The design and study of two classes of noncompetitive acetylcholinesterase inhibitors (AChEIs) which also function as NSAID prodrugs are reported. The most potent AChEIs disclosed contain an aromatic alkyl-aryl linker between an NSAID and a lipophilic choline mimic and they inhibit acetylcholinesterase (AChE) in the submicromolar range. These agents have the therapeutic potential to dually target inflammation by releasing an NSAID in vivo and activating the cholinergic antiinflammatory pathway via cholinergic up-regulation.Pro-inflammatory cytokine up-regulation plays a role in the pathogenesis of a wide range of disorders including osteoarthritis, 1 psoriasis, 2 multiple sclerosis, 3 and other autoimmune disorders. 4 Despite decades of research, non-steroidal anti-inflammatory drugs (NSAIDs) are still one of the most commonly used, highly effective treatments for such disorders. However, since chronic NSAID-use often leads to gastrointestinal (GI) side effects, NSAID ester prodrugs have been explored to mask the acidic GI-irritating portion of the NSAID. 5 For conditions such as arthritis, topical NSAID prodrugs are particularly useful as their therapeutic action is localized, resulting in minimal systemic side effects. 6 Alternately, acetylcholinesterase inhibitors (AChEIs) have implications in the treatment of severe inflammation resulting from sepsis, 7 endotoxemia, 8 and rheumatoid arthritis, 9 as well as in the treatment of neuroinflammation associated with Alzheimer's disease [10][11][12] and Myasthenia Gravis. 13 The administration of CNS-active AChEIs such as galanthamine depletes systemic pro-inflammatory cytokines and ameliorates both central and peripheral inflammation. 8 AChEIs seem to suppress inflammation via the cholinergic anti-inflammatory pathway, a mechanism by which the vagus nerve of the CNS regulates the production and release of tumor necrosis factor and other cytokines. 14,15 *Corresponding author. Tel.: 1-610-758-3464; fax.: 1-610-758-3461; ndh0@lehigh.edu. † Current address: PTC Therapeutics, Inc., South Plainfield, NJ 07080-2449, USA ‡ Current address: Digestive Care, Inc., Bethlehem, PA 18017-7059, USA Supplementary data Synthetic procedures, physical characterization of compounds, in vitro assay methods and Lineweaver-Burk plots can be found in the online version of this article.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Figure 1). 18 The synthesis and evaluation of these compounds as anti-inflammatory and anticholinesterase agents for topical or oral administration are presented herein. NIH Public AccessAuthor Manuscript Bioor...

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The effect of Ti-based Lewis acids on the reduction of alpha-fluoropropiophenone was examined to determine whether chelation control could be used to direct the diastereoselectivity of conversion to an alpha-fluoro alcohol. Pretreatment of alpha-fluoropropiophenone with TiCl4 followed by reduction with LiBH4 in diethyl ether or methylene chloride provided the syn diastereomer predominantly, while use of Ti(OiPr)4 under identical conditions provided the anti diastereomer as the major product. The products are consistent with a chelation-controlled mechanistic pathway in the former reduction and a nonchelation pathway in the latter case. Detailed 1H, 13C, and 19F NMR studies were consistent with chelation between TiCl4 and alpha-fluoropropiophenone under the reaction conditions utilized in this study. Reduction of other alpha-fluoroketones in the presence of TiCl4 also provided a high degree of diastereoselectivity in the conversion to alpha-fluoro alcohols, showing the generality of this approach.