Synthesis and Bioactivity of Novel Inhibitors for Type III Secretion System of Pseudomonas aeruginosa PAO1

Pseudomonas aeruginosa PAO1 is a Gram-negative, opportunistic bacterial human pathogen which infects immunocompromised individuals. The bacterium carries a type III secretion system (T3SS) as a major virulence determinant. The strategy of T3SS inhibitors is to prevent the bacterium from injecting effector proteins into the host, and causing a change in the pathophysiology of the host cells. Based on the structure of a known T3SS inhibitor of P. aeruginosa, 20 new alpha-phenoxyacetamide derivatives have been designed and synthesized, and the structure-activity relationship results for these new derivatives have been discussed. Five derivatives have shown strong inhibitory effect against exoS gene expression of P. aeruginosa, and among them, N-(2-pyridylmethyl)-2-(2,4-dichlorophenoxy)-butanamide (5r) has not only exhibited stronger potency than the known T3SS inhibitor, but also better solubility in aqueous solution.