新型 Sunifiram 氨基甲酸酯类化合物作为潜在的双重乙酰胆碱酯酶抑制剂和 NMDAR 共激动剂：基于模拟指导的类似物设计和药理学筛选。
Novel Sunifiram-carbamate hybrids as potential dual acetylcholinesterase inhibitor and NMDAR co-agonist: simulation-guided analogue design and pharmacological screening.
机构信息
Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, Fayoum University, Fayoum, Egypt.
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
出版信息
J Enzyme Inhib Med Chem. 2022 Dec;37(1):1241-1256. doi: 10.1080/14756366.2022.2068147.
An efficient method for synthesising NMDAR co-agonist Sunifiram (DM235), in addition to Sunifram-carbamate and anthranilamide hybrids, has been developed in high yields protecting group-free stepwise unsymmetric diacylation of piperazine using -acylbenzotiazole. Compounds , and exhibited promising nootropic activity by enhancing acetylecholine (ACh) release in A549 cell line. Moreover, the carbamate hybrid was found to exhibit higher potency than donepezil with IC = 18 ± 0.2 nM, 29.9 ± 0.15 nM for and donepezil, respectively. was also found to effectively inhibit AChE activity in rat brain (AChE = 1.266 ng/mL) compared to tacrine (AChE = 1.137 ng/ml). An assessment of the ADMET properties revealed that compounds and are drug-like and can penetrate blood-brain barrier. Findings presented here showcase highly potential cholinergic agents, with expected partial agonist activity towards glycine binding pocket of NMDAR which could lead to development and optimisation of novel nootropic drugs.
已开发出一种高效的方法来合成 NMDAR 共激动剂 Sunifiram（DM235），以及 Sunifram-氨基甲酸酯和邻苯二甲酰亚胺类混合物，采用 -酰基苯并噻唑对哌嗪进行无保护基逐步不对称二酰化反应，可高产率得到目标产物。化合物 、 和 通过增强 A549 细胞系中的乙酰胆碱（ACh）释放，表现出有前景的益智活性。此外，氨基甲酸酯类混合物 被发现比多奈哌齐具有更高的效力，其 IC = 18 ± 0.2 nM，而 和多奈哌齐的 IC = 分别为 29.9 ± 0.15 nM。与他克林（AChE = 1.137ng/ml）相比， 还被发现可有效抑制大鼠脑中的 AChE 活性（AChE = 1.266ng/mL）。对 ADMET 性质的评估表明，化合物 和 具有类药性，可穿透血脑屏障。这里呈现的研究结果展示了具有高度潜力的胆碱能药物，对 NMDAR 的甘氨酸结合口袋具有预期的部分激动剂活性，这可能导致新型益智药物的开发和优化。
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