Probing the ribosomal RNA A-site with functionally diverse analogues of paromomycin—synthesis of ring I mimetics

Methods were developed to selectively cleave the 2-amino-2-deoxy-α-d-glucopyranosyl ring in paromomycin. The preferentially N- and O-protected products were alkylated on the liberated C4 hydroxyl group of the deoxystreptamine subunit. Further manipulation furnished a series of aromatic, heteroaromatic, and aliphatic appendages as spatial mimics of ring I. Modest inhibitory activity was found against Staphylococcus aureus with two analogues (27 and 63), although cell-free functional transcription/translation assays were similar to paromomycin for analogue 27.