Synthesis of aziridines as potential inactivators of GlfH1, a novel glycosidase from Mycobacterium tuberculosis

Résumé

Tuberculosis is a lung disease caused by Mycobacterium tuberculosis, a bacterial pathogen. The infection affects 25% of the world's population and is the 13th leading cause of death. With the emergence of new resistance to standard antibiotic treatments, it is crucial to develop new therapies. The discovery of GlfH1, a galactofuranosidase involved in the degradation of the mycobacterial cell wall, has led to the development of a potential new therapeutic target. The role of GlfH1, an exo-β-D-galactofuranosidase, is to cleave the terminal galactofuranosyl residues of the galactan chain present in the arabinogalactan complex of the mycobacterial cell wall. The mechanism of GlfH1 is based on covalent catalysis, resulting in the retention of the configuration at the anomeric position. The formation of the covalent intermediate generated by this type of mechanism is the key to achieving irreversible inhibition of this glycosidase. It has been shown that glycomimetics bearing aziridine groups can potentially have a strong inhibitory effect due to their particular reactivity combining high ring tension and high electrophilic and cationic character to mimic the transition state. To inhibit GlfH1, one potential approach is to synthesise a glycomimetic of a galactofuranosyl residue carrying an aziridine. The strategy implemented consists of synthesising this aziridine from a cyclopentene precursor made from D-Galactose. The synthesis of this cyclopentene precursor was successfully carried out with an overall yield of 4% over eight steps. However, aziridine was not successfully introduced.

la date de réponse	19 janv. 2023
langue originale	Anglais
L'institution diplômante	Universite de Namur
Superviseur	Stephane Vincent (Promoteur)