Novel structural hybrids of pyrazolobenzothiazines with benzimidazoles as cholinesterase inhibitors

Sana Aslam; Sumera Zaib; Matloob Ahmad; John M Gardiner; Aqeel Ahmad; Abdul Hameed; Norbert Furtmann; Michael Gütschow; Jürgen Bajorath; Jamshed Iqbal

doi:10.1016/j.ejmech.2014.03.035

Novel structural hybrids of pyrazolobenzothiazines with benzimidazoles as cholinesterase inhibitors

Eur J Med Chem. 2014 May 6:78:106-17. doi: 10.1016/j.ejmech.2014.03.035. Epub 2014 Mar 13.

Authors

Affiliations

¹ Department of Chemistry, Government College Women University, Faisalabad 38000, Pakistan; School of Chemistry and Manchester Institute of Biotechnology, University of Manchester, Manchester M1 7DN, UK.
² Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan.
³ Department of Chemistry, Government College University, Faisalabad 38000, Pakistan.
⁴ School of Chemistry and Manchester Institute of Biotechnology, University of Manchester, Manchester M1 7DN, UK.
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.
⁸ Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan. Electronic address: drjamshed@ciit.net.pk.

PMID: 24681070
DOI: 10.1016/j.ejmech.2014.03.035

Abstract

Two series of novel pyrazolobenzothiazine-based hybrid compounds were efficiently synthesized starting from saccharin sodium salt. Pyrazolo[4,3-c][1,2]benzothiazine scaffolds were N-arylated by using p-fluorobenzaldehyde, followed by the incorporation of a benzimidazole or similar ring systems by treatment with arylenediamines. These phenylene-connected hybrid compounds were investigated as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Compounds 12d and 12k were the most potent AChE inhibitors with IC50 values of 11 and 13 nM, respectively, while 6j (IC50 = 17 nM) proved to be the most active inhibitor against BuChE with remarkable selectivity for BuChE over AChE. Molecular docking studies were also performed on human AChE and BuChE to suggest possible binding modes in which the inhibitor's extended structure is accommodated along the active site gorge of both enzymes.

Keywords: Benzimidazole; Cholinesterases; Docking studies; Hybrid compounds; Pyrazolobenzothiazine.

Publication types

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

MeSH terms

Acetylcholinesterase / metabolism*
Benzimidazoles / chemical synthesis
Benzimidazoles / chemistry
Benzimidazoles / pharmacology*
Butyrylcholinesterase / metabolism*
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Models, Molecular
Molecular Structure
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Structure-Activity Relationship
Thiazines / chemical synthesis
Thiazines / chemistry
Thiazines / pharmacology*

Substances

Benzimidazoles
Cholinesterase Inhibitors
Pyrazoles
Thiazines
Acetylcholinesterase
Butyrylcholinesterase