Design, Synthesis And Antibacterial Evaluation Of Adenosine Analogs As Tyrosyl-tRNA Synthetase Inhibitors

Microorganisms adopt diverse strategies to enhanced ability to survive in the presence of the wide use and abuse of antibiotics. Bacterial resistance to antibiotics is a serious threat to human health, which causes wide public concerns. Therefore, there is a pressing need for antiinfective drugs with a new mechanism or/and a novel scaffold. Based on the structure-based drug design and the bioisosterism, two series of adenosine analogs targeting tyrosyl-t RNA synthetase(Tyr RS) were designed and synthesized. In the first series, thirty nine substituted isopropylideneadenosin-5′-yl phenylacetates and substituted adenosin-5′-yl phenylacetates were demonstrated. As for the second series, thirty three 3-arylfuran-2(5H)-one-adenosine hybrids were synthesized and evaluated. The structure of the target compounds were characterized by 1H NMR, 13 C NMR, MS(EI) and elemental analyses. The results showed that some obtained compounds of both series displayed excellent antibacterial activity.The activity of the first series against Gram-negative bacteria(Escherichia coli ATCC 8739 and Pseudomonas aeruginosa ATCC 9027) is better than Gram-positive bacteria(Staphylococcus aureus ATCC 6538). The most potent compound((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl 2-(3-fluorophenyl)acetate(2f) shows MIC50 of 0.08μg/m L against P. aeruginosa in antibacterial assay, being more active than ciprofloxacin(MIC50 0.1μg/m L). The enzyme assays revealed that 2f is also a potent inhibitor with IC50 of 0.8±0.07μM against Tyr RS. Molecular dockings showed that 2f forms nine hydrogen-bonds with residues in the active site, providing an explanation for observations in biological assays. These inspiring results strongly suggest that 2f deserves to further research as a novel antibiotic.Such excellent results can also be found among the second series. The compound 9c(MIC50 0.55μg/m L, 0.09μg/m L) is the most active, showing better activity than ciprofloxacin(MIC50 0.64μg/m L, 0.1μg/m L) against Escherichia coli ATCC 8739 and Pseudomonas aeruginosa ATCC 9027, respectively. The enzyme assays revealed that 9c is a potent inhibitor with IC50 of 0.66±0.1μM against Tyr RS. Molecular dockings disclosed that introduction of adenosine moiety to the 3-arylfuran-2(5H)-one moiety not only provides several additional interactions but also maintains the binding mode of the 3-arylfuran-2(5H)-one moiety.The structure-activity relationships of the two series were well described through the further analysis of the activity evaluation results. These works have accumulated experience for looking for good Tyr RS inhibitors and lay the foundation of follow-up experiment. Furthermore, the study of molecular docking revealed the binding modes of these molecules with Tyr RS. These findings provide a guide for structural optimization.