title: Design and synthesis of novel cell wall inhibitors of Mycobacterium tuberculosis GlmM and GlmU.
abstract: GlmM and GlmU are key enzymes in the biosynthesis of UDP-N-acetyl-d-glucosamine (UDP-GlcNAc), an essential precursor of peptidoglycan and the rhamnose-GlcNAc linker region in the mycobacterial cell wall. These enzymes are involved in the conversion of two important precursors of UDP-GlcNAc, glucosamine-6-phosphate (GlcN-6-P) and glucosamine-1-phosphate (GlcN-1-P). GlmM converts GlcN-6-P to GlcN-1-P, GlmU is a bifunctional enzyme, whereby GlmU converts GlcN-1-P to GlcNAc-1-P and then catalyzes the formation of UDP-GlcNAc from GlcNAc-1-P and uridine triphosphate. In the present study, methyl 2-amino-2-deoxyl-α-d-glucopyranoside 6-phosphate (1α), methyl 2-amino-2-deoxyl-β-d-glucopyranoside 6-phosphate (1β), two analogs of GlcN-6-P, were synthesized as GlmM inhibitors; 2-azido-2-deoxy-α-d-glucopyranosyl phosphate (2) and 2-amino-2,3-dideoxy-3-fluoro-α-d-glucopyranosyl phosphate (3), analogs of GlcN-1-P, were synthesized firstly as GlmU inhibitors. Compounds 1α, 1β, 2, and 3 as possible inhibitors of mycobacterial GlmM and GlmU are reported herein. Compound 3 showed promising inhibitory activities against GlmU, whereas 1α, 1β and 2 were inactive against GlmM and GlmU even at high concentrations.
authors.affiliation: Institute of Microbiology, Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Yongmeng
authors.initials: Y
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Yufang
authors.initials: Y
authors.lastname: Ma
authors.forename: Xuebing
authors.initials: X
authors.lastname: Li
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002473:Cell Wall / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005944:Glucosamine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019298:Glucose-6-Phosphate / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005958:Glucosephosphates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; C532100:GlmU protein, Mycobacterium tuberculosis; D005958:Glucosephosphates; D009097:Multienzyme Complexes; C038515:glucosamine 1-phosphate; C001293:glucosamine 6-phosphate; D019298:Glucose-6-Phosphate; D005944:Glucosamine