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Mishra, Chandra Bhushan; Shalini, Shruti; Gusain, Siddharth; Kumar, Pawan; Kumari, Shikha; Choi, Yong-Sung; Kumari, Jyoti; Moku, Bala Krishna; Yadav, Anita Kumari; Prakash, Amresh; Jeon, Raok; Tiwari, Manisha
Biomedicine & pharmacotherapy, 20/May , Letnik: 174Journal Article
A novel small molecule based on benzothiazole-piperazine has been identified as an effective multi-target-directed ligand (MTDL) against Alzheimer's disease (AD). Employing a medicinal chemistry approach, combined with molecular docking, MD simulation, and binding free energy estimation, compound 1 emerged as a potent MTDL against AD. Notably, compound 1 demonstrated efficient binding to both AChE and Aβ1–42, involving crucial molecular interactions within their active sites. It displayed a binding free energy (ΔGbind) −18.64± 0.16 and −16.10 ± 0.18 kcal/mol against AChE and Aβ1–42, respectively. In-silico findings were substantiated through rigorous in vitro and in vivo studies. In vitro analysis confirmed compound 1 (IC50=0.42 μM) as an effective, mixed-type, and selective AChE inhibitor, binding at both the enzyme's catalytic and peripheral anionic sites. Furthermore, compound 1 demonstrated a remarkable ability to reduce the aggregation propensity of Aβ, as evidenced by Confocal laser scanning microscopy and TEM studies. Remarkably, in vivo studies exhibited the promising therapeutic potential of compound 1. In a scopolamine-induced memory deficit mouse model of AD, compound 1 showed significantly improved spatial memory and cognition. These findings collectively underscore the potential of compound 1 as a promising therapeutic candidate for the treatment of AD. Display omitted •A benzothiazole-piperazine-based small molecule has been developed as an effective MTDL against AD.•Compound 1 (IC50=0.421 μM) was a potent, mixed-type, and selective AChE inhibitor.•Compounds 1 at 50 μM effectively reduced the aggregation propensity of Aβ by 80.708%.•Compound 1 demonstrated potent neuroprotection in cells induced with H2O2 and OKA neurotoxicity.•Compound 1 showed improved spatial memory and cognition in the scopolamine-induced memory deficit mouse model of AD.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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