Some Synthetic Approaches to Glutamate AMPA Receptor Agonists Based on Isoxazolones

Abstract

Several approaches to the synthesis of derivatives of the antifungal antibiotic TAN-950A, which is also an agonist of glutamate at hippocampal neurons, are reported. Additions of isoxazolon-4-yl anions to methyleneoxazolidinones were not useful because addition occurred predominantly through N-2. Similarly addition of the isoxazolon-4-yl radicals to model Michael acceptors occurred predominantly through N-2. Racemic analogues of TAN-950A were prepared by reaction of isoxazolone Mannich bases with acetylaminomalonate or addition of β-ketoester anions to dehydroalanines. The best approach to enantiomerically pure analogues was by acylation of pyroglutamates, followed by reaction with hydroxylamine.(S)-Glutamic acid 1 (Scheme 1) is the predominant excitatory neurotransmitter in the mammalian central nervous system (CNS). Excitatory amino acid receptors are believed to play a variety of physiological roles in mammals, ranging from the processing of sensory information, to coordinated movement patterns, cognitive processes, learning, and memory. [1] Changes in glutamate transmission have been associated with several neurological disorders including acute neurodegeneration, pain, epilepsy, and possibly chronic neurodegenerative diseases such as Alzeimer's, Parkinson's, and Huntington's diseases, depression, drug dependency, and schizophrenia. [1] Glutamate combines with two types of CNS receptors. These are ionotropic receptors (iGluRs), which open an associated ion channel, and metabotropic receptors (mGluRs), which have seven transmembrane spanning regions and modulate secondary messenger systems.We are interested in one of the three subtypes of ionotropic receptors of (S)-glutamic acid, the receptors activated by AMPA (2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionate) 2. [2] Although extensive research has been carried out on the other sub-receptor sites, [3,4] the AMPA receptor subtype has received much less attention.

2,2′-((1,4-Dimethoxy-1,4-dioxobutane-2,3-diylidene)bis(azanylylidene))bis(quinoline-3-carboxylic acid)

“…They may be treated as useful tools in organic synthesis since they are small and easy to functionalize molecules that can be utilized to design novel bioactive compounds. It has been proven that these synthetic products exhibit antibacterial [1][2][3][4][5][6][7][8], antifungal [7][8][9][10][11][12][13][14][15][16], antitubercular [3], anticancer [3,6,17,18], antileucemic [5], antinflammatory [19][20][21], antiviral [22], anticonvulsant [1], antioxidant [2,7], and antiandrogenic [23,24] properties. They may act as inhibitors of p38 MAP kinases [25], protein kinase C [26], and protein-tyrosine phosphatase 1B, which consequently cause antiobesity effect [27,28].…”

“…They also find applications as GABA A receptor ligands [29] and glutamate receptor agonists [30][31][32], therefore they can affect learning and memory processes. Despite the molecular mechanism of antifungal action of isoxazol-5(2H)-ones such as TAN-950A [16] and drazoxolon [8,15] has not been established, it should be underlined that structurally similar antimicrobial oxazolidones such as posizolid, tedizolid, radezolid and linezolid or cycloserine serve as inhibitors of protein synthesis that prevent binding of N-formylmethionyl-tRNA to the ribosome. [33].…”