Identification of novel acetylcholinesterase inhibitors: Indolopyrazoline derivatives and molecular docking studies

Sridevi Chigurupati; Manikandan Selvaraj; Vasudevan Mani; Kesavanarayanan Krishnan Selvarajan; Jahidul Islam Mohammad; Balaji Kaveti; Hriday Bera; Vasanth Raj Palanimuthu; Lay Kek Teh; Mohd Zaki Salleh

doi:10.1016/j.bioorg.2016.05.002

Identification of novel acetylcholinesterase inhibitors: Indolopyrazoline derivatives and molecular docking studies

Bioorg Chem. 2016 Aug:67:9-17. doi: 10.1016/j.bioorg.2016.05.002. Epub 2016 May 13.

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Kedah, Malaysia. Electronic address: sridevi.phd@gmail.com.
² Integrative Pharmacogenomics Institute (iPROMISE), Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia; Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia. Electronic address: manifans@gmail.com.
³ Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia; Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraidah 51452, Saudi Arabia.
⁴ Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia.
⁵ Department of Pharmacology, Faculty of Medicine, AIMST University, Semeling, 08100 Bedong, Kedah, Malaysia.
⁶ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Kedah, Malaysia.
⁷ Department of Pharmaceutics, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Kedah, Malaysia.
⁸ Integrative Pharmacogenomics Institute (iPROMISE), Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia; Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia.

PMID: 27231830
DOI: 10.1016/j.bioorg.2016.05.002

Abstract

The synthesis of novel indolopyrazoline derivatives (P1-P4 and Q1-Q4) has been characterized and evaluated as potential anti-Alzheimer agents through in vitro Acetylcholinesterase (AChE) inhibition and radical scavenging activity (antioxidant) studies. Specifically, Q3 shows AChE inhibition (IC50: 0.68±0.13μM) with strong DPPH and ABTS radical scavenging activity (IC50: 13.77±0.25μM and IC50: 12.59±0.21μM), respectively. While P3 exhibited as the second most potent compound with AChE inhibition (IC50: 0.74±0.09μM) and with DPPH and ABTS radical scavenging activity (IC50: 13.52±0.62μM and IC50: 13.13±0.85μM), respectively. Finally, molecular docking studies provided prospective evidence to identify key interactions between the active inhibitors and the AChE that furthermore led us to the identification of plausible binding mode of novel indolopyrazoline derivatives. Additionally, in-silico ADME prediction using QikProp shows that these derivatives fulfilled all the properties of CNS acting drugs. This study confirms the first time reporting of indolopyrazoline derivatives as potential anti-Alzheimer agents.

Keywords: Acetylcholinesterase; Antioxidant; Indole; Molecular docking; Pyrazoline.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylcholinesterase / metabolism*
Antioxidants / chemical synthesis
Antioxidants / chemistry
Antioxidants / pharmacology*
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Humans
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology*
Molecular Docking Simulation
Molecular Structure
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Structure-Activity Relationship

Substances

Antioxidants
Cholinesterase Inhibitors
Indoles
Pyrazoles
Acetylcholinesterase