Jahan Humera, Choudhary Muhammad I, Shah Zarbad, Khan Khalid M, Rahman Atta-Ur
Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan.
Department of Chemistry, Bacha Khan University Charsadda, Khyber Pukhtoonkhwa, Pakistan.
Med Chem. 2017;13(6):577-584. doi: 10.2174/1573406413666170216150158.
Benzimidazoles are important pharmacophores in drug discovery, and currently its derivatives such as flubendazole, omeprazole, and astemizole are used for the treatment of anthelmintic, ulcerative, and histaminic diseases, respectively.
The aim of the current study was to investigate the antiglycation activity of nitrobenzimidazole derivatives against fructose-mediated human serum albumin (HSA) glycation. The study was also aimed at investigating the effects of newly identified antiglycation inhibitors on AGEsinduced intracellular reactive oxygen species (ROS) production, and associated impaired proliferation of the hepatocytes.
The present study focuses on the antiglycation activity of 6-nitrobenzimidazole derivatives 1-13 in in-vitro human serum albumin (HSA)- fructose model. These derivatives were also identified as non-toxic against 3T3 mouse fibroblast cell-line in MTT-based assay. The effect of the most promising derivative 5, 4-(6-nitro-1H-benzimidazol-2-yl)-1,2,3-benzenetriol, was studied in a dose dependent manner, co-incubated with fructose-derived AGEs (0- 200 μg/mL) on rat hepatocytes proliferation and associated intracellular generation of ROS via MTT-based assay and DCFHDA technique, respectively.
We found that derivative 5 ameliorates the elevated intracellular oxidative stress and associated diminished proliferation of the hepatocytes in response to AGEs.
In conclusion, we identified novel 6-nitrobenzimidazole derivatives as antiglycation agents through in-vitro, and cell-based models.
苯并咪唑是药物研发中重要的药效基团，目前其衍生物如氟苯达唑、奥美拉唑和阿司咪唑分别用于治疗驱虫、溃疡性和组胺性疾病。
本研究旨在探究硝基苯并咪唑衍生物对果糖介导的人血清白蛋白（HSA）糖基化的抗糖基化活性。该研究还旨在研究新发现的抗糖基化抑制剂对晚期糖基化终产物（AGEs）诱导的细胞内活性氧（ROS）生成以及肝细胞相关增殖受损的影响。
本研究聚焦于6-硝基苯并咪唑衍生物1-13在体外人血清白蛋白（HSA）-果糖模型中的抗糖基化活性。在基于MTT的实验中，这些衍生物对3T3小鼠成纤维细胞系也被鉴定为无毒。以剂量依赖方式研究了最有前景的衍生物5, 4-(6-硝基-1H-苯并咪唑-2-基)-1,2,3-苯三醇，分别通过基于MTT的实验和DCFHDA技术，与果糖衍生的AGEs（0-200μg/mL）共同孵育，观察其对大鼠肝细胞增殖及相关细胞内ROS生成的影响。
我们发现衍生物5可改善AGEs引起的细胞内氧化应激升高及肝细胞相关增殖减少的情况。
总之，我们通过体外和细胞模型鉴定出新型6-硝基苯并咪唑衍生物为抗糖基化剂。
