Identification of benzofused five-membered sultams, potent dual NOD1/NOD2 antagonists in vitro and in vivo

Nucleotide-binding oligomerization domain-containing proteins 1 and 2 play important roles in immune system activation. Recently, a shift has occurred due to the emerging knowledge that preventing nucleotide-binding oligomerization domains (NODs) signaling could facilitate the treatment of some cancers, which warrants the search for dual antagonists of NOD1 and NOD2. Herein, we undertook the synthesis and identification of a new class of derivatives of dual NOD1/NOD2 antagonists with novel benzofused five-membered sultams. Compound 14k was finally demonstrated to be the most potent molecule that inhibits both NOD1-and NOD2-stimulated NF-κB and MAPK signaling in vitro and in vivo. [Display omitted] •A new class of dual NOD1/NOD2 antagonists based on a novel benzofused five-membered sultam skeleton was synthesized.•Compound 14k exhibited promising potent inhibitory activity against NOD1/2 in vitro (IC50 = 1.05/0.93 μM).•Compound 14k had moderate inhibition effect on cytokine production in response to stimulation with MDP in vivo.