63153-56-0

Usage

InChI:InChI=1/C14H14N4O/c1-17-12(13(19)18(2)14(17)15)7-9-8-16-11-6-4-3-5-10(9)11/h3-8,15-16H,1-2H3/b12-7-,15-14-

Upstream product

• 487-89-8 Indole-3-carboxaldehyde 
• 34293-22-6 2-imino-1,3-dimethylimidazolidin-4-one 
• 138040-02-5 2-Dimethylamino-5-[1-(1H-indol-3-yl)-meth-(E)-ylidene]-1,3-dimethyl-4-oxo-4,5-dihydro-3H-imidazol-1-ium; iodide 
• 138040-01-4 2-Dimethylamino-5-[1-(1H-indol-3-yl)-meth-(E)-ylidene]-3,5-dihydro-imidazol-4-one 
• 56107-25-6 2-imino-1,3-dimethylimidazolidin-4-one hydroiodide 

Relevant academic research and scientific papers

Identification of aplysinopsin as a blood-brain barrier permeable scaffold for anti-cholinesterase and anti-BACE-1 activity

Aplysinopsins are a group of marine-derived indole alkaloids that display diverse array of pharmacological effects. However, their effect on anti-Alzheimer targets has not been reported. Herein, we report the synthesis of aplysinopsin (1) and its effect on cholinesterases and beta-site amyloid-precursor protein cleaving enzyme 1 (BACE-1). It inhibits electric eel acetylcholinesterase (AChE), equine serum butyrylcholinesterase (BChE), and human BACE-1 with IC50 values of 33.9, 30.3, and 33.7 μM, respectively, and excellent BBB permeability (Pe 8.92 × 10?6 cm/s). To optimize its sub-micromolar activity, the first-generation analogs were prepared and screened. Two most active analogs 5b and (Z)-8g were found to effectively permeate the BBB (Pe > 5 × 10?6 cm/s). The N-sulphonamide derivative 5b display better cholinesterase inhibition, whereas the other analog (Z)-8g strongly inhibits BACE-1 (IC50 0.78 μM) activity. The analog 5b interacts primarily with PAS of AChE, and thus exhibit a mixed-type of inhibition. In addition, aplysinopsin along with new analogs inhibited the self-induced Aβ1-42 aggregation. The data presented herein indicate that the aplysinopsin-scaffold holds a potential for further investigation as a multi-targeted anti-Alzheimer agent.

In vitro structure-activity relationships of aplysinopsin analogs and their in vivo evaluation in the chick anxiety-depression model

Aplysinopsins are tryptophan-derived natural products that have been isolated from a variety of marine organisms and have been shown to possess a range of biological activities. In vitro receptor binding assays showed that of the 12 serotonin receptor subtypes, analogues showed a high affinity for the 5-HT2B and 5-HT2C receptor subtypes, with selectivity for 5-HT2B over 5-HT2C. While no conclusions could be drawn about the number and position of N-methylations, bromination at C-4 and C-5 of the indole ring resulted in greater binding affinities, with Ki's as low as 35 nM. This data, combined with previous knowledge of the CNS activity of aplysinopsin analogs, suggested that these compounds may have potential as leads for antidepressant drugs. Compounds 3c, 3u, and 3x were evaluated in the chick anxiety-depression model to assess their in vivo efficacy. Compound 3c showed a modest antidepressant effect at a dose of 30 nM/kg in the animal model.

Synthesis and evaluation of aplysinopsin analogs as inhibitors of human monoamine oxidase A and B

Aplysinopsins are tryptophan-derived natural products that have been isolated from a variety of marine organisms. Previous studies have shown aplysinopsin analogs to possess a variety of biological activities, including modulation of neurotransmissions. A series of fifty aplysinopsin analogs was synthesized and assayed for monoamine oxidase A and B inhibitory activity. Three compounds displayed significant MAO inhibitory activity and selectivity. The compound (E)-5-[(6-bromo-1H-indol-3-yl)methylene]-2-imino-1,3- dimethylimidazolidin-4-one (3x) possessed an IC50 of 5.6 nM at MAO-A and had a selectivity index of 80.24. An SAR study revealed that multiple N-methylations, one of which should be at position N-2′, and bromination at C-5 or C-6 are important factors for MAO-A potency and selectivity.

Synthesis and structure-affinity relationships of novel small molecule natural product derivatives capable of discriminating between serotonin 5-HT1A, 5-HT2A, 5-HT2C receptor subtypes

Efforts to develop ligands that distinguish between clinically relevant 5-HT2A and 5-HT2C serotonin receptor subtypes have been challenging, because their sequences have high homology. Previous studies reported that a novel aplysinopsin belonging to a chemical class of natural products isolated from a marine sponge was selective for the 5-HT2C over the 5-HT2A receptor subtype. Our goal was to explore the 5-HT2A/2C receptor structure-affinity relationships of derivatives based on the aplysinopsin natural product pharmacophore. Twenty aplysinopsin derivatives were synthesized, purified and tested for their affinities for cloned human serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptor subtypes. Four compounds in this series had >30-fold selectivity for 5-HT2A or 5-HT2C receptors. The compound (E)-5-((5,6-dichloro-1H-indol-3-yl)methylene)- 2-imino-1,3-dimethylimidazolidin-4-one (UNT-TWU-22, 16) had approximately 2100-fold selectivity for the serotonin 5-HT2C receptor subtype: an affinity for 5-HT2C equal to 46 nM and no detectable affinity for the 5-HT1A or 5-HT2A receptor subtypes. The two most important factors controlling 5-HT2A or 5-HT2C receptor subtype selectivity were the combined R1,R3-alkylation of the imidazolidinone ring and the type and number of halogens on the indole ring of the aplysinopsin pharmacophore.

A new synthesis of aplysinopsin, a marine alkaloid and its analogues and their biological activities

Aplysinopsin (1) and its analogues (3a-3d, 6a-6e and 7d) have been synthesised and evaluated for their broad biological activities.Of the compounds tested, compound 3a, 4b, 5b and 7a show high order of in vitro antileishmanial activity.Compound 3a also shows moderate antiviral activity against Ranikhet disease virus (RDV) and compounds 4d, 4e, 5a, 5b, 6c, and 7d show moderate antimicrobial activity.

Synthesis of 2-Dimethylaminoimidazole Derivatives: A New Access to Indolyl-imidazole Alkaloids of Marine Origin.

The first preparation of 2-dimethylaminoimidazole 1a, a structural feature of several marine products was undertaken and its reactivity investigated.The synthesis of natural alkaloids 5 and 12b was achieved by direct coupling of the easily accessible oxidized 2-dimethylaminoimidazoles 7 and 8 with indole-3-carboxaldehyde and indole respectively, demonstrating the usefulness of this approach for other structurally related natural products. Key Words: indolyl-imidazoles; alkaloids; aplysinopsin; 2-dimethylaminoimidazole; marine products.

5-(Indol-3-ylmethylene)-1,3-dimethyl-2-methylamino-4-imidazolidinone

5-(Indol-3-ylmethylene)-1,3-dimethyl-2-methylimino-4-imidazolidinone and its geometric isomers, prepared, inter alia, from indole-3-aldehyde and 1,3-dimethyl-2-methylimino-4-imidazolidinone, are described. The end products are useful as antidepressants.