Synthesis and Evaluation of 1,2,4-oxadiazolidinones: The Search for Potential non-β-lactam β-lactamase Inhibitors.

β-lactam antibiotics have been the most widely used drug of choice to combat infectious disease caused by bacteria. Unfortunately, the effectiveness of these antibiotics is drastically threatened by bacterial β-lactamases. β-lactamases are currently responsible for the resistance to most β-lactam antibiotic drugs. For decades, β-lactam β-lactamases inhibitors have been used to reduce bacterial resistance, however, in this study, we will employ the use of 1,2,4-oxadiazolidinone derivatives as a non-β-lactam β-lactamases inhibitor against TEM-1 and P99 β-lactamases. The significance of oxadiazolidinone is the prominent five-membered ring in its structure, which is configurationally stable and present in other biologically active compounds such as linezolid and avibactam. Oxadiazolidinones were synthesized in two steps procedure using nitroalkanes and benzaldehyde as starting materials to produce nitrones, which in turn undergo 1,3- dipolar cycloaddition with substituted isocyanates to give the desired 1,2,4-oxadiazolidin analogs (2a, 2b, 2c and 3). Each product was purified and characterized using 1H NMR and 13C NMR, GC-MS, IR, and UV/Vis analysis. Following their successful synthesis and structural elucidation, they were tested with TEM-1 and P99 serine β-lactamase using Nitrocefin as the substrate to ascertain their effectiveness against β-lactamase. 2a, 2b, 2c and 3 showed inhibition ranging from 12-38 %