Novel acyclic deoxystreptamine mimetics targeting the ribosomal decoding site

Two scaffolds, one target: The bacterial ribosomal decoding site is the target for natural aminoglycoside antibiotics, which bind to an internal RNA loop and thereby interfere with translation fidelity. Synthetic aminoglycoside mimetics are thought to display similar antibiotic activity while avoiding established bacterial resistance mechanisms. We describe two complementary approaches towards novel aminoglycoside mimetics that recognize the decoding-site RNA and inhibit bacterial translation. In the first study, elements of both rational structure-based design and diversity-driven exploration were used to synthesize flexible acyclic mimetics (I a,b) of 2-deoxystreptamine. The second paper outlines the accurate replacement of the 2-deoxystreptamine pharmacophore by stereo-chemically defined aminomethyl - piperidine scaffolds (IIa,b).