Benzylpiperidine-Linked Diarylthiazoles as Potential Anti-Alzheimer’s Agents: Synthesis and Biological Evaluation

详细信息    查看全文

• 作者：Mahesh Shidore ; Jatin Machhi ; Kaushik Shingala ; Prashant Murumkar ; Mayank Kumar Sharma ; Neetesh Agrawal ; Ashutosh Tripathi ; Zalak Parikh ; Prakash Pillai ; Mange Ram Yadav
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：June 23, 2016
• 年：2016
• 卷：59
• 期：12
• 页码：5823-5846
• 全文大小：969K
• 年卷期：0
• ISSN：1520-4804

文摘

A novel series of hybrid molecules were designed and synthesized by fusing the pharmacophoric features of cholinesterase inhibitor donepezil and diarylthiazole as potential multitarget-directed ligands for the treatment of Alzheimer’s disease (AD). The compounds showed significant in vitro anticholinesterase (anti-ChE) activity, the most potent compound (44) among them showing the highest activity (IC₅₀ value of 0.30 ± 0.01 μM) for AChE and (1.84 ± 0.03 μM) for BuChE. Compound 44 showed mixed inhibition of AChE in the enzyme kinetic studies. Some compounds exhibited moderate to high inhibition of AChE-induced Aβ_1–42 aggregation and noticeable in vitro antioxidant and antiapoptotic properties. Compound 44 showed significant in vivo anti-ChE and antioxidant activities. Furthermore, compound 44 demonstrated in vivo neuroprotection by decreasing Aβ_1–42-induced toxicity by attenuating abnormal levels of Aβ_1–42, p-Tau, cleaved caspase-3, and cleaved PARP proteins. Compound 44 exhibited good oral absorption and was well tolerated up to 2000 mg/kg, po, dose without showing toxic effects.