Ethynylphenyl carbonates and carbamates as dual-action acetylcholinesterase inhibitors and anti-inflammatory agents.
Novel ethynylphenyl carbonates and carbamates containing carbon- and silicon-based choline mimics were synthesized from their respective phenol and aniline precursors and screened for anticholinesterase and anti-inflammatory activities. All molecules were micromolar inhibitors of acetylcholinesterase (AChE), with IC50s of 28-86 μM; the carbamates were two-fold more potent than the carbonates. Two of the most potent AChE inhibitors suppressed 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation by 40%. Furthermore, these molecules have physicochemical properties in the range of other CNS drugs. These molecules have the potential to treat inflammation; they could also dually target Alzheimer's disease through restoration of cholinergic balance and inflammation suppression.
Department of Chemistry, Lehigh University, Bethlehem, PA 18015, United States.
Jaya
J
Saxena
Department of Chemistry, Lehigh University, Bethlehem, PA 18015, United States; Incyte Corporation, Wilmington, DE 19803, United States.
David
D
Meloni
Department of Chemical Biology, Rutgers University, Piscataway, NJ 08854, United States.
Mou-Tuan
MT
Huang
Department of Environmental Health Science, New York Medical College, Valhalla, NY 10595, United States.
Diane E
DE
Heck
Department of Environmental and Occupational Medicine, Rutgers University, Piscataway, NJ 08854, United States.
Jeffrey D
JD
Laskin
Department of Chemistry, Lehigh University, Bethlehem, PA 18015, United States.
Ned D
ND
Heindel
Department of Chemistry, Lehigh University, Bethlehem, PA 18015, United States; Department of Chemistry, Muhlenberg College, Allentown, PA 18104, United States. Electronic address: young@muhlenberg.edu.
Sherri C
SC
Young
D000110:Acetylcholinesterase / Q000737:chemistry; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002254:Carbonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure
D000893:Anti-Inflammatory Agents; D002219:Carbamates; D002254:Carbonates; D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase
Acetylcholinesterase inhibitors; Alzheimer’s disease; Anti-inflammatory drugs; Carbamates; Carbonates