Design, synthesis, and antibacterial activity studies of novel aminoglycoside antibiotics

Through a chemical glycodiversification strategy, novel aminoglycoside antibiotics have been synthesized, using neamine as the core molecule, by diversifying the structures of ring III attached at O-5 (pyranmycin class) or at O-6 (kanamycin B class) position of 2-deoxystreptamine. By introducing ether-linked functionalities with varying chain length at O-3" of ring III, seven pyranmycin analogs have been synthesized. The synthesis of kanamycin B analogs is based on the regio- and stereoselective glycosylation reaction and 15 compounds have been synthesized. All the above synthesized aminoglycosides have been assayed against both susceptible and resistant bacteria and structure activity relationships (SAR) have been elucidated.; In order to revive the activity of aminoglycosides against resistant bacteria, the revealed lead compounds in both pyranmycin and kanamycin B libraries are subjected for further modification by attaching (S)-4-amino-2-hydroxylbutyryl (AHB) sidechain at N-1 position of 2-deoxystreptamine. For achieving the above design, a regioselective reduction of azide at the N-1 position of perazidoaminoglycosides utilizing Staudinger reaction has been studied. Accordingly, 11 novel aminoglycosides bearing AHB sidechain at N-1 position of 2-deoxystreptamine have been synthesized and the prominent antibacterial activities against resistant strains have been obtained. Several of them can serve as the leads for further structural modifications to yield optimal broad spectrum antibiotics for battling the problems caused by drug resistant pathogens.