Spirooxindole Derivatives as Emerging Scaffolds in Drug Discovery: Synthetic Strategies, Structure–Activity Relationship, and Biological Activities

Abstract

Spirooxindoles are a class of spirocyclic scaffolds in drug discovery, as the rigid frame and well‐defined substitution pattern can interact with various biological targets. Recent advances in synthetic methodologies, including multicomponent 1,3‐dipolar cycloadditions, organocatalytic cascades, and one‐pot protocols, have facilitated the efficient synthesis of a wide variety of derivatives for SAR studies. A diverse range of classes, including pyrrolidine, cyclopropyl carboxamide, carbamate, oxadiazoline, pyrrolizidine, and furan derivatives, show cytotoxicity in the submicromolar‐to‐low micromolar range with good selectivity. The SAR studies suggest that substitution on the isatin core generally enhances biological activity in individual series, especially with electron‐withdrawing groups, but these effects are scaffold dependent. Furthermore, spirooxindole derivatives have been reported to show antibacterial activity, including TrpRS inhibition, antimicrobial, acetylcholinesterase inhibition, α‐glucosidase inhibition, antiviral, and anticonvulsant activities. The recent patents, especially on MDM2 inhibitors and other anticancer agents with nanomolar potency, provide further evidence for the continued interest in spirooxindole‐based drug discovery. This review highlights the recent advancements in spirooxindole chemistry involving synthetic strategies, SAR, biological activities, and recent patents.