Adenosine analogs as inhibitors of tyrosyl-tRNA synthetase: Design, synthesis and antibacterial evaluation

Abstract Herein we describe the synthesis and evaluation of a series of adenosine analogs for in vitro antibacterial activity against Staphylococcus aureus , Escherichia coli and Pseudomonas aeruginosa . Out of these compounds, compound c6 has much stronger antibacterial potency against Pseudomonas aeruginosa than ciprofloxacin, and was determined to target tyrosyl-tRNA synthetase with IC 50 of 0.8 ± 0.07 μM. Structure–activity relationship analysis suggested that introduction of a fluorine atom at the 3′-position of benzene ring of the phenylacetyl moiety significantly increased affinities to the enzyme. In comparison with isopropylidene analogs, 2′,3′-deprotected compounds displayed higher inhibitory activity. Molecular dockings provided an explanation for observations in biological assays.