Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi 221 005, India.
Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi 221 005, India.
Bioorg Chem. 2019 Aug;89:103025. doi: 10.1016/j.bioorg.2019.103025. Epub 2019 May 31.
The novel hybrids bearing 4-aminopyridine (4-AP) tethered with substituted 1,3,4-oxadiazole nucleus were designed, synthesized, and evaluated for their potential AChE inhibitory property along with significant antioxidant potential. The inhibitory potential (IC) of synthesized analogs was evaluated against human cholinesterases (hAChE and hBChE) using Ellman's method. Among all the compounds, 9 with 4-hydroxyl substituent showed maximum hAChE inhibition with the non-competitive type of enzyme inhibition (IC = 1.098 µM; Ki = 0.960 µM). Further, parallel artificial membrane permeation assay (PAMPA-BBB) showed significant BBB permeability in most of the synthesized compounds. Meanwhile, compound 9 also inhibited AChE-induced Aβ aggregation (38.2-65.9%) by thioflavin T assay. The in vivo behavioral studies showed dose-dependent improvement in learning and memory by compound 9. The ex vivo studies also affirmed the significant AChE inhibition and antioxidant potential of compound 9 in brain homogenates.
新型杂合化合物被设计、合成并评价了其对乙酰胆碱酯酶（AChE）的抑制作用和显著的抗氧化潜力，这些化合物的核中带有取代的 1,3,4-恶二唑和 4-氨基吡啶（4-AP）。使用 Ellman 法评估了合成类似物对人胆碱酯酶（hAChE 和 hBChE）的抑制潜力。在所有化合物中，带有 4-羟基取代基的 9 号化合物对 hAChE 的抑制作用最强，为非竞争性酶抑制类型（IC=1.098µM；Ki=0.960µM）。此外，平行人工膜渗透测定（PAMPA-BBB）显示大多数合成化合物具有显著的 BBB 通透性。同时，化合物 9 还通过硫代黄素 T 测定抑制了 AChE 诱导的 Aβ聚集（38.2-65.9%）。体内行为研究表明，化合物 9 可剂量依赖性地改善学习和记忆能力。离体研究也证实了化合物 9 在脑匀浆中具有显著的 AChE 抑制和抗氧化潜力。
