Towards catalytic aminoglycoside: Probing the modification of kanamycin B at the 3′- and 4′-positions

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The chemistry of selective modification of kanamycin B at the 3′- and 4′-positions of ring I and the evaluation of the resulting derivatives in cell-free translation inhibition and MIC assays are presented. The first synthesis of 3′-epi-kanamycin B (4) and its 3′-amine analogue, 3′-amino-3′- deoxy-epi-kanamycin B (5) was accomplished from commercial kanamycin B. 4′-O-alkylation retained the antibacterial activity of the parent compound and afforded protection against certain kanamycin-resistant strains. The new derivative, compound 5, showed only a moderate reduction in activity and comparative molecular dynamics simulations within the bacterial rRNA decoding site suggested that such a modification can provide excellent positioning of the desired general acid arm in the targeted catalytic antibiotic.