Synthesis and inhibitory activity against MurA and MurZ enzymes of 4H-pyrano[2,3-d]pyrimidine–1H-1,2,3-triazole hybrid compounds having piperidine and morpholine rings

Abstract

A series of D-glucose-conjugated 4H-pyrano[2,3-d]pyrimidine–1H-1,2,3-triazole hybrid compounds 12a–g and 13a–g having piperidine and morpholine rings were synthesized by click chemistry between corresponding propargyl derivatives and azide of D-glucose using CuI@montmorillonite as a catalyst. Their inhibitory activities against E. coli MurA and S. aureus MurA and MurZ enzymes were examined. The morpholine ring at position 3 along with the ethoxy group at position 4 on the benzene nucleus made 1,2,3-triazole 13b become the most potent inhibitor in this series against all three enzymes, E. coli MurA as well as S. aureus MurA and MurZ with IC₅₀ values of 0.15 ± 0.05, 1.02 ± 0.05, and 1.21 ± 0.05 μM, respectively. This compound also exhibited a strong bacterial growth inhibitory activity against E. coli and S. aureus with MIC values of 0.78 and 1.56 μg mL⁻¹, respectively. Induced fit docking and molecular dynamics simulations were carried out on enzyme 1UAE in order to elucidate the inhibition potential of 13b against corresponding tested enzyme UDP-N-acetylglucosamine enolpyruvyl transferase MurA.