DESIGN, SYNTHESIS, SPECTRAL CHARACTERIZATION, AND STRUCTURE–ACTIVITY RELATIONSHIP STUDIES OF NOVEL SULFAMETHOXAZOLE-BASED THIAZOLIDINONE DERIVATIVES AS POTENTIAL ANTIBACTERIAL AGENTS

Background: The rapid emergence of antimicrobial resistance has significantly reduced the therapeutic effectiveness of existing antibiotics, creating an urgent need for the development of new antibacterial agents. Sulfonamides, particularly Sulfamethoxazole, remain important due to their inhibition of bacterial folic acid biosynthesis; however, increasing resistance has limited their clinical utility. Objective: The present study aimed to design, synthesize, characterize, and evaluate novel sulfamethoxazole derivatives containing Schiff base, thiazolidinone, and chalcone pharmacophores for enhanced antibacterial activity. Methods: A series of sulfamethoxazole derivatives were synthesized through a multistep synthetic pathway. Initially, sulfamethoxazole was condensed with substituted benzaldehydes to form Schiff base intermediates (M1). These intermediates were cyclized with thioglycolic acid to obtain thiazolidinone derivatives (M2), which were further modified to produce chalcone analogues (M3a–f). The synthesized compounds were characterized using Fourier-transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance (¹H-NMR), and elemental (CHNS) analysis. Antibacterial activity was evaluated in vitro against selected Gram-positive and Gram-negative bacterial strains. Results: Spectral and elemental analyses confirmed the successful synthesis of the target compounds. Biological evaluation revealed that several synthesized derivatives exhibited improved antibacterial activity compared to sulfamethoxazole. Structure–activity relationship (SAR) studies demonstrated that compounds containing electron-withdrawing substituents such as –Cl and –NO₂ showed superior antibacterial activity, while electron-donating substituents produced moderate effects. The incorporation of thiazolidinone and chalcone moieties significantly enhanced biological activity. Conclusion: The synthesized sulfamethoxazole derivatives demonstrated promising antibacterial potential, particularly those bearing electron-withdrawing substituents. The study suggests that structural modification of sulfamethoxazole through incorporation of Schiff base, thiazolidinone, and chalcone pharmacophores may provide an effective strategy for the development of novel antibacterial agents to combat antimicrobial resistance.