Phenylpiperazine Derivatives Research Articles

BMY 7378, a selective α1D-adrenoceptor antagonist, is a new angiotensin converting enzyme inhibitor: In silico, in vitro and in vivo approach

BMY 7378 is a multitarget drug primarily known for its selective antagonism of α1D-adrenoceptors (α1D-AR), exhibiting both hypotensive effects and the ability to prevent or reverse angiotensin II-induced vascular hypertrophy. Notably, BMY 7378 contains a phenylpiperazine moiety, a structural feature associated with angiotensin-converting enzyme (ACE) inhibition. This study aimed to investigate ACE inhibition as a potential pharmacological mechanism of BMY 7378. Using an in silico approach we predicted BMY 7378 interactions with the ACE active site, followed by in vitro activity assays. Additionally, ACE protein expression in the heart was analyzed following four weeks of BMY 7378 treatment in 7–8-month-old spontaneously hypertensive rats (SHR). All assays were benchmarked against captopril, a standard ACE inhibitor. In silico results showed that BMY 7378 binds to the ACE active site, though with reduced interaction with Zn701 (73.7 % compared to captopril), likely due to the pKa of its amino group. The inhibitory concentration 50 (IC50) for BMY 7378 was 136 μM, lower than other reported phenylpiperazine derivatives. Furthermore, BMY 7378 significantly increased ACE expression in the hearts of SHR, with an increase of 8.5-fold compared to captopril. In conclusion, BMY 7378 exhibits dual activity as an α1D-AR antagonist and an ACE inhibitor, making it a promising pharmacological tool for investigating and potentially treating hypertension and its associated cardiovascular complications.

Rational Design, Synthesis, Molecular Docking, and Biological Evaluations of New Phenylpiperazine Derivatives of 1,2-Benzothiazine as Potential Anticancer Agents.

The aim of this study was to obtain new, safe, and effective compounds with anticancer activity since cancer is still the leading cause of mortality worldwide. The rational design of new compounds was based on the introduction of differentially substituted phenylpiperazines into the 1,2-benzothiazine scaffold as a reference for the structures of recent topoisomerase II (Topo II) inhibitors such as dexrazoxane and XK-469. The newly designed group of 1,2-benzothiazine derivatives was synthesized and tested on healthy (MCF10A) and cancer (MCF7) cell lines, alone and in combination with doxorubicin (DOX). In addition, molecular docking studies were performed both to the DNA-Topo II complex and to the minor groove of DNA. Most of the tested compounds showed cytotoxic activity comparable to doxorubicin, a well-known anticancer drug. The compound BS230 (3-(4-chlorobenzoyl)-2-{2-[4-(3,4-dichlorophenyl)-1-piperazinyl]-2-oxoethyl}-4-hydroxy-2H-1,2-benzothiazine 1,1-dioxide) showed the best antitumor activity with lower cytotoxicity towards healthy cells and at the same time stronger cytotoxicity towards cancer cells than DOX. Moreover, molecular docking studies showed that BS230 has the ability to bind to both the DNA-Topo II complex and the minor groove of DNA. Binding of the minor groove to DNA was also proven by fluorescence spectroscopy.

In silico insights into the design of novel NR2B-selective NMDA receptor antagonists: QSAR modeling, ADME-toxicity predictions, molecular docking, and molecular dynamics investigations

Based on a structural family of thirty-two NR2B-selective N-Methyl-D-Aspartate receptor (NMDAR) antagonists, two phenylpiperazine derivatives labeled C37 and C39 were conceived thanks to molecular modeling techniques, as novel NMDAR inhibitors exhibiting the highest analgesic activities (of pIC50 order) against neuropathic pain, with excellent ADME-toxicity profiles, and good levels of molecular stability towards the targeted protein of NMDA receptor. Initially, the quantitative structure-activity relationships (QSARs) models were developed using multiple linear regression (MLR), partial least square regression (PLSR), multiple non-linear regression (MNLR), and artificial neural network (ANN) techniques, revealing that analgesic activity was strongly correlated with dipole moment, octanol/water partition coefficient, Oxygen mass percentage, electronegativity, and energy of the lowest unoccupied molecular orbital, whose the correlation coefficients of generated models were: 0.860, 0.758, 0.885 and 0.977, respectively. The predictive capacity of each model was evaluated by an external validation with correlation coefficients of 0.703, 0.851, 0.778, and 0.981 respectively, followed by a cross-validation technique with the leave-one-out procedure (CVLOO) with Q2cv of 0.785, more than Y-randomization test, and applicability domain (AD), in addition to Fisher’s and Student’s statistical tests. Thereafter, ten novel molecules were designed based on MLR QSAR model, then predicted with their ADME-Toxicity profiles and subsequently examined for their similarity to the drug candidates. Finally, two of the most active compounds (C37 and C39) were chosen for molecular docking and molecular dynamics (MD) investigations during 100 ns of MD simulation time in complex with the targeted protein of NMDA receptor (5EWJ.pdb).

Novel phenylpiperazine derivatives as potent transient receptor potential vanilloid 1 antagonists.

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel, which is considered a highly validated target for pain perception. Repeated activation with agonists to desensitize receptors or use the antagonists can both exert analgesic effects. In this work, two series of novel phenylpiperazine derivatives were designed, synthesized, and evaluated for the invitro receptor inhibitory activity and invivo analgesic activity. Among them, L-21 containing sulfonylurea group was identified with potent TRPV1 antagonistic activity and analgesic activity in various pain models. At the same time, L-21 exhibited low risk of hyperthermia side effect. These results indicated that L-21 is a promising candidate for further development of novel TRPV1 antagonist to treat pain.

Docking, synthesis, and anticancer assessment of novel quinoline-amidrazone hybrids

A group of new amidrazone compounds that include a quinoline component was produced through the reaction of hydrazonyl chloride, derived from 6-aminoquinoline, with appropriate secondary cyclic amines. The new compounds were confirmed through 1H-NMR, 13C-NMR, FTIR, and HRMS, and further verified by single-crystal X-ray diffraction. The antitumor potential of the synthesized compounds was tested against lung cancer (A549) and breast cancer (MCF-7) cell lines. Among the compounds, the ethyl carboxylate and o-hydroxy phenyl piperazine derivatives (10d and 10g) exhibited the strongest activity against both cell lines, with IC50 values of 43.1 and 59.1 μM for the lung and breast cancer cell lines, respectively. Moreover, the most potent compounds were subsequently docked into the c-Abl kinase binding site (PDB code: 1IEP) as a possible anticancer mechanism. In-silico ADMET study shows acceptable pharmacokinetic properties, and the toxicity profile for the most potent compounds is non-carcinogenic.

Anti-virulence activity of novel (1-heteroaryloxy-2-hydroxypropyl)- phenylpiperazine derivatives against both wild-type and clinical drug-resistant Candida albicans strains.

Candida albicans is an important human fungal pathogen. Our previous study disclosed that aryloxy-phenylpiperazine skeleton was a promising molecule to suppress C. albicans virulence by inhibiting hypha formation and biofilm formation. In order to deeply understand the efficacy and mechanism of action of phenylpiperazine compounds, and obtain new derivatives with excellent activity against C. albicans, hence, we synthesized three series of (1-heteroaryloxy-2-hydroxypropyl)-phenylpiperazines and evaluated their inhibitory activity against C. albicans both in vitro and in vivo in this study. Compared with previously reported aryloxy-phenylpiperazines, part of these heteroaryloxy derivatives improved their activities by strongly suppressing hypha formation and biofilm formation in C. albicans SC5314. Especially, (9H-carbazol-4-yl)oxy derivatives 25, 26, 27 and 28 exhibited strong activity in reducing C. albicans virulence in both human cell lines in vitro and mouse infection models in vivo. The compound 27 attenuated the virulence of various clinical C. albicans strains, including clinical drug-resistant C. albicans strains. Moreover, additive effects of the compound 27 with antifungal drugs against drug-resistant C. albicans strains were also discussed. Furthermore, the compound 27 significantly improved the composition and richness of the faecal microbiota in mice infected by C. albicans. These findings indicate that these piperazine compounds have great potential to be developed as new therapeutic drugs against C. albicans infection.

Pharmacological targeting of G protein-coupled receptor heteromers

A main rationale for the role of G protein-coupled receptor (GPCR) heteromers as targets for drug development is the putative ability of selective ligands for specific GPCRs to change their pharmacological properties upon GPCR heteromerization. The present study provides a proof of concept for this rationale by demonstrating that heteromerization of dopamine D1 and D3 receptors (D1R and D3R) influences the pharmacological properties of three structurally similar selective dopamine D3R ligands, the phenylpiperazine derivatives PG01042, PG01037 and VK4–116. By using D1R-D3R heteromer-disrupting peptides, it could be demonstrated that the three D3R ligands display different D1R-D3R heteromer-dependent pharmacological properties: PG01042, acting as G protein-biased agonist, counteracted D1R-mediated signaling in the D1R-D3R heteromer; PG01037, acting as a D3R antagonist cross-antagonized D1R-mediated signaling in the D1R-D3R heteromer; and VK4–116 specifically acted as a ß-arrestin-biased agonist in the D1R-D3R heteromer. Molecular dynamics simulations predicted potential molecular mechanisms mediating these qualitatively different pharmacological properties of the selective D3R ligands that are dependent on D1R-D3R heteromerization. The results of in vitro experiments were paralleled by qualitatively different pharmacological properties of the D3R ligands in vivo. The results supported the involvement of D1R-D3R heteromers in the locomotor activation by D1R agonists in reserpinized mice and L-DOPA-induced dyskinesia in rats, highlighting the D1R-D3R heteromer as a main pharmacological target for L-DOPA-induced dyskinesia in Parkinson’s disease. More generally, the present study implies that when suspecting its pathogenetic role, a GPCR heteromer, and not its individual GPCR units, should be considered as main target for drug development.

Receptor mapping using methoxy phenyl piperazine derivative: Preclinical PET imaging

This study aimed at assessing 2-methoxyphenyl piperazine derivative for its binding specificity and suitability in mapping metabotropic glutamate receptor subtype 1, which is implicated in several neuropsychiatric disorders. N-(2-(4-(2-Methoxyphenyl)piperazin-1-yl)ethyl)-N-methylpyridin-2-amine was synthesised and evaluated for brain imaging subsequent to radiolabelling with [11C] radioisotope via methylation process in 98.9% purity and 52 ± 6% yield (decay corrected). The specific activity was in the range of 72–93 GBq/µmol. The haemolysis of blood was 2–5% for initial 4 hr and remained < 10% after 24 h of incubation indicating low toxicity. In vitro autoradiograms after coincubation with unlabelled ligand confirmed the high uptake of the PET radioligand in the mGluR1 receptor rich regions.The PET as well as biodistribution studies also showed high activity in the brain with a direct correlation between receptor abundance distribution pattern and tracer activity. The biodistribution analyses revealed initial high brain uptake (4.18 ± 0.48). The highest uptake was found in cerebellum (SUV 4.7 ± 0.2), followed by thalamus (SUV 3.5 ± 0.1), and striatum (SUV 3 ± 0.1). In contrast, pons had negligible tracer activity. The high uptake observed in all the regions with known mGluR1 activity indicates suitability of the ligand for mGluR1 imaging.

Synthesis and Biological Evaluation of 99mTc-Labeled Phenylpiperazine Derivatives as Selective Serotonin-7 Receptor Ligands for Brain Tumor Imaging.

With a poor prognosis, glioblastoma multiforme is the most aggressive tumor of the central nervous system in humans. The aim of this study was to develop novel tracers for the tumor targeting and imaging of overexpressed serotonin-7 receptors (5-HT7Rs) in U-87 MG glioma xenografted nude mice. Two phenylpiperazine derivatives named as PHH and MPHH were designed, and the corresponding radiotracers 99mTc-PHH and 99mTc-MPHH were synthesized in high radiochemical purity (>95%). 99mTc-MPHH showed a higher affinity to 5-HT7Rs on U-87 MG cells compared to 99mTc-PHH. In biodistribution studies, the radiocomplexes showed good brain uptake at 15 min combined with good radioactivity retention in the brain for 240 min. Regional rabbit brain studies indicated a higher radioactivity concentration in the hippocampus and diencephalon than in the cerebellum. Compared to 99mTc-MPHH, the 99mTc-PHH exhibited a significantly increased tumor uptake at 15 and 60 min, but the rapid blood clearance of 99mTc-MPHH led to enhanced tumor-to-muscle ratios at 240 min. A significant reduction in tumor uptake 60 min after an injection of pimozide (5-HT7 receptor antagonist) confirms the tumor uptake was receptor-mediated specifically. The tumor-to-contralateral muscle tissue ratio of 99mTc-PHH and 99mTc-MPHH in nude mice with U-87 MG xenograft was measured (5.25 and 4.65) at 60 min as well as (6.25 and 6.76) at 240 min, respectively.

Synthesis and acaricidal activity of phenylpiperazine derivatives.

We synthesized 33 new phenylpiperazine derivatives and assessed their acaricidal activity. These derivatives were synthesized through sequential reactions consisting of the sulfonylation of 2-substituted 4-methylaniline with chlorosulfonic acid, reduction with red phosphorus and iodine, alkylation by alkyl halide, cyclization with bis(2-chloroethyl)amine hydrochloride, and N-substitution reaction of phenylpiperazines with various reagents. All phenylpiperazines synthesized were evaluated for acaricidal activity and their structure–activity relationships discussed, it was found that 4-substituted 1-[2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfanyl)phenyl]piperazine derivatives exhibited good acaricidal activity. Among them, 1-[2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfanyl)phenyl]-4-(trifluoromethylsulfonyl) piperazine showed the highest level of activity against Tetranychus urticae and provided a high level of activity against Tetranychus kanzawai and Panonychus citri. In addition, studies on the effect at various stages of T. urticae exhibited that this compound showed good activity against both adults and eggs.

QSAR, QSTR, and molecular docking studies of the anti-proliferative activity of phenylpiperazine derivatives against DU145 prostate cancer cell lines

BackgroundProstate cancer is the most common non-cutaneous cancer in males and accounts for about 4% of all cancer-related deaths in males annually. In silico methods provide faster, economical, and environmentally friendly alternatives to the traditional trial and error method of lead identification and optimization. This study, therefore, was aimed at building a robust QSAR and QSTR model to predict the anti-proliferate activity and toxicity of some phenylpiperazine compounds against the DU145 prostate cancer cell lines and normal prostate epithelial cells as well as carry out molecular docking studies between the compounds and the androgen receptor.ResultsGenetic Function Algorithm–Multilinear Regression approach was employed in building the QSAR and QSTR model. The QSAR model built had statistical parameters R2 = 0.7792, R2adj. = 0.7240, Q2cv = 0.6607, and R2ext = 0.6049 and revealed the anti-proliferate activity to be strongly dependent on the molecular descriptors: VR3_Dzp, VE3_Dzi, Kier3, RHSA, and RDF55v. The QSTR model, on the other hand, had statistical parameters R2 = 0.8652, R2adj. = 0.8315, Q2cv = 0.7788, and R2ext = 0.6344. The toxicity of the compounds was observed to be dependent on the descriptors MATS8c, MATS3s, ETA_EtaP_F, and RDF95m. The molecular descriptors in both models were poorly correlated (R < 0.4) and had variance inflation factors < 3. Molecular docking studies between the androgen receptor and compounds 25 and 32 revealed the compounds primarily formed hydrogen, halogen, and hydrophobic interactions with the receptor.ConclusionFindings from this study can be employed in in silico design of novel phenylpiperazine compounds. It can also be employed in predicting the toxicity and anti-proliferate activity of other phenylpiperazine compounds against DU145 prostate cancer cell lines.

Design and synthesis of phenylpiperazine derivatives as potent anticancer agents for prostate cancer.

Novel thiourea (5a, 5b) and thiazolidinone derivatives (6a, 6b) were synthesized by hybridizing molecules starting from the compound 6-(4-phenylpiperazin-1-yl)pyridin-3-amine (4) which is known to show anticancer activity. The synthesis of the leading compound was carried out by using 1-(5-nitropyridin-2-yl)-4-phenylpiperazine (3) which was obtained by a novel method of the reaction of 2-chloro-5-nitropyridine (1) and N-phenylpiperazine (2). The structures of the compounds were confirmed using FTIR, 1 H NMR, 13 C NMR, HRMS spectroscopic methods and elemental analysis. The organic molecules were tested for their anticancer activities against prostate cancer (PC) cell lines: DU 145, PC-3 and LNCaP. As the compound 5a exerted the highest cytotoxic activity, IC50 concentrations of compound 5a were further investigated in terms of morphology, colony-forming ability, RNA expression, fragmented DNA and cell cycle distributions of PC cell lines. Overall data revealed that compound 5a treatment induces apoptosis and DNA fragmentation in PC cell lines and inhibits cell cycle progression resulting in the accumulation of cells in either the G1 or the S phases.

The Stability Study of a Novel Phenylpiperazine Derivative

The Stability Study of a Novel Phenylpiperazine Derivative

(1-aryloxy-2-hydroxypropyl)-phenylpiperazine derivatives suppress Candida albicans virulence by interfering with morphological transition.

SummaryClinical treatment of Candida albicans infections has become more difficult due to the limited development of antifungal agents and the rapid emergence of drug resistance. In this study, we demonstrate the synthesis of a series of piperazine derivatives and the evaluation of their inhibitory activity against C. albicans virulence. Thirty‐four (1‐aryloxy‐2‐hydroxypropyl)‐phenylpiperazine derivatives, including 25 new compounds, were synthesized and assessed for their efficacy against the physiology and pathogenesis of C. albicans. Several compounds strongly inhibited the morphological transition and virulence of C. albicans cells, although they did not influence the growth rate of the fungal pathogen. A leading novel compound, (1‐(4‐ethoxyphenyl)‐4‐(1‐biphenylol‐2‐hydroxypropyl)‐piperazine), significantly attenuated C. albicans virulence by interfering with the process of hyphal development, but it showed no cytotoxicity against human cells at a micromolar level. These findings suggest that (1‐aryloxy‐2‐hydroxypropyl)‐phenylpiperazine derivatives could potentially be developed as novel therapeutic agents for the clinical treatment of C. albicans infections by interfering with morphological transition and virulence.

Predictive Modeling of Phenylpiperazine Derivatives for Renin Inhibition.

The renin–angiotensin–aldosterone system is the well established endocrine system having significant role in preserving hemodynamic stability. Renin is secreted from the juxtaglomerular cells of the kidney. Phenylpiperazine derivatives have been reported as human renin inhibitor. To perform predictive QSAR modeling for 27 phenylpiperazine derivatives as renin enzyme inhibitors. The IC50 values for purified human renin were taken as biological activity. Physicochemical properties were calculated on Dragon software, version 5.5. Hierarchical Multiple Regression was performed to obtain quantitative structure--activity relationship model which again validated internally and externally. The selected best QSAR model was having the correlation coefficient (R2) of 0.843, predicted correlation coefficient (R2pred) of 0.867. The predictive ability of the selected model was established by leaving one-out cross-validation. Different Rm2 matrices were also calculated to validate the model externally. The quantitative structure activity relationship study indicates that CIC2, BIC2 and R7v descriptors have a very important role in renin enzyme and ligand interaction. The developed model can be applied to design new effective renin enzyme inhibitors.

Structure-Function Analysis of Phenylpiperazine Derivatives as Intestinal Permeation Enhancers.

A major obstacle preventing oral administration of macromolecular therapeutics is poor absorption across the intestinal epithelium into the bloodstream. One strategy to improve transport across this barrier is the use of chemical permeation enhancers. Several molecular families with permeation enhancing potential have been identified previously, including piperazines. In particular, 1-phenylpiperazine has been shown to enhance transepithelial transport with minimal cytotoxicity compared to similarly effective molecules. To better understand how the chemistry of 1-phenylpiperazine affects its utility as an intestinal permeation enhancer, this study examined a small library of 13 derivatives of 1-phenylpiperazine. The efficacy and cytotoxicity of 13 phenylpiperazine compounds were assessed in a Caco-2 model of the intestinal epithelium. Efficacy was measured using the paracellular diffusion marker calcein as well as by immunostaining and confocal imaging of Caco-2 monolayers. Of the 13 derivatives, two enhanced the permeability of the fluorescent marker calcein over 100-fold. It was found that hydroxyl or primary amine substitutions on the phenyl ring significantly increased toxicity, while aliphatic substitutions resulted in efficacy and toxicity profiles comparable to 1-phenylpiperazine. Several potent derivatives, including 1-methyl-4-phenylpiperazine and 1-(4-methylphenyl)piperazine, displayed lower toxicity than 1-phenylpiperazine, suggesting promise in future applications.

In silico screening of dicarboxylic acids for cocrystallization with phenylpiperazine derivatives based on both cocrystallization propensity and solubility advantage

In silico screening was performed to search for binary solids in which a phenylpiperazine-derivative drug was cocrystallized with a dicarboxylic acid. The phenylpiperazine derivative could be any of 61 such drugs, while the dicarboxylic acid could be any of nine such acids. The uniqueness of this approach was that two criteria had to be fulfilled simultaneously, namely a high propensity for cocrystallization and a sufficient solubility advantage. Using the mixing enthalpies of selected pairs of crystal formers with high affinities for one another permitted the classification of candidates with a high probability of cocrystallization. Further modeling of the solubility advantage allowed the identification of many binary solids that potentially exhibit significantly enhanced solubility in water. Based on the computed values for the mixing enthalpies and solubility advantage factors, it was concluded that dicarboxylic acids are both excellent coformers for cocrystallization with phenylpiperazines and very good solubility enhancers; indeed, the use of dicarboxylic acids as coformers would allow the degree of dissolution to be tuned for many of the studied drugs. The observed similarities of the cocrystallization landscapes of the studied drugs and excipients were also explored.

Synthesis of phenylpiperazine derivatives of 1,4-benzodioxan as selective COX-2 inhibitors and anti-inflammatory agents

1-((2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4-substituted-phenylpiperazine moiety was prepared and has been found to be a new and selective ligand for the enzyme cyclooxygenase-2 (COX-2). The biological activity of compound 3k as anti-inflammatory agent was further investigated both in vitro and in vivo. Notably, compound 3k exhibited the best anti-inflammatory activity among the eleven designed compounds with no toxicity, as determined by the ulcerogenic activity. Computational docking studies also showed that compound 3k has interaction with COX-2 key residues in the active site. Compound 3k maybe a new anti-inflammatory lead-candidate as powerful and novel non-ulcerogenic.

New 4-Acyl-1-phenylaminocarbonyl-2-phenylpiperazine Derivatives as Potential Inhibitors of Adenovirus Infection. Synthesis, Biological Evaluation, and Structure-activity Relationships.

The search for human adenovirus (HAdV)-specific antiviral drugs for the treatment of HAdV infections in immunocompromised patients continues to be a challenging goal for medicinal chemistry. Here, we report the synthesis, biological evaluation, and structure-activity relationships of a small molecules library. We have identified six phenylpiperazine derivatives that significantly inhibited HAdV infection. These six compounds showed the capacity to block HAdV and, in addition, human cytomegalovirus (HCMV) replications at low micromolar concentration, with little or no cytotoxicity. On the basis of our biological studies, these molecules block HAdV and HCMV infections in different phases of their life cycle, providing potential candidates for the development of a new family of antiviral drugs for the treatment of infections by DNA viruses.

Antidepressant- and Anxiolytic-Like Effects of New Dual 5-HT₁A and 5-HT₇ Antagonists in Animal Models.

The aim of this study was to further characterize pharmacological properties of two phenylpiperazine derivatives: 1-{2-[2-(2,6-dimethlphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazynine hydrochloride (HBK-14) and 2-[2-(2-chloro-6-methylphenoxy)ethoxy]ethyl-4-(2- methoxyphenyl)piperazynine dihydrochloride (HBK-15) in radioligand binding and functional in vitro assays as well as in vivo models. Antidepressant-like properties were investigated in the forced swim test (FST) in mice and rats. Anxiolytic-like activity was evaluated in the four-plate test in mice and elevated plus maze test (EPM) in rats. Imipramine and escitalopram were used as reference drugs in the FST, and diazepam was used as a standard anxiolytic drug in animal models of anxiety. Our results indicate that HBK-14 and HBK-15 possess high or moderate affinity for serotonergic 5-HT2, adrenergic α1, and dopaminergic D2 receptors as well as being full 5-HT1A and 5-HT7 receptor antagonists. We also present their potent antidepressant-like activity (HBK-14—FST mice: 2.5 and 5 mg/kg; FST rats: 5 mg/kg) and (HBK-15—FST mice: 1.25, 2.5 and 5 mg/kg; FST rats: 1.25 and 2.5 mg/kg). We show that HBK-14 (four-plate test: 2.5 and 5 mg/kg; EPM: 2.5 mg/kg) and HBK-15 (four-plate test: 2.5 and 5 mg/kg; EPM: 5 mg/kg) possess anxiolytic-like properties. Among the two, HBK-15 has stronger antidepressant-like properties, and HBK-14 displays greater anxiolytic-like activity. Lastly, we demonstrate the involvement of serotonergic system, particularly 5-HT1A receptor, in the antidepressant- and anxiolytic-like actions of investigated compounds.