title: Inhibitors of the acetyltransferase domain of N-acetylglucosamine-1-phosphate-uridylyltransferase/glucosamine-1-phosphate-acetyltransferase (GlmU). Part 2: Optimization of physical properties leading to antibacterial aryl sulfonamides.
abstract: A previously described aryl sulfonamide series, originally found through HTS, targets GlmU, a bifunctional essential enzyme involved in bacterial cell wall synthesis. Using structure-guided design, the potency of enzyme inhibition was increased in multiple isozymes from different bacterial species. Unsuitable physical properties (low LogD and high molecular weight) of those compounds prevented them from entering the cytoplasm of bacteria and inhibiting cell growth. Further modifications described herein led to compounds that possessed antibacterial activity, which was shown to occur through inhibition of GlmU. The left-hand side amide and the right-hand side sulfonamides were modified such that enzyme inhibitory activity was maintained (IC(50) <0.1 μM against GlmU isozymes from Gram-negative organisms), and the lipophilicity was increased giving compounds with LogD -1 to 3. Antibacterial activity in an efflux-pump deficient mutant of Haemophilus influenzae resulted for compounds such as 13.
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. Sue_Stokes@vrtx.com
authors.forename: Suzanne S
authors.initials: SS
authors.lastname: Stokes
authors.forename: Robert
authors.initials: R
authors.lastname: Albert
authors.forename: Ed T
authors.initials: ET
authors.lastname: Buurman
authors.forename: Beth
authors.initials: B
authors.lastname: Andrews
authors.forename: Adam B
authors.initials: AB
authors.lastname: Shapiro
authors.forename: Oluyinka M
authors.initials: OM
authors.lastname: Green
authors.forename: Andrew R
authors.initials: AR
authors.lastname: McKenzie
authors.forename: Ludovic R
authors.initials: LR
authors.lastname: Otterbein
mesh_terms: D000123:Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000577:Amides / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006193:Haemophilus influenzae / Q000187:drug effects / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010078:Oxazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000577:Amides; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D010078:Oxazines; D013449:Sulfonamides; D000123:Acetyltransferases; C428383:glucosamine-1-phosphate acetyltransferase; D009713:Nucleotidyltransferases; C023226:UDPacetylglucosamine pyrophosphorylase