Synthesis of novel 5-(aroylhydrazinocarbonyl)escitalopram as cholinesterase inhibitors

Mehr-Un Nisa; Munawar A Munawar; Amber Iqbal; Asrar Ahmed; Muhammad Ashraf; Qurra-Tul-Ann A Gardener; Misbahul A Khan

doi:10.1016/j.ejmech.2017.06.036

Synthesis of novel 5-(aroylhydrazinocarbonyl)escitalopram as cholinesterase inhibitors

Eur J Med Chem. 2017 Sep 29:138:396-406. doi: 10.1016/j.ejmech.2017.06.036. Epub 2017 Jun 30.

Authors

Mehr-Un Nisa¹, Munawar A Munawar², Amber Iqbal³, Asrar Ahmed⁴, Muhammad Ashraf³, Qurra-Tul-Ann A Gardener⁵, Misbahul A Khan⁶

Affiliations

¹ Institute of Chemistry, University of the Punjab, Lahore 54590, Pakistan; Department of Chemistry, Division of Science & Technology, University of Education, Township, Lahore 54770, Pakistan.
² Institute of Chemistry, University of the Punjab, Lahore 54590, Pakistan. Electronic address: mamunawar.chem@pu.edu.pk.
³ Department of Chemistry, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan.
⁴ Department of Chemistry, Division of Science & Technology, University of Education, Township, Lahore 54770, Pakistan.
⁵ School of Biological Sciences, University of the Punjab, Lahore 54590, Pakistan.
⁶ Institute of Chemistry, University of the Punjab, Lahore 54590, Pakistan; Department of Chemistry, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan.

PMID: 28688279
DOI: 10.1016/j.ejmech.2017.06.036

Abstract

A novel series of 5-(aroylhydrazinocarbonyl)escitalopram (58-84) have been designed, synthesized and tested for their inhibitory potential against cholinesterases. 3-Chlorobenzoyl- (71) was found to be the most potent compound of this series having IC₅₀ 1.80 ± 0.11 μM for acetylcholinesterase (AChE) inhibition. For the butyrylcholinesterase (BChE) inhibition, 2-bromobenzoyl- (76) was the most active compound of the series with IC₅₀ 2.11 ± 0.31 μM. Structure-activity relationship illustrated that mild electron donating groups enhanced enzyme inhibition while electron withdrawing groups reduced the inhibition except o-NO₂. However, size and position of the substituents affected enzyme inhibitions. . In docking study of AChE, the ligands 71, 72 and 76 showed the scores of 5874, 5756 and 5666 and ACE of -64.92,-203.25 and -140.29 kcal/mol, respectively. In case of BChE, ligands 71, 76 and 81 depicted high scores 6016, 6150 and 5994 with ACE values -170.91, -256.84 and -235.97 kcal/mol, respectively.

Keywords: Acetylcholinesterase; Alzheimer's disease; Butyrylcholinesterase; Enzyme inhibition; Escitalopram.

MeSH terms

Acetylcholinesterase / metabolism*
Animals
Butyrylcholinesterase / metabolism*
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Citalopram / analogs & derivatives*
Citalopram / chemical synthesis
Citalopram / chemistry
Citalopram / pharmacology
Dose-Response Relationship, Drug
Electrophorus
Horses
Molecular Structure
Structure-Activity Relationship

Substances

Cholinesterase Inhibitors
Citalopram
Acetylcholinesterase
Butyrylcholinesterase