10.1016/j.ejmech.2011.04.011
The research focuses on the development of second-generation sulfonamide inhibitors targeting the D-glutamic acid-adding enzyme (MurD), a key enzyme in bacterial cell wall synthesis and an important antibacterial drug-discovery target. The study aimed to optimize the activity of these inhibitors by incorporating conformationally rigid analogues of D-glutamic acid into their structure, hypothesizing that molecular rigidification would enhance binding affinity and inhibitory activity. The researchers synthesized two series of new sulfonamide inhibitors based on naphthalene-N-sulfonyl-DGlu derivatives and evaluated their inhibitory activities against MurD from E. coli. The most active compounds showed significantly better inhibitory activities than the parent compounds, confirming the advantage of molecular rigidification in the design of MurD inhibitors. High-resolution NMR spectroscopy and X-ray crystallography were used to examine the binding modes of the best inhibitors, providing valuable insights for further development of potential antibacterial sulfonamide inhibitors. Chemicals used in the process included various naphthalene-N-sulfonyl-DGlu derivatives, rigidified D-glutamic acid mimetics, and other reagents necessary for the synthesis and testing of these inhibitors.
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