Journal of Medicinal Chemistry p. 5823 - 5846 (2016)
Update date:2022-08-15
Topics:
Shidore, Mahesh
Machhi, Jatin
Shingala, Kaushik
Murumkar, Prashant
Sharma, Mayank Kumar
Agrawal, Neetesh
Tripathi, Ashutosh
Parikh, Zalak
Pillai, Prakash
Yadav, Mange Ram
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 Aβ1-42 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 Aβ1-42-induced toxicity by attenuating abnormal levels of Aβ1-42, 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.
View MoreShangHai Ruiyi Medical Technology Co.,Ltd.
Contact:+86-21-54718086
Address:No951 Jianchuan RD,Minhang District
website:http://www.sigmaaldrich.com
Contact:800 558-9160
Address:Industriestrasse 25CH-9471 Buchs SGSwitzerland
Contact:0086-29-89196322
Address:North of the Fifth Keji Road, Hi-Tech Industrial Zone, Xi'an City, Shaanxi Province, China
SHOUGUANG BOYU CHEMICAL CO.,LTD
Contact:+86-536-8256719
Address:ROOM 1101&1103,BUILDING D,ZHONGTU MANSION,NO.6565 EAST FUSHOU STREET,WEIFANG CITY,SHANDONG,CHINA.
Ji'an Hairui Natural Plant Co. Ltd.
Contact:0796-8105528
Address:Meilin industry park, Qingyuan district Ji'an City, Jiangxi Province
Doi:10.1002/anie.200700816
(2007)Doi:10.1016/j.tet.2007.04.102
(2007)Doi:10.1021/ja071698k
(2007)Doi:10.1021/jo00206a023
(1985)Doi:10.1134/S1070328406110054
(2006)Doi:10.1021/jo01036a011
(1963)