Spiro thiochromene–oxindoles as novel anti-inflammatory agents: design, sustainable synthesis, in vitro and in silico evaluations

Abstract

A one-pot, acid-, base-, and metal-free, multicomponent strategy has been developed to synthesize spiro thiochromene–oxindole derivatives as potential anti-inflammatory agents. The synthesized compounds were screened in vitro for their anti-inflammatory activity by inhibiting heat-induced Bovine Serum Albumin (BSA) denaturation assay, revealing moderate to good efficacy. Compounds 4e, 4k, and 4h exhibited the highest activity, inhibiting BSA denaturation by 90.97–95.45% at 800 μg mL⁻¹ concentration with half maximal inhibitory concentration (IC₅₀) values of 127.477 ± 2.285, 190.738 ± 3.561, and 285.806 ± 8.894 μg mL⁻¹, respectively. For mechanistic insights in silico studies were conducted, revealing binding affinities of the active compounds with cyclooxygenase-2 (COX-2) protein, with binding energies of −8.9 kcal mol⁻¹ (4e), −8.7 kcal mol⁻¹ (4k), and −8.6 kcal mol⁻¹ (4h). Bioactivity and pharmacokinetic parameters were further analyzed, encompassing ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) characteristics. This study highlights the potential of spiro thiochromene–oxindoles as anti-inflammatory agents, warranting further exploration as potential leads. The synthetic strategy for these target compounds utilizes taurine as an eco-friendly bio-organic catalyst, facilitating an acid-, base-, and metal-free intramolecular C–S and C–C bond formation in aqueous media. The reaction involves a one-pot, three-component Knoevenagel–Thia-Michael cascade between substituted isatins, 1,3-dicarbonyls, and 2-naphthalene thiol. Key features of this green protocol include high yields, cost-efficiency, non-toxicity, atom economy, and acid-, base-, and metal-free synthesis in water. Additionally, the catalyst exhibits excellent reusability, maintaining its activity across three cycles with easy recovery, while product isolation is achieved through simple filtration, eliminating the need for chromatographic purification and organic solvents. These attributes underscore this approach's synthetic and environmental advantages, highlighting its potential for broader application in the development of anti-inflammatory agents.