Gebeş-Alperen Büşra, Evren Asaf Evrim, Sağlik Özkan Begüm Nurpelin, Karaburun Ahmet Cagri, Gundogdu-Karaburun Nalan
Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Anadolu University, 26470 Eskişehir, Turkey.
ACS Omega. 2025 Jul 22;10(30):32829-32843. doi: 10.1021/acsomega.5c01432. eCollection 2025 Aug 5.
Neurological disorders represent a significant burden on human health, particularly as global life expectancy continues to rise. Among these conditions, Alzheimer's disease is notably prevalent. Of greater concern, if left untreated or unaddressed, Alzheimer's disease can progress to dementia, leading to severe cognitive decline and a substantial reduction in quality of life. In this study, 15 novel benzofuran-azacyclic hybrids were designed and synthesized. The final compounds were evaluated for their inhibitory potency on AChE and BACE-1 enzymes, and in silico studies were performed to clarify their binding modes. Finally, structure-activity relationships (SARs) were proposed for future studies. The results indicated that the most promising compound is , which contains -(2-hydroxyethyl)-piperazine and benzofuran moieties. These moieties effectively occupied the substrate channel of the AChE enzyme and the catalytic cleft of the BACE-1 enzyme. Additionally, compounds (benzyl piperidine) and (2-furoyl piperazine) showed dual inhibitory activity on both enzymes. In conclusion, the tubular form with a stopper group shows great potential for the treatment of Alzheimer's disease, as it blocks the entrance cavity of the AChE active pocket for the substrate and increases the stability of the inactive BACE-1 enzyme. Moreover, electrolytes, specifically sodium ions in this case, play a crucial role in stabilizing the -BACE-1 protein complex. For further studies, we suggest that the tubular form with a stopper can serve as a potential pharmacophore and an appropriate starting point for drug development.
神经疾病给人类健康带来了巨大负担，尤其是在全球预期寿命持续上升的情况下。在这些疾病中，阿尔茨海默病尤为普遍。更令人担忧的是，如果不进行治疗或处理，阿尔茨海默病会发展为痴呆症，导致严重的认知衰退和生活质量大幅下降。在本研究中，设计并合成了15种新型苯并呋喃 - 氮杂环杂化物。对最终化合物进行了乙酰胆碱酯酶（AChE）和β - 分泌酶1（BACE - 1）酶抑制活性评估，并进行了计算机模拟研究以阐明其结合模式。最后，提出了构效关系（SARs）以供未来研究。结果表明，最有前景的化合物是 ，它含有 -（2 - 羟乙基）- 哌嗪和苯并呋喃部分。这些部分有效地占据了AChE酶的底物通道和BACE - 1酶的催化裂隙。此外，化合物 （苄基哌啶）和 （2 - 呋喃甲酰哌嗪）对两种酶均表现出双重抑制活性。总之，带有封端基团的管状形式在治疗阿尔茨海默病方面显示出巨大潜力，因为它阻断了AChE活性口袋中底物的入口腔，并增加了无活性BACE - 1酶的稳定性。此外，电解质，在这种情况下特别是钠离子，在稳定 -BACE - 1蛋白复合物中起着关键作用。对于进一步的研究，我们建议带有封端的管状形式可作为潜在的药效团和药物开发的合适起点。
