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A series of flavonol derivatives containing piperazine and quinoxaline had been designed and synthesized. The biological activity test results showed that some of the target compounds had good antifungal activity against various fungi. N5 had the best antifungal activity against Phomopsis sp (P.s.) and Phytophthora capsica (P.c.). The half maximal effective concentration (EC50) was 12.9 and 25.8 µg/mL against P.s. and P.c., respectively, which were better than azoxystrobin (Az, 25.4 and 71.1 µg/mL). In addition, the protective and curative activities of N5 against kiwifruit were 85.9 and 67.0% at 200 µg/mL in vivo, which were better than that of Az (65.9 and 57.0%). The protective and curative activities against chili leaves were 80.6 and 66.5% at 200 µg/mL, which were better than that of Az (77.6 and 60.0%). The scanning electron microscopy (SEM) experiment showed that the action of N5 caused the mycelium to bend and fold, changed its morphology and caused damaged to the mycelium. Through the measurement of relative conductivity, leakage of cytoplasmic contents and determination of malondialdehyde (MDA) content indicated that N5 could damage the integrity of pathogenic fungal cell membranes, change the permeability of cell membranes, and affect the normal growth of mycelium.

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The urease enzyme is recognized as a valuable therapeutic agent for treating the virulent Helicobacter pylori bacterium because of its pivotal role in aiding the colonization and growth of the bacterium within the gastric mucosa. In order to control the harmful consequences of bacterial infections, urease inhibition presents itself as a promising and effective approach. The current research aimed to synthesize pyridylpiperazine-based carbodithioate derivatives 5a-5n and 7a-7n that could serve as potential drug candidates for preventing bacterial infections through urease inhibition. The synthesized carbodithioate derivatives 5a-5n and 7a-7n were explored to assess their ability to inhibit the urease enzyme after their structural explication by gas chromatography-mass spectrometry (GC-MS). In the in vitro evaluation with thiourea as a standard drug, it was observed that all the synthesized compounds exhibited significant inhibitory activity compared to the reference drug. Among the compounds tested, 5j (bearing an o-tolyl moiety) emerged as the most effective inhibitor, displaying strong urease inhibition with an IC50 value of 5.16 ± 2.68 µM. This IC50 value is notably lower than that of thiourea (23 ± 0.03 µM), indicating the significantly most potent potential of inhibition. In molecular docking of 5j within the active site of urease, numerous noteworthy interactions were identified.

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Objective: Diabetic nephropathy (DN) is a serious complication that may occur during the later stages of diabetes, and can be further exacerbated by podocyte damage. Piperazine ferulate (PF) has well-defined nephroprotective effects and is used clinically in the treatment of chronic nephritis and other kidney diseases. However, the renoprotective effects and mechanisms of PF on DN are not clear. This study aims to investigate the protective effect of PF on DN and its mechanism of action, to inform the clinical application of PF in DN treatment. Methods: Network pharmacology was performed to predict the mechanism of action of PF in DN. Male Sprague Dawley rats were intraperitoneally injected with STZ (60 mg/kg) to establish a DN model, and then assessed for renal injury after 12 weeks of administration. In vitro, rat podocytes were treated with 25 mmol/L glucose and cultured for 24 h, followed by an assessment of cell injury. Results: Our results showed that PF significantly improved renal function, reduced renal pathological changes, decreased inflammatory response, and alleviated podocyte damage in DN rats. PF also attenuated glucose-induced podocyte injury in vitro. Regarding molecular mechanisms, our study demonstrated that PF downregulated the expression of genes and proteins related to AGE-RAGE-mediated inflammatory signaling. Conclusion: In summary, PF exerts its renoprotective effects by decreasing inflammation and protecting against podocyte injury through the inhibition of the AGE/RAGE/NF-κB/NLRP3 pathway. Overall, these data support the clinical potential of PF as a renoprotective agent in DN.

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To overcome the poor solubility, permeability, and bioavailability of the plant isoflavone daidzein (DAI), a novel salt of DAI with anhydrous piperazine (PIP) was obtained based on cocrystallization strategy. The new salt DAI-PIP was characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared (FT-IR) spectroscopy, and optical microscopy. The results showed that the maximum apparent solubility (Smax) of DAI-PIP increased by 7.27-fold and 1000-fold compared to DAI in pH 6.8 buffer and water, respectively. The peak apparent permeability coefficient (P app ) of DAI-PIP in the Caco-2 cell model was 30.57 ± 1.08 × 10-6 cm/s, which was 34.08% higher than that of DAI. Additionally, compared to DAI, the maximum plasma concentration (Cmax) value of DAI-PIP in beagle dogs was approximately 4.3 times higher, and the area under the concentration-time curve (AUC0-24) was approximately 2.4 times higher. This study provides a new strategy to enhance the dissolution performance and bioavailability of flavonoid drugs, laying a foundation for expanding their clinical applications.

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OBJECTIVE: Resveratrol-piperazine cocrystals have been obtained by ultrasound (US) and microwave-assisted (MW) techniques, using the solution and slurry-based methods, to study the influence of the synthesis method on the resulting cocrystal properties, and scalability of the processes. The potential of these cocrystals is represented by the unique properties of their components, resveratrol, and piperazine, which could be also used in veterinary practice. Resveratrol has antimicrobial, antiviral and anticarcinogenic properties, while piperazine can be used in the treatment of parasitic infections. METHODS: The influence of ultrasound and microwave-assisted treatment was studied by varying synthesis parameters such as reaction time, temperature, and US or MW power. The main advantage of using these methods is represented by shorter synthesis time compared to conventional methods, resulting in the direct formation of the cocrystals. RESULTS: All samples were obtained in high purity, above 97%. Cocrystal yield correlated positively with ultrasound reaction time, while temperature was not found to influence the microwave synthesis yield up to 50°C, in the case of solution-based methods. MW and US-assisted solution-based methods lead to yields between 52.9 and 68.1%. In the case of the slurry-based method, a minimum reaction time of 5 min leads to the formation of cocrystals with high purity. The resveratrol-piperazine cocrystal's solubility and in vitro antibacterial activity were also evaluated, showing promising results. CONCLUSIONS: Ultrasound and microwave-assisted techniques offer a viable alternative for synthesizing resveratrol-piperazine cocrystals with short reaction times, high yield, and purity, suitable for scalable resveratrol-piperazine cocrystals.

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2,5-disubstituted N,N'-alkylpiperazines represent an interesting target in organic synthesis both for pharmaceutical or agrochemical applications and as a promising class of ligands in coordination chemistry. We report here a microwave-enhanced synthesis of these compounds starting from non-activated N-alkyl aziridines in the presence of catalytic amounts of simple ammonium metallates. A remarkable TOF of 2787.9 h-1 has been observed in the case of [TBA]2[ZnI4] as the catalyst (catalyst loading 0.1 mol%) and with an almost complete selectivity (up to 97%) in favor of both diastereoisomers (meso and chiral form) of the target 2,5-disubstituted piperazines, obtained in 1:1 ratio. The two isomers are easily separated, because the meso form precipitates in pure from the reaction crude. A stereochemical investigation and the unprecedented isolation of 2,6-disubstituted N,N'-alkylpiperazines allowed us to shed light on the reaction mechanism.

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A base-induced synthesis of 2-(4-(2-(phenylthio)ethyl)piperazinyl) acetonitriles by reaction of disulfides, 1-(chloromethyl)-4-aza-1-azonia bicyclo[2.2.2]octane chloride and trimethylsilyl cyanide is reported. The scope of the method is demonstrated with 30 examples. The reaction mechanism research indicates that the three-component reaction would be a SN2 reaction. The products exhibit good activities towards advanced synthesis of aqueous soluble acyl-CoA: cholesterol O-acyltransferase-1 (ACAT-1) inhibitors. Our work is superior as it uses less-odor disulfides as carbon sources and EtOH as solvent in a water and dioxygen insensitive reaction system, followed by a simple purification process.

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Both cyclopropyl amide and piperazine sulfonamide functional groups are known for their various biological properties used for drug development. Herein, we synthesized nine new derivatives with different substituent groups incorporating these moieties and screened them for their anti-osteoclast differentiation activity. After analyzing the structure-activity relationship (SAR), the inhibitory effect against osteoclastogenesis was determined to be dependent on the lipophilicity of the compound. Derivative 5b emerged as the most effective dose-dependent inhibitor after TRAP staining with an IC50 of 0.64 µM against RANKL-induced osteoclast cells. 5b was also able to suppress F-acting ring formation and bone resorption activity of osteoclasts in vitro. Finally, well-acknowledged gene and protein osteoclast-specific marker expression levels were decreased after 5b administration on primary murine osteoclast cells.

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Brown rot of stone fruit, a disease caused by the ascomycete fungus Monilinia fructicola, has caused significant losses to the agricultural industry. In order to explore and discover potential fungicides against M. fructicola, thirty-one novel mandelic acid derivatives containing piperazine moieties were designed and synthesized based on the amide skeleton. Among them, target compound Z31 exhibited obvious in vitro antifungal activity with the EC50 value of 11.8 mg/L, and significant effects for the postharvest pears (79.4 % protective activity and 70.5 % curative activity) at a concentration of 200 mg/L. Antifungal activity for the target compounds was found to be significantly improved by the large steric hindrance of the R1 groups and the electronegative of the piperazines in the molecular structure, according to a three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis. Further mechanism studies have demonstrated that the compound Z31 can disrupt cell membrane integrity, resulting in increased membrane permeability, release of intracellular electrolytes, and affect the normal growth of hyphae. Additional, morphological study also indicated that Z31 may disrupt the integrity of the membrane by inducing generate excess endogenous reactive oxygen species (ROS) and resulting in the peroxidation of cellular lipids, which was further verified by the detection of malondialdehyde (MDA) content. These studies have provided the basis for the creation of novel fungicides to prevent brown rot in stone fruits.

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Multi-target directed ligands (MTDLs) have recently been popularized due to their outstanding efficacy in combating the complicated features of Alzheimer's disease. This study details the synthesis of piperazine-quinoline-based MTDLs through a multicomponent Petasis reaction, targeting multiple factors such as AChE, BuChE, metal chelation to restore metal dyshomeostasis, and antioxidant activity. Some of the synthesized compounds exhibited notable inhibitory activity against AChE and BuChE enzymes at specific concentrations. Among the synthesized compounds compound (95) containing a 4-chloroaniline moiety and a 4-methoxybenzyl group displayed the most promising inhibitory activities against AChE (IC50 3.013 µM) and BuChE (IC50 = 3.144 µM). Compound (83) featuring 2-methoxyaniline and 4-fluorobenzyl substituents, exhibited the highest BuChE inhibition (IC50 1.888 µM). Notably, compound (79) demonstrated 93-times higher selectivity for BuChE over AChE. Molecular docking and molecular dynamics simulations were also performed to explore the binding modes and stability of these compounds with the AChE amd BuChE proteins. Further, kinetics study was performed against AChE for comounds (83 and 95) which indicated mixed inhibition of the enzyme by these compounds, Amongs the synthesized compounds, nine compounds were assessed for their antioxidant activity, displaying significant antioxidant properties with IC50 values ranging from 156 µM to 310 µM. Moreover, all the compounds demonstrated metal chelating tendency with Cu+2, Zn+2, Fe+2, Fe+3 and Al+3. This study provides insights into the design of novel MTDLs, highlighting compound (95) as a potential candidate for combating Alzheimer's disease.

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New series of benzimidazole incorporating piperazine moieties in single molecular framework has been reported. The structures of the synthesized derivatives were assigned by 1H-NMR, 13C-NMR, and HR-MS techniques. The hybrid derivatives were evaluated for their acetylcholinesterase and butyrylcholinesterase inhibition effect. All the synthesized analogs showed good to moderate inhibitory effect ranging from IC50 value 0.20 ± 0.01 µM to 0.50 ± 0.10 µM for acetylcholinesterase and from IC50 value 0.25 ± 0.01 µM to 0.70 ± 0.10 µM for butyrylcholinesterase except one that showed least potency with IC50 value 1.05 ± 0.1 µM and 1.20 ± 0.1 µM. The differences in inhibitory potential of synthesized compounds were due to the nature and position of substitution attached to the main ring. Additionally, molecular docking study was carried out for most active in order to explore the binding interactions established by ligand (active compounds) with the active residues of targeted AChE & BuChE enzyme.

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The 1:1 resveratrol-piperazine cocrystal was successfully synthesized and scaled-up to 300 g scale with the mechanochemical method, as a result of investigating key process parameters, namely the solvent and the grinding time. The use of water, ethanol or ethanol-water mixtures and reaction times up to 50 min were evaluated relative to the dry grinding process. Cocrystal formation and purity were monitored through X-ray diffraction and calorimetry measurements. The dry grinding resulted in an incomplete cocrystal formation, while the use of water or water-ethanol mixture yielded a monohydrate solid phase. Pure ethanol was found to be the optimal solvent for large-scale cocrystallization, as it delivered cocrystals with high crystallinity and purity after 10-30 min grinding time at the laboratory scale. Notably, a relatively fast reaction time (30-60 min) was sufficient for the completion of cocrystallization at larger scales, using a planetary ball mill and a plant reactor. Also, the obtained cocrystal increases the aqueous solubility of resveratrol by 6%-16% at pH = 6.8. Overall, this study highlights the potential of solvent-assisted mechanochemical synthesis as a promising new approach for the efficient production of pure resveratrol-piperazine cocrystals.

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Diabetes mellitus is a severe endocrine disease that affects more and more people every year. Modern medical chemistry sets itself the task of finding effective and safe drugs against diabetes. This review provides an overview of potential antidiabetic drugs based on three heterocyclic compounds, namely morpholine, piperazine, and piperidine. Studies have shown that compounds containing their moieties can be quite effective in vitro and in vivo for the treatment of diabetes and its consequences.

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BACKGROUND: To discover more efficient agricultural antimicrobial agents, a series of new quinazoline derivatives containing both a piperazine linker and the N-acetyl moiety were prepared and assessed for their antibacterial and antifungal activities. RESULTS: All the target compounds were characterized by 1H and 13C NMR as well as high-resolution mass spectrometry (HRMS), and the chemical structure of the most potent compound E19 incorporating a 4-trifluoromethoxy substituent was clearly confirmed via single crystal X-ray diffraction measurements. The bioassay results indicated that some compounds possessed notable inhibitory effects in vitro against the bacterium Xanthomonas oryzae pv. oryzicola (Xoc). For example, compound E19 had an EC50 (effective concentration for 50% activity) value of 7.1 µg/mL towards this pathogen, approximately 15- and 10-fold more effective than the commercial bactericides thiodiazole copper and bismerthiazol (EC50 = 110.2 and 72.4 µg/mL, respectively). Subsequently, the mechanistic studies showed that compound E19 likely exerted its antibacterial efficacies by altering the cell morphology, increasing the permeability of bacterial cytoplasmic membrane, suppressing the production of bacterial extracellular polysaccharides and the extracellular enzyme activities (amylase and cellulase), and blocking the swimming motility of Xoc. Moreover, the proteomic analysis revealed that compound E19 could reduce the bacterial flagellar biosynthesis and decrease the flagellar motility by down-regulating the expression of the related differential proteins. CONCLUSION: Compound E19 exhibited good potential for further development as a bactericide candidate for control of Xoc. © 2024 Society of Chemical Industry.

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Poly(ionic liquid)s combine the unique properties of ionic liquids (ILs) within ionic polymers holding significant promise for energy storage applications. It is reported here the synthesis and characterization of a new family of poly(ionic liquid)s synthesized from cationic piperazinium ionic liquid monomers. The cationic poly(acrylamide piperazinium) in combination with sulfonamide anions like bis(trifluoromethanesulfonyl) imide (TFSI) and bis(fluorosulfonyl) imide (FSI) are characterized as solid polymer electrolytes. The polymer electrolytes in combination with pyrrolidonium ILs and LiFSI show high ionic conductivity, 5×10-3 S cm-1 at 100 °C. Piperazinium polymer electrolytes show excellent compatibility with lithium metal reversible plating and stripping at high current density and low temperature 40 °C.

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Bacterial diseases pose a significant threat to the sustainable production of crops. Given the unsatisfactory performance and poor eco-compatibility of conventional bactericides, here we present a series of newly structured bactericides that are inspiringly designed by aurone found in plants of the Asteraceae family. These aurone-derived compounds contain piperazine sulfonamide motifs and have shown promising in vitro performance against Xanthomonas oryzae pv. oryzae, Xanthomonas oryzae pv. oryzicola and Xanthomonas axonopodis pv. citri, in particular, compound II23 achieved minimum half-maximal effective concentrations of 1.06, 0.89, and 1.78 µg/mL, respectively. In vivo experiments conducted in a greenhouse environment further revealed that II23 offers substantial protective and curative effects ranging between 68.93 and 70.29% for rice bacterial leaf streak and 53.17-64.43% for citrus bacterial canker, which stands in activity compared with lead compound aurone and commercial thiodiazole copper. Additional physiological and biochemical analyses, coupled with transcriptomics, have verified that II23 enhances defense enzyme activities and chlorophyll levels in rice. Significantly, it also stimulates the accumulation of abscisic acid (ABA) and upregulates the expression of key genes OsPYL/RCAR5, OsBIPP2C1, and OsABF1, thereby activating the ABA signaling pathway in rice plants under biological stress from bacterial infections.

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Amphotericin B (AmB) induced liver and kidney injury is often responsible for hepatic and renal dysfunction. Therefore, the protection strategy on liver and renal functions in patients treated with AmB should be emphasized. In this paper, diammonium glycyrrhizinate (DG) and piperazine ferulate (PF) were taken as the research object to study its hepatoprotective and neuroprotective effect on AmB-induced liver and kidney damage in vitro and in vivo. The microplate method and ELISA kits were employed for the biochemical detection in the serum and urine of mice. Flow cytometric analysis and western blotting analysis were conducted to study the mechanism of DG and PF. Our results confirmed the prevention capacity of DG and PF on AmB-induced liver and kidney injury through the alleviation of pathological changes and enzyme reducing action. Furthermore, DG and PF suppressed ROS-mediated mitochondrial apoptosis in AmB-treated mice and cells through Caspase pathway and Caspase-independent AIF pathway. In summary, DG and PF could protect AmB-induced hepatotoxicity and nephrotoxicity by disrupting oxidative stress and apoptosis.

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The versatile basic structure of piperazine allows for the development and production of newer bioactive molecules that can be used to treat a wide range of diseases. Piperazine derivatives are unique and can easily be modified for the desired pharmacological activity. The two opposing nitrogen atoms in a six-membered piperazine ring offer a large polar surface area, relative structural rigidity, and more acceptors and donors of hydrogen bonds. These properties frequently result in greater water solubility, oral bioavailability, and ADME characteristics, as well as improved target affinity and specificity. Various synthetic protocols have been reported for piperazine and its derivatives. In this review, we focused on recently published synthetic protocols for the synthesis of the piperazine and its derivatives. The structure-activity relationship concerning different biological activities of various piperazine-containing drugs has also been highlighted to provide a good understanding to researchers for future research on piperazines.

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Benzene sulfonamides are an important biological substituent for several activities. In this study, hybridization of benzene sulfonamide with piperazine derivatives were investigated for their antioxidant capacity and enzyme inhibitory potencies. Six molecules were synthesized and characterized. DPPH, ABTS, FRAP, CUPRAC, chelating and phosphomolybdemum assays were applied to evaluate antioxidant capacities. Results show that compounds have high antioxidant capacity and compound 4 has the best antioxidant activity among them. Compound 4 has higher antioxidant activity than references for FRAP (IC50: 0.08 mM), CUPRAC (IC50: 0.21 mM) and phosphomolybdenum (IC50: 0.22 mM) assays. Besides this, compound 4 has moderate DPPH and ABTS antioxidant capacity. Furthermore, enzyme inhibition activities of these molecules were investigated against AChE, BChE, tyrosinase, α-amylase and α-glucosidase enzymes. It was revealed that all compounds have good enzyme inhibitory potential except for α-amylase enzyme. The best inhibitory activities were observed for AChE with compound 5 the same value (IC50: 1.003 mM), for BChE with compounds 2 and 5 the same value (IC50: 1.008 mM), for tyrosinase compound 4 (IC50: 1.19 mM), and for α-glucosidase with compound 3 (IC50: 1.000 mM). Docking studies have been conducted with these molecules, and the results correlate well with the inhibitory assays.

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Depression is a debilitating mental illness that has a significant impact on an individual's psychological, social, and physical life. Multiple factors, such as genetic factors and abnormalities in neurotransmitter levels, contribute to the development of depression. Monoamine oxidase inhibitors, tricyclic antidepressants, serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors, and atypical and new-generation antidepressants are well-known drug classes. SSRIs are the commonly prescribed antidepressant medications in the clinic. Genetic variations impacting serotonergic activity in people can influence susceptibility to diseases and response to antidepressant therapy. Gene polymorphisms related to 5-hydroxytryptamine (5-HT) signaling and subtypes of 5-HT receptors may play a role in the development of depression and the response to antidepressants. SSRIs binding to 5-HT reuptake transporters help relieve depression symptoms. Research has been conducted to identify a biomarker for detecting depressive disorders to identify new treatment targets and maybe offer novel therapy approaches. The pharmacological potentials of the piperazine-based compounds led researchers to design new piperazine derivatives and to examine their pharmacological activities. Structure-activity relationships indicated that the first aspect is the flexibility in the molecules, where a linker of typically a 2-4 carbon chain joins two aromatic sides, one of which is attached to a piperazine/phenylpiperazine/benzyl piperazine moiety. Newly investigated compounds having a piperazine core show a superior antidepressant effect compared to SSRIs in vitro/in vivo.