Design, Synthesis, and Antimicrobial Activity Evaluation of 5-(3/4-Hydroxybenzylidene)thiazolidine-2,4-dione Derivatives

Thiazolidine-2,4-dione (TZD), a privileged scaffold, is a versatile pharmacophore and outstanding sulphur-containing heterocyclic compound found in various drugs. In this work, forty-two substituted 5-arylidene-1,3-thiazolidine-2,4-diones derivatives have been designed and synthesized by introducing sulfonyl groups, benzoyl groups, and amide groups into 5-(3/4-hydroxybenzylidene)thiazolidine-2,4-dione through Knoevenagel condensation, and their antibacterial activities were evaluated in vitro. As a result, thirty-five compounds were new compounds, and seven compounds were known compounds. The in vitro assay results disclosed that compared with B/C-series, A-series compounds presented remarkable antimicrobial activity against S. aureus, E. faecalis, and E. faecium. All twenty-one synthesized A-series compounds exhibited excellent antibacterial activity against S. aureus (MIC80 ≤ 128 µg/mL). Among these, three compounds demonstrated the highest anti-E. faecalis activities (MIC80 = 8 µg/mL), while E. faecium showed antibacterial susceptibility to A-series compounds except two of the investigated compounds p-cyanophenyl and p-trifluoromethoxyphenyl substituted sulfonate esters. In contrast, the B-series displayed limited activity, with only three compounds showing measurable anti-S. aureus effects, among which substituted phenyl benzoates exhibited the best antibacterial action against E. faecium (MIC80 = 64 µg/mL). The C-series compounds demonstrated the weakest activity profile, with two N-substituted acetamides (N-phenyl and N-methylphenyl) displaying moderate anti-S. aureus activity (MIC80 = 128 µg/mL), which merely compound N-o-nitrophenyl was sensitive to E. faecalis (MIC80 = 256 µg/mL). SAR analysis revealed that synthetic TZD-derivatives with substituted sulfonyl groups significantly enhanced antibacterial activity against all tested Gram-positive bacterial strains. These molecules may serve as lead compounds for developing more effective and less toxic antibacterial agents.