Abstract:
In this study, Antarctic Latrunculia sponge-derived discorhabdin G was considered a hit for developing potential lead compounds acting as cholinesterase inhibitors. The hypothesis on the pharmacophore moiety suggested through molecular docking allowed us to simplify the structure of the metabolite. ADME prediction and drug-likeness consideration provided valuable support in selecting 5-methyl-2H-benzo[h]imidazo[1,5,4-de]quinoxalin-7(3H)-one as a candidate molecule. It was synthesized in a four-step sequence starting from 2,3-dichloronaphthalene-1,4-dione and evaluated as an inhibitor of electric eel acetylcholinesterase (eeAChE), human recombinant AChE (hAChE), and horse serum butyrylcholinesterase (BChE), together with other analogs obtained by the same synthesis. The candidate molecule showed a slightly lower inhibitory potential against eeAChE but better inhibitory activity against hAChE than discorhabdin G, with a higher selectivity for AChEs than for BChE. It acted as a reversible competitive inhibitor, as previously observed for the natural alkaloid. The findings from the in vitro assay were relatively consistent with the data available from the AutoDock Vina and Protein-Ligand ANTSystem (PLANTS) calculations.
摘要:
在这项研究中,南极Latrunculia海绵衍生的discorhabdinG被认为是开发潜在的先导化合物作为胆碱酯酶抑制剂的打击。通过分子对接提出的关于药效基团部分的假设使我们能够简化代谢物的结构。ADME预测和药物相似性考虑为选择5-甲基-2H-苯并[h]咪唑并[1,5,4-de]喹喔啉-7(3H)-酮作为候选分子提供了宝贵的支持。它是从2,3-二氯萘-1,4-二酮开始的四步合成,并被评估为鳗鱼乙酰胆碱酯酶(eeAChE)的抑制剂,人重组AChE(hAChE),和马血清丁酰胆碱酯酶(BChE),与通过相同合成获得的其他类似物一起。候选分子对eeAChE的抑制潜力略低,但对hAChE的抑制活性优于discorhabdinG,对AChE的选择性高于对BChE的选择性。它充当可逆的竞争性抑制剂,正如以前观察到的天然生物碱。来自体外测定的发现与可从AutoDockVina和蛋白质-配体ANTSystem(PLANTS)计算获得的数据相对一致。