Design and Synthesis of New Dual Binding Site Cholinesterase Inhibitors: in vitro Inhibition Studies with in silico Docking

Muhammad Yar; Marek Bajda; Rana Atif Mehmood; Lala Rukh Sidra; Nisar Ullah; Lubna Shahzadi; Muhammad Ashraf; Tayaba Ismail; Sohail Anjum Shahzad; Zulfiqar Ali Khan; Syed Ali Raza Naqvi; Nasir Mahmood

doi:10.2174/15701808113106660078

Design and Synthesis of New Dual Binding Site Cholinesterase Inhibitors: in vitro Inhibition Studies with in silico Docking

Lett Drug Des Discov. 2014 Mar;11(3):331-338. doi: 10.2174/15701808113106660078.

Authors

Affiliations

¹ Interdisciplinary Research Center in Biomedical Materials, COMSATS Institute of Information Technology, Lahore, 54000, Pakistan.
² Faculty of Chemistry, University of Warsaw, 02-093 Warsaw, Pasteura 1, Poland and Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Cracow, Medyczna 9, Poland.
³ Department of Chemistry, Government College University, Lahore, 54000, Pakistan.
⁴ Department of Chemistry, King Fahd University of Petroleum and Minerals, Dhahran, 31261, Saudi Arabia.
⁵ Department of Biochemistry & Biotechnology, The Islamia University of Bahawalpur, Bahawalpur, 63100, Pakistan.
⁶ Department of Chemistry, COMSATS Institute of Information Technology, Abbottabad, 22060, Pakistan.
⁷ Department of Allied Sciences and Chemical Pathology, University of Health Sciences, Lahore, 54600, Pakistan.

Abstract

Cholinesterases (ChEs) play a vital role in the regulation of cholinergic transmission. The inhibition of ChEs is considered to be involved in increasing acetylcholine level in the brain and thus has been implicated in the treatment of Alzheimer's disease. We have designed and synthesized a series of novel indole derivatives and screened them for inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Most of the tested compounds exhibited inhibitory activity against AChE and BChE. Among them 4f and 6e showed the highest AChE inhibitory activity with IC₅₀ 91.21±0.06 and 68.52±0.04 μM, respectively. However compound 5a exhibited the highest inhibitory activity against BChE (IC₅₀ 55.21±0.12 μM).

Keywords: Acetylcholinesterase; Alzheimer’s disease; Butyrylcholinesterase; Hydrazides; Indole derivatives; Molecular docking; SAR..