Design, Synthesis, and Evaluation of β‑Lactamase Inhibitors as Potential Therapeutics for Antimicrobial Resistance

Antimicrobial resistance is a global health threat affecting millions of people worldwide. The situation has been exacerbated by the emergence of β-lactamase enzymes that can hydrolyze the β-lactam rings within the antibiotics. This makes antibiotics incapable of preventing bacterial infections. The abuse of β-lactam antibiotics is instigating bacterial resistance, thus causing the antibiotics to fail. There is a need to develop newer drugs that can tackle these β-lactamases and overcome bacterial infections. Thienopyrimidines have exhibited diverse biological activities as promising potent antibacterial agents. We synthesized a wide array of substituted thienopyrimidines using a highly divergent approach to introduce different groups involving Suzuki and Sonogashira coupling reactions, aromatic nucleophilic substitution, and alkylation reactions. Novel thienopyrimidines were tested against Pseudomonas aeruginosa and Staphylococcus aureus, showed inhibitory activity, and were further tested for β-lactamase activity. In-depth investigation revealed that 4-(2-(tert-butyl)-thieno-[2,3-d]-pyrimidin-4-yl)-morpholine demonstrated exceptional results compared to cefixime (control). To evaluate the compound's potency in combination therapy, synergistic effects were observed when imipenem was administered alongside our potent compound, resulting in a significantly enhanced minimum inhibitory effect against clinical isolates of S. aureus. The findings from this study hold substantial pharmacological significance in addressing the growing threat of bacterial resistance, particularly associated with β-lactamase enzymes.