Sharma Himadri, Sharma Niti, An Seong Soo A
Department of Bionano Technology, Gachon Bionano Research Institute, Gachon University, 1342 Seongnam-daero, Sujeong-gu, Seongnam-si 461-701, Gyeonggi-do, Republic of Korea.
Molecules. 2025 Jul 26;30(15):3138. doi: 10.3390/molecules30153138.
The present study investigated the neuroprotective potential of the carbazole derivatives murrayanol, mahanimbine, murrayafoline A, and 9-methyl-9H-carbazole-2-carbaldehyde using in silico and in vitro assays. The pharmacokinetic properties and potential toxicity (ADME/T) of the carbazole derivatives were assessed to evaluate their prospects as up-and-coming drug candidates. Molecular docking was used to investigate the interactions of the compounds with Aβ (PDB: 1IYT, 2BEG, and 8EZE) and AChE receptors (PDB: 4EY7 and 1C2B). The results from the in vitro assays were used to validate and support the findings from the in silico assays. The compounds demonstrated significant inhibition of acetylcholinesterase (AChE), a key target in neurodegenerative disorders. Murrayanol and mahanimbine presented superior inhibitory activity (IC ~0.2 μg/mL), outperforming the reference drug, galantamine. The inhibition mechanisms were competitive (murrayanol, murrayafoline A, and 9-methyl-9H-carbazole-2-carbaldehyde) and non-competitive (mahanimbine), supported by low Ki values and strong docking affinities. The compounds also proved effective in reducing Aβ fibrillization (murrayanol: 40.83 ± 0.30%; murrayafoline A: 33.60 ± 0.55%, mahanimbine: 27.68 ± 2.71%). These findings highlight carbazoles as promising scaffolds for multifunctional agents in AD therapy. Further optimization and mechanistic studies are warranted to advance their development into clinically relevant neuroprotective agents.
本研究使用计算机模拟和体外实验，研究了咔唑衍生物米仔兰醇、马汉九里香碱、九里香叶碱A和9-甲基-9H-咔唑-2-甲醛的神经保护潜力。评估了咔唑衍生物的药代动力学性质和潜在毒性（ADME/T），以评估它们作为新兴药物候选物的前景。利用分子对接研究了这些化合物与Aβ（蛋白质数据银行编号：1IYT、2BEG和8EZE）及乙酰胆碱酯酶受体（蛋白质数据银行编号：4EY7和1C2B）的相互作用。体外实验结果用于验证和支持计算机模拟实验的结果。这些化合物对乙酰胆碱酯酶（AChE）有显著抑制作用，而乙酰胆碱酯酶是神经退行性疾病中的一个关键靶点。米仔兰醇和马汉九里香碱表现出卓越的抑制活性（IC50约为0.2μg/mL），优于参比药物加兰他敏。抑制机制为竞争性（米仔兰醇、九里香叶碱A和9-甲基-9H-咔唑-2-甲醛）和非竞争性（马汉九里香碱），低Ki值和强对接亲和力证明了这一点。这些化合物还被证明能有效减少Aβ纤维化（米仔兰醇：40.83±0.30%；九里香叶碱A：33.60±0.55%，马汉九里香碱：27.68±2.71%）。这些发现凸显了咔唑作为阿尔茨海默病治疗中多功能药物的有前景的骨架。有必要进行进一步优化和机制研究，以推动其发展成为临床相关的神经保护剂。
