Design and synthesis of novel spirocyclic oxindole based hybrid scaffolds: in silico docking approach towards therapeutic target exploration

Abstract

The isatin derivatives exhibit various pharmacological activities, including antihypertensive, anti-inflammatory, and ACE-inhibitory effects. The synthetic flexibility of isatin makes it valuable for synthesising various heterocycles, including pharmacologically potent spirocyclic derivatives. In this paper, an efficient procedure is employed for the synthesis of novel alkyne-appended spiro[indoline-3,3′-pyrrolizin]-2-one derivatives (6–8) as a potential anti-inflammatory agent predicted by molecular docking via a catalyst-free reaction from alkyne isatin, the starting material. Subsequently, these compounds were treated with the azide derivative of isatin to get the triazolated derivatives (11–14), which were further reacted with L-hydroxyproline in ethanol in the presence of InCl₃ as a catalyst to get the final products (15–19). Molecular docking studies of all the synthesised ligands were carried out to examine the interactions of the ligands with the active sites of the COX-2, a key enzyme in the inflammatory pathways responsible for prostaglandin synthesis. All the synthesised compounds have shown good binding affinity towards the targeted enzyme. Herein, compound 19 displayed the highest binding affinity, −10.3 kcal mol⁻¹, among all the synthesised compounds. Thus, the synthesised compound holds the potential to exhibit anti-inflammatory activity similar to that of celecoxib, the standard reference drug.