Synthesis and evaluation of antibacterial activity of new thieno[2,3-d]pyrimidine hybrid compounds targeting dihydropteroate synthase to combat antibiotic resistance.

The rising threat of antibiotic resistance demands innovative approaches to combat infectious diseases. This study explores new thieno[2,3-d]pyrimidine-based hybrid compounds targeting dihydropteroate synthase (DHPS), a critical enzyme in bacterial folate synthesis but absent in human cells. The compounds were designed using bioisosteric replacements and spacer variations. Biological evaluations revealed promising activity against Staphylococcus aureus. Compounds 5b, 14a, and 14b exhibited potent antibacterial effects with MIC values as low as 4 μg/mL for 5b. Time-dependent killing studies demonstrated rapid bactericidal action, superior to vancomycin for 5b and 14b. Additionally, these compounds disrupted biofilm formation and eradicated established biofilms. Plasma stability assays showed reduced efficacy in complex fluids, indicating potential challenges in clinical application. Notably, resistance development against 5b was minimal, underscoring its potential as a durable antimicrobial agent. This study underscores the promise of targeting conserved DHPS sites in developing effective treatments for resistant Gram-positive infections while addressing biofilm-related challenges in chronic infections.