Antioxidant properties of Knoevenagel-type indoles

Indole compounds represent a valuable scaffold in medicinal chemistry being embedded in several pharmacologically active molecules including anti-inflammatory, analgesic, plant growth regulator, antimicrobial, anticonvulsant, antifungal, antihistamine and antioxidant agents. The reactivity of the atypical Vilsmeier reagent I (obtained in situ by the reaction of benzoyl chloride and DMF), allowed the isolation of Knovenagel-type indoles (KtIs) 1 through a two-step, one-pot procedure. The reaction involved the formation of iminium salt intermediates II that were reacted with a proper active methylene reagent to afford the regioselective synthesis of desired compounds. Selected KtIs showed nanomolar antiproliferative activity against leukaemia, breast and renal cancer cell lines and tubulin was identified as a potential pharmacological target for the active compounds. To further investigate the pharmacological potential of KtIs and test the versatility of the developed procedure, a small library of differently substituted compounds was prepared (derivatives 1a-g). The synthesized KtIs bear modifications on the indole substructure (i.e., R and W groups) as well as different substituents of the exocyclic double bond (X and Y groups). The cytotoxicity against SH-SY5Y neuroblastoma cells and the antioxidant properties of derivatives 1a-g were preliminary evaluated by MTT and DPPH assay, respectively. The collected biological results and the derived structure-activity relationships will be discussed. The current work has been funded by European Union - Next Generation EU, PRIN 2022, project code 2022EM9P43, CUP D53D23011750006