Raigar Ashok Kumar, Saini Kamlesh, Jyoti Nirmal, Kapavarapu Ravi Kumar, Guleria Anjali
Department of Chemistry, University of Rajasthan Jaipur-302004 Rajasthan India
Department of Pharmaceutical Chemistry and Phytochemistry, Nirmala College of Pharmacy Atmakur Mangalgiri Andhra Pradesh India.
RSC Adv. 2025 Jan 2;15(1):261-275. doi: 10.1039/d4ra07990f.
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 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 concentration with half maximal inhibitory concentration (IC) values of 127.477 ± 2.285, 190.738 ± 3.561, and 285.806 ± 8.894 μg mL, respectively. For mechanistic insights studies were conducted, revealing binding affinities of the active compounds with cyclooxygenase-2 (COX-2) protein, with binding energies of -8.9 kcal mol (4e), -8.7 kcal mol (4k), and -8.6 kcal mol (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.
已开发出一种一锅法、无酸、无碱、无金属的多组分策略来合成螺硫代色烯-氧化吲哚衍生物，作为潜在的抗炎剂。通过抑制热诱导的牛血清白蛋白（BSA）变性试验对合成的化合物进行抗炎活性筛选，结果显示出中等至良好的效果。化合物4e、4k和4h表现出最高活性，在800μg/mL浓度下抑制BSA变性率为90.97 - 95.45%，半数最大抑制浓度（IC）值分别为127.477±2.285、190.738±3.561和285.806±8.894μg/mL。为了深入了解作用机制，进行了相关研究，揭示了活性化合物与环氧合酶-2（COX-2）蛋白的结合亲和力，结合能分别为-8.9 kcal/mol（4e）、-8.7 kcal/mol（4k）和-8.6 kcal/mol（4h）。进一步分析了生物活性和药代动力学参数，包括ADMET（吸收、分布、代谢、排泄和毒性）特征。这项研究突出了螺硫代色烯-氧化吲哚作为抗炎剂的潜力，值得作为潜在先导物进行进一步探索。这些目标化合物的合成策略利用牛磺酸作为一种环保的生物有机催化剂，在水性介质中促进无酸、无碱、无金属的分子内C-S和C-C键形成。该反应涉及取代靛红、1,3 - 二羰基化合物和2 - 萘硫醇之间的一锅法三组分Knoevenagel - Thia - Michael级联反应。这种绿色方法的关键特性包括高产率、成本效益、无毒、原子经济性以及在水中无酸、无碱、无金属的合成。此外，该催化剂表现出优异的可重复使用性，在三个循环中保持其活性且易于回收，同时通过简单过滤即可实现产物分离，无需色谱纯化和有机溶剂。这些特性强调了该方法在合成和环境方面的优势，突出了其在抗炎剂开发中更广泛应用的潜力。
