Synthesis and evaluation of tetrahydrobarbazoles targeting the b sliding clamp

The β sliding clamp is an emerging antibiotic target that increases the transcription rate and processivity of the bacterial replisome1. Blocking the protein-interaction interface with small molecules should prevent the protein from interacting with polymerases, leading to SOS response and eventually to cell death. We have synthesized a series of racemic tetrahydrocarbazoles based on a literature inhibitor2 that probe this binding pocket and have tested them towards the E.coli b-clamp using saturation transfer difference NMR-based assay. To obtained binders with higher activity enantiopure derivatives were synthesized starting with a classical resolution. Although, binding to the b-clamp is confirmed, the compounds have low activity in culture, possibly due to poor cell wall penetration. Instead, the fluoro-containing compounds prepared are now evaluated as probes in NMR-based screening methods for identifying new b-clamp inhibitors.