2. Academic Validation
  3. Bioactive Indanes: Design, synthesis and bioactivity investigation of 2,2-substituted Indane derivatives, a new bioactive Indane scaffold

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

  • Bioorg Chem. 2025 Mar 9:159:108352. doi: 10.1016/j.bioorg.2025.108352.
Tao Zhang 1,  Kit Chan 2,  Abdulilah Ece 3,  Robin Daly 4,  Aoife Cannon 5,  Gaia A Scalabrino 6,  Neil Frankish 7,  Jacintha O'Sullivan 8,  Padraig Fallon 9,  Helen Sheridan 10
Affiliations

Affiliations

  • 1 School of Food Science and Environmental Health, Technological University Dublin, Grangegorman, Dublin 7, Ireland; Trino Therapeutics Ltd, The Tower, Trinity Technology and Enterprise Campus, Dublin 2, Ireland.; Drug Discovery Group, School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. Electronic address: tao.zhang@TUDublin.ie.
  • 2 Drug Discovery Group, School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. Electronic address: chanki@tcd.ie.
  • 3 Department of Medical Biochemistry, Faculty of Medicine, Biruni University, İstanbul TR-34015, Türkiye. Electronic address: aece@biruni.edu.tr.
  • 4 Drug Discovery Group, School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. Electronic address: dalyro@tcd.ie.
  • 5 Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Dublin 8, Ireland. Electronic address: cannona@tcd.ie.
  • 6 Trino Therapeutics Ltd, The Tower, Trinity Technology and Enterprise Campus, Dublin 2, Ireland.; The Trinity Centre for Natural Products Research (NatPro), School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland. Electronic address: scalabrg@tcd.ie.
  • 7 Trino Therapeutics Ltd, The Tower, Trinity Technology and Enterprise Campus, Dublin 2, Ireland.; Drug Discovery Group, School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. Electronic address: nfrnkish@tcd.ie.
  • 8 Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Dublin 8, Ireland. Electronic address: osullij4@tcd.ie.
  • 9 School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. Electronic address: pfallon@tcd.ie.
  • 10 Trino Therapeutics Ltd, The Tower, Trinity Technology and Enterprise Campus, Dublin 2, Ireland.; Drug Discovery Group, School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; Department of Medical Biochemistry, Faculty of Medicine, Biruni University, İstanbul TR-34015, Türkiye; The Trinity Centre for Natural Products Research (NatPro), School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland. Electronic address: hsheridn@tcd.ie.
PMID: 40090151 DOI: 10.1016/j.bioorg.2025.108352
Abstract

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.

Keywords

5-LOX inhibitors; Bi-benzyl indanes; Cytotoxicity screening; Inflammatory bowel disease (IBD); Molecular dynamics; Structure-activity relationships.

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