Design and synthesis of sorbicillinoid-derived bibenzyl and brominated analogues as anti-inflammatory agents

Sorbicillinoids, a class of Fungal metabolites, have shown promising anti-inflammatory activity. Considering the importance of the biphenyl pharmacophore in anti-inflammatory agents and the favorable role of halogenation in optimizing drug-like properties, we designed and synthesized a series of novel sorbicillinoid derivatives. This study reports the first preparation of 12 sorbicillinoid-based bibenzyl analogues and two brominated sorbicillinoid analogues. Their anti-inflammatory effects were assessed in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages by measuring nitric oxide (NO) production and the expression of key inflammation-related proteins. Most analogues inhibited NO release and downregulated the expression of these proteins to varying degrees. Notably, the bibenzyl analogue 1i exhibited dose-dependent suppression of NO production, with potency comparable to the lead compound JNUTS013 (12a). Furthermore, 1i exerted superior activity in suppressing the expression of iNOS, COX-2, and NLRP3, and showed a strong binding affinity with NLRP3 (-6.76 kcal/mol). These findings highlight 1i as a promising anti-inflammatory lead compound and its underlying mechanism may involve the interaction with NLRP3.