PeQuiM - Laboratory of Research in Medicinal Chemistry, Institute of Chemistry, Federal University of Alfenas, MG 37133-840, Brazil.
Laboratory of Molecular Pharmacology, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, RJ 21941-902, Brazil.
Bioorg Med Chem. 2022 Oct 1;71:116952. doi: 10.1016/j.bmc.2022.116952. Epub 2022 Aug 1.
The search for new drug candidates against Alzheimer's disease (AD) remains a complex challenge for medicinal chemists due to its multifactorial pathogenesis and incompletely understood physiopathology. In this context, we have explored the molecular hybridization of pharmacophore structural fragments from known bioactive molecules, aiming to obtain a novel molecular architecture in new chemical entities capable of concomitantly interacting with multiple targets in a so-called multi-target directed ligands (MTDLs) approach. This work describes the synthesis of 4-hydroxymethyl)piperidine-N-benzyl-acyl-hydrazone derivatives 5a-l, designed as novel MTDLs, showing improved multifunctional properties compared to the previously reported parent series of N-benzyl-(3-hydroxy)piperidine-acyl-hydrazone derivatives 4. The new improved derivatives were studied in silico, regarding their mode of interaction with AChE enzyme, and in vitro, for evaluation of their effects on the selective inhibition of cholinesterases, cellular antioxidant, and neuroprotective activities as their cytotoxicity in human neuroblastoma (SH-SY5Y) cells. Overall, compound PQM-181 (5 k) showed the best balanced selective and non-competitive inhibition of AChE (IC = 5.9 μM, SI > 5.1), with an additional antioxidant activity (IC = 7.45 µM) against neuronal t-BOOH-induced oxidative stress and neuroprotective ability against neurotoxicity elicited by both t-BOOH and OAβ, and a moderate ability to interfere in Aβ aggregates, with low cytotoxicity and good predictive druggability properties, suggesting a multifunctional pharmacological profile suitable for further drug development against AD.
由于阿尔茨海默病（AD）的发病机制复杂，病理生理学尚未完全阐明，因此寻找新的抗 AD 药物仍然是医学化学家面临的一项复杂挑战。在这种情况下，我们探索了已知生物活性分子的药效团结构片段的分子杂交，旨在获得一种新的分子结构，这种结构能够在新的化学实体中同时与多个靶标相互作用，这就是所谓的多靶标导向配体（MTDL）方法。本工作描述了 4-羟甲基）哌啶-N-苄基酰基腙衍生物 5a-l 的合成，设计为新型 MTDL，与之前报道的 N-苄基（3-羟基）哌啶酰腙衍生物 4 的母体系列相比，显示出更好的多功能特性。新的改进衍生物在计算机上研究了它们与 AChE 酶相互作用的模式，以及在体外研究了它们对选择性抑制胆碱酯酶、细胞抗氧化和神经保护活性的影响，以及它们在人神经母细胞瘤（SH-SY5Y）细胞中的细胞毒性。总的来说，化合物 PQM-181（5k）对 AChE 的选择性和非竞争性抑制作用最好（IC=5.9μM，SI>5.1），具有额外的抗氧化活性（IC=7.45µM），可对抗神经元 t-BOOH 诱导的氧化应激和 t-BOOH 和 OAβ 引起的神经毒性的神经保护作用，以及适度的干扰 Aβ 聚集的能力，具有低细胞毒性和良好的预测药物特性，表明具有多功能药理学特征，适合进一步开发治疗 AD 的药物。
