Piperidine glycosides targeting the ribosomal decoding site.

As has been outlined in the accompanying report, synthetic aminoglycoside mimetics constitute lead compounds for the development of novel antibiotics that might achieve antibacterial potency comparable to the natural aminoglycosides without being compromised by bacterial resistance mechanisms specific to the chemical constitution of these natural compounds. Threedimensional structures of the bacterial decoding-site RNA complexed with aminoglycosides 3] have guided our efforts for rational, structure-based design of readily accessible aminoglycoside mimetics (Figure 1). In this report, we outline a novel approach to linking the 6 aminoglucosamine moiety, conserved among many potent natural aminoglycosides, to conformationally restricted 3-(aminomethyl)piperidine scaffolds that mimic the unique spatial arrangement of functional groups in 2-deoxystreptamine (2DOS) required for the recognition of the decoding-site RNA target (Figure 1c ± e). The exocyclic bis-equatorial 1,3-diamine motif of 2-DOS is incorporated into the cyclic piperidine scaffold, which was designed by molecular modeling based on the crystal structure of paromomycin bound to the bacterial decoding site (Figure 1). Three different substitution patterns have been used to generate eight piperidine derivatives of glucosamine (see Table 1), among them the representative hydroxymethyl compound 1 (Figure 1c). The 5-hydroxymethyl substituent in the piperidine glycoside 1 was designed to mimic the 4-hydroxy group of paromamine (Figure 1d), which forms a key interaction with a tightly bound water molecule at the deepgroove edge of the U1406 U1495 base pair in the decoding-site target (Figure 1e). Several other piperidine glycosides were synthesized to explore alternative substitution patterns of the 3-(aminomethyl)piperidine scaffold (see Table 1).