Department of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran.
Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
Mol Divers. 2022 Feb;26(1):489-503. doi: 10.1007/s11030-021-10307-2. Epub 2021 Sep 7.
A new series of quinolotacrine hybrids including cyclopenta- and cyclohexa-quinolotacrine derivatives were designed, synthesized, and assessed as anti-cholinesterase (ChE) agents. The designed derivatives indicated higher inhibitory effect on the acetylcholinesterase (AChE) with IC values of 0.285-100 µM compared to butyrylcholinesterase (BChE) with IC values of > 100 µM. Of these compounds, cyclohexa-quinolotacrine hybrids displayed a little better anti-AChE activity than cyclopenta-quinolotacrine hybrids. Compound 8-amino-7-(3-hydroxyphenyl)-5,7,9,10,11,12-hexahydro-6H-pyrano[2,3-b:5,6-c'] diquinolin-6-one (6m) including 3-hydroxyphenyl and cyclohexane ring moieties exhibited the best AChE inhibitory activity with IC value of 0.285 µM. The kinetic and molecular docking studies indicated that compound 6m occupied both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE as a mixed inhibitor. Using neuroprotective assay against HO-induced cell death in PC12 cells, the compound 6h illustrated significant protection among the assessed compounds. In silico ADME studies estimated good drug-likeness for the designed compounds. As a result, these quinolotacrine hybrids can be very encouraging AChE inhibitors to treat Alzheimer's disease. A novel series of quinolotacrine hybrids were designed, synthesized, and evaluated against AChE and BChE enzymes as potential agents for the treatment of AD. The hybrids showed good to significant inhibitory activity against AChE (0.285-100 μM) compared to butyrylcholinesterase (BChE) with IC values of > 100 μM. Among them, compound 8-amino-7-(3-hydroxyphenyl)-5,7,9,10,11,12-hexahydro-6H-pyrano[2,3-b:5,6-c'] diquinolin-6-one (6 m) bearing 3-hydroxyphenyl moiety and cyclohexane ring exhibited the highest anti-AChE activity with IC value of 0.285 μM. The kinetic and molecular docking studies illustrated that compound 6 m is a mixed inhibitor and binds to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE.
设计、合成了一系列新的喹喔啉并吖啶类化合物，包括环戊基和环己基喹喔啉并吖啶衍生物，并将其评估为抗胆碱酯酶（ChE）药物。与对丁酰胆碱酯酶（BChE）的抑制作用（IC 值大于 100μM）相比，设计的衍生物对乙酰胆碱酯酶（AChE）的抑制作用更强，IC 值为 0.285-100μM。这些化合物中，环己基喹喔啉并吖啶类化合物对 AChE 的抑制活性略优于环戊基喹喔啉并吖啶类化合物。含 3-羟基苯基和环己烷环的 8-氨基-7-(3-羟基苯基)-5,7,9,10,11,12-六氢-6H-吡喃并[2,3-b:5,6-c']二喹啉-6-酮（6m）表现出最好的 AChE 抑制活性，IC 值为 0.285μM。动力学和分子对接研究表明，化合物 6m 作为一种混合抑制剂，占据 AChE 的催化阴离子部位（CAS）和外周阴离子部位（PAS）。在评估化合物对 PC12 细胞中 HO 诱导的细胞死亡的神经保护作用时，化合物 6h 在评估的化合物中表现出显著的保护作用。基于计算机的 ADME 研究估计了设计化合物具有良好的类药性。因此，这些喹喔啉并吖啶类化合物可能是治疗阿尔茨海默病非常有希望的 AChE 抑制剂。设计、合成了一系列新型喹喔啉并吖啶类化合物，用作潜在的 AD 治疗药物，以 AChE 和 BChE 酶为靶点进行了评估。与对丁酰胆碱酯酶（BChE）的抑制作用（IC 值大于 100μM）相比，这些化合物对乙酰胆碱酯酶（AChE）具有良好到显著的抑制活性（IC 值为 0.285-100μM）。其中，含 3-羟基苯基和环己烷环的 8-氨基-7-(3-羟基苯基)-5,7,9,10,11,12-六氢-6H-吡喃并[2,3-b:5,6-c']二喹啉-6-酮（6m）表现出最高的 AChE 抑制活性，IC 值为 0.285μM。动力学和分子对接研究表明，化合物 6m 是一种混合抑制剂，与 AChE 的催化阴离子部位（CAS）和外周阴离子部位（PAS）结合。
