Design, Synthesis, In Silico Evaluation of New 3‐Indolylmethyl Oxindoles

A BF<inf>3</inf>·OEt<inf>2</inf> catalyzed chemo- and regioselective Michael type addition of indoles with ?,?-unsaturated oxindole esters has been developed to synthesize new designed 3-indolylmethyl oxindole scaffolds in excellent yields (61%–88%). Notably, the reaction exhibits high site-selectivity, favoring C-3 indole addition to the ?-position of the enone moiety while retaining full tolerance to the ester functionality. This metal-free protocol offers the first selective access to biologically important NH-free indolyl frameworks in a single step, relevant to naturally occurring indole alkaloids, including those isolated from the indole-3-carbinol-induced culture of Daldinia eschscholzii. In silico studies of the synthesized compounds revealed strong binding affinities to key bacterial enzymes (Staphylococcus aureus FtsZ, Sortase A, Thioredoxin Reductase) and cancer-related human proteins (Bcl-2, KSP, EGFR). Several compounds showed dual-targeting potential, highlighting their promise as multifunctional therapeutic candidates. © 2025 Wiley-VCH GmbH.