Novel multi-targeted agents for Alzheimer's disease: Synthesis,biological evaluation,and molecular modeling of novel 2-[4-(4-substitutedpiperazin-1-yl)phenyl]benzimidazoles |
| |
| Affiliation: | 1. Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ankara, Turkey;2. Hacettepe University, Faculty of Pharmacy, Department of Biochemistry, Ankara, Turkey;1. Medicinal Chemistry and Pharmacology, CSIR – Indian Institute of Chemical Technology, Hyderabad 500007, India;2. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India;3. Department of Chemistry Sri Venkateswara University, Tirupati 517 502, India;1. Department of Chemistry, Government College Women University, Faisalabad 38000, Pakistan;2. School of Chemistry and Manchester Institute of Biotechnology, University of Manchester, Manchester M1 7DN, UK;3. Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan;4. Department of Chemistry, Government College University, Faisalabad 38000, Pakistan;5. HEJ Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan;6. Pharmaceutical Institute, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany;7. Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Dahlmannstr. 2, D-53113 Bonn, Germany;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100 Ankara, Turkey;2. Medicinal Chemistry & Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science–Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500 078, Andhra Pradesh, India;1. Department of Organic Chemistry, Faculty of Pharmaceutical Chemistry, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran;2. The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, 1417614411, Iran;3. Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran;4. Hacettepe University, Faculty of Pharmacy, Department of Biochemistry, Ankara, Turkey;5. Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran;6. Department of Medicinal Chemistry, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran;1. Drug Design and Development Research Group, Department of Chemistry, Faculty of Science, University of Malaya, Malaysia;2. Aurigene Discovery Technologies (Malaysia) Sdn. Bhd, Malaysia;3. Aurigene Discovery Technologies (India) Ltd, India;4. Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Malaysia;5. School of Pharmacy, International Medical University, 57000 Kuala Lumpur, Malaysia |
| |
| Abstract: | The present study describes the synthesis, pharmacological evaluation (BChE/AChE inhibition, Aβ antiaggregation, and neuroprotective effects), and molecular modeling studies of novel 2-[4-(4-substitutedpiperazin-1-yl)phenyl]benzimidazole derivatives. The alkyl-substituted derivatives exhibited selective inhibition on BChE with varying efficiency. Compounds 3b and 3d were found to be the most potent inhibitors of BChE with IC50 values of 5.18 and 5.22 μM, respectively. The kinetic studies revealed that 3b is a partial non-competitive BChE inhibitor. Molecular modeling studies also showed that the alkyl-substituted derivatives were able to reach the catalytic anionic site of the BChE. The compounds with an inhibitory effect on BChE were subsequently screened for their Aβ antiaggregating and neuroprotective activities. Compounds 3a and 3b exerted a potential neuroprotective effect against H2O2 and Aβ-induced cytotoxicity in SH-SY5Y cells. Collectively, 3b was found as the most promising compound for the development of multi-target directed ligands against Alzheimer’s disease. |
| |
| Keywords: | Benzimidazole Alzheimer's disease Butyrylcholinesterase Aβ aggregation Neuroprotection |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
