title: Total synthesis of [Ψ[C(═NH)NH]Tpg(4)]vancomycin and its (4-chlorobiphenyl)methyl derivative: impact of peripheral modifications on vancomycin analogues redesigned for dual D-Ala-D-Ala and D-Ala-D-Lac binding.
abstract: The total synthesis of two key analogues of vancomycin containing single-atom exchanges in the binding pocket (residue 4 amidine and thioamide) are disclosed as well as their peripherally modified (4-chlorobiphenyl)methyl (CBP) derivatives. Their assessment indicates that combined pocket amidine and CBP peripherally modified analogues exhibit a remarkable spectrum of antimicrobial activity (VSSA, MRSA, VanA and VanB VRE) and impressive potencies (MIC = 0.06-0.005 μg/mL) against both vancomycin-sensitive and -resistant bacteria and likely benefit from two independent and synergistic mechanisms of action. Like vancomycin, such analogues are likely to display especially durable antibiotic activity not prone to rapidly acquired clinical resistance.
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Akinori
authors.initials: A
authors.lastname: Okano
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakayama
authors.forename: Alex W
authors.initials: AW
authors.lastname: Schammel
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry; D001665:Binding Sites; D004151:Dipeptides / Q000737:chemistry*; D007773:Lactates / Q000737:chemistry*; D008968:Molecular Conformation; D013237:Stereoisomerism; D014640:Vancomycin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D004151:Dipeptides; D007773:Lactates; C078877:alanyllactate; C002956:alanylalanine; D014640:Vancomycin; D000409:Alanine