Bioactive Indanes: Design, synthesis and bioactivity investigation of 2,2-substituted Indane derivatives, a new...

The indane scaffold, prevalent in bioactive natural products, underpins numerous therapeutics. Our group developed a series of 1,2-indane dimers, including PH46A (9), for inflammatory and autoimmune diseases. This study details the design, synthesis and characterisation of 21 compounds, including 2,2-disubstituted indanones (16a-16h), indanols (17a-17h), and indanes (18a-18h). These compounds were tested in vitro and in vivo using the murine dextran sulphate sodium (DSS) model of inflammatory bowel disease (IBD). Cytotoxicity screening in THP-1 macrophages and SW480 cells revealed increased cytotoxicity with indene ring substitution at C2, with 18d emerging as potent. In lipoxygenase (LOX) assays, 18a, 18d, and 18c exhibited significant 5-LOX inhibition, with 18d comparable to zileuton. Selective 5-LOX inhibition over 15-LOX indicated distinct ligand-isozyme interactions, potentially informing novel inhibitor development. Cytokine profiling identified compounds with optimal C1 and C2 substituents, particularly 18d, which inhibited IL-6, IL-1β, TNF-α, and IFN-γ in THP-1 macrophages and IL-8 in SW480 cells. In vivo DSS colitis model testing showed significant disease activity index reduction (p < 0.01) with 18d. Subsequent to molecular docking, molecular docking simulations predicted stable binding of 18c and 18d to 5-LOX under mimicked physiological conditions. These findings offer insights into indane-based therapeutic drug development for IBD, highlighting cost reductions by minimising stereochemistry complexity.