle necessary for latent tuberculosis infection, and their iron-chelating properties were investigated. Two derivatives, 5-bromosalicylaldehyde-S-(4-fluorobenzyl)-isothiosemicarbazone and salicylaldehyde-S-(4-bromobenzyl)-isothiosemicarbazone, influenced the isocitrate lyase activity and caused a better inhibition at 10 μmol/L than 3-nitropropionic acid, a standard inhibitor. The compounds were also found to act as exogenous chelators of iron, which is an obligate cofactor for many mycobacterial enzymes. Due to their low cytotoxicity, together with the activity against isocitrate lyase and the ability to sequester iron ions, the compounds belong to potential antibiotics with the main effect on mycobacteria.

Department of Clinical Microbiology University Hospital Hradec Králové Czech Republic

Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Charles University Hradec Králové Czech Republic

Faculty of Pharmacy in Hradec Králové Department of Inorganic and Organic Chemistry Charles University Hradec Králové Czech Republic

Institute of Organic Chemistry and Biochemistry The Academy of Sciences of the Czech Republic Prague Czech Republic

Regional Institute of Public Health Ostrava Czech Republic

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