Pharmaceutical Chemistry Research Laboratory I, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi - 221005, India.
Institute of Pharmacy, Harish Chandra PG College, Varanasi, India.
Bioorg Chem. 2024 Feb;143:107082. doi: 10.1016/j.bioorg.2023.107082. Epub 2024 Jan 2.
The multi-target directed ligand (MTDL) discovery has been gaining immense attention in the development of therapeutics for Alzheimer's disease (AD). The strategy has been evolved as an auspicious approach suitable to combat the heterogeneity and the multifactorial nature of AD. Therefore, multi-targetable chalcone derivatives bearing N-aryl piperazine moiety were designed, synthesized, and evaluated for the treatment of AD. All the synthesized compounds were screened for thein vitro activityagainst acetylcholinesterase (AChE), butylcholinesterase (BuChE), β-secretase-1 (BACE-1), and inhibition of amyloid β (Aβ) aggregation. Amongst all the tested derivatives, compound 41bearing unsubstituted benzylpiperazine fragment and para-bromo substitution at the chalcone scaffold exhibited balanced inhibitory profile against the selected targets. Compound 41 elicited favourable permeation across the blood-brain barrier in the PAMPA assay. The molecular docking and dynamics simulation studies revealed the binding mode analysis and protein-ligand stability ofthe compound with AChE and BACE-1. Furthermore,itameliorated cognitive dysfunctions and signified memory improvement in thein-vivobehavioural studies (scopolamine-induced amnesia model). Theex vivobiochemical analysis of mice brain homogenates established the reduced AChE and increased ACh levels. The antioxidant activity of compound 41 was accessed with the determination of catalase (CAT) and malondialdehyde (MDA) levels. The findings suggested thatcompound 41, containing a privileged chalcone scaffold, can act as a lead molecule for developing AD therapeutics.
多靶标导向配体（MTDL）的发现在阿尔茨海默病（AD）治疗药物的开发中受到了极大的关注。该策略已演变为一种有前途的方法，适合对抗 AD 的异质性和多因素性质。因此，设计、合成了具有 N-芳基哌嗪部分的多靶标查耳酮衍生物，并对其进行了治疗 AD 的评价。所有合成的化合物均进行了体外乙酰胆碱酯酶（AChE）、丁酰胆碱酯酶（BuChE）、β-分泌酶-1（BACE-1）活性筛选以及抑制淀粉样β（Aβ）聚集活性筛选。在所测试的衍生物中，化合物 41 具有未取代的苄基哌嗪片段和查尔酮骨架上的对位溴取代基，对所选靶标表现出平衡的抑制谱。化合物 41 在 PAMPA 测定中表现出有利的血脑屏障通透性。分子对接和动力学模拟研究揭示了化合物与 AChE 和 BACE-1 的结合模式分析和蛋白-配体稳定性。此外，它在体内行为研究（东莨菪碱诱导的健忘症模型）中改善了认知功能障碍并显著改善了记忆。小鼠脑匀浆的体外生化分析建立了 AChE 的降低和 ACh 水平的增加。通过测定过氧化氢酶（CAT）和丙二醛（MDA）水平评估了化合物 41 的抗氧化活性。研究结果表明，含有特权查尔酮骨架的化合物 41 可以作为开发 AD 治疗药物的先导分子。
