Kaur Avneet, Wakode Sharad, Pathak Dharam P, Sharma Vidushi, Shakya Ashok K
Department of Pharmaceutical Chemistry, Delhi Institute of Pharmaceutical Sciences and Research (DIPSAR), Mehrauli-Badarpur Road, PushpVihar, Sector-3, New Delhi-110017, India.
Faculty of Pharmacy & Medical Sciences, Al-Ahliyya Amman University, PO BOX 263, Amman 19328, Jordan.
Med Chem. 2018;14(7):660-673. doi: 10.2174/1573406414666180322091832.
Non-steroidal anti-inflammatory drugs are widely used for many years, but the chronic use of NSAID's leads to gastric side effects, ulceration and kidney problems. These side effects are due to non-selective inhibition of COX-2 along with COX-1. Therefore, it is imperative to develop novel and selective COX-2 inhibitors.
In this paper wehave synthesized a series of novel hybrids comprising of substituted-N- (3,4,5-trimethoxyphenyl)-benzo[d]oxazole derivatives and screened for the treatment of inflammation.
The structures of the obtained compounds were elucidated by elemental and spectral analysis (ATR-FTIR, 1H NMR, 13C NMR, Mass spectroscopy). All of the compounds were evaluated for cyclooxygenase (COX-1/COX-2) inhibitory activity by in vitro enzymatic assay. The compound which showed COX-2 activity (3a - 3e, 3g - 3h, 3k, 3m and 3o) was further screened for in vivo anti-inflammatory activity and ulcerogenic liability. Molecular docking study was also performed with resolved crystal structure of COX-2 to understand the binding mechanism of newly synthesized inhibitors in the active site of COX-2enzyme.
The in vitro COX-1 and COX-2 inhibitory studies showed that the synthesized compounds potentially inhibited COX-2 (IC50 = 0.04 - 26.41 µM range) over COX-1 (IC50 = 0.98 - 33.33 µM range). The in vivo studies predicted that compounds 3c (70.9%, 0.6±0.22), 3m (68.1%, 1.9±0.41) and 3o (70.4%, 1.7±0.27) produced more efficacy against carrageenan induced paw edema and less ulcerogenic effect, as compared to standard ibuprofen (65.9%, 2.2±0.44). The results of docking studies were found to be concordant with the biological evaluation studies of the prepared compound.
Among all the tested compounds, 2-Chloro-N-(2-(3,4,5-trimethoxyphenyl)- benzo[d]oxazol-5-yl)-benzamide (3c) was the most potent anti-inflammatory agent and has less ulcerogenic potential. This series of compound can be explored more for development of safer and more active anti-inflammatory agents.
非甾体抗炎药已广泛使用多年，但长期使用非甾体抗炎药会导致胃部副作用、溃疡和肾脏问题。这些副作用是由于对COX - 2和COX - 1的非选择性抑制所致。因此，开发新型选择性COX - 2抑制剂势在必行。
本文合成了一系列由取代的N - （3,4,5 - 三甲氧基苯基） - 苯并[d]恶唑衍生物组成的新型杂化物，并对其进行抗炎治疗筛选。
通过元素分析和光谱分析（ATR - FTIR、1H NMR、13C NMR、质谱）阐明所得化合物的结构。通过体外酶促试验评估所有化合物的环氧化酶（COX - 1/COX - 2）抑制活性。对显示COX - 2活性的化合物（3a - 3e、3g - 3h、3k、3m和3o）进一步进行体内抗炎活性和致溃疡倾向筛选。还利用COX - 2的解析晶体结构进行分子对接研究，以了解新合成抑制剂在COX - 2酶活性位点的结合机制。
体外COX - 1和COX - 2抑制研究表明，合成的化合物对COX - 2（IC50 = 0.04 - 26.41 μM范围）的抑制作用优于COX - 1（IC50 = 0.98 - 33.33 μM范围）。体内研究预测，与标准布洛芬（65.9%，2.2±0.44）相比，化合物3c（70.9%，0.6±0.22）、3m（68.1%，1.9±0.41）和3o（70.4%，1.7±0.27）对角叉菜胶诱导的爪肿胀产生的疗效更高，且致溃疡作用更小。对接研究结果与所制备化合物的生物学评价研究结果一致。
在所有测试化合物中，2 - 氯 - N - （2 - （3,4,5 - 三甲氧基苯基） - 苯并[d]恶唑 - 5 - 基） - 苯甲酰胺（3c）是最有效的抗炎剂，且致溃疡潜力较小。这一系列化合物可进一步探索用于开发更安全、更有效的抗炎剂。
