Total Syntheses and Initial Evaluation of [Ψ[C(═S)NH]Tpg⁴]vancomycin, [Ψ[C(═NH)NH]Tpg⁴]vancomycin, [Ψ[CH₂NH]Tpg⁴]vancomycin, and Their (4-Chlorobiphenyl)methyl Derivatives: Synergistic Binding Pocket and Peripheral Modifications for the Glycopeptide Antibiotics

Abstract

Full details of studies are disclosed on the total syntheses of binding pocket analogues of vancomycin bearing the peripheral L-vancosaminyl-1,2-D-glucosyl disaccharide that contain changes to a key single atom in the residue-4 amide (residue-4 carbonyl O → S, NH, H2) designed to directly address the underlying molecular basis of resistance to vancomycin. Also disclosed are studies piloting the late-stage transformations conducted on the synthetically more accessible C-terminus hydroxymethyl aglycon derivatives and full details of the peripheral chlorobiphenyl functionalization of all of the binding-pocket-modified vancomycin analogues designed for dual D-Ala-D-Ala/D-Ala-D-Lac binding. Their collective assessment indicates that combined binding pocket and chlorobiphenyl peripherally modified analogues exhibit a remarkable spectrum of antimicrobial activity (VSSA, MRSA, and VanA and VanB VRE) and impressive potencies against both vancomycin-sensitive and vancomycin-resistant bacteria (MICs = 0.06-0.005 and 0.5-0.06 μg/mL for the amidine and methylene analogues, respectively) and likely benefit from two independent and synergistic mechanisms of action, only one of which is dependent on D-Ala-D-Ala/D-Ala-D-Lac binding. Such analogues are likely to display especially durable antibiotic activity that is not prone to rapidly acquired clinical resistance.