Miliutina Mariia, Ejaz Syeda Abida, Khan Shafi Ullah, Iaroshenko Viktor O, Villinger Alexander, Iqbal Jamshed, Langer Peter
Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany.
Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad, Pakistan.
Eur J Med Chem. 2017 Jan 27;126:408-420. doi: 10.1016/j.ejmech.2016.11.036. Epub 2016 Nov 17.
New and convenient methods for the functionalization of the 4-quinolone scaffold at positions C-1, C-3 and C-6 were developed. The 4-quinolone derivatives were evaluated for their inhibitory potential on alkaline phosphatase isozymes. Most of the compounds exhibit excellent inhibitory activity and moderate selectivity. The IC values on tissue non-specific alkaline phosphatase (TNAP) were in the range of 1.34 ± 0.11 to 44.80 ± 2.34 μM, while the values on intestinal alkaline phosphatase (IAP) were in the range of 1.06 ± 0.32 to 192.10 ± 3.78 μM. The most active derivative exhibits a potent inhibition on IAP with a ≈14 fold higher selectivity as compared to TNAP. Furthermore, molecular docking calculations were performed for the most potent inhibitors to show their binding interactions within the active site of the respective enzymes.
开发了在4-喹诺酮骨架的C-1、C-3和C-6位进行官能化的新型便捷方法。对4-喹诺酮衍生物对碱性磷酸酶同工酶的抑制潜力进行了评估。大多数化合物表现出优异的抑制活性和适度的选择性。对组织非特异性碱性磷酸酶（TNAP）的IC值在1.34±0.11至44.80±2.34μM范围内，而对肠碱性磷酸酶（IAP）的值在1.06±0.32至192.10±3.78μM范围内。活性最高的衍生物对IAP表现出强效抑制作用，与TNAP相比，选择性高约14倍。此外，对最有效的抑制剂进行了分子对接计算，以显示它们在各自酶活性位点内的结合相互作用。
