Both Staphylococcus aureus and Staphylococcus epidermidis can form biofilms on natural surfaces or abiotic surfaces, such as medical implants, resulting in biofilm-associated diseases that are refractory to antibiotic treatment. We previously reported a promising antibacterial compound (Compound 2) and its derivatives with bactericidal and anti-biofilm activities against both S. epidermidis and S. aureus. We have further evaluated the antibacterial activities of four Compound 2 derivatives (H2-38, H2-39, H2-74 and H2-81) against 163 clinical strains of S. epidermidis and S. aureus, including methicillin-susceptible and methicillin-resistant strains, as well as biofilm-forming and non-biofilm-forming strains. The four derivatives inhibited the planktonic growth of all of the clinical staphylococcal isolates, including methicillin-resistant S. aureus and methicillin-resistant S. epidermidis and displayed bactericidal activities against both immature (6 h) and mature (24 h) biofilms formed by the strong biofilm-forming strains. The derivatives, which all target YycG, will help us to develop new antimicrobial agents against multidrug-resistant staphylococci infections and biofilm-associated diseases.

•Halogenated thiazolo[3,2-a]pyrimidine-3-one derivatives were synthesized.•The antibacterial, antibiofilm and hemolytic activities of compounds were tested.•Compounds 4e, 4f, 8b and 8c showed good antibacterial and antibiofilm activity.•Compound 4e exhibited good inhibitory activities on YycG kinase.With an intention to potent inhibitors of YycG histidine kinase, a series of halogenated thiazolo[3,2-a]pyrimidin-3-one carboxylic acid derivatives were synthesized and evaluated for their antibacterial, antibiofilm and hemolytic activities. The majority of the compounds showed good activity against Staphylococcus epidermidis and Staphylococcus aureus, with MIC values of 1.56–6.25 μM, simultaneously presented promising antiobifilm activity against S. epidermidis ATCC35984 at 50 μM. The test of inhibitory activity on YycG kinase suggested the antibacterial activities of these derivatives are based on inhibiting the enzyme activity of the YycG HK domain. The hemolytic activity test suggested these compounds exhibited in vitro antibacterial activity at non-hemolytic concentrations.Halogenated thiazolo[3,2-a]pyrimidin-3-one derivatives 4e, 4f, 8b and 8c exhibited promising antibacterial, antibiofilm, and no hemolytic activities. Compound 4e showed good inhibitory activity on YycG kinase.

Treating staphylococcal biofilm-associated infections is challenging. Based on the findings that compound 2 targeting the HK domain of Staphylococcus epidermidis YycG has bactericidal and antibiofilm activities against staphylococci, six newly synthesized derivatives were evaluated for their antibacterial activities. The six derivatives of compound 2 inhibited autophosphorylation of recombinant YycG′ and the IC50 values ranged from 24.2 to 71.2 μM. The derivatives displayed bactericidal activity against planktonic S. epidermidis or Staphylococcus aureus strains in the MIC range of 1.5–3.1 μM. All the derivatives had antibiofilm activities against the 6- and 24-h biofilms of S. epidermidis. Compared to the prototype compound 2, they had less cytotoxicity for Vero cells and less hemolytic activity for human erythrocytes. The derivatives showed antibacterial activities against clinical methicillin-resistant staphylococcal isolates. The structural modification of YycG inhibitors will assist the discovery of novel agents to eliminate biofilm infections and multidrug-resistant staphylococcal infections.

A green and efficient method has been developed for the cross-coupling of 2-mercaptobenzothiazoles with aryl iodides in water. The reactions proceeded smoothly under ligand-free conditions in the presence of TBAB to give the corresponding products in good yields. The protocol showed good tolerance toward a variety of functional groups. A substrate-promoted mechanism for this catalytic reaction has been proposed.

A simple and mild method for the coupling of aryl halides with amino alcohols and diamines is described. The reactions can be performed under ligand-free and solvent-free conditions, and generate the products in good yield.

Rational designed novel thiazolidiones were synthesized and evaluated for antibiofilm activity. The active derivatives were not only potent inhibitors of Staphylococcus epidermidis biofilm growth but also efficient antibacterial agents. 3f showed 4-fold higher activity (6.25 μM) in the biofilms dispersal assay and significantly higher antibacterial activity (MIC 3.125 μM) in comparison to the 3-(5-((6- (ethoxycarbonyl)-5-(benzo[1,3]dioxol-5-yl)-3-oxo-7-phenyl- thiazolo[3,2-a]pyrimidin-2(5H)-ylidene)methyl)furan-2-yl)benzoic acid (1).Research highlights► 17 thiazolidione derivatives were designed, synthesized and evaluated as novel antibiofilm agents. ► The bioactivity study revealed that 9 compounds showed comparable or superior activities to that of compound 1. ► The structure-activity relationships (SAR) of the thiazolidione in the context of antibiofilm activity were probed in this article. ► The 3f showed a 4-fold higher activity (6.25 μM) and significantly higher antibacterial activity (MIC = 3.125 μM) in comparison to compound 1.

A series of novel 2-arylimino-3-aryl-thiazolidine-4-ones was designed, synthesized and tested for in vitro antibiofilm activity against Staphylococcus epidermidis. Among them tested, some compounds with carboxylic acid groups showed good antibiofilm activity. The antibiofilm concentration of 1x was 6.25 μM. The structure–activity relationships revealed that incorporation of 2-phenylfuran moiety could greatly enhance antibiofilm activity of thiazolidine-4-one.The minimal inhibitory concentration (MIC), minimal bactericidal concentration (MBC) and antibiofilm concentration assay of 1x were 6.25 μM, 25 μM and 6.25 μM against Staphylococcus epidermidis, respectively.