Synthesis and Evaluation of Novel 5‐O‐(4‐C‐Aminoalkyl‐β‐D‐ribofuranosyl) Apramycin Derivatives for the Inhibition of Gram‐Negative Pathogens Carrying the Aminoglycoside Phosphotransferase(3′)‐Ia Resistance Determinant

• Published in: Helvetica chimica acta Vol. 106; no. 11
• Main Authors: Lubriks, Dmitrijs, Haldimann, Klara, Kiliç, Fatmanur, Hartmann, Maximilian, Böttger, Erik C., Hobbie, Sven N., Suna, Edgars, Crich, David
• Format: Journal Article
• Language: English
• Published: Zürich Wiley Subscription Services, Inc 01-11-2023
• Subjects: aminoglycoside modifying enzymes; Aminoglycoside phosphotransferase; Aminoglycosides; Antibacterial activity; antibacterial agents; antiribosomal activity; Apramycin; glycosides; glycosylation; Pathogens; Phosphotransferase; Protein biosynthesis; Protein synthesis; Ribose; Ribosomes
• ISSN: 0018-019X; 1522-2675
• DOI: 10.1002/hlca.202300138

We report the synthesis and evaluation of two new apramycin 5‐O‐β‐d‐ribofuranosides, or apralogs, carrying aminoalkyl branches at the ribofuranose 4‐position. This novel modification conveys excellent activity for the inhibition of protein synthesis by wild‐type bacterial ribosomes and correspondingly high antibacterial activity against several Gram‐negative pathogens. Notably, these new modifications overcome the reduction of antibacterial activity in other 2‐deoxystreptamine‐type aminoglycosides carrying a 5‐O‐ribofuranosyl moiety when challenged by the presence of an aminoglycoside phosphotransferase enzyme capable of acting on the ribose 5‐position.