Khan Muhammad T, Nadeem Humaira, Khan Arif-Ullah, Abbas Muzaffar, Arif Muazzam, Malik Nadia Shamshad, Malik Zulkifal, Javed Ibrahim
Department of Pharmaceutical Chemistry, Riphah International University, Islamabad, Pakistan.
Department of Pharmacology, Riphah International University, Islamabad, Pakistan.
Drug Dev Res. 2020 Dec;81(8):1057-1072. doi: 10.1002/ddr.21728. Epub 2020 Aug 11.
Benzimidazole is an important pharmacophore for clinically active drugs against inflammation and treatment of pain, however, it is associated with gastrointestinal side effects. Here we synthesized benzimidazole based agents with significant analgesic/anti-inflammatory potential but with less gastrointestinal adverse effects. In this study, we synthesized novel, orally bioavailable 2-mercaptobenzimidazole amino acid conjugates (4a-4o) and screened them for analgesic, anti-inflammatory and gastro-protective effects. The synthesized 2-mercaptbenzimidazole derivatives were characterized for their structure using FTIR, H NMR and C NMR spectroscopic techniques. The 2-mercaptobenzimidazole amino acid conjugates have found to possess potent analgesic, anti-inflammatory and gastroprotective activities, particularly with compound 4j and 4k. Most of the compounds exhibited remarkable anti-ulcer and antisecretory effects. Molecular docking studies were carried out to study the binding affinities and interactions of the synthesized compounds with target proteins COX-2 (PDB ID: 3LN1) and H /K -ATPase (PDB ID: 5Y0B). Our results support the clinical promise of these newly synthesized 2-mercaptobezimidazol conjugates as a component of therapeutic strategies for inflammation and analgesia, for which the gastric side effects are always a major limitation.
苯并咪唑是用于治疗炎症和疼痛的临床活性药物的重要药效基团，然而，它会引发胃肠道副作用。在此，我们合成了具有显著镇痛/抗炎潜力但胃肠道副作用较小的基于苯并咪唑的药物。在本研究中，我们合成了新型的、口服生物可利用的2-巯基苯并咪唑氨基酸缀合物（4a - 4o），并对它们的镇痛、抗炎和胃保护作用进行了筛选。使用傅里叶变换红外光谱（FTIR）、氢核磁共振（¹H NMR）和碳核磁共振（¹³C NMR）光谱技术对合成的2-巯基苯并咪唑衍生物的结构进行了表征。已发现2-巯基苯并咪唑氨基酸缀合物具有强效的镇痛、抗炎和胃保护活性，尤其是化合物4j和4k。大多数化合物表现出显著的抗溃疡和抗分泌作用。进行了分子对接研究，以研究合成化合物与靶蛋白环氧化酶-2（COX-2，蛋白质数据银行ID：3LN1）和氢/钾-ATP酶（蛋白质数据银行ID：5Y0B）的结合亲和力及相互作用。我们的结果支持了这些新合成的2-巯基苯并咪唑缀合物作为炎症和镇痛治疗策略组成部分的临床前景，而胃副作用一直是此类治疗的主要限制因素。
