Benek Ondrej, Soukup Ondrej, Pasdiorova Marketa, Hroch Lukas, Sepsova Vendula, Jost Petr, Hrabinova Martina, Jun Daniel, Kuca Kamil, Zala Dominykas, Ramsay Rona R, Marco-Contelles José, Musilek Kamil
Department of Toxicology and Military Pharmacy, Department of Epidemiology, Faculty of Military Health Sciences, University of Defense, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic.
National Institute of Mental Health, Topolova 748, 250 67, Klecany, Czech Republic.
ChemMedChem. 2016 Jun 20;11(12):1264-9. doi: 10.1002/cmdc.201500383. Epub 2015 Oct 2.
Novel indolotacrine analogues were designed, synthesized, and evaluated as potential drugs for the treatment of Alzheimer's disease. By using a multitarget-directed ligand approach, compounds were designed to act simultaneously as cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors. The compounds were also evaluated for antioxidant, cytotoxic, hepatotoxic, and blood-brain barrier (BBB) permeability properties. Indolotacrine 9 b (9-methoxy-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-amine) showed the most promising results in the in vitro assessment; it is a potent inhibitor of acetylcholinesterase (AChE IC50 : 1.5 μm), butyrylcholinesterase (BChE IC50 : 2.4 μm) and MAO A (IC50 : 0.49 μm), and it is also a weak inhibitor of MAO B (IC50 : 53.9 μm). Although its cytotoxic (IC50 : 5.5±0.4 μm) and hepatotoxic (IC50 : 1.22±0.11 μm) profiles are not as good as those of the standard 7-methoxytacrine (IC50 : 63±4 and 11.50±0.77 μm, respectively), the overall improvement in the inhibitory activities and potential to cross the BBB make indolotacrine 9 b a promising lead compound for further development and investigation.
设计、合成了新型吲哚他辛类似物，并将其作为治疗阿尔茨海默病的潜在药物进行评估。通过多靶点导向配体方法，设计的化合物可同时作为胆碱酯酶（ChE）和单胺氧化酶（MAO）抑制剂发挥作用。还对这些化合物的抗氧化、细胞毒性、肝毒性和血脑屏障（BBB）通透性进行了评估。吲哚他辛9 b（9-甲氧基-2,3,4,6-四氢-1H-吲哚并[2,3-b]喹啉-11-胺）在体外评估中显示出最有前景的结果；它是乙酰胆碱酯酶（AChE IC50：1.5 μm）、丁酰胆碱酯酶（BChE IC50：2.4 μm）和MAO A（IC50：0.49 μm）的强效抑制剂，也是MAO B的弱抑制剂（IC50：53.9 μm）。尽管其细胞毒性（IC50：5.5±0.4 μm）和肝毒性（IC50：1.22±0.11 μm）不如标准的7-甲氧基他克林（分别为IC50：63±4和11.50±0.77 μm），但抑制活性的总体改善以及穿过血脑屏障的潜力使吲哚他辛9 b成为进一步开发和研究的有前景的先导化合物。
