Bajad Nilesh Gajanan, Jangra Jatin, T A Gajendra, Kumar Ashok, Krishnamurthy Sairam, Singh Sushil Kumar
Pharmaceutical Chemistry Research Laboratory I, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi 221005, India.
Pharmaceutical Chemistry Research Laboratory I, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi 221005, India.
Int J Biol Macromol. 2025 Apr;301:140436. doi: 10.1016/j.ijbiomac.2025.140436. Epub 2025 Jan 28.
The multi-target directed ligands (MTDLs) strategy has been evolved as the propitious approach for the development of therapeutics for Alzheimer's disease (AD). In an earlier report, we described the novel series of chalcone derivatives bearing N-aryl piperazine scaffold as MTDLs for the treatment of AD. Herein, we report the lead optimization of the series culminating in potent, multi-targeting compounds (32-57), evaluated through in-vitro and in-vivo biological studies. The optimal compound 48 exhibited potent inhibitory activities against AChE (IC = 2.89 ± 0.706 μM), BuChE (IC = 0.151 ± 0.089 μM), along with BACE-1 (% inhibition = 36.64 ± 1.343 %) and amyloid-β aggregation inhibition. Compound 48 showed excellent blood-brain barrier permeability (Pe = 7.28 ± 0.474 × 10 cm s) in PAMPA assay and was found safe in the in vivo acute oral toxicity study. The molecular binding interaction pattern and protein-ligand stability was displayed by lead compound 48 with selected targets. Furthermore, in-vivo behavioural studies demonstrated the amelioration of cognitive dysfunctions and significant memory improvement in Y-maze test (scopolamine-induced amnesia model) in mice on the administration of compound 48 at a dose of 20 mg/kg. The reduction in the level of AChE and increased in ACh activity was observed in ex vivo biochemical analysis. Moreover, compound 48 displayed antioxidant potential on measurement of catalase (CAT) and malondialdehyde (MDA) activity in ex vivo analysis. We anticipate that compound 48, from the pyrazoline series, may be a lead molecule for the discovery of safe and effective therapeutic agents for AD.
多靶点导向配体（MTDLs）策略已发展成为开发阿尔茨海默病（AD）治疗药物的有利方法。在早期的一份报告中，我们描述了一系列带有N-芳基哌嗪支架的新型查尔酮衍生物作为治疗AD的MTDLs。在此，我们报告了该系列的先导优化，最终得到了通过体外和体内生物学研究评估的强效、多靶点化合物（32-57）。最佳化合物48对乙酰胆碱酯酶（AChE，IC = 2.89 ± 0.706 μM）、丁酰胆碱酯酶（BuChE，IC = 0.151 ± 0.089 μM）以及β-分泌酶-1（BACE-1，抑制率 = 36.64 ± 1.343%）具有强效抑制活性，并能抑制淀粉样β蛋白聚集。化合物48在PAMPA试验中显示出优异的血脑屏障通透性（Pe = 7.28 ± 0.474 × 10 cm/s），并且在体内急性口服毒性研究中被发现是安全的。先导化合物48与选定靶点的分子结合相互作用模式和蛋白质-配体稳定性得到了展示。此外，体内行为学研究表明，在以20 mg/kg的剂量给予化合物48后，小鼠在Y迷宫试验（东莨菪碱诱导的失忆模型）中的认知功能障碍得到改善，记忆力显著提高。在离体生化分析中观察到AChE水平降低和ACh活性增加。此外，在离体分析中测量过氧化氢酶（CAT）和丙二醛（MDA）活性时，化合物48显示出抗氧化潜力。我们预计，吡唑啉系列中的化合物48可能是发现用于AD的安全有效治疗药物的先导分子。
