Discovery of Quinazolin-4(3 H)-ones as NLRP3 Inflammasome Inhibitors: Computational Design, Metal-Free Synthesis, and in Vitro Biological Evaluation.

NLRP3 inflammasome is an important therapeutic target for a number of human diseases. Herein, computationally designed series of quinazolin-4(3 H)-ones were synthesized using iodine-catalyzed coupling of arylalkynes (or styrenes) with O-aminobenzamides. The key event in this transformation involves the oxidative cleavage of the C-C triple/double bond and the release of formaldehyde. The reaction relies on the C-N bond formation along with the C-C bond cleavage under metal-free conditions. The nitro-substituted quinazolin-4(3 H)-one 2k inhibited NLRP3 inflammasome (IC 5 μM) via the suppression of IL-1β release from ATP-stimulated J774A.1 cells.