title: Synthesis and evaluation of novel 4-[(3H,3aH,6aH)-3-phenyl)-4,6-dioxo-2-phenyldihydro-2H-pyrrolo[3,4-d]isoxazol-5(3H,6H,6aH)-yl]benzoic acid derivatives as potent acetylcholinesterase inhibitors and anti-amnestic agents.
abstract: The present study was designed to synthesize and evaluate pyrrolo-isoxazole benzoic acid derivatives as potential acetylcholinesterase (AChE) inhibitors for the management of Alzheimer's disease. The synthesis of pyrrolo-isoxazole benzoic acid derivatives involved ring opening cyclization of p-aminobenzoic acid with maleic anhydride to yield maleanilic acid, which in turn afforded N-arylmaleimide via ring closed cyclization. Azomethine-N-oxides were obtained by condensation of N-arylhydroxylamine with differently substituted benzaldehydes followed by refluxing of N-arylmaleimide with differently substituted azomethine-N-oxides to pyrrolo-isoxazole benzoic acid derivatives as cis- and trans-stereoisomers. The synthesized compounds were evaluated in vitro for AChE inhibitory activity in rat brain homogenate with donepezil as standard AChE inhibitor. Thereafter, the most potent test compound was evaluated for in vitro butyrylcholinesterase inhibitory activity and in vivo memory evaluation in scopolamine (0.4mg/kg)-induced amnesia in mice by employing Morris water maze test. All pyrrolo-isoxazole benzoic acid derivatives demonstrated potent AChE inhibitory activity. Most of compounds exhibited similar activity to donepezil and four of them (7h, 7i, 8i, and 8h, IC(50)=19.1±1.9-17.5±1.5nM) displayed higher inhibitory activity as compared to donepezil (21.5±3.2nM) with compound 8ia (IC(50)=17.5±1.5nM) being the most active one. The test compound 8ia also ameliorated scopolamine-induced amnesia in mice in terms of restoration of time spent in target quadrant (TSTQ) and escape latency time (ELT). It may be concluded that pyrrolo-isoxazole benzoic acid derivatives may be employed as potential AChE inhibitors.
authors.affiliation: Department of Chemistry, Punjabi University, Patiala 147002, Punjab, India.
authors.forename: Preet
authors.initials: P
authors.lastname: Anand
authors.forename: Baldev
authors.initials: B
authors.lastname: Singh
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D003500:Cyclization; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism
chemical_list: D001565:Benzoates; D002800:Cholinesterase Inhibitors; D007555:Isoxazoles; D018696:Neuroprotective Agents; D011758:Pyrroles; C571817:cis-4-((3H,3aH,6aH)-3-(4-methoxyphenyl)-4,6-dioxo-2p-tolydihydro-2H-pyrrolo(3,4-d)isoxazol-5(3H,6H,6aH)-yl)benzoic acid; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase