Open AccessInfluence of ring size in conformationally restricted ring I analogs of paromomycin on antiribosomal and antibacterial activity
Author(s) -
Michael G. Pirrone,
Sven N. Hobbie,
Andrea Vasella,
Erik C. Böttger,
David Crich
Publication year - 2021
Publication title -
rsc medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.754
H-Index - 55
ISSN - 2632-8682
DOI - 10.1039/d1md00214g
Subject(s) - paromomycin , ring (chemistry) , chemistry , side chain , selectivity , ring size , stereochemistry , antibacterial activity , ideal (ethics) , crystallography , antibiotics , aminoglycoside , biology , biochemistry , bacteria , organic chemistry , polymer , philosophy , epistemology , catalysis , genetics
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.