Inhibitors of glucosamine-6-phosphate synthase as potential antimicrobials or antidiabetics – synthesis and properties

Abstract

Glucosamine-6-phosphate synthase (GlcN-6-P synthase) is known as a promising target for antimicrobial agents and antidiabetics. Several compounds of natural or synthetic origin have been identified as inhibitors of this enzyme. This set comprises highly selective l -glutamine, amino sugar phosphate or transition state intermediate cis -enolamine analogues. Relatively low antimicrobial activity of these inhibitors, poorly penetrating microbial cell membranes, has been improved using the pro-drug approach. On the other hand, a number of heterocyclic and polycyclic compounds demonstrating antimicrobial activity have been presented as putative inhibitors of the enzyme, based on the results of molecular docking to GlcN-6-P synthase matrix. The most active compounds of this group could be considered promising leads for development of novel antimicrobial drugs or antidiabetics, provided their selective toxicity is confirmed.

Logic programming-based Minimal Cut Sets reveal consortium-level therapeutic targets for chronic wound infections

“…Interestingly, while glucosamine-6-phosphate synthase was identified as an essential reaction in both single-species models, the lethal phenotype conferred by deleting this reaction would be recovered by a simple exchange of acetylglucosamine between the bacteria. Therefore, efforts using therapeutic agents which inhibit this enzyme 52 would need to consider the potential role of acetylglucosamine found in the environment or leaked by resistant bacteria in the consortia.…”

A Metabolome and Microbiome Analysis of Acute Myeloid Leukemia: Insights into the Carnosine–Histidine Metabolic Pathway

“…UDP-GlcNAc is the donor sugar for O-GlcNAcylation, and studies had shown that increased O-GlcNAcylation could promote the progression of hepatocellular carcinoma [ 39 ]. In addition, the synthesis enzyme of Glucosamine 6-phosphate, Glucosamine-6-phosphate synthetase, is also considered a potential carcinofetal marker [ 40 ] and a promising target for antimicrobial and antidiabetic drugs [ 41 ]. Therefore, the alterations in AML glucose metabolism primarily manifest as enhanced glycolysis, antioxidant activity, and glycosylation modifications.…”

Synthesis, pharmacological evaluation, and in silico study of new 3-furan-1-thiophene-based chalcones as antibacterial and anticancer agents

“…In order to investigate the binding affinity of these new 3-furan-1-thiophene-based chalcones against the respective proteins, in silico studies were performed on GlcN-6-P synthase (glucosamine-6-phosphate synthase), the target enzyme for antimicrobial drugs [ 34 ] and colchicine binding site in tubulin, are the target receptors for anticancer drugs [ 35 ]. GlcN-6-P synthase binding site involves eight amino acids, these are Thr302, Ser303, Ser347, Gln348, Ser349, Thr352, Val399, and Ala602, while the binding pocket of tubulin comprises Val181, Leu248, Ala250, Leu255, Met259, Ala316, and Lys352.…”