Derivatization of Dihydropyrrolidone-Thiadiazole Heterocyclic Compounds and an Evaluation of their Antibacterial and Anti-Biofilm Activities

Abstract

AbstractDihydropyrrolidone-thiadiazole inhibitors targeting YycG histidine kinase have been designed, synthesized and evaluated for their antibacterial, bactericidal, anti-biofilm, cytotoxic and hemolytic activities, and for their ability to promote autophosphorylation. 4-(Benzofuran-2-carbonyl)-1-(5-(benzylthio)-1,3,4-thiadiazol-2-yl)-3-hydroxy-5-(2-hydroxyphenyl)-1,5-dihydro-2H-pyrrol-2-one exhibits the best bacteriostatic activity against Gram-positive bacteria such as S. epidermidis SE1457, MSSA SA113, and E. faecalis FB1 (MIC = 3.13–25 μM). Its antibacterial activity against methicillin-sensitive Staphylococcus aureus (MSSA) SA113 is comparable to that of linezolid. Most of the products exhibit good inhibitory effects against the biofilms of the tested strains. Among the products, three show strong inhibitory effects on the biofilm formation of S. epidermidis SE1457, MSSA SA113, and E. faecalis FB1, and their inhibition rates reach more than 90% at 6.25 μM. Cytotoxicity and hemolytic activity tests suggest that all the synthesized compounds have little effect on the growth of mammalian cells (Vero cells) and exhibit no hemolytic activity toward healthy human red blood cells.