title: Novel structural hybrids of pyrazolobenzothiazines with benzimidazoles as cholinesterase inhibitors.
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.
authors.affiliation: 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.
authors.forename: Sana
authors.initials: S
authors.lastname: Aslam
authors.affiliation: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan.
authors.forename: Sumera
authors.initials: S
authors.lastname: Zaib
authors.affiliation: Department of Chemistry, Government College University, Faisalabad 38000, Pakistan.
authors.forename: Matloob
authors.initials: M
authors.lastname: Ahmad
authors.affiliation: School of Chemistry and Manchester Institute of Biotechnology, University of Manchester, Manchester M1 7DN, UK.
authors.forename: John M
authors.initials: JM
authors.lastname: Gardiner
authors.affiliation: School of Chemistry and Manchester Institute of Biotechnology, University of Manchester, Manchester M1 7DN, UK.
authors.forename: Aqeel
authors.initials: A
authors.lastname: Ahmad
authors.affiliation: HEJ Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan.
authors.forename: Abdul
authors.initials: A
authors.lastname: Hameed
authors.affiliation: Pharmaceutical Institute, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Furtmann
authors.affiliation: Pharmaceutical Institute, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gütschow
authors.affiliation: 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.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bajorath
authors.affiliation: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan. Electronic address: drjamshed@ciit.net.pk.
authors.forename: Jamshed
authors.initials: J
authors.lastname: Iqbal
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002091:Butyrylcholinesterase / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001562:Benzimidazoles; D002800:Cholinesterase Inhibitors; D011720:Pyrazoles; D013843:Thiazines; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Benzimidazole; Cholinesterases; Docking studies; Hybrid compounds; Pyrazolobenzothiazine