Ethynylphenyl carbonates and carbamates as dual-action acetylcholinesterase inhibitors and anti-inflammatory agents

• Published in: Bioorganic & medicinal chemistry letters Vol. 25; no. 23; pp. 5609 - 5612
• Main Authors: Saxena, Jaya, Meloni, David, Huang, Mou-Tuan, Heck, Diane E., Laskin, Jeffrey D., Heindel, Ned D., Young, Sherri C.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.12.2015; Elsevier
• Subjects: Acetylcholinesterase - chemistry; Acetylcholinesterase inhibitors; Alzheimer’s disease; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Anti-inflammatory drugs; Carbamates; Carbamates - chemical synthesis; Carbamates - chemistry; Carbamates - pharmacology; Carbonates; Carbonates - chemical synthesis; Carbonates - chemistry; Carbonates - pharmacology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Humans; Inhibitory Concentration 50; Life Sciences & Biomedicine; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Acetylcholinesterase inhibitors; Carbamates; Carbonates; Alzheimer’s disease; Anti-inflammatory drugs; RIVASTIGMINE; ALZHEIMERS-DISEASE; CARBOXYLESTERASES; HALOMETHYLATED DERIVATIVES; NERVE AGENTS; INACTIVATION; MULTIPLE-SCLEROSIS; INFLAMMATION; Alzheimer's disease; LEWY BODIES; DIHYDROCOUMARINS
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2015.10.039

[Display omitted] 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 28–86μM; 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.