Design and Synthesis of Aminoglycoside Antibiotics to Selectively Target 16S Ribosomal RNA Position 1408

Abstract

AbstractThe glucopyranosyl moiety (ring I) of paromomycin was modified in a search for novel aminoglycoside antibiotics. The key intermediates were the 4′,6′‐O‐benzylidenated N‐Boc derivative 3 and the azido analogue 18. The bromobenzoates 4 and 19 were prepared by treating the benzylidene acetals 3 and 18, respectively, with N‐bromosuccinimide (NBS), and the diol 8 was obtained by hydrogenolysis of 3. The C(6′)‐deoxy derivative 5 was obtained from 4 by treatment with Bu3SnH. Selective fluorodehydroxylation of 8 gave the fluoro derivative 9. The pseudotrisaccharide 13 was obtained by reductive fragmentaion of the iodo compound 12 obtained from the bromobenzoate 4. The 3′,6′‐anhydro derivative 20 was obtained upon deacetylation of 19. Standard deprotection gave the C(6′)‐deoxy compound 7, the fluoro compound 11, the pseudotrisaccharide 15, and the 3′,6′‐anhydro‐paromomycin 22. As compared to paromomycin, the C(6′)‐deoxy and fluorodeoxy derivatives 7 and 11 showed a lower activity against both wild type 1408A and 1408G mutant ribosomes. A lower activity was also found for the 3′,6′‐anhydro derivative 22 and for the pseudotrisaccharide 15.