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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 in vitro receptor inhibitory activity and in vivo 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. [ABSTRACT FROM AUTHOR]

Intracellular protein delivery has been a major challenge due to various physiological barriers including low proteolytic stability and poor membrane permeability of the biologics. Nanoparticles were widely proposed to deliver cargo proteins into cells by endocytosis, however, the materials and complexes with proteins are often entrapped in endosomes and subject to lysosome degradation. In this study, we report a piperazine modified dendrimer for stabilizing the complexes via a combination of electrostatic interaction and hydrophobic interactions. The complexes show rapid cell internalization and the loaded proteins are released into the cytosols as early as half an hour post incubation. Mechanism study suggests that the complexes are endocytosed into cells via caveolae-based pathways, which could be inhibited by inhibitors such as genistein, filipin III, brefeldin A and nystatin. The phenylpiperazine-modified polymer enables the delivery of cargo proteins with reserved bioactivity and show high permeability in three-dimensional cell spheroids. The results prove the beneficial roles of phenylpiperazine ligands in polymer-mediated cytosolic protein delivery systems. We synthesized a list of piperazine and derivatives modified dendrimers as cytosolic protein delivery vectors via facile reactions. Phenylpiperazine modification enables the efficient protein binding through the combination of electrostatic, hydrogen bonding and hydrophobic interactions. Phenylpiperazine modified dendrimers were internalized into the cells via a caveolae-based endo/lysosome-independent path and could release the cargo proteins into the cytosols as early as half an hour post incubation. Phenylpiperazine modified dendrimers delivered cargo proteins with reserved bioactivity and showed high permeability in three-dimensional cell spheroids [Display omitted] [ABSTRACT FROM AUTHOR]

Piperazine derivatives are a group of compounds with a psychostimulant effect. They are an alternative to illegal drugs. They are being searched for recreational use due to their psychoactive and hallucinogenic effects. The high popularity of these compounds can be noticed all over the world due to easy purchase, lack of legal regulations and incorrect assessment of the safety of use. The recreational use of piperazine derivatives can often result in chronic and acute health problems and additionally with unpredictable remote effects. It is also common to take mixtures of psychoactive compounds. This hinders the correct diagnosis and treatment of patients with poisoning. The presented work is an illustration of the wide problem of piperazine derivatives abuse. The health effects and the possibility of identifying these compounds in preparations and biological material are described.

[Display omitted] The decades-long effort to deliver peptide drugs orally has resulted in several clinically successful formulations. These formulations are enabled by the inclusion of permeation enhancers that facilitate the intestinal absorption of peptides. Thus far, these oral peptide drugs have been limited to peptides less than 5 kDa, and it is unclear whether there is an upper bound of protein size that can be delivered with permeation enhancers. In this work, we examined two permeation enhancers, 1-phenylpiperazine (PPZ) and sodium deoxycholate (SDC), for their ability to increase intestinal transport of a model macromolecule (FITC-Dextran) as a function of its size. Specifically, the permeability of dextrans with molecular weights of 4, 10, 40, and 70 kDa was assessed in an in vitro and in vivo model of the intestine. In Caco-2 monolayers, both PPZ and SDC significantly increased the permeability of only FD4 and FD10. However, in mice, PPZ and SDC behaved differently. While SDC improved the absorption of all tested sizes of dextrans, PPZ was effective only for FD4 and FD10. This work is the first report of PPZ as a permeation enhancer in vivo , and it highlights the ability of permeation enhancers to improve the absorption of macromolecules across a broad range of sizes relevant for protein drugs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Two series of new benzodiazepines were synthesized and the target compounds (E1 - 10 and G1 - 10) were evaluated for antianxiety and skeletal muscle relaxant activity as CNS agents in albino mice. The chemical structures of the compounds were confirmed on the basis of their TLC, IR, 1H NMR and 13C NMR analysis. In computational studies, the physicochemical similarity of the target compounds was assessed by calculating from a set of physicochemical properties using software programs and test compounds demonstrated moderate physiochemical similarity with respect to diazepam. Log P values of the target compounds indicates good penetration to CNS. Molecular docking studies revealed that the target compounds correctly dock into the binding pocket of the GABA A receptor, while their bioavailability/drug-likeness was predicted to be acceptable but requires future optimization. The test compounds (E1 - 10 and G1 - 10) were screened for antianxiety and skeletal muscle relaxant activity using Elevated plus maze and Rotarod method respectively. Among them, the compounds E10 and G7 showed maximum potency as CNS agents. [ABSTRACT FROM AUTHOR]

Abstract Aims The dopamine D3 receptor (D3R) is a pharmacotherapeutic target for drug dependence. We have successfully imaged human D3Rs using radiolabeled LS-3-134, an arylamide phenylpiperazine with moderate selectivity for the D3R over D2R and low efficacy at the D2 and D3R. In this study, we screened for effects of LS-3-134 as a potential anti-cocaine therapeutic. Methods Male rats were pretreated with LS-3-134 (0, 1.0, 3.2, or 5.6 mg/kg, IP) 15 min prior to tests for its effects on spontaneous and cocaine-induced locomotion. We next investigated the effects of LS-3-134 (0, 1.0, 3.2, 5.6, or 10.0 mg/kg, IP) on operant responding on a multiple variable-interval (VI) 60-second schedule with alternating cocaine (0.375 mg/kg, IV) and sucrose (45 mg) reinforcer components. Additionally, we tested LS-3-134 (5.6 mg/kg, IP) effects on a progressive ratio (PR) schedule of cocaine reinforcement, on extinction of cocaine-seeking behavior, and on reinstatement of extinguished cocaine-seeking behavior by cocaine-associated light/tone cues. Results LS-3-134 did not alter spontaneous locomotion, but reduced cocaine-induced locomotion, break points on the high-effort progressive ratio schedule of reinforcement, and responding during extinction and cue reinstatement. In contrast, LS-3-134 did not alter cocaine or sucrose reinforcement on the low-effort multiple VI 60-second schedule. Conclusions The effects of LS-3-134 are similar to other dopamine D3 low efficacy partial agonists and antagonists in attenuating cocaine intake under high effort schedules of reinforcement and in attenuating cocaine-seeking behavior elicited by cocaine-associated cues. These findings are consistent with the anti-craving profile of other dopamine D3 drugs. [ABSTRACT FROM AUTHOR]

Monoamine oxidase inhibitors (MAOIs) are potential drug candidates for the treatment of various neurological disorders like Parkinson’s disease, Alzheimer’s disease and depression. In the present study, two series of 4-substituted phenylpiperazine and 1-benzhydrylpiperazine ( 1 – 21 ) derivatives were synthesized and screened for their MAO-A and MAO-B inhibitory activity using Amplex Red assay. Most of the synthesized compounds were found selective for MAO-B isoform except compounds 3 , 7 , 8 , 9 and 13 (MAO-A selective) while compound 11 was non-selective. In the current series, compound 12 showed most potent MAO-B inhibitor activity with IC 50 value of 80 nM and compound 7 was found to be most potent MAO-A inhibitor with IC 50 value of 120 nM and both the compounds were found reversible inhibitors. Compound 8 was found most selective MAO-A inhibitor while compound 20 was found most selective inhibitor for MAO-B isoform. In the cytotoxicity evaluation, all the compounds were found non-toxic to SH-SY5Y and IMR-32 cells at 25 µM concentration. In the ROS studies, compound 8 (MAO-A inhibitor) reduced the ROS level by 51.2% while compound 13 reduced the ROS level by 61.81%. In the molecular dynamic simulation studies for 30 ns, compound 12 was found quite stable in the active cavity of MAO-B. Thus, it can be concluded that phenyl- and 1-benzhydrylpiperazine derivatives are promising MAO inhibitors and can act as a lead to design potent, and selective MAO inhibitors for the treatment of various neurological disorders. [ABSTRACT FROM AUTHOR]

[Display omitted] • A new series of oxadiazole clubbed piperazines (5a-j) was designed, synthesized and evaluated for MAO inhibitory potential. • In this series, compounds 5f and 5 g displayed most potent, selective and reversible inhibition of MAO-A enzyme. • These compounds also exhibited neuroprotective and free radical scavenging potential without toxicity against SH-SY5Y cells. • In FST and TST studies, 5f and 5 g exhibited potential antidepressant-like behaviour similar to standard drug fluoxetine. Piperazine derivatives have been of great interest to medicinal chemists in the development of antidepressant drugs due to their distinct molecular and structural features along with their pharmacological profile. In this study, we have designed and synthesized a series of 10 compounds of piperazine clubbed oxadiazole derivatives (5a-j) and screened for their MAO inhibitory activity. Compound 5f and 5 g were found to be the most potent MAO-A inhibitors of the series with IC 50 values of 0.96 ± 0.04 µM µM and 0.81 ± 0.03 µM, respectively with a selectivity index of 18-folds and 9-folds over MAO-B isoform. The compounds were found to be reversible inhibitors of MAO-A with no cytotoxicity against SH-SY5Y neuronal cells. The compounds also displayed good antioxidant activity. Further, in vivo TST studies revealed that both the compounds 5f and 5 g possessed good anti-depressant-like activity and reduced the immobility time significantly although were found inactive in FST studies. The molecular docking studies revealed that both compounds fit well at the active site of MAO-A enzyme as similar to clorgyline and form a stable complex. The results were confirmed via molecular dynamic studies which demonstrate the stable complex formation between MAO-A and 5f & 5 g. The appropriate drug-like characteristics with favourable ADMET profile, these molecules presented this piperazine clubbed oxadiazole structural framework as a key pharmacophore for the development of new antidepressant molecules along with strong candidature for further clinical investigations. [ABSTRACT FROM AUTHOR]

Heterocyclic molecules have been frequently investigated to possess various biological activities during the last few decades. The present work elaborates the synthesis and enzymatic inhibition potentials of a series of sulfonamides. A series of 1-arylsulfonyl-4-Phenylpiperazine (3a-n) geared up by the reaction of 1-phenylpiperazine (1) and different (un)substituted alkyl/arylsulfonyl chlorides (2a-n), under defined pH control using water as a reaction medium. The synthesized molecules were characterized by 1H-NMR, 13C-NMR, IR and EI-MS spectral data. The enzyme inhibition study was carried on α-glucosidase, lipoxygenase (LOX), acetyl cholinesterase (AChE) and butyryl cholinesterase (BChE) enzymes supported by docking simulation studies and the IC50 values rendered a few of the synthesized molecules as moderate inhibitors of these enzymes where, the compound 3e exhibited comparatively better potency against α-glucosidase enzyme. The synthesized compounds showed weak or no inhibition against LOX, AChE and BChE enzymes. [ABSTRACT FROM AUTHOR]

We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3β inhibitors from our promising compounds containing a 2-phenylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3β inhibitors. SAR studies focused on the phenyl moiety revealed that a 4-fluoro-2-methoxy group afforded potent inhibitory activity toward GSK-3β. Based on docking studies, new hydrogen bonding between the nitrogen atom of the piperazine moiety and the oxygen atom of the main chain of Gln185 has been indicated, which may contribute to increased activity compared with that of the corresponding phenylmorpholine analogues. Effect of the stereochemistry of the phenylpiperazine moiety is also discussed. [ABSTRACT FROM AUTHOR]

In the search for new hypotensive agents some new aroxyalkyl or aroxyethoxyethyl derivatives of piperazine have been synthesized and evaluated for their pharmacological properties. Pharmacological tests included receptor binding assays toward adrenergic receptors α 1 , α 2 and β 1 , additionally 5-HT 1A , functional bioassay and in vivo evaluation of hypotensive activity as well as antidepressant-like potential. All the tested compounds exhibited α 1 -antagonistic properties, three of them possessed also hypotensive activity in rats. The most promising compound 3 1-[4-(2,6-dimethylphenoxy)butyl]-4-(2-methoxyphenyl)piperazine hydrochloride was a selective α 1 receptor antagonist ( K i = 23.5 ± 1.3, α 1 /α 2 = 15.77, p K B = 8.538 ± 0.109). It was active in all tested doses in vivo (1, 0.5, and 0.1 mg/kg) and it reduced blood pressure by 10–13% at the dose of 1 mg/kg (rats, i.v.). Compound 5 1-[2-(2,3-dimethylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine dihydrochloride exhibited the lowest dose for antidepressant-like activity 5 mg/kg b.w. (mice, i.p.) without influence on spontaneous activity (mice, i.p.). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Simultaneous targeting of dopamine D 2 and 5-HT 2A receptors for the treatment of schizophrenia is one key feature of typical and atypical antipsychotics. In most of the top-selling antipsychotic drugs like aripiprazole and risperidone, high affinity to both receptors can be attributed to the presence of 1,4-disubstituted aromatic piperazines or piperidines as primary receptor recognition elements. Taking advantage of our in-house library of phenylpiperazine-derived dopamine receptor ligands and experimental data, we established highly significant CoMFA and CoMSIA models for the prediction of 5-HT 2A over D 2 selectivity. Subsequently, the models were applied to identify the selective candidates 55 – 57 from our newly synthesized library of GPCR ligands comprising a pyrazolo[1,5- a ]pyridine head group and a 1,2,3-triazole based linker unit. The test compound 57 showed subnanomolar a K i value (0.64 nM) for 5-HT 2A and more than 10- and 30-fold selectivity over the dopamine receptor isoforms D 2S and D 2L , respectively. [ABSTRACT FROM AUTHOR]

A series of phenylpiperazine derivatives ( 3a – 3q ) were designed and synthesized. In vitro assays indicated that several phenylpiperazine derivatives had excellent antiproliferative properties against four cancer cell lines including multidrug-resistant cancer cell lines, with IC 50 values in the low micromolar range. The average IC 50 of the most active compound 3b is 0.024 μM to the MCF-7 cell line. In addition, the mechanism of action of these new analogues was investigated by molecular docking studies, insulin-like growth factor 1-receptor (IGF-1R) kinase assay and apoptosis induced assay. These studies confirmed that these new phenylpiperazine derivatives maintain their mechanisms of action by disrupting IGF-1R kinase. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) remains a serious global health problem that lacks an effective cure. Although the introduction of protease inhibitors to the current standard-of-care interferon/ribavirin therapy for HCV infection has improved sustained virological response of genotype 1-infected patients, these inhibitors exacerbate already problematic side effects. Thus, new HCV antivirals are urgently needed. Using a cell-protection screen previously developed in our laboratory, we evaluated 30,426 compounds for inhibitors of potentially any stage of the HCV life cycle and identified 49 new HCV inhibitors. The two most potent hits, hydroxyzine and chlorcyclizine, belong to the family of benzhydrylpiperazines and were found to inhibit the entry of cell culture-produced HCV with IC50 values of 19 and 2.3 nM, respectively, and therapeutic indices of >500 and >6500. Both compounds block HCV entry at a late stage of entry prior to viral fusion and their inhibitory activities are highly dependent on the host's cholesterol content. Both compounds are currently used in the clinic for treating allergy-related disorders and the reported peak plasma level (160 nM) and estimated liver concentration (1.7 μM) of hydroxyzine in humans are much higher than the molecule's anti-HCV IC90 in cell culture (64 nM). Further studies are therefore justified to evaluate the use of these molecules in an anti-HCV therapeutic regimen. [ABSTRACT FROM AUTHOR]

[Display omitted] • Eighteen phenylpiperazine-phenylacetate derivatives with hypnotic potencies were synthesized. • Compound 10 showed apparently rapid recovery and higher safety than propanidid in animal models. • Compound 10 had a greater binding affinity for the GABA A receptor and a lower affinity for the off-target receptors. In this paper, we designed and synthesized a series of novel phenylpiperazine-phenylacetate derivatives as rapid recovery hypnotic agents. The best compound 10 had relatively high affinity for the GABA A receptor and low affinity for thirteen other off-target receptors. In three animal models (mice, rats, and rabbits), compound 10 exerted potent hypnotic effects (HD 50 = 5.2 mg/kg in rabbits), comparable duration of the loss of righting reflex (LORR), and significant shorter recovery time (time to walk) than propanidid. Furthermore, compound 10 (TI = 18.1) showed higher safety profile than propanidid (TI = 14.7) in rabbits. Above results suggested that compound 10 may have predictable and rapid recovery profile in anesthesia. [ABSTRACT FROM AUTHOR]

Abstract: An association between α1-adrenoceptor affinities, hERG K+-antagonistic properties and antiarrhythmic activities for a series of phenylpiperazine derivatives of hydantoin (2a–21a) was investigated. New compounds were synthesized and tested for their affinity for α1-adrenoceptors in radioligand binding assay using [3H]-prazosin as a selective radioligand. Antiarrhythmic activities in adrenaline- and barium chloride-induced arrhythmia models, an influence of the phenylpiperazine derivatives on the ECG-components and blood pressure were tested in vivo in normotensive rats. The hERG K+-antagonistic properties of the most potent antiarrhythmic agents were investigated in silico by the use of program QikProp. The highest α1-adrenoceptor affinity (K i =4.7nM) and the strongest antiarrhythmic activity in adrenaline induced arrhythmia (ED50 =0.1mg/kg) was found for 1-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-3-methyl-5,5-diphenylimidazolidine-2,4-dione hydrochloride (19a). The results indicated a significant correlation between α1-AR affinities (pK i) and antiarrhythmic activity (ED50) in adrenaline model (R2 =0.92, p <0.005). Influence of the examined phenylpiperazine hydantoin derivatives on hERG K+ channel, predicted by means of in silico methods, suggested their hERG K+-blocking properties. [Copyright &y& Elsevier]

Abstract: Twenty-two new 1-[2-oxo-2-(4-phenylpiperazin-1-yl)ethyl]pyrrolidine-2,5-diones were synthesized and tested for anticonvulsant activity. Initial anticonvulsant screening was performed using standard maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens in mice. Several compounds were tested additionally in the 6-Hz psychomotor seizure model. The neurotoxicity was determined applying the rotarod test. Excluding one compound, all other molecules were found to be effective in at least one seizure model. The most active were 1-(2-oxo-2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)pyrrolidine-2,5-dione (14), 1-{2-[4-(4-chlorophenyl)piperazin-1-yl]-2-oxoethyl}-3-methylpyrrolidine-2,5-dione (17), 1-{2-[4-(4-chlorophenyl)piperazin-1-yl]-2-oxoethyl}-3,3-dimethylpyrrolidine-2,5-dione (23) and 3,3-dimethyl-1-(2-oxo-2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)pyrrolidine-2,5-dione (26). These compounds showed high activity in the 6-Hz psychomotor seizure test as well as were active in the maximal electroshock and subcutaneous pentylenetetrazole (14 and 23) screens. Initial SAR studies for anticonvulsant activity have been discussed. [Copyright &y& Elsevier]

Abstract: Electrochemical oxidation of 1-(4-(4-hydroxyphenyl)piperazin-1-yl)ethanone (1) has been studied in the presence of arylsulfinic acids (3a–c) as nucleophiles in aqueous solutions using cyclic voltammetry and controlled-potential coulometry methods. The results revealed that quinone-imine derived from oxidation of 1 participates in Michael type addition reaction with 3a–c and via an EC mechanism converts to the corresponding new phenylpiperazine derivatives. The present work has led to the development of a facile and environmentally friendly reagent-less electrochemical method for synthesis of some new phenylpiperazine derivatives in aqueous solutions with high atom economy and safe waste under ambient conditions and in an undivided cell using a carbon electrode. [ABSTRACT FROM AUTHOR]

Abstract: Taking advantage of our in-house experimental data on dopamine D3 receptor modulators, we have successfully established highly significant CoMFA and CoMSIA models (). These models were carefully investigated to assure their stability and predictivity () and subsequently applied to guide experimental investigations on the synthesis and receptor binding of three conformationally restricted D3 ligands. Besides the high D3 affinity, the test compound 45, incorporating a trans-1,4-cyclohexylene partial structure, exhibited improved (∼3200-fold) selectivity over the D4 subtype. [Copyright &y& Elsevier]

Abstract: The binding properties of cationic porphyrin–phenylpiperazine hybrids to calf thymus (CT) DNA were investigated by using absorption, fluorescence and circular dichroism (CD) spectra, and the apparent affinity binding constants (K app) of the porphyrins for CT DNA were determined by using a competition method with ethidium bromide (EB). Intercalation of porphyrin into CT DNA occurred when two phenylpiperazines were introduced at cis position onto the periphery of cationic porphyrin. The photocleavages of pBR322 plasmid DNA by the porphyrins were consistent with the values of K app. With [porphyrin]/[DNA base pairs] ratio increased, the binding mode tended to be outside binding, and the cleavage abilities of the porphyrins varied. In the presence of sodium azide, a quencher of 1O2, the cleavage of DNA by the porphyrin of intercalation was less inhibited. [Copyright &y& Elsevier]

The present experiment explored the anorectic and adipsic effects of fluprazine hydrochloride, a phenylpiperazine compound. Thirty-eight albino rats were randomly assigned either to a control saline group (six rats) or to groups (eight subjects each) receiving an IP dose of fluprazine in saline (1.25, 2.5, 5 or 10 mg/kg). No anorectic effect of the drug doses was observed 30, 60, 90, 120, 180 and 240 min, and 24 h after drug injection. However, water drinking was significantly decreased 30 min after drug administration, with 5 and 10 mg/kg, compared to saline. [ABSTRACT FROM AUTHOR]

The diastereomers of 3,N,N′-trimethyl-2-phenyl-1,4-piperazine dihydrochloride (TPP) were tested for their effects on NA, DA and 5-HT uptake in synaptosomes prepared from hypothalamus, corpus striatum, and frontal cortex, respectively. The diastereomers differed with respect to their inhibitory properties. (2 R, 3 R)-TPP was more potent than the other diastereomers on NA and DA uptake, whereas (2 S, 3 S)-TPP was least potent. In contrast, the (2 S, 3 S)- and ( 2 S, 3 R)-diastereomers of TPP were more potent than (2 R, 3 R)- and (2 R, 3 S)-TPP as inhibitors of 5-HT uptake. None of the diastereomers affected monoamine oxidase activity. The findings show that the diastereomers of TPP interact stereoselectively with neuronal mechanisms for monoamine uptake, and that the ( S)-configuration at the 2 carbon is important for inhibitory actions of TPP on 5-HT uptake. [ABSTRACT FROM AUTHOR]

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., (© Pesticide Science Society of Japan 2021. This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) License (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Cyclic voltammetry, controlled-potential coulometry, chronoamperometry, chronocoulometry and chronopotentiometry methods were used for the electrochemical study of 1-acetyl-4-(4-hydroxyphenyl)piperazine (APIP) in the presence of triphenylphosphine (TPP) as a nucleophile. The data show that electrochemically generated APIP ox can serve as a Michael acceptor for nucleophilic attack by TPP to yield a new phosphonium betaine (APTP). In this work, we prepared a new product in good yield and purity by reaction of TPP with APIP ox in an undivided cell equipped with carbon anode. Based on an EC mechanism, the observed homogeneous rate constant (k obs) of the Michael addition reaction of APIP ox with TPP were estimated by comparing the experimental cyclic voltammograms with the digital simulated results. Furthermore, electrochemical oxidation of APIP has been studied both experimentally and theoretically to provide insight into the influence of natural charge and thermodynamic stability parameters on the type of chemical reaction which follows APIP ox. In addition, the synthesized compound was evaluated for in vitro antibacterial. Image 1 • Electrochemical synthesis of a new phosphonium betaine. • Electrochemical study of 1-acetyl-4-(4-hydroxyphenyl)piperazine in the absence and presence of triphenylphosphine. • Antimicrobial activity of synthesized phosphonium betaine. • Computational studies on 1-acetyl-4-(4-hydroxyphenyl)piperazine and synthesized phosphonium betaine. • Mechanistic studies. [ABSTRACT FROM AUTHOR]

In this work, a novel series of arylisoxazole-phenylpiperazines were designed, synthesized, and evaluated toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Our results revealed that [5-(2-chlorophenyl)-1,2-oxazol-3-yl](4-phenylpiperazin-1-yl)methanone (5c) was the most potent AChE inhibitor with IC 50 of 21.85 μm. It should be noted that most of synthesized compounds showed no BChE inhibitory activity and [5-(2-fluorophenyl)-1,2-oxazol-3-yl](4-phenylpiperazin-1-yl)methanone (5a) was the most active anti-BChE derivative (IC 50 =51.66 μm). Also, kinetic studies for the AChE and BChE inhibitory activity of compounds 5c and 5a confirmed that they have simultaneously bound to the catalytic site (CS) and peripheral anionic site (PAS) of both AChE and BChE. Furthermore, docking study of compound 5c showed desired interactions of that compound with amino acid residues located in the active and peripheral anionic sites. Compound 5c was also evaluated for its BACE1 inhibitory activity and demonstrated IC 50 =76.78 μm. Finally, neuroprotectivity of compound 5c on Aβ-treated neurotoxicity in PC12 cells depicted low activity., (© 2019 Wiley-VHCA AG, Zurich, Switzerland.)

Background: A series of new N-(2-benzoyl-4-chlorophenyl)-2-(4-(substituted phenyl) piperazin-1-yl) acetamides (3a-j) have been synthesized by the chloroacetylation of 2-amino-5- chlorbenzophenone which was further reacted with substituted phenylpiperazine., Material: The chemical structures of the compounds were confirmed on the basis of their TLC, IR, 1HNMR, 13CNMR and by elemental analysis. The physicochemical similarity of the target compounds with respect to standard drug diazepam was assessed by calculating from a set of physicochemical properties using software programs., Conclusion: Molecular docking studies revealed that the target compounds correctly dock into the binding pocket of the GABAA receptor, while their bioavailability/drug-likeness was predicted to be acceptable but requires future optimization. The anxiolytic and skeletal muscle relaxant activity of the target compounds (3a-j) were evaluated in albino mice. Among them, compound 3h showed potent anxiolytic and skeletal muscle relaxant activity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Eighteen new 5-benzylidene-3-(4-arylpiperazin-1-ylmethyl)-2-thioxo-imidazolidin-4-ones were designed as hybrid structures from previously reported anticonvulsant compounds, synthesized and tested for anticonvulsant activity. Initial anticonvulsant screening was performed using the strychnine (2 mg/kg IP) potent generalized-induced seizure and pentylenetetrazole (PTZ) (60 mg/kg IP) acute clonic-induced convulsion screens in mice. All the molecules were found to be effective in at least one seizure model, compounds 10, 13, 15, 17, and 18 were active against both types of seizures induced. Compound 13 turned out to be the most active candidate within the strychnine model, having an average survival time of 6 min close to that of the positive control phenytoin, while compound 8 showed 100% protection from the induced PTZ seizures, resembling the protection of the positive control phenobarbital. Initial SAR studies for anticonvulsant activity are discussed., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)