TY - JOUR
T1 - Structure-Activity Relationships of Novel Tryptamine-Based Inhibitors of Bacterial Transglycosylase
AU - Sosič, Izidor
AU - Anderluh, Marko
AU - Sova, Matej
AU - Gobec, Martina
AU - Mlinarič Raščan, Irena
AU - Derouaux, Adeline
AU - Amoroso, Ana
AU - Terrak, Mohammed
AU - Breukink, Eefjan
AU - Gobec, Stanislav
PY - 2015/12/3
Y1 - 2015/12/3
N2 - Penicillin-binding proteins represent well-established, validated, and still very promising targets for the design and development of new antibacterial agents. The transglycosylase domain of penicillin-binding proteins is especially important, as it catalyzes polymerization of glycan chains, using the peptidoglycan precursor lipid II as a substrate. On the basis of the previous discovery of a noncovalent small-molecule inhibitor of transglycosylase activity, we systematically explored the structure-activity relationships of these tryptamine-based inhibitors. The main aim was to reduce the nonspecific cytotoxic properties of the initial hit compound and concurrently to retain the mode of its inhibition. A focused library of tryptamine-based compounds was synthesized, characterized, and evaluated biochemically. The results presented here show the successful reduction of the nonspecific cytotoxicity, and the retention of the inhibition of transglycosylase enzymatic activity, as well as the ability of these compounds to bind to lipid II and to have antibacterial actions.
AB - Penicillin-binding proteins represent well-established, validated, and still very promising targets for the design and development of new antibacterial agents. The transglycosylase domain of penicillin-binding proteins is especially important, as it catalyzes polymerization of glycan chains, using the peptidoglycan precursor lipid II as a substrate. On the basis of the previous discovery of a noncovalent small-molecule inhibitor of transglycosylase activity, we systematically explored the structure-activity relationships of these tryptamine-based inhibitors. The main aim was to reduce the nonspecific cytotoxic properties of the initial hit compound and concurrently to retain the mode of its inhibition. A focused library of tryptamine-based compounds was synthesized, characterized, and evaluated biochemically. The results presented here show the successful reduction of the nonspecific cytotoxicity, and the retention of the inhibition of transglycosylase enzymatic activity, as well as the ability of these compounds to bind to lipid II and to have antibacterial actions.
U2 - 10.1021/acs.jmedchem.5b01482
DO - 10.1021/acs.jmedchem.5b01482
M3 - Article
C2 - 26588190
SN - 0022-2623
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
ER -