2,5-Disubstituted 1,3,4-oxadiazoles are privileged versatile scaffolds in medicinal chemistry that have exhibited diverse biological activities. Acetyl- (AChE) and butyrylcholinesterase (BChE) inhibitors are used, e.g., to treat dementias and myasthenia gravis. 5-Aryl-1,3,4-oxadiazoles decorated with dodecyl linked via nitrogen, sulfur or directly to this heterocycle have been designed as potential inhibitors of AChE and BChE. They were prepared from commercially available or in-house prepared hydrazides by reaction with dodecyl isocyanate to form hydrazine-1-carboxamides 2 (yields 67–98%) followed by cyclization using p-toluenesulfonyl chloride and triethylamine in 41–100% yields. Thiadiazole isostere was also synthesized. The derivatives were screened for inhibition of AChE and BChE using Ellman’s spectrophotometric method. The compounds showed a moderate dual inhibition with IC₅₀ values of 12.8–99.2 for AChE and from 53.1 µM for BChE. All the heterocycles were more efficient inhibitors of AChE. The most potent inhibitor, N-dodecyl-5-(pyridin-4-yl)-1,3,4-thiadiazol-2-amine 3t, was subjected to advanced reversibility and type of inhibition evaluation. Structure–activity relationships were identified. Many oxadiazoles showed lower IC₅₀ values against AChE than established drug rivastigmine. According to molecular docking, the compounds interact non-covalently with AChE and BChE and block entry into enzyme gorge and catalytic site, respectively.

中文翻译：

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长烷基修饰的 5-Aryl-1,3,4-oxadiazol-2-amines 及其类似物：合成、乙酰胆碱酯酶和丁酰胆碱酯酶抑制及对接研究

2,5-二取代 1,3,4-恶二唑是药物化学中特殊的多功能支架，具有多种生物活性。乙酰基 (AChE) 和丁酰胆碱酯酶 (BChE) 抑制剂用于例如治疗痴呆和重症肌无力。5-Aryl-1,3,4-oxadiazoles 装饰有十二烷基通过氮、硫或直接连接到该杂环上，已被设计为 AChE 和 BChE 的潜在抑制剂。它们由市售或内部制备的酰肼通过与异氰酸十二烷基酯反应形成肼-1-甲酰胺2（产率 67-98%）然后使用p环化制备-甲苯磺酰氯和三乙胺，产率为 41-100%。还合成了噻二唑等排体。使用 Ellman 分光光度法筛选衍生物对 AChE 和 BChE 的抑制作用。这些化合物显示出中等的双重抑制作用，AChE 的 IC ₅₀值为 12.8–99.2，BChE 的 IC 50 值为 53.1 µM。所有杂环都是更有效的 AChE 抑制剂。对最有效的抑制剂N -dodecyl-5-(pyridin-4-yl)-1,3,4-thiadiazol-2-amine 3t进行了高级可逆性和抑制类型评估。确定了结构-活性关系。许多恶二唑的 IC _50较低抗 AChE 的值高于已建立的药物卡巴拉汀。根据分子对接，这些化合物与 AChE 和 BChE 非共价相互作用，并分别阻止进入酶峡谷和催化位点。