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...
A simple and general 'one-pot' procedure for the synthesis of 2,9-diarylpurines with one or multiple hydroxyl groups in the 2-aryl unit is described, from the reaction of 5-amino-4-amidinoimidazoles with phenolic aldehydes.Purines have attracted attention of the scientific community mainly due to their biological activity. 1 During the last decade, purine derivatives were identified as a promising new class of antitubercular agents. The research was focused on the synthesis of nucleoside analogues as siderophore biosynthesis inhibitors 2 and on non-nucleosides. 3 In the non-nucleoside series, purines having an aryl, a small alkyl, or a proton on N-9 were essentially inactive, whereas 9-benzyl-6-(2-furyl)purines, 3b,h,j 9-sulfonyl-6-mercaptopurines, or 6-alkylthiopurines 3e,k were highly potent. In addition, we recently described the first example of 2,9-diarylpurines ( Figure 1) active against Mycobacterium tuberculosis. 4 The results from biological evaluation showed that the potency of the compounds depends on the substituents in N-9, C-2, and C-6 of the purine core. The presence of a 4-tolyl group in N-9 and a 3-hydroxyphenyl or a 4-hydroxyphenyl substituent in C-2 combined with a secondary amine in C-6 proved to be important features for activity ( Figure 1) but a clear structure-activity correlation pattern could not be identified. 4 Figure 1 Hit compounds active on Mycobacterium tuberculosisA number of synthetic methods were developed to incorporate functional groups in the purine core, but costly reagents are usually required. 5a,b In our research group purine derivatives have been obtained by a simple and inexpensive synthetic approach that uses the versatile reactivity of a substituted imidazole. 4,5c-l The 6-amino-2,9-diarylpurines ( Figure 1) are a new promising scaffold active against Mycobacterium tuberculosis and the presence of hydroxyl groups in the aryl subunit in C-2 was considered an important feature for activity. The microorganism needs iron for the biochemical processes, and multiple hydroxyl groups in the phenolic subunit could enhance the complexation with the metal. This perception prompted us to develop a new synthetic approach that would allow the efficient synthesis of purines 6 (Table 1) having a phenolic subunit in C-2 with two and three hydroxyl substituents. The previous method only allowed the introduction of phenolic units with one hydroxyl group as the reaction with polyphenolic aldehydes, performed in basic medium, was very slow (8-54 d) and extensive degradation occurred. 4 Herein we describe a new and general synthetic approach for 6-amino-9-aryl-2-hydroxy or 2-(polyhydroxyphenyl)purines 6 using imidazole 1, phenolic aldehydes 2, and a cascade of acid and base catalysis. When compound 1a (Scheme 1) was combined with 3,4,5-trihydroxybenzaldehyde (2a) in ethanol at 0°C, using trifluoroacetic acid as catalyst, the starting materials were dissolved and a new white solid precipitated after five minutes. This compound was identified as the trifluoroacetate salt of starting materi...
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