Yt Kamal, Gautam Girendra Kumar, Mishra Arun Kumar, Parveen Baby Rabiya, Kumar Arvind, Singh Mhaveer, Singh Harpreet
Drug Design Laboratory, School of Pharmaceutical Sciences, IFTM University, 244102, Moradabad, India.
Department of Pharmaceutical Chemistry, Shri Ram College of Pharmacy, Muzaffarnagar, 251001, India.
Heliyon. 2024 Nov 15;10(22):e40300. doi: 10.1016/j.heliyon.2024.e40300. eCollection 2024 Nov 30.
The present study is aimed to investigate the anti-inflammatory activities of thirteen substituted-isoxazole derivatives (5a-5m). Isoxazole is a key pharmacophore in medicinal chemistry, known for its broad range of pharmacological activities.This study explores the synthesis and anti-inflammatory potential of thirteen substituted-isoxazole derivatives (5a-5m), with and being novel compounds.
The primary objectives were to synthesize some novel substituted isoxazole derivatives, evaluate their interaction with cyclooxygenase (COX-1/2) enzymes through computational methods, and assess their anti-inflammatory effectiveness in laboratory animals.
Substituted chalcones (0.01 mol) (2a-2m), sodium ethoxide (0.01 mol), and hydroxylamine hydrochloride (0.01 mol) were dissolved in absolute ethanol (15 ml), and then the mixture was refluxed for 6 h in an oil bath and monitored by TLC (ethyl acetate:hexane 7:3 v/v as eluent; a UV lamp was used to visualize the plates). After the completion of the reaction, as per TLC, the contents of the reaction mixture were poured into ice-cold water (50 ml). The obtained precipitates were filtered, washed two times, dried for 2 h at room temperature, and then recrystallized with ethenol. The structures of these compounds were confirmed via Fourier transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance (H NMR) spectroscopy, carbon-13 nuclear magnetic resonance (C NMR) spectroscopy, and mass spectrometry. Anti-inflammatory activity was evaluated using the carrageenan-induced rat paw edema method.
The results indicated that three compounds ( and ) demonstrated significant anti-inflammatory potential (% edema inhibition 75.68, 74.48, & 71.86 in 2 h and 76.71, 75.56, & 72.32 in 3 h) with modest effectiveness (0.83, 0.81 & 0.71), low toxicity, and minimal adverse effects. The molecular docking analyses further elucidated the interaction with the active site COX-2 enzyme (PDB ID: 4COX) using Autodock Vina. The compounds and -8.7, -8.5, and -8.4 indicate good binding affinity (kcal/mol) and H-bond interaction with residues such as Cys41, Ala151, and Arg120 for COX-2, which also carried out RMSD values of 2.174, 41.13, and 22.25, which are decisive for the reported anti-inflammatory activity of diverse compounds.
The findings indicate that isoxazole derivatives have modest antiinflammatory potential, with compounds ( and ) acting as lead molecules to be studied further for pain relief with fewer adverse effects.
本研究旨在探究13种取代异恶唑衍生物（5a - 5m）的抗炎活性。异恶唑是药物化学中的关键药效基团，以其广泛的药理活性而闻名。本研究探索了13种取代异恶唑衍生物（5a - 5m）的合成及抗炎潜力，其中[具体化合物]为新化合物。
主要目的是合成一些新型取代异恶唑衍生物，通过计算方法评估它们与环氧化酶（COX - 1/2）的相互作用，并在实验动物中评估其抗炎效果。
将取代查耳酮（0.01 mol）（2a - 2m）、乙醇钠（0.01 mol）和盐酸羟胺（0.01 mol）溶解于无水乙醇（15 ml）中，然后将混合物在油浴中回流6小时，并通过薄层色谱法（TLC）监测（以乙酸乙酯:己烷7:3 v/v作为洗脱剂；用紫外灯观察薄板）。反应完成后，根据TLC结果，将反应混合物的内容物倒入冰冷的水（50 ml）中。所得沉淀物经过过滤、洗涤两次、在室温下干燥2小时，然后用乙醇重结晶。这些化合物的结构通过傅里叶变换红外光谱（FT - IR）、质子核磁共振（H NMR）光谱、碳 - 13核磁共振（C NMR）光谱和质谱进行确认。使用角叉菜胶诱导的大鼠足爪肿胀法评估抗炎活性。
结果表明，三种化合物（[具体化合物]）具有显著的抗炎潜力（2小时内水肿抑制率分别为75.68%、74.48%和71.86%，3小时内分别为76.71%、75.56%和72.32%），有效性适中（0.83、0.81和0.71），毒性低，不良反应最小。分子对接分析使用Autodock Vina进一步阐明了与活性位点COX - 2酶（PDB ID: 4COX）的相互作用。化合物[具体化合物]的结合亲和力良好（- 8.7、- 8.5和- 8.4 kcal/mol），与COX - 2的Cys41、Ala151和Arg120等残基存在氢键相互作用，其RMSD值分别为2.174、41.13和22.25，这些值对于多种化合物报道的抗炎活性具有决定性意义。
研究结果表明异恶唑衍生物具有适度的抗炎潜力，化合物（[具体化合物]）作为先导分子有待进一步研究以减轻疼痛且不良反应较少。
