Innovative antibacterial compounds targeting the bacterial transferase MraY ; Composés antibactériens innovants ciblant la transférase bactérienne MraY

Antibiotics resistance is a serious public health threat that recent prospective studies predict to be responsible for 10 million deaths per year by 2050. In order to fight the continuous emergence of multi-resistant bacteria, the development of new antibacterial agents is necessary. The bacterial transferase MraY is a transmembrane enzyme involved in the biosynthesis of bacterial peptidoglycan and is essential for their survival. With no equivalent in eukaryotes, it is currently not the target of any drug and is therefore a prime target for the development of new antibiotics. Its crystallographic structure has recently been solved allowing the rational design of inhibitors. Moreover, natural inhibitors of MraY with a complex structure such as muraymycins are known and some of them display good anti-bacterial activities. The objective of this work is to develop the synthesis of simplified analogues of these natural inhibitors, with an original structure, based on the aminoribosyl uridine skeleton common to these inhibitors and essential to their activity. The functionalization of this skeleton in C5' by a cyano ethyl or an amino ethyl group paves the way to the introduction of various spacers, oxadiazole or tetrazole, respectively, on which chemical diversity is brought. The synthesis strategy involves a diastereoselective glycosylation reaction between two key intermediates, prepared on a scale of several hundred milligrams: - a derivative of D-ribose fluorinated in the anomeric position; - a derivative substituted in the 5' position of uridine by a cyano ethyl or a masked amino ethyl group, resulting from a single epoxide obtained in a stereocontrolled way. The resulting pharmacophores are then engaged for the cyano derivative in the synthesis of an amidoxime followed by its O-alkylation with various acid chlorides and cyclization to oxadiazoles or for the amino derivative in a multi-component Ugi-azide reaction at the origin of the corresponding tetrazoles. The biological activity of the molecules was ...