Department of Pharmacy, School of Health Sciences, Frederick University, Nicosia 1036, Cyprus.
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
Molecules. 2024 Aug 8;29(16):3763. doi: 10.3390/molecules29163763.
Degenerative conditions, such as neurodegenerative disorders (Alzheimer's disease (AD), Parkinson's disease (PD)) and cardiovascular diseases, are complex, multifactorial disorders whose pathophysiology has not been fully elucidated yet. As a result, the available treatment options cannot eliminate these diseases radically, but only alleviate the symptoms. Both inflammatory processes and oxidation are key factors in the development and evolution of neurodegeneration, while acetylcholinesterase inhibitors are the most used therapeutic options against AD. In this work, following the multi-targeting compound approach, we designed and synthesized a series of proline and gamma-aminobutyric acid (GABA) amides with various acidic moieties that possess an antioxidant and/or anti-inflammatory potency. Proline is the pharmacophore of nootropic drugs (e.g., piracetam) used for memory improvement, while GABA is the main inhibitory neurotransmitter in the central nervous system. The designed molecules were subjected to a preliminary screening of their bioactivity in antioxidant and anti-inflammatory assays, as well as against acetylcholinesterase. Most of the synthesized compounds could inhibit lipid peroxidation (IC as low as 8 μΜ) and oxidative protein glycation (inhibition of up to 48%) and reduce the 2,2-diphenyl-1-picrylhydrazyl free radical (DPPH). In addition, all of the compounds were moderate inhibitors of lipoxygenase (LOX) (up to 46% at 100 μΜ) and could decrease carrageenan-induced paw edema in rats by up to 55%. Finally, some of the compounds were moderate acetylcholinesterase inhibitors (IC as low as 219 μΜ). The results confirmed the design rationale, indicating that the compounds could be further optimized as multi-targeting molecules directed against degenerative conditions.
退行性疾病，如神经退行性疾病（阿尔茨海默病（AD）、帕金森病（PD））和心血管疾病，是复杂的、多因素的疾病，其病理生理学尚未完全阐明。因此，现有的治疗方法不能从根本上消除这些疾病，而只能缓解症状。炎症过程和氧化都是神经退行性变发展和演变的关键因素，而乙酰胆碱酯酶抑制剂是治疗 AD 的最常用的治疗选择。在这项工作中，我们遵循多靶点化合物方法，设计并合成了一系列具有各种酸性部分的脯氨酸和γ-氨基丁酸（GABA）酰胺，这些化合物具有抗氧化和/或抗炎作用。脯氨酸是改善记忆的益智药物（如吡拉西坦）的药效团，而 GABA 是中枢神经系统中的主要抑制性神经递质。设计的分子经过抗氧化和抗炎测定以及对乙酰胆碱酯酶的初步筛选，以测试其生物活性。大多数合成化合物可以抑制脂质过氧化（IC 低至 8 μM）和氧化蛋白糖基化（抑制高达 48%），并减少 2,2-二苯基-1-苦基肼自由基（DPPH）。此外，所有化合物都是脂氧合酶（LOX）的中度抑制剂（在 100 μM 时高达 46%），并能使角叉菜胶诱导的大鼠足肿胀减少高达 55%。最后，一些化合物是中度乙酰胆碱酯酶抑制剂（IC 低至 219 μM）。结果证实了设计原理，表明这些化合物可以进一步优化为针对退行性疾病的多靶点分子。
