title: Synthesis and application of a bromomethyl substituted scaffold to be used for efficient optimization of anti-virulence activity.
abstract: Pilicides are a class of compounds that attenuate virulence in Gram negative bacteria by blocking the chaperone/usher pathway in Escherichia coli. It has also been shown that compounds derived from the peptidomimetic scaffold that the pilicides are based on can prevent both Aβ aggregation and curli formation. To facilitate optimizations towards the different targets, a new synthetic platform has been developed that enables fast and simple introduction of various substituents in position C-7 on the peptidomimetic scaffold. Importantly, this strategy also enables introduction of previously unattainable heteroatoms in this position. Pivotal to the synthetic strategy is the synthesis of a C-7 bromomethyl substituted derivative of the ring-fused dihydrothiazolo 2-pyridone pilicide scaffold. From this versatile and reactive intermediate various heteroatom-linked substituents could be introduced on the scaffold including amines, ethers, amides and sulfonamides. In addition, carbon-carbon bonds could be introduced to the sp(3)-hybridized bromomethyl substituted scaffold by Suzuki-Miyaura cross couplings. Evaluation of the 24 C-7 substituted compounds in whole-bacterial assays provided important structure-activity data and resulted in the identification of a number of new pilicides with activity as good or better than those developed previously.
authors.affiliation: Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Chorell
authors.forename: Christoffer
authors.initials: C
authors.lastname: Bengtsson
authors.forename: Thomas
authors.initials: T
authors.lastname: Sainte-Luce Banchelin
authors.forename: Pralay
authors.initials: P
authors.lastname: Das
authors.forename: Hanna
authors.initials: H
authors.lastname: Uvell
authors.forename: Arun K
authors.initials: AK
authors.lastname: Sinha
authors.forename: Jerome S
authors.initials: JS
authors.lastname: Pinkner
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Hultgren
authors.forename: Fredrik
authors.initials: F
authors.lastname: Almqvist
mesh_terms: D000438:Alcohols / Q000737:chemistry; D000588:Amines / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001386:Azides / Q000737:chemistry; D002244:Carbon / Q000737:chemistry; D004926:Escherichia coli / Q000187:drug effects* / Q000472:pathogenicity*; D010084:Oxidation-Reduction; D014774:Virulence / Q000187:drug effects
chemical_list: D000438:Alcohols; D000588:Amines; D000900:Anti-Bacterial Agents; D001386:Azides; D002244:Carbon