Evaluation of the Mycobactericidal Effect of Thio-functionalized Carbohydrate Derivatives

Abstract

Sugars with heteroatoms other than oxygen have attained considerable importance in glycobiology and in drug design since they are often more stable in blood plasma due to their resistance to enzymes, such as glycosidases, phosphorylases and glycosyltransferases. The replacement of oxygen atoms in sugars with sulfur forms thio-sugars, which are potentially useful for the treatment of diabetes and some bacterial and viral infections. Here, we evaluated the antibacterial activity of thio-functionalized carbohydrate derivatives. A set of 21 compounds was screened against acid-fast <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>), gram-negative <i>Escherichia coli</i> and gram-positive <i>Staphylococcus aureus.</i> The tested carbohydrate derivatives were most effective against tubercle bacilli, with as many as five compounds (thioglycoside <b>6</b>, thiosemicarbazone <b>16A</b>, thiosemicarbazone <b>20</b>, aminothiadiazole <b>23</b>, and thiazoline <b>26</b>) inhibiting its growth with MIC₅₀ ≤ 50 µM/CFU. Only two compounds (aminothiadiazole <b>23</b> and thiazoline <b>26</b>) were able to inhibit the growth of <i>E. coli</i> at concentrations below 1 mM, and one of them, aminothiadiazole <b>23</b>, inhibited the growth of <i>S. aureus</i> at a concentration ≤1 mM. The five compounds affecting the growth of mycobacteria were either thiodisaccharides (<b>6</b>, <b>16A</b>, and <b>20</b>) or thioglycosides (<b>23</b> and <b>26</b>). All of these compounds (<b>6</b>, <b>16A</b>, <b>20</b>, <b>23</b>, and <b>26</b>) were able to inhibit the growth of <i>Mtb</i> deposited within human macrophages. However, three of the five selected compounds (<b>6</b>, <b>23</b>, and <b>26</b>) exhibited relatively high cytotoxicity in mouse fibroblasts at micromolar concentrations. The selected thio-sugars are very promising compounds, thus making them candidates for further modifications that would decrease their cytotoxicity against eukaryotic cells without affecting their antimycobacterial potential.