Design, Synthesis, and Bioactivity Evaluations of 3-Methylenechroman-2-one Derivatives as Thioredoxin Reductase (TrxR) Inhibitors

Abstract

We aimed to design and synthesize 3-methylenechroman-2-one derivatives and test their potency as TrxR1 inhibitors. A convenient and easy-to-handle synthetic approach to 3-methylenechroman-2-ones was developed. The in vitro inhibitory activity towards recombinant TrxR1 was determined for the obtained compounds. The most potent representatives exhibited submicromolar TrxR1 inhibition activity (IC₅₀ varied from 0.29 μM to 10.2 μM). Structure-activity relationship analysis indicates the beneficial role of the substituent at the position C-6 of the core of chroman-2-one, where the derivatives containing halogen are the most active among the scope of compounds obtained. The most potent TrxR1 inhibitor of the series was further examined in in vitro cell-based assays to assess cytotoxic effects on various cancer cell lines, and to evaluate their influence on cell apoptosis.

Keywords: 3-Methylenechroman-2-one; Michael acceptors; TrxR inhibitors.