Influence of ring size in conformationally restricted ring I analogs of paromomycin on antiribosomal and antibacterial activity. Issue 9 (13th August 2021)

• Record Type: Journal Article
• Authors: Pirrone, Michael G.; Hobbie, Sven N.; Vasella, Andrea; Böttger, Erik C.; Crich, David
• Is Part Of: RSC medicinal chemistry. Volume 12:Issue 9(2021)
• Page Start: 1585
• Page End: 1591
• Publication Date: 2021-08-13
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1039/d1md00214g
• Languages: English
• ISSNs: 2632-8682

Abstract

Abstract : Aminoglycosides with conformationally locked side chains and small hydrophobic patches show increased anti-bacterial activity and ribosomal selectivity. Fine tuning of side chain orientation indicates that the gt conformation is ideal for binding. Abstract : In order to further investigate the importance of the conformation of the ring I side chain in aminoglycoside antibiotic binding to the ribosomal target several derivatives of paromomycin were designed with conformationally locked side chains. By changing the size of the appended ring between O-4′ and C-6′ used to restrict the motion of the side chain, the position of the C-6′ hydroxy group was fine tuned to probe for the optimal conformation for inhibition of the ribosome. While the changes in orientation of the 6′-hydroxy group cannot be completely dissociated from the size and hydrophobicity of the conformation-restricting ring, overall, it is apparent that the preferred conformation of the ring I side chain for interaction with A1408 in the decoding A site of the bacterial ribosome is an ideal gt conformation, which results in the highest antimicrobial activity as well as increased selectivity for bacterial over eukaryotic ribosomes.