Novel fused pyridine derivatives containing pyrimidine moiety as prospective tyrosyl-tRNA synthetase inhibitors: Design, synthesis, pharmacokinetics and molecular docking studies

Thirteen fused pyridine derivatives have been designed, synthesized and characterized by ¹H NMR, ¹³C NMR and IR spectral data and elemental analysis. Their in vitro antimicrobial activity was investigated against some pathogenic bacteria and fungi and the majority of them showed excellent to moderate activity, especially compounds 10 and 18 displaying the potent inhibitory effect against K. pneumoniae with MIC values of 2.44 mM and 8.10 mM, respectively. Their pharmacokinetic assessment also revealed promising druglikeness characteristics and ADME properties. The binding interactions of the most active analogues were performed through molecular docking against Staphylococcus aureus tyrosyl-tRNA synthetase. Results revealed that the enhanced activity of compound 10 can be modulated by the establishment, in 10-tyrosyltRNA synthetase complex, of hydrogen bond interactions between the lone pair of sulfur atom of the thiophen-3-amine ring and the hydrogen atom of the hydroxyl group of TYR 170 of 3.80 Å. These findings suggest that analogues 10 and 18 can be served as best candidates for designing and discovering of novel antimicrobial agents.