EcGUS has drawn considerable attention for its role as a target in alleviating serious GIAEs. In this study, a series of 72 (thio)urea derivatives were designed, synthesised, and biologically assayed. The bioassay results revealed that E-9 (IC₅₀ = 2.68 μM) exhibited a promising inhibitory effect on EcGUS, surpassing EcGUS inhibitor D-saccharic acid-1,4-lactone (DSL, IC₅₀ = 45.8 μM). Additionally, the inhibitory kinetic study indicated that E-9 (K_i = 1.64 μM) acted as an uncompetitive inhibitor against EcGUS. The structure-activity relationship revealed that introducing an electron-withdrawing group into the benzene ring at the para-position is beneficial for enhancing inhibitory activity against EcGUS. Furthermore, molecular docking analysis indicated that E-9 has a strong affinity to EcGUS by forming interactions with residues Asp 163, Tyr 472, and Glu 504. Overall, these results suggested that E-9 could be a potent EcGUS inhibitor, providing valuable insights and guidelines for the development of future inhibitors targeting EcGUS.

With the development of antimicrobial agents, researchers have developed new strategies through key regulatory systems to block the expression of virulence genes without affecting bacterial growth. This strategy can minimize the selective pressure that leads to the emergence of resistance. Quorum sensing (QS) is an intercellular communication system that plays a key role in the regulation of bacterial virulence and biofilm formation. Studies have revealed that the QS system controls 4–6% of the total number of P. aeruginosa genes, and quorum sensing inhibitors (QSIs) could be a promising target for developing new prevention and treatment strategies against P. aeruginosa infection. In this study, four series of phenyloxadiazole and phenyltetrazole sulfoxide derivatives were synthesized and evaluated for their inhibitory effects on P. aeruginosa PAO1 biofilm formation. Our results showed that 5b had biofilm inhibitory activity and reduced the production of QS-regulated virulence factors in P. aeruginosa. In addition, silico molecular docking studies have shown that 5b binds to the P. aeruginosa QS receptor protein LasR through hydrogen bond interaction. Preliminary structure–activity relationship and docking studies show that 5b has broad application prospects as an anti-biofilm compound, and further research will be carried out in the future to solve the problem of microbial resistance.

Bicyclo[n.1.1]alkyl skeletons are of significant interest as bioisosteres of phenyl groups for lead drug modification. Common strategies for their synthesis utilize bicyclo[1.1.0]butanes, wherein the electron-withdrawing groups serve solely as activating groups to facilitate the cleavage of the bridged σ bond, leading to ring expansion by an insertion manner. In this work, we utilize ketones in bicyclo[1.1.0]butane as both activating and reacting groups, promoting a tandem nucleophilic addition/intramolecular Horner-Wadsworth-Emmons olefination process by a distinct exo-cyclic annulation manner. The approach enables the synthesis of diverse bicyclo[2.1.1]hexenes (52 examples, up to 96% yield). A series of transformations have been carried out on bicyclo[2.1.1]hexenes to synthesize bicyclo[2.1.1]hexane/hexene analogues of sonidegib, and the physicochemical properties and anti-tumor activities of these analogues have been investigated. In addition, this approach enables the discovery of aggregation-induced emission properties in this distinctive ring skeleton.