Laboratory of Organic and Medicinal Chemistry, Department of Chemistry, Central University of Punjab, Bathinda, Punjab 151401, India.
Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, Punjab 151401, India.
ACS Chem Neurosci. 2024 Jul 17;15(14):2565-2585. doi: 10.1021/acschemneuro.4c00007. Epub 2024 May 25.
Alzheimer's disease is a complex neurological disorder linked with multiple pathological hallmarks. The interrelation of therapeutic targets assists in the enhancement of cognitive decline through interference with overall neuronal transmission. We have synthesized and screened various chromone derivatives as potential multitarget-directed ligands for the effective treatment of Alzheimer's disease. The synthesized compounds exhibited multipotent activity against AChE, BuChE, MAO-B, and amyloid β aggregation. Three potent compounds, i.e., , , and were identified that displayed remarkable activities against different targets. These compounds displayed IC values of 80 nM, 2.52 μM, and 140 nM against the AChE enzyme, respectively, and IC values of 2.07 μM, 70 nM, and 450 nM against the MAO-B isoform, respectively. displayed potent activity against self-induced Aβ aggregation with inhibition of 58.3%. In the ROS inhibition studies, the most potent compounds reduced the intracellular ROS levels up to 80% in SH-SY5Y cells at 25 μM concentration. The compounds were found to be neuroprotective and noncytotoxic even at a concentration of 25 μM against SH-SY5Y cells. In silico studies showed that the compounds were nicely accommodated in the active sites of the receptors along with thermodynamically stable orientations. Compound exhibited a balanced multitargeting profile against AChE, BuChE, MAO-B, and Aβ enzymes and was further evaluated for in vivo activities on the scopolamine-induced zebrafish model. was found to ameliorate the cognitive decline in zebrafish brains by protecting them against scopolamine-induced neurodegeneration. Thus, , , and were identified as potent multitarget-directed ligands with a balanced activity profile against different targets and can be developed as therapeutics for AD.
阿尔茨海默病是一种复杂的神经退行性疾病，与多种病理特征有关。治疗靶点的相互关系通过干扰整体神经元传递来辅助认知能力下降的改善。我们合成并筛选了各种色酮衍生物作为潜在的多靶点定向配体，用于有效治疗阿尔茨海默病。合成的化合物表现出对 AChE、BuChE、MAO-B 和淀粉样β聚集的多效活性。鉴定出三种有效的化合物 、 和 ，它们对不同的靶点表现出显著的活性。这些化合物对 AChE 酶的 IC 值分别为 80 nM、2.52 μM 和 140 nM，对 MAO-B 同工酶的 IC 值分别为 2.07 μM、70 nM 和 450 nM。 对自诱导的 Aβ聚集表现出强烈的活性，抑制率为 58.3%。在 ROS 抑制研究中，最有效的化合物在 25 μM 浓度下将 SH-SY5Y 细胞内的 ROS 水平降低了 80%。即使在 25 μM 的浓度下，这些化合物对 SH-SY5Y 细胞也表现出神经保护作用且无细胞毒性。计算机模拟研究表明，化合物在受体的活性部位中得到了很好的容纳，并且具有热力学稳定的取向。化合物 对 AChE、BuChE、MAO-B 和 Aβ 酶表现出平衡的多靶点特性，并且在东莨菪碱诱导的斑马鱼模型上进一步评估了其体内活性。 被发现可以通过保护斑马鱼大脑免受东莨菪碱诱导的神经退行性变来改善其认知能力下降。因此， 、 和 被鉴定为具有针对不同靶标平衡活性谱的有效多靶点定向配体，可作为 AD 的治疗药物进行开发。
