title: Synthesis, cytotoxicity and molecular modelling studies of new phenylcinnamide derivatives as potent inhibitors of cholinesterases.
abstract: The present study reports the synthesis of cinnamide derivatives and their biological activity as inhibitors of both cholinesterases and anticancer agents. Controlled inhibition of brain acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) may slow neurodegeneration in Alzheimer's diseases (AD). The anticholinesterase activity of phenylcinnamide derivatives was determined against Electric Eel acetylcholinesterase (EeAChE) and horse serum butyrylcholinesterase (hBChE) and some of the compounds appeared as moderately potent inhibitors of EeAChE and hBChE. The compound 3-(2-(Benzyloxy)phenyl)-N-(3,4,5-trimethoxyphenyl)acrylamide (3i) showed maximum activity against EeAChE with an IC50 0.29 ± 0.21 μM whereas 3-(2-chloro-6-nitrophenyl)-N-(3,4,5-trimethoxyphenyl)acrylamide (3k) was proved to be the most potent inhibitor of hBChE having IC50 1.18 ± 1.31 μM. To better understand the enzyme-inhibitor interaction of the most active compounds toward cholinesterases, molecular modelling studies were carried out on high-resolution crystallographic structures. The anticancer effects of synthesized compounds were also evaluated against cancer cell line (lung carcinoma). The compounds may be useful leads for the design of a new class of anticancer drugs for the treatment of cancer and cholinesterase inhibitors for Alzheimer's disease (AD).
authors.affiliation: Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan.
authors.forename: Aamer
authors.initials: A
authors.lastname: Saeed
authors.affiliation: Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan.
authors.forename: Parvez Ali
authors.initials: PA
authors.lastname: Mahesar
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: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan.
authors.forename: Muhammad Siraj
authors.initials: MS
authors.lastname: Khan
authors.affiliation: Institute of Biomedical and Genetic Engineering, PO Box 2891, Sector G-9/1, Islamabad, Pakistan.
authors.forename: Abdul
authors.initials: A
authors.lastname: Matin
authors.affiliation: Department of Bioinformatics, Fraunhofer Institute SCAI, Sankt Augustin, Germany.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Shahid
authors.affiliation: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan; Department of Pharmaceutical Sciences, 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; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002091:Butyrylcholinesterase / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Alzheimer's disease; Cholinesterases inhibitors; Cytotoxicity; Molecular docking; Phenylcinnamide derivatives