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 <i>Pseudomonas aeruginosa</i> and <i>Staphylococcus aureus</i>, showed inhibitory activity, and were further tested for β-lactamase activity. In-depth investigation revealed that 4-(2-(<i>tert</i>-butyl)-thieno-[2,3-<i>d</i>]-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 <i>S. aureus</i>. The findings from this study hold substantial pharmacological significance in addressing the growing threat of bacterial resistance, particularly associated with β-lactamase enzymes.