A New Approach to the Synthesis of <i>N</i>,<i>N</i>‐Dialkyladenine Derivatives

Alves, M. I. Caetano; Carvalho, M. Alice; Carvalho, Sílvia; Dias, Alice; Fernandes, F.; Proença, M. Fernanda

doi:10.1002/ejoc.200700416

Cited by 18 publications

(8 citation statements)

References 33 publications

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“…These compounds are all members of the 9-methyl-purine family, with N6 substituent being either N-methyl piperazine or piperidine and an aryl derivative in position 2. Their preparation followed a new synthetic approach, where a substituted imidazole, obtained according to a previously described procedure [20] was combined with a substituted aldehyde under appropriate experimental conditions (unpublished results). The products were isolated in yields ranging from 40 to 65%.…”

Section: Resultsmentioning

confidence: 99%

Identification of Novel Scaffolds from an Original Chemical Library as Potential Antipsychotics

et al. 2009

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The ligand-based virtual screening of an original chemical library, using atypical antipsychotics as query compounds led to the identification of a novel scaffold with inhibitory activity at the 5-HT 2A serotonin receptor. The hit compounds were confirmed by pharmacological evaluation at the 5-HT 2A receptor and complemented by the selection of other representatives of the same chemical family within our chemical library. A promising scaffold of 6-(pyperazin-1-yl) purine was identified, and the binding mode is illustrated with an automated docking exploration on a homology built model of the 5-HT 2A receptor. The present results constitute an excellent starting point for the discovery of new chemical entities with antipsychotic activity.Schizophrenia is a severe disorder that affects around 24 million people worldwide, typically beginning in late adolescence or early adulthood. It constitutes one of the major psychiatric disorders in the world, and it can impair functioning through the loss of the acquired capability of earning ones own livelihood or through the disruption of studies [1]. Up to date, pharmacological therapy with antipsychotics constitutes the most effective way to maintain most of the symptoms under control. Nowadays, clozapine, discovered nearly 50 years ago, remains as the gold standard antipsychotic, being the only licensed drug indicated for treatment-resistant schizophrenia. However, its use is restricted to these cases mainly due to the risk of agranulocytosis, its major adverse effect [2]. Based on its high affinity at the serotonin 5-HT 2A receptors, modulating its intermediate affinity over dopamine D 2 receptor, a putative mechanism of action of the so-called atypical antipsychotic drugs has been primary established by the Meltzer index, which is the relationship between the affinities at the aforementioned receptors [3]. However, recent multirreceptorial profiling of clozapine has shown its affinity at several aminergic G protein-coupled receptors (GPCRs) [4], opening a new scenario where the beneficial effects of atypical antipsychotics on cognition, negative symptoms, and the low incidence of EPS are mediated by a complex blend of interactions. Therefore, there has been growing interest in the discovery of new compounds that exhibit a similar pharmacological profile as clozapine, but possessing clozapine-unrelated chemical structures.Three dimensional ligand-based virtual screening (3D-LBVS) represents a good strategy to retrieve original, chemically different compounds from a chemical database, displaying similar pharmacological profile to a given compound with clinical interest [5,6]. This statement is not in disagreement with the excellent performance of 2D-based LBVS methodologies, as it has been noted by several authors [6,7]. For the particular case of antipsychotics, however, 3D-LBVS appears as an especially well suited technique attending to the following reasons: i) The target proteins are several aminergic receptors of the GPCR superfamily. Even if the traditional h...

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Section: Resultsmentioning

confidence: 99%

Identification of Novel Scaffolds from an Original Chemical Library as Potential Antipsychotics

et al. 2009

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“…Additionally, reactions with isocyanates gave biimidazoles and 6‐carboxamidino purines [30,31] . It was also found that imidazoles 1 suffer nucleophilic attack by secondary amines with elimination of HCN [27] . Later, it was possible to establish that the attack of primary amines or hydrazines also arises to give the corresponding 4‐carboxamidino or 4‐carboxamidrazono imidazoles, respectively, through a similar pathway, as long as a catalytical amount of acetic or trifluoroacetic (TFA) acid, was used [32,33] .…”

Section: Resultsmentioning

confidence: 99%

“…The synthesis of the target molecules of this work (compounds 3) was achieved starting from the accessible 5-amino-4cyanoformimidoyl imidazoles 1, which were prepared according to a previously developed method. [23][24][25][26][27] Past work demonstrated that these precursors easily reacted with electrophiles, [16] and 2-amino-6-(2thiazolyl)purine [17] ], and the new analogues developed by the research group (2-amino-6-cyanopurine), with respective photophysical properties. affording 6-cyanopurines, isoguanines and imidazolyl triazoles through condensation with acetic anhydride or ethylchloroformate.…”

Section: Resultsmentioning

confidence: 99%

“…Materials and instruments : All compounds were fully characterized by elemental analysis and spectroscopic data. The 5‐amino‐4‐cyanoformimidoyl imidazoles 1 a – l used in this work were prepared according to previously described procedures [23–27] . The reactions were monitored by thin layer chromatography (TLC) using silica gel 60F254 (Merck).…”

Section: Methodsmentioning

confidence: 99%

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Highly Fluorescent 2‐Aminopurine Derivatives: Synthesis, Photo‐physical Characterization, and Preliminary Cytotoxicity Evaluation

et al. 2023

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New fluorescent nucleobase analogues (FBAs) are emerging as extraordinarily useful tools for DNA labelling technologies. The highly fluorescent adenine analogue 2-aminopurine (2AP) is still the most used within the few hundreds of newly FBAs synthesized, but its excitation in the UV region demands for high energy sources endangering living cells. New and highly fluorescent 2AP derivatives, 2-amino-6-cyanopurines, were obtained using simpler but efficient synthesis method. All the new compounds exhibit advantageous photophysical proper-ties over 2AP, showing absorption and emission bands ranging the visible region (blue-green region), high fluorescence quantum yields and Stokes' shifts, especially in non-protic organic solvents. Density Functional Theory calculations (DFT) of electronic and vibrational structure were performed, allowing to predict absorption and emission spectra. In addition, these 2amino-6-cyanopurines exhibit little to no toxicity in assays using yeast cells.

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“…The 5-amino-4-cyanoformimidoylimidazoles 22a – h used in this work were synthesised according to previously described procedures [ 43 ], compounds 23 were obtained following procedures reported in [ 44 , 45 , 46 ], and compounds 24 – 25 were synthesised according to procedures described in [ 47 ]. Solvents and other chemicals commercially available were used as shipped.…”

Section: Methodsmentioning

confidence: 99%

Synthesis of Novel 2,9-Disubstituted-6-morpholino Purine Derivatives Assisted by Virtual Screening and Modelling of Class I PI3K Isoforms

et al. 2023

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The phosphatidylinositol-3 kinase (PI3K) pathway is one of the most frequently activated pathogenic signalling cascades in a wide variety of cancers. In the last 15 years, there has been an increase in the search for selective inhibitors of the four class I isoforms of PI3K, as they demonstrate better specificity and reduced toxicity in comparison to existing inhibitors. A ligand-based and target-based rational drug design strategy was employed to build a virtual library of 105 new compounds. Through this strategy, the four isoforms were compared regarding their activity pocket availability, amino acid sequences, and prone interactions. Additionally, a known active scaffold was used as a molecular base to design new derivatives. The virtual screening of the resultant library toward the four isoforms points to the obtention of 19 selective inhibitors for the PI3Kα and PI3Kγ targets. Three selective ligands, one for α-isoform and two for γ-isoform, present a ∆ (∆Gbinding) equal or greater than 1.5 Kcal/mol and were identified as the most promising candidates. A principal component analysis was used to establish correlations between the affinity data and some of the physicochemical and structural properties of the ligands. The binding modes and interactions established by the selective ligands in the active centre of the α and γ isoforms of PI3K were also investigated. After modelling studies, a synthetic approach to generate selective ligands was developed and applied in synthesising a set of derivatives that were obtained in good to excellent yield.

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A New Approach to the Synthesis of N,N‐Dialkyladenine Derivatives

Cited by 18 publications

References 33 publications

Identification of Novel Scaffolds from an Original Chemical Library as Potential Antipsychotics

Identification of Novel Scaffolds from an Original Chemical Library as Potential Antipsychotics

Highly Fluorescent 2‐Aminopurine Derivatives: Synthesis, Photo‐physical Characterization, and Preliminary Cytotoxicity Evaluation

Synthesis of Novel 2,9-Disubstituted-6-morpholino Purine Derivatives Assisted by Virtual Screening and Modelling of Class I PI3K Isoforms

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