Synthesis and evaluation of novel dihydropyrimidine–oxadiazole hybrid scaffolds as anticholinesterase agents: SAR and in-silico studies

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-07-04 DOI:10.1016/j.bmcl.2025.130327

Ramesh Ambatwar , Pooja Singh , Lokesh Chandrakar , Suman Ghosh , Ashok K. Datusalia , Gopal L. Khatik

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Abstract

Alzheimer's disease (AD) is the most prevalent form of dementia all around the globe and currently poses a significant challenge to the healthcare system. Currently, available drugs only slow the progression of this disease rather than provide a proper cure for it. Acetylcholinesterase (AChE) enzyme is mainly responsible for the progression of AD, and its management can be done by developing its inhibitors, such as anticholinesterases. We have synthesized a series of novel dihydropyrimidine–oxadiazole hybrids (8a–8ad) via one-pot economic Biginelli reaction using cobalt perchlorate catalyst. The synthesized compounds were subjected to anticholinesterase activity, which showed promising inhibition of the AChE enzyme. Among all the compounds, 8u (IC₅₀ = 0.050 ± 0.007 μM) and 8v (IC₅₀ = 0.057 ± 0.004 μM) were found to be the most potent. Furthermore, molecular docking and molecular dynamics simulations were employed to gain deeper insights into the interactions at the enzyme's active site. The results demonstrated that the compound exhibited conformational stability similar to the reference inhibitor, donepezil.

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新型抗胆碱酯酶药物二氢嘧啶-恶二唑杂化支架的合成与评价：合成孔径及硅基研究。

阿尔茨海默病（AD）是全球最普遍的痴呆症形式，目前对医疗保健系统构成了重大挑战。目前，可用的药物只能减缓这种疾病的进展，而不能为它提供适当的治疗。乙酰胆碱酯酶（AChE）是AD发展的主要原因，其控制可以通过开发其抑制剂，如抗胆碱酯酶来完成。以高氯酸钴为催化剂，通过一锅经济Biginelli反应合成了一系列新的二氢嘧啶-恶二唑杂化合物（8a-8ad）。合成的化合物具有抗胆碱酯酶活性，对乙酰胆碱酯酶具有良好的抑制作用。在所有的化合物8 u (IC₅₀ = 0.050 ±0.007  μM)和8 v (IC₅₀ = 0.057 ±0.004  μM)被发现是最有效的。此外，采用分子对接和分子动力学模拟来深入了解酶活性位点的相互作用。结果表明，该化合物具有与参比抑制剂多奈哌齐相似的构象稳定性。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.