Synthetic Progress Towards Ring Expanded 2,3,4,9-tetrahydro 1H-carbazol-1 amines as Antivirulence Agents for UPEC
Activation of the CpxRA system in Gram-negative bacteria reduces excretion of virulence factors in multiple infectious pathogens. 2,3,4,9-tetrahydro 1H-carbazol-1 amines are known to inhibit CpxA phosphatase activity, thus activating the CpxRA system in Escherichia coli. A first-generation structure-activity relationship (SAR) established compound 26 as a hit compound, with an EC50 of 1.1 μM. Here, we report the ongoing synthesis for a second-generation SAR with two main focuses: C-ring expansion/contraction and C-ring conjugation. Because of the necessity of the (R) configuration at the C1 amine for activity, this approach emphasizes minor changes to the position of said amine in three-dimensional space and the subsequent effect on activity.