Short Communication: Novel Di- and Triselenoesters as Effective Therapeutic Agents Inhibiting Multidrug Resistance Proteins in Breast Cancer Cells.

Breast cancer has the highest incidence rate among all malignancies worldwide. Its high mortality is mainly related to the occurrence of multidrug resistance, which significantly limits therapeutic options. In this regard, there is an urgent need to develop compounds that would overcome this phenomenon. There are few reports in the literature that selenium compounds can modulate the activity of P-glycoprotein (MDR1). Therefore, we performed in silico studies and evaluated the effects of the novel selenoesters EDAG-1 and EDAG-8 on BCRP, MDR1, and MRP1 resistance proteins in MCF-7 and MDA-MB-231 breast cancer cells. The cytometric analysis showed that the tested compounds (especially EDAG-8) are inhibitors of BCRP, MDR1, and MRP1 efflux pumps (more potent than the reference compounds-novobiocin, verapamil, and MK-571). An in silico study correlates with these results, suggesting that the compound with the lowest binding energy to these transporters (EDAG-8) has a more favorable spatial structure affecting its anticancer activity, making it a promising candidate in the development of a novel anticancer agent for future breast cancer therapy.

Recent Development of Fluoroquinolone Derivatives as Anticancer Agents.

Cancer is the second leading cause of death in the world following cardiovascular disease. Its treatment, including radiation therapy and surgical removal of the tumour, is based on pharmacotherapy, which prompts a constant search for new and more effective drugs. There are high costs associated with designing, synthesising, and marketing new substances. Drug repositioning is an attractive solution. Fluoroquinolones make up a group of synthetic antibiotics with a broad spectrum of activity in bacterial diseases. Moreover, those compounds are of particular interest to researchers as a result of reports of their antiproliferative effects on the cells of the most lethal cancers. This article presents the current progress in the development of new fluoroquinolone derivatives with potential anticancer and cytotoxic activity, as well as structure-activity relationships, along with possible directions for further development.

Synthesis, Docking, and Machine Learning Studies of Some Novel Quinolinesulfonamides-Triazole Hybrids with Anticancer Activity.

In the presented work, a series of 22 hybrids of 8-quinolinesulfonamide and 1,4-disubstituted triazole with antiproliferative activity were designed and synthesised. The title compounds were designed using molecular modelling techniques. For this purpose, machine-learning, molecular docking, and molecular dynamics methods were used. Calculations of the pharmacokinetic parameters (connected with absorption, distribution, metabolism, excretion, and toxicity) of the hybrids were also performed. The new compounds were synthesised via a copper-catalysed azide-alkyne cycloaddition reaction (CuAAC). 8-N-Methyl-N-{[1-(7-chloroquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methyl}quinolinesulfonamide was identified in in silico studies as a potential strong inhibitor of Rho-associated protein kinase and as a compound that has an appropriate pharmacokinetic profile. The results obtained from in vitro experiments confirm the cytotoxicity of derivative 9b in four selected cancer cell lines and the lack of cytotoxicity of this derivative towards normal cells. The results obtained from silico and in vitro experiments indicate that the introduction of another quinolinyl fragment into the inhibitor molecule may have a significant impact on increasing the level of cytotoxicity toward cancer cells and indicate a further direction for future research in order to find new substances suitable for clinical applications in cancer treatment.

Evaluation of anticancer activity of novel platinum(II) bis(thiosemicarbazone) complex against breast cancer.

The study aims to synthesize a novel bis(thiosemicarbazone) derivative based on platinum (thioPt) and evaluate its anticancer properties against MFC-7 and MDA-MB-231 breast cancer cells. A new platinum complex was synthesised by reacting K2PtCl4 with 2,2'-(1,2-diphenylethane-1,2-diylidene)bis(hydrazine-1-carbothioamide) in ethanol in the presence of K2CO3. In the obtained complex, the platinum atom is coordinated by a conjugated system = N-NC-S-The structures of the new compound were characterised using NMR spectroscopy, HR MS, IR, and X-ray structural analysis. The obtained results of the cytotoxicity assay indicate that compound thioPt had potent anticancer activity (MCF-7: 61.03 ± 3.57 µM, MDA-MB-231: 60.05 ± 5.40 µM) with less toxicity against normal MCF-10A breast epithelial cells, even compared to the reference compound (cisplatin). In addition, subsequent experiments found that thioPt induces apoptosis through both an extrinsic (↑caspase 8 activity) and intrinsic (↓ΔΨm) pathway, which ultimately leads to an increase in active caspase 3/7 levels. The induction of autophagy and levels of proteins involved in this process (LC3A/B and Beclin-1) were examined in MCF-7 and MDA-MB-231 breast cancer cells exposed to tested compounds (thio, thioPt, cisPt) at a concentration of 50 µM for 24 h. Based on these results, it can be concluded that thio and thioPt do not significantly affect the autophagy process. This demonstrates their superiority over cisplatin, which can stimulate cancer cell survival through its effect on stimulation of autophagy.

Design, Synthesis and Biological Evaluation of Quinoline-8-Sulfonamides as Inhibitors of the Tumor Cell-Specific M2 Isoform of Pyruvate Kinase: Preliminary Study.

Cancer cells need to carefully regulate their metabolism to keep them growing and dividing under the influence of different nutrients and oxygen levels. Muscle isoform 2 of pyruvate kinase (PKM2) is a key glycolytic enzyme involved in the generation of ATP and is critical for cancer metabolism. PKM2 is expressed in many human tumors and is regulated by complex mechanisms that promote tumor growth and proliferation. Therefore, it is considered an attractive therapeutic target for modulating tumor metabolism. Various modulators regulate PKM2, shifting it between highly active and less active states. In the presented work, a series of 8-quinolinesulfonamide derivatives of PKM2 modulators were designed using molecular docking and molecular dynamics techniques. New compounds were synthesized using the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. Compound 9a was identified in in silico studies as a potent modulator of muscle isoform 2 of pyruvate kinase. The results obtained from in vitro experiments confirmed the ability of compound 9a to reduce the intracellular pyruvate level in A549 lung cancer cells with simultaneous impact on cancer cell viability and cell-cycle phase distribution. Moreover, compound 9a exhibited more cytotoxicity on cancer cells than normal cells, pointing to high selectivity in the mode of action. These findings indicate that the introduction of another quinolinyl fragment to the modulator molecule may have a significant impact on pyruvate levels in cancer cells and provides further directions for future research to find novel analogs suitable for clinical applications in cancer treatment.

Interaction between moxifloxacin and Mcl-1 and MITF proteins: the effect on growth inhibition and apoptosis in MDA-MB-231 human triple-negative breast cancer cells.

BACKGROUND: Microphthalmia-associated transcription factor (MITF) activates the expression of genes involved in cellular proliferation, DNA replication, and repair, whereas Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing apoptosis. The objective of the present study was to verify whether the interaction between moxifloxacin (MFLX), one of the fluoroquinolones, and MITF/Mcl-1 protein, could affect the viability, proliferation, and apoptosis in human breast cancer using both in silico and in vitro models. METHODS: Molecular docking analysis (in silico), fluorescence image cytometry, and Western blot (in vitro) techniques were applied to assess the contribution of MITF and Mcl-1 proteins in the MFLX-induced anti-proliferative and pro-apoptotic effects on the MDA-MB-231 breast cancer cells. RESULTS: We indicated the ability of MFLX to form complexes with MITF and Mcl-1 as well as the drug's capacity to affect the expression of the tested proteins. We also showed that MFLX decreased the viability and proliferation of MDA-MB-231 cells and induced apoptosis via the intrinsic death pathway. Moreover, the analysis of the cell cycle progression revealed that MFLX caused a block in the S and G2/M phases. CONCLUSIONS: We demonstrated for the first time that the observed effects of MFLX on MDA-MB-231 breast cancer cells (growth inhibition and apoptosis induction) could be related to the drug's ability to interact with MITF and Mcl-1 proteins. Furthermore, the presented results suggest that MITF and Mcl-1 proteins could be considered as the target in the therapy of breast cancer.

Design, Sustainable Synthesis and Biological Evaluation of a Novel Dual α2A/5-HT7 Receptor Antagonist with Antidepressant-Like Properties.

The complex pathophysiology of depression, together with the limits of currently available antidepressants, has resulted in the continuous quest for alternative therapeutic strategies. Numerous findings suggest that pharmacological blockade of α2-adrenoceptor might be beneficial for the treatment of depressive symptoms by increasing both norepinephrine and serotonin levels in certain brain areas. Moreover, the antidepressant properties of 5-HT7 receptor antagonists have been widely demonstrated in a large set of animal models. Considering the potential therapeutic advantages in targeting both α2-adrenoceptors and 5-HT7 receptors, we designed a small series of arylsulfonamide derivatives of (dihydrobenzofuranoxy)ethyl piperidines as dually active ligands. Following green chemistry principles, the designed compounds were synthesized entirely using a sustainable mechanochemical approach. The identified compound 8 behaved as a potent α2A/5-HT7 receptor antagonist and displayed moderate-to-high selectivity over α1-adrenoceptor subtypes and selected serotonin and dopaminergic receptors. Finally, compound 8 improved performance of mice in the forced swim test, displaying similar potency to the reference drug mirtazapine.

Lipophilicity, Pharmacokinetic Properties, and Molecular Docking Study on SARS-CoV-2 Target for Betulin Triazole Derivatives with Attached 1,4-Quinone.

A key parameter in the design of new active compounds is lipophilicity, which influences the solubility and permeability through membranes. Lipophilicity affects the pharmacodynamic and toxicological profiles of compounds. These parameters can be determined experimentally or by using different calculation methods. The aim of the research was to determine the lipophilicity of betulin triazole derivatives with attached 1,4-quinone using thin layer chromatography in a reverse phase system and a computer program to calculate its theoretical model. The physiochemical and pharmacokinetic properties were also determined by computer programs. For all obtained parameters, the similarity analysis and multilinear regression were determined. The analyses showed that there is a relationship between structure and properties under study. The molecular docking study showed that betulin triazole derivatives with attached 1,4-quinone could inhibit selected SARS-CoV-2 proteins. The MLR regression showed that there is a correlation between affinity scoring values (ΔG) and the physicochemical properties of the tested compounds.

The application of in silico experimental model in the assessment of ciprofloxacin and levofloxacin interaction with main SARS-CoV-2 targets: S-, E- and TMPRSS2 proteins, RNA-dependent RNA polymerase and papain-like protease (PLpro)-preliminary molecular docking analysis.

BACKGROUND: The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified at the end of 2019. Despite growing understanding of SARS-CoV-2 in virology as well as many molecular studies, except remdesivir, no specific anti-SARS-CoV-2 drug has been officially approved. METHODS: In the present study molecular docking technique was applied to test binding affinity of ciprofloxacin and levofloxacin-two commercially available fluoroquinolones, to SARS-CoV-2 S-, E- and TMPRSS2 proteins, RNA-dependent RNA polymerase and papain-like protease (PLPRO). Chloroquine and dexamethasone were used as reference positive controls. RESULTS: When analyzing the molecular docking data it was noticed that ciprofloxacin and levofloxacin possess lower binding energy with S protein as compared to the references. In the case of TMPRSS2 protein and PLPRO protease the best docked ligand was levofloxacin and in the case of E proteins and RNA-dependent RNA polymerase the best docked ligands were levofloxacin and dexamethasone. Moreover, a molecular dynamics study also reveals that ciprofloxacin and levofloxacin form a stable complex with E- and TMPRSS2 proteins, RNA polymerase and papain-like protease (PLPRO). CONCLUSIONS: The revealed data indicate that ciprofloxacin and levofloxacin could interact and potentially inhibit crucial SARS-CoV-2 proteins.

Molecular Structure, In Vitro Anticancer Study and Molecular Docking of New Phosphate Derivatives of Betulin.

A series of 30-diethylphosphate derivatives of betulin were synthesized and evaluated for their in vitro cytotoxic activity against human cancer cell lines, such as amelanotic melanoma (C-32), glioblastoma (SNB-19), and two lines of breast cancer (T47D, MDA-MB-231). The molecular structure and activities of the new compounds were also compared with their 29-phosphonate analogs. Compounds 7a and 7b showed the highest activity against C-32 and SNB-19 cell lines. The IC50 values for 7a were 2.15 and 0.91 µM, and, for 7b, they were 0.76 and 0.8 µM for the C-32 and SNB-19 lines, respectively. The most potent compounds, 7a and 7b, were tested for their effects on markers of apoptosis, such as H3, TP53, BAX, and BCL-2. For the whole series of phosphate derivatives, a lipophilicity study was performed, and the ADME parameters were calculated. The most active products were docked to the active site of the EGFR protein. The relative binding affinity of selected phosphate betulin derivatives toward EGFR was compared with standard erlotinib on the basis of ChemScore and KDEEP score. Positively, all derivatives docked inside the cavity and showed significant interactions. Moreover, a molecular dynamics study also reveals that ligands 7a,b form stable complexes and the plateau phase started after 7 ns.

Design, synthesis and biological activity of 1,4-quinone moiety attached to betulin derivatives as potent DT-diaphorase substrate.

In this research, betulin derivatives were bonded to the 1,4-quinone fragment by triazole linker. Furthermore, the enzymatic assay used has shown that these compounds are a good DT-diaphorase (NQO1) substrates as evidenced by increasing enzymatic conversion rates relative to that of streptonigrin. The anticancer activities of the hybrids were tested against a panel of human cell lines, like: melanoma, ovarian, breast, colon, and lung cancers. The structure-activity relationship showed that the activity depends on the type of 1,4-quinone moiety and the tumor cell lines used. It was also found that the anticancer effects were increasing against the cell line with higher NQO1 protein level, like: breast (T47D, MCF-7), colon (Caco-2), and lung (A549) cancers. The transcriptional activity of the gene encoding a proliferation marker (H3 histone), cell cycle regulators (p53 and p21) and apoptosis pathway (BCL-2 and BAX) for selected compounds were determined. The molecular docking study was carried out to examine the interaction between the hybrids and NQO1 enzyme. The computational simulation showed that the type of the 1,4-quinone moiety influences location of the compound in the active site of the enzyme. It is worth noting that the study of new hybrids of betulin as substrate for NQO1 protein may lead to new medical therapeutic applications in the future.

Ciprofloxacin and moxifloxacin could interact with SARS-CoV-2 protease: preliminary in silico analysis.

BACKGROUND: A large body of research has focused on fluoroquinolones. It was shown that this class of synthetic antibiotics could possess antiviral activity as a broad range of anti-infective activities. Based on these findings, we have undertaken in silico molecular docking study to demonstrate, for the first time, the principle for the potential evidence pointing ciprofloxacin and moxifloxacin ability to interact with COVID-19 Main Protease. METHODS: In silico molecular docking and molecular dynamics techniques were applied to assess the potential for ciprofloxacin and moxifloxacin interaction with COVID-19 Main Protease (Mpro). Chloroquine and nelfinavir were used as positive controls. RESULTS: We revealed that the tested antibiotics exert strong capacity for binding to COVID-19 Main Protease (Mpro). According to the results obtained from the GOLD docking program, ciprofloxacin and moxifloxacin bind to the protein active site more strongly than the native ligand. When comparing with positive controls, a detailed analysis of the ligand-protein interactions shows that the tested fluoroquinolones exert a greater number of protein interactions than chloroquine and nelfinavir. Moreover, lower binding energy values obtained from KDEEP program were stated when compared to nelfinavir. CONCLUSIONS: Here, we have demonstrated for the first time that ciprofloxacin and moxifloxacin may interact with COVID-19 Main Protease (Mpro).

Phosphate Derivatives of 3-Carboxyacylbetulin: SynThesis, In Vitro Anti-HIV and Molecular Docking Study.

Lupane-type pentacyclic triterpenes such as betulin and betulinic acid play an important role in the search for new therapies that would be effective in controlling viral infections. The aim of this study was the synthesis and evaluation of in vitro anti-HIV-1 activity for phosphate derivatives of 3-carboxyacylbetulin 3-5 as well as an in silico study of new compounds as potential ligands of the C-terminal domain of the HIV-1 capsid-spacer peptide 1 (CA-CTD-SP1) as a molecular target of HIV-1 maturation inhibitors. In vitro studies showed that 28-diethoxyphosphoryl-3-O-(3',3'-dimethylsuccinyl)betulin (compound 3), the phosphate analog of bevirimat (betulinic acid derivative, HIV-1 maturation inhibitor), has IC50 (half maximal inhibitory concentration) equal to 0.02 µM. Compound 3 inhibits viral replication at a level comparable to bevirimat and is also more selective (selectivity indices = 1250 and 967, respectively). Molecular docking was used to examine the probable interaction between the phosphate derivatives of 3-carboxyacylbetulin and C-terminal domain (CTD) of the HIV-1 capsid (CA)-spacer peptide 1 (SP1) fragment of Gag protein, designated as CTD-SP1. Compared with interactions between bevirimat (BVM) and the protein, an increased number of strong interactions between ligand 3 and the protein, generated by the phosphate group, were observed. These compounds might have the potential to also inhibit SARS-CoV2 proteins, in as far as the intrinsically imprecise docking scores suggest.

The role of MITF and Mcl-1 proteins in the antiproliferative and proapoptotic effect of ciprofloxacin in amelanotic melanoma cells: In silico and in vitro study.

Mcl-1 is a potent antiapoptotic protein which is amplified in many human cancer, while microphthalmia associated transcription factor (MITF) promotes cell proliferation and has pro-survival role. The study was designed to examine whether the interaction between ciprofloxacin, one of the fluoroquinolones derivative, and MITF/Mcl-1 proteins affects C32 melanoma cells viability, proliferation and induces apoptosis. Preliminary molecular docking studies, Western blot analysis and fluorescence image cytometry were applied to demonstrate the signaling pathway underlying antiproliferative and proapoptotic effect of the drug. In silico analysis showed that ciprofloxacin possess the ability to form complexes with MITF and Mcl-1proteins. This phenomenon was confirmed by in vitro experimental model where the drug was found to decrease MITF and increase Mcl-1 expression at the protein level. Moreover, we found that ciprofloxacin decreases the cell viability and exerts anti-proliferative effect on amelanotic C32 melanoma cells. Image cytometric studies showed that the tested drug induced GSH depletion and apoptosis via intrinsic death pathway leading to DNA fragmentation. Analysis of the cell cycle distribution revealed that ciprofloxacin caused a block in the G2/M phase. This is the first study that characterized the role of MITF and Mcl-1 proteins in the antiproliferative and pro-apoptotic effect of ciprofloxacin towards amelanotic melanoma cells, opening the possibility to use of this drug as a potential agent for the treatment of melanoma.

New Phosphorus Analogs of Bevirimat: Synthesis, Evaluation of Anti-HIV-1 Activity and Molecular Docking Study.

Since the beginning of the human immunodeficiency virus (HIV) epidemic, many groups of drugs characterized by diverse mechanisms of action have been developed, which can suppress HIV viremia. 3-O-(3',3'-Dimethylsuccinyl) betulinic acid, known as bevirimat (BVM), was the first compound in the class of HIV maturation inhibitors. In the present work, phosphate and phosphonate derivatives of 3-carboxyacylbetulinic acid were synthesized and evaluated for anti-HIV-1 activity. In vitro studies showed that 30-diethylphosphonate analog of BVM (compound 14a) has comparable effects to BVM (half maximal inhibitory concentrations (IC50) equal to 0.02 µM and 0.03 µM, respectively) and is also more selective (selectivity indices: 3450 and 967, respectively). To investigate the possible mechanism of antiviral effect of 14a, molecular docking was carried out on the C-terminal domain (CTD) of HIV-1 capsid (CA)-spacer peptide 1 (SP1) fragment of Gag protein, designated as CTD-SP1, which was described as a molecular target for maturation inhibitors. Compared with interactions between BVM and the protein, an increased number of strong interactions between ligand 14a and protein, generated by the phosphonate group, was observed.

Betulin-1,4-quinone hybrids: Synthesis, anticancer activity and molecular docking study with NQO1 enzyme.

Betulin-1,4-quinone hybrids were obtain by connecting two active structures with a linker. This strategy allows for obtaining compounds showing a high biological activity and better bioavailability. In this research, synthesis, anticancer activity and molecular docking study of betulin-1,4-quinone hybrids are presented. Newly synthesized compounds were characterized by 1H, 13C NMR, IR and HR-MS. Hybrids were tested in vitro against a panel of human cell lines including glioblastoma, melanoma, breast and lung cancer. They showed a high cytotoxic activity depending on the type of 1,4-quinone moiety and the applied tumor cell lines. It was found that cytotoxic activities of the studied hybrids were increasing against the cell line with higher NQO1 protein level, like melanoma (C-32), breast (MCF-7) and lung (A-549) cancer. Selected hybrids were tested on the transcriptional activity of the gene encoding a proliferation marker (H3 histone), a cell cycle regulators (p53 and p21) and an apoptosis pathway (BCL-2 and BAX). The obtained results suggested that the tested compounds caused a mitochondrial apoptosis pathway in A549 and MCF-7 cell lines. The molecular docking was used to examine the probable interaction between the hybrids and human NAD[P]H-quinone oxidoreductase (NQO1) protein. The computational studies showed that the type of the 1,4-quinone moiety affected the location of the compound in the active site of the enzyme. Moreover, it was shown that an interaction of 1,4-quinone fragment with the hydrophobic matrix of the active site near Tyr128, Phe178, Trp105 and FAD cofactor could explain the observed increase of TP53 gene expression.

New phosphate derivatives of betulin as anticancer agents: Synthesis, crystal structure, and molecular docking study.

Betulin derivatives exhibit an antiproliferative activity and have been tested for many cancer cell lines. This paper describes a new series of 3-phosphate derivatives of betulin bearing different substituents at C28 position. The synthesized compounds were tested in vitro for their antiproliferative effect against human leukemia (MV-4-11 and CCRF/CEM), lung carcinoma (A549), prostate cancer (DU 145), melanoma (Hs 294T) cell lines, and murine leukemia P388. To explore the possible mechanism of anticancer activity for the most in vitro active compounds (4, 5, 7 and 8) and betulin, molecular docking was performed to the binding sites of potential anticancer targets, described for the various triterpene derivatives, including topoisomerase I and II, epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGFR), transcription factor NF-κB, anti-apoptotic protein Bcl-2 and peroxisome proliferator-activated receptor (PPARγ). According to the results of the docking, the best fit to the binding pocket of PPARγ was shown by compound 4.

Biological Activity and In Silico Study of 3-Modified Derivatives of Betulin and Betulinic Aldehyde.

A series of 3-substituted derivatives of betulin and betulinic aldehyde were synthesized as promising anticancer agents. The newly triterpenes were tested against five human cancer cell lines like biphenotypic B myelomonocytic leukaemia (MV-4-11), adenocarcinoma (A549), prostate (Du-145), melanoma (Hs294T), breast adenocarcinoma (MCF-7) and normal human mammary gland (MCF-10A). The compound 9 showed towards Du-145, MCF-7 and Hs294T cells significant antiproliferative activity with IC50 ranging from 7.3 to 10.6 µM. The evaluation of ADME properties of all compounds also includes their pharmacokinetic profile. The calculated TPSA values for synthetized derivatives are in the range between 43.38 Ų and 55.77 Ų suggesting high oral bioavailability. The molecular docking calculations showed that triterpene 9 fits the active site of the serine/threonine protein kinase Akt.

Structural determinants influencing halogen bonding: a case study on azinesulfonamide analogs of aripiprazole as 5-HT1A, 5-HT7, and D2 receptor ligands.

A series of azinesulfonamide derivatives of long-chain arylpiperazines with variable-length alkylene spacers between sulfonamide and 4-arylpiperazine moiety is designed, synthesized, and biologically evaluated. In vitro methods are used to determine their affinity for serotonin 5-HT1A, 5-HT6, 5-HT7, and dopamine D2 receptors. X-ray analysis, two-dimensional NMR conformational studies, and docking into the 5-HT1A and 5-HT7 receptor models are then conducted to investigate the conformational preferences of selected serotonin receptor ligands in different environments. The bent conformation of tetramethylene derivatives is found in a solid state, in dimethyl sulfoxide, and as a global energy minimum during conformational analysis in a simulated water environment. Furthermore, ligand geometry in top-scored complexes is also bent, with one torsion angle in the spacer (τ2) in synclinal conformation. Molecular docking studies indicate the role of halogen bonding in complexes of the most potent ligands and target receptors.

Novel multi-target azinesulfonamides of cyclic amine derivatives as potential antipsychotics with pro-social and pro-cognitive effects.

Currently used antipsychotics are characterized by multireceptor mode of action. While antagonism of dopamine D2 receptors is responsible for the alleviation of "positive" symptoms of schizophrenia and the effects at other, particularly serotonergic receptors are necessary for their additional therapeutic effects, there is no consensus regarding an "ideal" target engagement. Here, a detailed SAR analysis in a series of 45 novel azinesulfonamides of cyclic amine derivatives, involving the aryl-piperazine/piperidine pharmacophore, central alicyclic amine and azinesulfonamide groups has led to the selection of (S)-4-((2-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)pyrrolidin-1-yl)sulfonyl)isoquinoline (62). The polypharmacology profile of 62, characterized by partial 5-HT1AR agonism, 5-HT2A/5-HT7/D2/D3R antagonism, and blockade of SERT, reduced the "positive"-like, and "negative"-like symptoms of psychoses. Compound 62 produced no catalepsy, demonstrated a low hyperprolactinemia liability and displayed pro-cognitive effects in the novel object recognition task and attentional set-shifting test. While association of in vitro features with the promising in vivo profile of 62 is still not fully established, its clinical efficacy should be verified in further stages of development.