Synthesis, bacteria activity and molecular simulation of D-galactose-conjugated thiosemicarbazones of 3-aryl-4-formylsydnones

A series of D-galactose-conjugated substituted 4-formylsydnone thiosemicarbazones 4a-j were designed and synthesized from appropriate substituted 3-aryl-4-formylsydnones 2a-j and tetra-O-acetyl-β-d-galactopyranose 3. These synthesized thioureas exhibited the remarkable inhibitory activity against both selected Gram-(+)- and Gram-(–)-bacteria. Amongst them, thiosemicarbazones 4a,b,c,f,j were the most potent inhibitors against Gram-(+) bacterial strains with MIC values of 0.78–1.56 μg/mL, while compounds 4b,c,g,j had the most inhibitions against Gram-(–) bacterial ones with MIC values of 0.78–1.56 μg/mL. The thiosemicarbazones 4b, 4c, 4 f and that contain simultaneously two methyl or methyl/nitro substituents on benzene ring exhibited the strong inhibition against both Gram-(+), including MRSA bacterium, and Gram-(–) bacterial strains with MIC values of 0.78–1.56 μg/mL. In addition, compound 4j had strongest potent inhibitory activity against S. aureus DNA Gyrase and compound 4b was the strongest inhibitor against S. aureus Topoisomerase IV. Almost all of the most potential compounds had low toxicity to WI-38 normal cell line. The in silico studies, including predictive ADMET and induced fit docking simulations, for the most potential compounds were performed. Molecular dynamics simulations applied for two most potential complexes 4b/URN and 4j/4URO to understand their mechanism of active interaction for these respective enzymes.