Singh Madan, Karthikeyan Chandrabose, Waiker Digambar Kumar, Tiwari Akhilesh, Shrivastava Sushant K, Sousa Sérgio F, Kiriwan Duangnapa, Martins Fábio G, Moorthy Narayana Subbiah Hari Narayana
Cancept Therapeutics Laboratory, Department of Pharmacy, Indira Gandhi National Tribal University, Amarkantak, 484887 India.
Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, UP 221005 India.
3 Biotech. 2025 May;15(5):134. doi: 10.1007/s13205-025-04295-5. Epub 2025 Apr 18.
Natural products have long served as versatile templates for discovering lead molecules against various targets of pharmacological interest. Kojic acid, a fungal metabolite epitomizes this versatility as it elicits broad-spectrum biological properties. Described herein is a series of heteroaryl thiol-linked kojic acid derivatives that demonstrate potent acetylcholinesterase (AChE) inhibition along with anti-amyloid-β (Aβ) aggregation activity and blood brain barrier (BBB) permeability highlighting their potential as a novel class of Anti-Alzheimer's therapeutics. Seventeen kojic acid derivatives, synthesized by incorporating three different heterocyclic thiols, were evaluated for in vitro AChE inhibition employing Ellman's method. The most potent analogs identified from the AChE inhibition studies were further evaluated for binding to the peripheral anionic site (PAS) of AChE using the propidium iodide (PI) displacement assay, anti-amyloid-β (Aβ) aggregation inhibition using the thioflavin T assay, and BBB permeability using the PAMPA-BBB assay. Obtained findings indicated that two compounds and bearing a 5-methoxybenzo[d]thiazol-2-yl)thio moiety and 5-phenyl-1,3,4-oxadiazol- 2-yl)thio moiety, respectively, elicited potent AChE inhibition (IC₅₀ < 5 µM), moderate anti-Aβ aggregation effects and good BBB permeability. The molecular docking studies of compound along with its molecular dynamics simulations at peripheral anionic site (PAS) of enzyme AChE provided structural insights into the binding mode of these derivatives. Taken together, the findings of this study establish heteroaryl thiol-linked kojic acid derivatives as a valuable molecular framework for developing anti-Alzheimer's therapeutics that target both cholinergic dysfunction and amyloid-β aggregation.
The online version contains supplementary material available at 10.1007/s13205-025-04295-5.
长期以来，天然产物一直是发现针对各种药理学相关靶点的先导分子的通用模板。曲酸是一种真菌代谢产物，体现了这种多功能性，因为它具有广谱的生物学特性。本文描述了一系列杂芳基硫醇连接的曲酸衍生物，这些衍生物表现出强大的乙酰胆碱酯酶（AChE）抑制活性以及抗淀粉样β蛋白（Aβ）聚集活性和血脑屏障（BBB）通透性，突出了它们作为新型抗阿尔茨海默病治疗药物的潜力。通过引入三种不同的杂环硫醇合成了17种曲酸衍生物，采用埃尔曼法评估其体外AChE抑制活性。从AChE抑制研究中鉴定出的最有效的类似物，进一步使用碘化丙啶（PI）置换试验评估其与AChE外周阴离子位点（PAS）的结合，使用硫黄素T试验评估其抗淀粉样β蛋白（Aβ）聚集抑制作用，并使用PAMPA - BBB试验评估其BBB通透性。所得结果表明，两种分别带有5 - 甲氧基苯并[d]噻唑 - 2 - 基）硫基和5 - 苯基 - 1,3,4 - 恶二唑 - 2 - 基）硫基的化合物 和 表现出强大的AChE抑制作用（IC₅₀ < 5 μM）、适度的抗Aβ聚集作用和良好的BBB通透性。对化合物 及其在酶AChE外周阴离子位点（PAS）的分子动力学模拟进行的分子对接研究，为这些衍生物的结合模式提供了结构上的见解。综上所述，本研究结果确立了杂芳基硫醇连接的曲酸衍生物作为开发针对胆碱能功能障碍和淀粉样β蛋白聚集的抗阿尔茨海默病治疗药物的有价值分子框架。
在线版本包含可在10.1007/s13205 - 025 - 04295 - 5获取的补充材料。
