Synthetic derivatives of natural polyphenols targeting the mycobacterial cell wall

PhD thesis defended by Sydney VILLAUME (Prof. Stéphane VINCENT) - 15/10/2018

Prof. Stéphane VINCENT, UNamur, Laboratory of Bio-Organic Chemistry (CBO)


Bert MAES (University of Antwerp), Gwilherm EVANO (ULB), Steve LANNERS, président (UNamur), Johan WOUTERS (UNamur), Stéphane VINCENT, promoteur (UNamur)


Among the different enzymes involved in the biosynthesis of the Mycobacterium tuberculosis cell wall, UDP-Galactopyranose mutase (UGM) plays a key role in the mycobacterial virulence and survival. This unique flavoenzyme is responsible of the interconversion of UDP-galactopyranose into UDP-galactofuranose.

We proposed in this PhD thesis work to identify novel UGM inhibitors. To do so, we reported in a first part the medium-throughput screening of a library of natural compounds against the targeted mutase. This initial screening permitted to identify two potent lead compounds issued from the same family: the flavonoids. Indeed, both quercetin and luteolin showed very interesting inhibitory activities against UGM. Synthetic analogues of those two hits allowed the establishment of a Structure-Activity Relationship (SAR). The structures of the most potent inhibitors serve as good starting point for further design.

Several positions of the flavonoid moiety were investigated by synthesizing quercetin and luteolin derivatives. Those synthetic polyphenol compounds were assayed against MtUGM using two different methods. Measurement of the minimal inhibitory concentration on model mycobacterial cells and cytotoxicity assay on lung cells were also performed for the best inhibitors identified. The most potent inhibitor of this series exhibited significantly lower cytotoxicity towards lung cells than the initial natural products.

In the last section of this thesis, other classes of molecule were synthesized as flavonoids isosters. Those nitrogen-containing heterocycles included quinolones, quinolines and indoles moieties.