One of the major mechanisms of resistance to ribosome‐targeting antibiotics is the modification of ribosomal RNA (rRNA). Specific methyltransferase enzymes, for example, confer high‐level resistance to aminoglycosides by selectively methylating the 16S rRNA in the ribosomal decoding center. These enzymes have been detected globally and pose a threat to the continued use of aminoglycosides. Compound 1 , a dehydroamino amide inhibitor of the m 1 A1408 methyltransferase NpmA, was previously disclosed and identified using high‐throughput virtual screening. Here, the synthesis and biological evaluation of rationally designed analogs of 1 has been reported. Guided by molecular docking, additional putative inhibitors of NpmA, as well as the functionally related m 7 G1405 methyltransferase RmtB, varying in each region of the original scaffold are disclosed. A modular, fragment‐based synthesis enables access to 17 analogs, which exhibits mixed activity against NpmA and RmtB, including several that are selective for RmtB. The structure–activity relationship determined for the dehydroamino amide series will guide continued research against this target class with the aim of developing a toolkit for selective‐ or pan‐16S rRNA methyltransferase inhibition.
Deprez et al. (Mon,) studied this question.