Synthesis, Pharmacology, and Structure−Activity Relationships of Novel Imidazolones and Pyrrolones as Modulators of GABA_AReceptors

Abstract

New series of imidazolones and pyrrolones were synthesized. The compounds were tested regarding their anxiolytic properties due to modulation of the GABAA receptor response. Several derivatives exhibit considerable pharmacological activity while lacking the typical side effects of benzodiazepine receptor agonists. 1-(4-chlorophenyl)-4-morpholin-1-yl-1,5-dihydro-imidazol-2-one (2) and 1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-one (3) were protective in the pentylenetetrazole test in rats with oral ED50 of 27.4 and 12.8 mg/kg and TD50 (rotarod) of >500 and 265 mg/kg, respectively. The minimum effective dose in the Vogel conflict test was 3 mg/kg for both compounds. Common structure-activity relationship and comparative molecular field analysis models of the various series of derivatives could be established which are in accordance with a GABAA mediated pharmacological action. The findings fit well into an established pharmacophore model. This model is refined by an additional steric restriction feature.

Synthesis of spiro 3-bromo-4,5-dihydroisoxazoles via [1,3]dipolar cycloaddition reactions

“…[10][11][12] The 3-isoxazolidone nucleus constitutes the basic skeleton of natural compounds such as the antibiotic, D-cycloserine, 13 the L-canavanine catabolite, 14 and a series of compounds that have been designed in medicinal chemistry as ligands for different receptors of the central nervous system. 15 The construction of isoxazoline and isoxazole rings by the 1,3-dipolar cycloaddition (13DC) of a nitrile oxide to an alkene or alkyne has proven to be extremely useful. [5][6][7][8][9]16 In continuation of our interest in the synthesis of heterocyclic compounds based on multicomponent reactions (MCRs), 17 we describe the synthesis of spiro 3-bromo-4,5-dihydroisoxazoles 7 in high yields via the two-component condensation reaction of 5-benzylidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-triones 3 and dibromoformaldoxime (6) in THF using KHCO 3 at room temperature (Scheme 1).…”

Citric acid as a green and naturally biodegradable catalyst promoted convenient synthesis of polysubstituted dihydro-2-oxypyrrole derivatives via four-condensation reaction of dialkylacetylenedicarboxylate, formaldehyde and amines

“…In addition to, single-use citric acid sachets have been used as an inducement to get heroin users to exchange their dirty needles for clean needles in an attempt to decrease the spread of HIV and hepatitis [3].Synthesis of the pyrrole rings has attracted great interests due to biological and pharmaceutical properties. They have been used as human cytomegalovirus( HCMV) protease [4], CD45 protein tyrosinphosphatase [5], anti-cancer [6], also, Thiomarinol A4 as antibiotic has pyrrole rings [7], many of number alkaloids with biological activities have pyrrole rings [8], and these rings have been used as UCS1025A [9], Oteromycin [10]. In addition, these rings have been used HIV integrase [11], and they have also herbicidal [12] activities.…”

Novel 4-thiazolidinone derivatives as agonists of benzodiazepine receptors: design, synthesis and pharmacological evaluation

“…The binding site of BZDs is located between α and γ subunits (Rudolph and Knoflach, 2011[16]; Alerno et. al., 2012[2]; Grunwald et al, 2006[8]).…”