26477-09-8Relevant academic research and scientific papers
Inhibitory activity on cholinesterases produced by aryl-phthalimide derivatives: green synthesis, in silico and in vitro evaluation
Andrade-Jorge, Erik,Padilla-Martínez, Itzia I.,Ruiz-Maciel, Omar,Sánchez-Labastida, Luis A.,Soriano-Ursúa, Marvin A.,Trujillo-Ferrara, José G.
, (2020)
Background: Alzheimer’s disease (AD) is characterized by cognitive impairment and loss of immediate memory resulting from neuronal death in different brain areas, mainly those producing acetylcholine. Acetylcholinesterase inhibitors improve cognitive function, delay mental deterioration, and reduce other symptoms. Despite being the cornerstone for treating mild–moderate AD, these compounds are only palliative agents and often have severe adverse effects. Recently, butyrylcholinesterase (BuChE) has been found to be involved in AD. The aim of this study was to synthesize a series of six phthalimides with structural relationship with monoamines and evaluate them in vitro and in silico as AChE and BuChE inhibitors. In addition, a modified version of the Bonting and Featherstone method for determining AChE activity was adapted for the assessment of BuChE activity. Results: Six molecules (dioxoisoindolines A–F) were synthesized in good yields using a green chemistry approach. Dioxoisoindolines E and F were more active for AChE, with a Ki of 232 and 193 μM, respectively. Contrarily, dioxoisoindolines C and D showed up to fivefold greater selectivity for BuChE than AchE, with a Ki of 200 and 100 μM, respectively. The competitive inhibitory activity of the latter two molecules was similar to that of the reference compounds. Molecular docking demonstrated the participation of carbonyl carbons and aromatic rings in the high affinity of dioxoisoindoles for cholinesterases. Conclusion: The modified version of the Bonting and Featherstone method was successfully adapted to quantify BuChE activity. Dioxoisoindolines C and D displayed greater inhibition of BuChE versus AChE, with good inhibition of both enzymes. Thus, they are promising lead compounds for developing new BuChE/AChE inhibitors. [Figure not available: see fulltext.]
Isoindolines/isoindoline-1,3-diones as AChE inhibitors against Alzheimer’s disease, evaluated by an improved ultra-micro assay
Andrade-Jorge, Erik,Sánchez-Labastida, Luis A.,Soriano-Ursúa, Marvin A.,Guevara-Salazar, Juan A.,Trujillo-Ferrara, José G.
, p. 2187 - 2198 (2018)
Alzheimer’s disease (AD), the most common form of dementia, is characterized by a progressive degeneration of the brain that leads to loss of memory and deterioration of others cognitive functions. The only drugs currently approved for treating AD are AChE inhibitors (AChEIs). We previously tested a novel isoindoline-1,3-dione, finding potent inhibition of AChE, in part because the two carbonyl groups of phthalimide facilitate hydrogen bonds with the enzyme. The aims of the present study were: (A) To achieve a faster and cheaper technique with a reduced quantity of reactive, without significant difference in the validation of the results, by modifying the version of the method described by Bonting and Featherstone. (B) To test new isoindolines and dioxoisoindolines as AChEIs and see if the carbonyl group is really important for affinity. Both families of compounds (isoindolines and dioxoisoindolines) had an inhibitory effect. The enzymatic inhibitions produced by isoindolines were uncompetitive, whereas that evoked by dioxoisoindolines were competitive. One of the isoindoline derivatives (IsoB with a Ki of 88–160μM) showed about 5-fold greater inhibition of AChE than its corresponding dioxoisoindoline. According to molecular docking performed, dioxoisoindolines apparently interact with the catalytic active site, the peripheral anionic site, and the aromatic patch, which can explain the kind of inhibition observed. Due to the uncompetitive inhibition of isoindolines, their inhibitory behavior could not be explored in silico. We afforded a faster and more efficient method, while yielding similar results than Bonting and Featherstone method. Additionally, we demonstrated that carbonyl group affects the kind of inhibition and the affinity.
Novel synthesis of isoindoline/isoindoline-1,3-dione derivatives under solventless conditions and evaluation with the human D2 receptor
Andrade-Jorge, Erik,Bahena-Herrera, José R.,Garcia-Gamez, Jesus,Padilla-Martínez, Itzia I.,Trujillo-Ferrara, José G.
, p. 2420 - 2431 (2017)
Isoindolines are the focus of much research because of being an important family of compounds present in a wide array of bioactive molecules. Although many different pathways of synthesis have been described, they do not follow green chemistry principles. The aim of this contribution was to develop a green synthesis technique for isoindolines/dioxoisoindolines. These compounds derived from analogs of important biogenic amines were tested in silico (on the human dopamine receptor D2) to predict their affinities and some pharmacokinetic parameters. One of them, YaI-01, was evaluated in vivo in a Parkinsonism mouse model. Seven molecules, including three isoindolines and four dioxoisoindolines, were synthesized using simple heating and relatively quick solventless reactions. They were then purified with a methodology as green as possible. Since no published crystal structure exists for dopamine receptor D2, it was necessary to generate and validate a homology model for molecular docking studies of the seven molecules synthesized presently. Docking was performed to assess affinity in terms of binding energy (?G). Apart from pharmacokinetic parameters, Lipinski’s rule of five and some properties of toxicity from QSAR models were evaluated. Whereas no risk was found for the isoindolines, there was evidence of three kinds of toxicity for the isoindoline-1,3-dione compounds. Overall, the in silico analysis suggests that the three isoindolines herein tested have the best properties as ligands of the dopamine receptor D2, interacting with the main amino acid residues at its allosteric binding site. YaI-01 (254 μmol/kg) reverted Parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
Synthesis of new amides based on N-Phthaloyl-α-Amino Acids
Tukhtaev,Yusupov,Vinogradova
, p. 3049 - 3058 (2021/05/28)
N-phthaloyl derivatives of aliphatic α-amino acids were synthesized using phthalanhydride under standard conditions. The optimization reaction carried out by the thermal method to obtain the amides of these N-phthaloyl amino acids resulted in transimitted rather than amidation. The target amides of N-phthaloyl-α-amino acids were obtained by acylation of the amine with the corresponding acid chloroanhydrides in dichloromethane. These results were compared with the results of a similar acylation in a non-polar solvent (benzene). The dependence of the direction of the reaction on the duration of the acylation and the amount of amine used was established. The conditions for the formation of the corresponding N-phthaloyl-α-amino acid amides and asymmetric phthalic acid diamides were found. It is noteworthy that the formation of diamides is directly proportional to the equivalent amount of amine and the duration of the reaction, which makes it possible to purposefully control the synthesis in one reactor.
Difluoromethylthiolation of Phenols and Related Compounds with a HF2CSO2Na/Ph2PCl/Me3SiCl System
Huang, Zhongyan,Matsubara, Okiya,Jia, Shichong,Tokunaga, Etsuko,Shibata, Norio
supporting information, p. 934 - 937 (2017/02/26)
A novel HF2CSO2Na/Ph2PCl/Me3SiCl system is disclosed for the late-stage direct difluoromethylthiolation of Csp2 and Csp3 nucleophiles. Difluoromethylthiolation of phenols and naphthols proceeded nicely under this system to regioselectively provide corresponding SCF2H compounds in good yields. Other substrates such as indoles, pyrroles, pyrazoles, enamines, ketones, and β-keto esters were also transformed to corresponding SCF2H products in good yields. The late-stage direct difluoromethylthiolation of a number of natural products and pharmaceutically attractive molecules was also achieved.
IinQ attenuates systemic inflammatory responses via selectively impairing the Myddosome complex formation upon TLR4 ligation
Kang, Kidong,Won, Minho,Yuk, Jae-Min,Park, Chan-Yong,Byun, Hee Sun,Park, Kyeong Ah,Lee, So-Ra,Kang, Young-Goo,Shen, Han-Ming,Lee, Ill Young,Hur, Gang Min
, p. 52 - 66 (2016/11/30)
A specific small-molecule inhibitor of the TLR4 signaling complex upstream of the IKK would likely provide therapeutic benefit for NF-κB-mediated inflammatory disease. We previously identified brazilin as a selective upstream IKK inhibitor targeting the Myddosome complex. In this study, using a cell-based ubiquitination assay for IRAK1 and a chemical library comprising a series of structural analogues of brazilin, a novel small molecule, 2-hydroxy-5,6-dihydroisoindolo[1,2-a]isoquinoline-3,8-dione (IinQ), was identified as a selective and potent inhibitor of IRAK1-dependent NF-κB activation upon TLR4 ligation. In RAW264.7 macrophages, IinQ drastically suppressed activation of upstream IKK signaling events including membrane-bound IRAK1 ubiquitination and IKK phosphorylation by the TLR4 ligand, resulting in reduced expression of proinflammatory mediators including IL-6, TNF-α, and nitric oxide. Interestingly, IinQ did not suppress NF-κB activation via the TLR3 ligand, DNA damaging agents, or a protein kinase C activator, indicating IinQ is specific for TLR4 signaling. Analysis of upstream signaling events further confirmed that IinQ disrupts the MyD88-IRAK1-TRAF6 complex formation induced by LPS treatment, without affecting TLR4 oligomerization. Moreover, intravenous administration of IinQ significantly reduced lethality and attenuated systemic inflammatory responses in an in vivo mouse model of endotoxin shock following LPS challenge. Thus, IinQ represents a novel class of brazilin analogues with improved potency and specificity toward disruption of Myddosome complex formation in TLR4 signaling, indicating that IinQ may be a promising therapeutic candidate for the treatment of systemic inflammatory diseases.
Synthesis of bis-Tetrahydroisoquinolines Based on Homoveratrylamine and Dibasic Acids. 2.
Saidov,Levkovich,Alimova,Vinogradova
, p. 1099 - 1104 (2014/03/21)
Bis-tetrahydroisoquinolines were prepared from homoveratrylamine and phthalic acids using a Bischler-Napieralski reaction. Their structures were confirmed by IR and NMR spectral data.
Multimetallic iridium-tin (Ir-Sn3) catalyst in N-acyliminium ion chemistry: Synthesis of 3-substituted isoindolinones via intra- and intermolecular amidoalkylation reaction
Maity, Arnab Kumar,Roy, Sujit
, p. 2627 - 2642 (2014/09/30)
The multimetallic iridium-tritin (Ir-Sn3) complex [Cp*Ir(SnCl3)2{SnCl2(H2O) 2}] (1) proved to be a highly effective catalyst towards C-OH bond activation of γ-hydroxylactams, leading to a nucleophilic substitution reaction known as the α-amidoalkylation reaction. Catalyst 1 can be easily synthesized from the reaction of (pentamethylcyclocyclopentadienyl)iridium dichloride dimer {[Cp*IrCl2]2} and tin(II) dichloride (SnCl2). In terms of catalyst loading, reaction conditions and yields of the product formed, 1 is found to be superior compared to classical Lewis acid catalysts. Different carbon (arenes, heteroarenes, allyltrimethylsilane, 1,3-dicarbonyls) and heteroatom (alcohols, thiols, amides and sulfonamides) nucleophiles have been successfully employed in the intramolecular and intermolecular alkylations, as well as in heterocyclization reactions. In the majority of cases good to excellent yields of 3-substituted isoindolinones and 5-substituted pyrrolidin-2-ones have been obtained. Besides, the reactions are also atom economical and salt free. It is proposed that the multimetallic Ir-Sn3 catalyst behaves as a mild and selective Lewis acid to activate the γ-hydroxylactam towards the formation of the N-acyliminium ion; the latter being trapped by potent nucleophiles leading to the desired products.
Bronsted acid assisted activation of imide carbonyl group: Regioselective synthesis of isoindoloisoquinolinone alkaloid (±)-nuevamine
Selvakumar, Jayaraman,Ramanathan, Chinnasamy Ramaraj
supporting information; experimental part, p. 7643 - 7646 (2011/12/03)
Activation of imide carbonyl group with trifluoromethanesulfonic acid facilitates the intramolecular cyclization of phenethylphthalimides to give a fused isoindoloisoquinolinone skeleton. The first one pot regioselective synthesis of isoindoloisoquinolinone alkaloid (±)-nuevamine has been successfully executed using this methodology.
An unusual reactivity of BBr3: Accessing tetrahydroisoquinoline units from N-phenethylimides
Selvakumar, Jayaraman,Makriyannis, Alexandros,Ramanathan, Chinnasamy Ramaraj
supporting information; experimental part, p. 4056 - 4058 (2010/10/21)
Isoindoloisoquinalinone, pyrroloisoquinolinone and benzo[a]quinolizinone units are constructed via intramolecular cyclization of the methoxy substituted N-phenethylimides using BBr3.
