Ugi 5-center-4-component reaction of α-amino aldehydes and its application in synthesis of 2-oxopiperazines.

A synthetic route leading to densely functionalized 2-oxopiperazines is presented. The strategy employs a 5-center-4-component variant of Ugi multicomponent reaction followed by a deprotection/cyclization sequence. N-Boc-α-amino aldehydes were used for the first time as carbonyl components in a key Ugi 5-center-4-component reaction (U-5C-4CR). It is shown that the presented synthetic route can lead to rigid, heterocyclic scaffolds, as demonstrated by the synthesis of tetrahydro-2H-pyrazino[1,2-a]pyrazine-3,6,9(4H)-trione ß-turn mimetic and derivatives of 1,6-dioxooctahydropyrrolo[1,2-a]pyrazine and 3,8-dioxohexahydro-3H-oxazolo[3,4-a]pyrazine.

Synthesis and biological evaluation of novel 3-(5-substituted-1H-indol-3-yl)pyrrolidine-2,5-dione derivatives with a dual affinity for serotonin 5-HT1A receptor and SERT.

The serotonin 1A (5-HT1A) receptors and serotonin transporter (SERT) are important biological targets in the treatment of diseases of the central nervous system, especially for depression. In this study, new 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives linked with the 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole moiety were synthesised and evaluated for their affinity for 5-HT1A receptor and serotonin reuptake inhibition. Selected compounds were then tested for their affinity for D2, 5-HT2A, 5-HT6 and 5-HT7 receptors, and also in in vitro metabolic stability assays in human microsomes. Finally, in vivo assays allowed us to evaluate the agonist-antagonist properties of pre- and postsynaptic 5-HT1A receptors. 3-(1-(4-(3-(5-methoxy-1H-indol-3-yl)-2,5-dioxopyrrolidin-1-yl)butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-5-carbonitrile (4f) emerged as the most promising compound from the series, due to its favourable receptor binding profile (Ki(5-HT1A) = 10.0 nM; Ki(SERT) = 2.8 nM), good microsomal stability and 5-HT1A receptor agonistic activity.

Novel multi-target ligands of dopamine and serotonin receptors for the treatment of schizophrenia based on indazole and piperazine scaffolds-synthesis, biological activity, and structural evaluation.

Schizophrenia is a chronic mental disorder that is not satisfactorily treated with available antipsychotics. The presented study focuses on the search for new antipsychotics by optimising the compound D2AAK3, a multi-target ligand of G-protein-coupled receptors (GPCRs), in particular D2, 5-HT1A, and 5-HT2A receptors. Such receptor profile may be beneficial for the treatment of schizophrenia. Compounds 1-16 were designed, synthesised, and subjected to further evaluation. Their affinities for the above-mentioned receptors were assessed in radioligand binding assays and efficacy towards them in functional assays. Compounds 1 and 10, selected based on their receptor profile, were subjected to in vivo tests to evaluate their antipsychotic activity, and effect on memory and anxiety processes. Molecular modelling was performed to investigate the interactions of the studied compounds with D2, 5-HT1A, and 5-HT2A receptors on the molecular level. Finally, X-ray study was conducted for compound 1, which revealed its stable conformation in the solid state.

Discovery of novel arylpiperazine-based DA/5-HT modulators as potential antipsychotic agents - Design, synthesis, structural studies and pharmacological profiling.

Schizophrenia is a mental disorder with a complex pathomechanism involving many neurotransmitter systems. Among the currently used antipsychotics, classical drugs acting as dopamine D2 receptor antagonists, and drugs of a newer generation, the so-called atypical antipsychotics, can be distinguished. The latter are characterized by a multi-target profile of action, affecting, apart from the D2 receptor, also serotonin receptors, in particular 5-HT2A and 5-HT1A. Such profile of action is considered superior in terms of both efficacy in treating symptoms and safety. In the search for new potential antipsychotics of such atypical receptor profile, an attempt was made to optimize the arylpiperazine based virtual hit, D2AAK3, which in previous studies displayed an affinity for D2, 5-HT1A and 5-HT2A receptors, and showed antipsychotic activity in vivo. In this work, we present the design of D2AAK3 derivatives (1-17), their synthesis, and structural and pharmacological evaluation. The obtained compounds show affinities for the receptors of interest and their efficacy as antagonists/agonists towards them was confirmed in functional assays. For the selected compound 11, detailed structural studies were carried out using molecular modeling and X-ray methods. Additionally, ADMET parameters and in vivo antipsychotic activity, as well as influence on memory and anxiety processes were evaluated in mice, which indicated good therapeutic potential and safety profile of the studied compound.

Synthesis of new 4-butyl-arylpiperazine-3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives and evaluation for their 5-HT1A and D2 receptor affinity and serotonin transporter inhibition.

A series of novel 4-butyl-arylpiperazine-3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives were synthesized and evaluated for their 5-HT1A/D2 receptor affinity and serotonin reuptake inhibition. The compounds exhibited high affinity for the 5-HT1A receptor, (especially 4dKi = 0.4 nM) which depended on the substitution pattern at the phenylpiperazine moiety. From this series screen, compound 4c emerged with promising mixed receptor profiles for the 5-HT1A/D2 receptors and the serotonin transporter (Ki = 1.3 nM, 182 nM and 64 nM, respectively).

Synthesis and biological evaluation of new multi-target 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives with potential antidepressant effect.

A series of novel 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives were synthesised and evaluated for their 5-HT1A/D2/5-HT2A/5-HT6/5-HT7 receptor affinity and serotonin reuptake inhibition. Most of the evaluated compounds displayed high affinities for 5-HT1A receptors (e.g., 4cKi = 2.3 nM, 4lKi = 3.2 nM). The antidepressant activity of the selected compounds was screened in vivo using the forced swim test (FST). The results indicate that compound MW005 (agonist of the pre- and postsynaptic 5-HT1A receptor) exhibited promising affinities for the 5-HT1A/SERT/D2/5-HT6/5-HT7 receptors and showed an antidepressant-like activity in the FST model.

Synthesis and biological investigations of 3ß-aminotropane arylamide derivatives with atypical antipsychotic profile.

This work is a continuation of our previous research, concentrating this time on lead structure modification to increase the 5-HT1A receptor affinity and water solubility of designed compounds. Therefore, the compounds synthesised within the present project included structural analogues of 3ß-acylamine derivatives of tropane with the introduction of a methyl substituent in the benzyl ring and a 2-quinoline, 3-quinoline, or 6-quinoline moiety. A series of novel 3ß-aminotropane derivatives was evaluated for their affinity for 5-HT1A, 5-HT2A, and D2 receptors, which allowed for the identification of compounds 12e, 12i, and 19a as ligands with highest affinity for the tested receptors; they were then subjected to further evaluation in preliminary in vivo studies. Selected compounds 12i and 19a displayed antipsychotic properties in the d-amphetamine-induced and MK-801-induced hyperlocomotor activity test in mice. Moreover, compound 19a showed significant antidepressant-like activity in the forced swim test in mice.

Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT(1A) activity. Part 5.

A series of novel 4-aryl-pyrido[1,2-c]pyrimidine derivatives containing a 1-(2-quinoline)piperazine moiety was synthesized. The chemical structure of new compounds was confirmed by FT-IR, (1)H NMR, (13)C NMR and HRMS spectra as well as elemental analysis. Affinity of the novel pyrido[1,2-c]pyrimidine derivatives for 5-HT1A, 5-HT2A receptors and serotonin transporter (SERT) was evaluated in an in vitro radioligand binding assay. Tested compounds showed moderate to high affinity for 5-HT1AR and SERT and low affinity for 5-HT2AR. Selected ligands were subjected to in vivo tests, such as induced hypothermia and the forced swimming test in mice, which determined presynaptic agonistic activity of the ligands 8d, 8e, 9d and 9e and presynaptic antagonistic activity of the ligands 8a, 8b, 9a, 9b. Additionally, metabolic stability evaluation was performed for selected ligands, proving that a para-substitution in the 4-aryl-pyrido[1,2-c]pyrimidine moiety leads to an increase in stability, whereas a substitution in the ortho-position lowers the stability.

Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity. Part 4.

This project describes the synthesis, pharmacological and pharmacodynamic tests on two series of novel derivatives of 2H-pyrido[1,2-c]pyrimidine with potential binary binding to 5-HT1A receptors and SSRI + serotonin transporters. The influence of piperidinyl-indole (8.1-8.7) and tetrahydropyridinyl-indole (8.8-8.32) residues and indole 5-position substituents (R3 = Br, Cl, F) present in the pharmacophore element of ligands on their binding to both molecular targets was tested. A considerable impact of piperidinyl-indole residue on binding to both targets was confirmed and compounds with a high binding affinity were identified: Ki 5-HT1A = 12.4 nM; Ki SERT = 15.6 nM 8.1; Ki 5-HT1A = 5.6 nM; Ki SERT = 20.7 nM 8.7, while the presence of a tetrahydropyridinyl-indole residue was found to reduce the affinity of ligands to 5-HT1AR. The presence of chlorine (R3) in this series resulted in a notable reduction in binding to both targets (5-HT1A and SERT). Selected compounds had their metabolic stability in a first-pass test (human liver microsomes, NADPH) determined in vitro, and R1 and R2 substituents present on the terminal residue of pyrido[1,2-c]pyrimidine were recognized as having an impact on stability.

Model structure-activity relationship studies of potential tropane 5HT1A, 5HT2A, and D2 receptor ligands.

The two-stages studies of structure-activity relationship for model ligands of 5HT1A, 5HT2A, and D2 receptors were performed. On the first stage, the pharmacophores of two potential ligands of known in vitro binding to 5HT1A, 5HT2A, D2 receptors and model pharmacophore of strongly interacting D2 receptor ligands were found and their parameters were related to affinity data. The analyzed parameters were hydrophobic, hydrophilic, aromatic, donor and acceptor of proton centers. The geometry of spatial distribution of these properties was also investigated in comparative analysis. The studied, model compounds were two 3ß-acylamine derivatives of tropane. The second stage includes docking of studied compounds to D2 receptor model and the comparison of its quality with in vivo binding data. The obtained results are consistent with in vitro binding data and applied procedure accurate estimates the affinity of potential ligands to D2 receptors.

Synthesis and biological evaluation of novel pyrrolidine-2,5-dione derivatives as potential antidepressant agents. Part 1.

A series of 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives was synthesized and their biological activity was evaluated. The chemical structures of the newly prepared compounds were confirmed by (1)H NMR, (13)C NMR and ESI-HRMS spectra data. All tested compounds proved to be potent 5-HT1A receptor and serotonin transporter protein (SERT) ligands. Among them, compounds 15, 18, 19 and 30 showed significant affinity for 5-HT1A and SERT. Computer docking simulations carried out for compounds 15, 31 and 32 to models of 5-HT1A receptor and SERT confirm the results of biological tests. Due to high affinity for the 5-HT1A receptor and moderate affinity for SERT, compounds 31, 32, 35, and 37 were evaluated for their affinity for D2L, 5-HT6, 5-HT7 and 5-HT2A receptors. In vivo tests, in turn, resulted in determining the functional activity of compounds 15, 18, 19 and 30 to the 5-HT1A receptor. The results of these tests indicate that all of the ligands possess properties characteristic of 5-HT1A receptor agonists.