RESUMO
The non-aqueous solid-liquid biphasic solvent of 2-amino-2-methyl-1-propanol (AMP)/piperazine (PZ)/dipropylene glycol dimethyl ether (DME) features a high CO2 absorption loading, favorable phase separation behavior and high regeneration efficiency. Different with the liquid-liquid phase change solvent, the reaction kinetics of CO2 capture into solid-liquid biphasic solvent was rarely studied. In the present work, the reaction kinetics of CO2 absorption into AMP/PZ/DME solid-liquid biphasic solvent was investigated into the double stirred kettle reactor. The absorption reaction followed a pseudo-first-order kinetic model according to the zwitterion mechanism. The overall reaction rate constant (kov) and the enhancement factor (E) of CO2 absorption both increased with increasing temperature. The total mass transfer resistance of the absorbent decreased with increasing temperature and increased with increasing absorption loading, so the higher reaction temperature was conducive to the absorption, and the liquid phase mass transfer resistance was the main factor affecting the absorption rate.
Assuntos
Dióxido de Carbono , Solventes , Dióxido de Carbono/química , Cinética , Solventes/química , Modelos Químicos , Piperazinas/química , Piperazina/química , PropanolaminasRESUMO
Alzheimer disease (AD) is characterized by progressive loss of memory. Synaptic loss is now the best correlate of cognitive dysfunction in patients with Alzheimer's disease. Thus, restoration or limitation of synapse loss is a promising strategy for pharmacotherapy of AD. N-N substituted piperazines are widely used chemical compounds for drug interventions to treat different illnesses including CNS diseases such as drug abuse, mental and anxiety disorders. Piperazine derivatives are small molecules that are usually well tolerated and cross blood brain barrier (BBB). Thus, disubstituted piperazines are good tools for searching and developing novel disease-modifying drugs. Previously, we have determined the piperazine derivative, 51164, as an activator of TRPC6 in dendritic spines. We have demonstrated synaptoprotective properties of 51164 in AD mouse models. However, 51164 was not able to cross BBB. Within the current study, we identified a novel piperazine derivative, cmp2, that is structurally similar to 51164 but is able to cross BBB. Cmp2 binds central part of monomeric TRPC6 in similar way as hypeforin does. Cmp2 selectively activates TRPC6 but not structurally related TRPC3 and TRPC7. Novel piperazine derivative exhibits synaptoprotective properties in culture and slices and penetrates the BBB. In vivo study indicated cmp2 (10 mg/kg I.P.) reversed deficits in synaptic plasticity in the 5xFAD mice. Thus, we suggest that cmp2 is a novel lead compound for drug development. The mechanism of cmp2 action is based on selective TRPC6 stimulation and it is expected to treat synaptic deficiency in hippocampal neurons.
Assuntos
Doença de Alzheimer , Hipocampo , Neurônios , Piperazinas , Canal de Cátion TRPC6 , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Piperazinas/farmacologia , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Canal de Cátion TRPC6/metabolismo , Camundongos , Humanos , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Piperazina/química , Piperazina/farmacologia , Canais de Cátion TRPC/metabolismo , Modelos Animais de DoençasRESUMO
Four new alkaloids, vibripyrrolidine A (1), vibripiperazine A (2), and vibridiazinane A, B (3, 4), comprising one pyrrolidine, one piperazine, and two diazinane alkaloids, along with two known analogs (5, 6), were isolated from the marine bacterium Vibrio ruber ZXR-93 cultured in ISP2 medium. Their chemical structures were elucidated by analysis of their 1D and 2D NMR, mass spectra, and electronic circular dichroism (ECD) calculations. Compounds 1 and 3-6 showed vigorous antibacterial activity against Staphylococcus aureus, with MIC values ranging from 0.96 to 7.81 µg/mL. Moreover, compound 1 exhibited robust anti-inflammatory activity in vitro using the LPS-induced RAW264.7 macrophage model. All compounds also showed moderate antineoplastic activity against cervical cancer cells (HeLa) and gastric cancer cells (SGC-7901).
Assuntos
Alcaloides , Antibacterianos , Testes de Sensibilidade Microbiana , Pirrolidinas , Staphylococcus aureus , Vibrio , Humanos , Alcaloides/farmacologia , Alcaloides/química , Alcaloides/isolamento & purificação , Camundongos , Animais , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Pirrolidinas/química , Pirrolidinas/farmacologia , Células RAW 264.7 , Staphylococcus aureus/efeitos dos fármacos , Vibrio/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Estrutura Molecular , Piperazina/química , Piperazina/farmacologia , Linhagem Celular Tumoral , Piperazinas/farmacologia , Piperazinas/química , Piperazinas/isolamento & purificação , Células HeLaRESUMO
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.
Assuntos
Cristalização , Micro-Ondas , Piperazinas , Resveratrol , Resveratrol/química , Resveratrol/farmacologia , Resveratrol/síntese química , Piperazinas/química , Piperazinas/síntese química , Piperazinas/farmacologia , Piperazina/química , Solubilidade , TemperaturaRESUMO
Piperazine is an important functional unit of many clinically approved drugs, including chemotherapeutic agents. In the current study, methyl piperazine was incorporated and eight salicylaldehyde-derived piperazine-functionalized hydrazone ONN-donor ligands (L) and their Pt(II) complexes (L-PtCl) were prepared. The structures of all these ligands (L1-L8) and Pt(II) complexes (C1-C8) were determined using 1H and 13C NMR, UV-vis, FT-IR and HR-ESI MS analyses, whereas the structures of C1, C5, C6, C7 and C8 were determined in the solid state using single crystal X-ray diffraction analysis. Solution state stabilities of C3, C4, C5 and C6 were determined via time-dependent UV-vis spectroscopy. All these complexes (C1-C8) were studied for their anticancer effect in pancreatic ductal adenocarcinoma cells, including BxPC3, MIAPaCa-2 and PANC1 cells. C1-C8 displayed a potential cytotoxic effect in all these cancer cells, among which C5, C6 and C8 showed the strongest inhibitory effect in comparison with standard chemotherapeutic agents, including 5-fluorouracil (5-FU), cisplatin (CP), oxaliplatin and doxorubicin (DOX). C5, C6 and C8 suppressed the growth of pancreatic cancer cells in a dose-dependent manner. Moreover, C5, C6 and C8 inhibited clonogenic potential and invasion ability and induced apoptosis in PANC1 cells. Importantly, C5, C6 and C8 synergized the anticancer effect with PARP inhibitors, including olaparib, veliparib and niraparib, in pancreatic cancer cells, thus suggesting an important role of C5, C6 and C8 in induction of apoptosis in combination with PARP inhibitors. C5 combined with PARP inhibitors induced caspase3/7 activity and suppressed ATP production. Mechanistically, C5, C6 and C8 inhibited EZH2 protein expression to suppress EZH2-dependent tumorigenesis. Overall, these results highlighted the importance of these piperazine-functionalized Pt(II) complexes as potential anticancer agents to suppress pancreatic ductal adenocarcinoma tumorigenesis by targeting the EZH2-dependent pathway.
Assuntos
Aldeídos , Antineoplásicos , Apoptose , Proteína Potenciadora do Homólogo 2 de Zeste , Hidrazonas , Neoplasias Pancreáticas , Piperazina , Inibidores de Poli(ADP-Ribose) Polimerases , Apoptose/efeitos dos fármacos , Humanos , Hidrazonas/química , Hidrazonas/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Ligantes , Aldeídos/química , Aldeídos/farmacologia , Piperazina/química , Piperazina/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/química , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Linhagem Celular Tumoral , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/metabolismo , Proliferação de Células/efeitos dos fármacos , Piperazinas/farmacologia , Piperazinas/química , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/química , Compostos Organoplatínicos/síntese químicaRESUMO
In the context of structural investigation and optimization of various potential EGFR inhibitors, a novel series of asymmetrical piperazine-tethered trisubstituted thiophene-3-carboxamide selenide derivatives were synthesized and evaluated for their antiproliferative potential against selected human cancer cell lines. These derivatives, built based on a previously identified hit molecule, were synthesized via multiple-step reactions, including optimization of the C-Se cross-coupling reaction. Two compounds, 17i and 18i, displayed significant cytotoxicity (IC50 value: 4.82 ± 0.80 µM and 1.43 ± 0.08 µM) against HCT116 and A549 cancer cell lines, respectively. Quantitative analysis of apoptotic stages using Annexin V-FITC/PI double staining validated their apoptotic potential. Further, compound 18i demonstrated a remarkable inhibition of EGFR kinase, with an IC50 concentration of 42.3 nM. The lead compound 18i, with remarkable in vitro cytotoxicity, apoptosis induction capability, and EGFR inhibition, emerges as a promising candidate for anticancer therapy.
Assuntos
Antineoplásicos , Apoptose , Proliferação de Células , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB , Simulação de Acoplamento Molecular , Piperazina , Piperazinas , Inibidores de Proteínas Quinases , Tiofenos , Humanos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Tiofenos/química , Tiofenos/farmacologia , Tiofenos/síntese química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Estrutura Molecular , Piperazina/química , Piperazina/farmacologia , Piperazina/síntese química , Apoptose/efeitos dos fármacos , Piperazinas/química , Piperazinas/farmacologia , Piperazinas/síntese química , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/síntese química , Linhagem Celular TumoralRESUMO
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.
Assuntos
Hipoglicemiantes , Morfolinas , Piperazina , Piperidinas , Humanos , Piperidinas/química , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Morfolinas/química , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Piperazina/química , Piperazina/farmacologia , Animais , Piperazinas/química , Piperazinas/farmacologia , Piperazinas/síntese química , Piperazinas/uso terapêutico , Diabetes Mellitus/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
A series of novel vindoline-piperazine conjugates were synthesized by coupling 6 N-substituted piperazine pharmacophores at positions 10 and 17 of Vinca alkaloid monomer vindoline through different types of linkers. The in vitro antiproliferative activity of the 17 new conjugates was investigated on 60 human tumor cell lines (NCI60). Nine compounds presented significant antiproliferative effects. The most potent derivatives showed low micromolar growth inhibition (GI50) values against most of the cell lines. Among them, conjugates containing [4-(trifluoromethyl)benzyl]piperazine (23) and 1-bis(4-fluorophenyl)methyl piperazine (25) in position 17 of vindoline were outstanding. The first one was the most effective on the breast cancer MDA-MB-468 cell line (GI50 = 1.00 µM), while the second one was the most effective on the non-small cell lung cancer cell line HOP-92 (GI50 = 1.35 µM). The CellTiter-Glo Luminescent Cell Viability Assay was performed with conjugates 20, 23, and 25 on non-tumor Chinese hamster ovary (CHO) cells to determine the selectivity of the conjugates for cancer cells. These compounds exhibited promising selectivity with estimated half-maximal inhibitory concentration (IC50) values of 2.54 µM, 10.8 µM, and 6.64 µM, respectively. The obtained results may have an impact on the design of novel vindoline-based anticancer compounds.
Assuntos
Antineoplásicos , Proliferação de Células , Cricetulus , Piperazina , Piperazinas , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Células CHO , Animais , Piperazinas/farmacologia , Piperazinas/química , Piperazinas/síntese química , Proliferação de Células/efeitos dos fármacos , Piperazina/química , Piperazina/farmacologia , Vimblastina/análogos & derivados , Vimblastina/farmacologia , Vimblastina/química , Vimblastina/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Relação Estrutura-Atividade , Sobrevivência Celular/efeitos dos fármacosRESUMO
A new series of piperazine derivatives were synthesized and studied with the aim of obtaining dual inhibitors of P-glycoprotein (P-gp) and carbonic anhydrase XII (hCA XII) to synergistically overcome the P-gp-mediated multidrug resistance (MDR) in cancer cells expressing the two proteins, P-gp and hCA XII. Indeed, these hybrid compounds contain both P-gp and hCA XII binding groups on the two nitrogen atoms of the heterocyclic ring. All compounds showed good inhibitory activity on each protein (P-gp and hCA XII) studied individually, and many of them showed a synergistic effect in the resistant HT29/DOX and A549/DOX cell lines which overexpress both the target proteins. In particular, compound 33 displayed the best activity by enhancing the cytotoxicity and intracellular accumulation of doxorubicin in HT29/DOX and A549/DOX cells, thus resulting as promising P-gp-mediated MDR reverser with a synergistic mechanism. Furthermore, compounds 13, 27 and 32 induced collateral sensitivity (CS) in MDR cells, as they were more cytotoxic in resistant cells than in the sensitive ones; their CS mechanisms were extensively investigated.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Inibidores da Anidrase Carbônica , Anidrases Carbônicas , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Piperazinas , Humanos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Piperazinas/farmacologia , Piperazinas/química , Piperazinas/síntese química , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/síntese química , Anidrases Carbônicas/metabolismo , Doxorrubicina/farmacologia , Doxorrubicina/química , Piperazina/química , Piperazina/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Células HT29 , Relação Estrutura-Atividade , Linhagem Celular Tumoral , Estrutura Molecular , Células A549RESUMO
Starting from our previously reported nonnucleoside reverse transcriptase inhibitor (NNRTI, 3), continuous efforts were made to enhance its potency and safety through a structure-based drug design strategy. This led to the discovery of a series of novel piperidine-biphenyl-diarylpyrimidines (DAPYs). Compound 10p, the most active compound in this series, exhibited an EC50 value of 6 nM against wide-type HIV-1 strain, which was approximately 560-fold more potent than the initial compound 3 (EC50 = 3.36 µM). Furthermore, significant improvements were observed in cytotoxicity and selectivity (CC50 > 202.17 µM, SI > 33144) compared to compound 3 (CC50 = 14.84 µM, SI = 4). Additionally, compound 10p demonstrated increased inhibitory activity against clinically mutant virus strains (EC50 = 7-63 nM). Further toxicity evaluation revealed that compound 10p exhibited minimal CYP enzyme and hERG inhibition. Importantly, single-dose acute toxicity testing did not result in any fatalities or noticeable pathological damage in mice. Therefore, compound 10p can be regarded as a lead candidate for guiding further development of biphenyl-diarylpyrimidine NNRTIs with favorable druggability for HIV therapy.
Assuntos
Fármacos Anti-HIV , Compostos de Bifenilo , Descoberta de Drogas , Transcriptase Reversa do HIV , HIV-1 , Piperidinas , Pirimidinas , Inibidores da Transcriptase Reversa , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/síntese química , Relação Estrutura-Atividade , Piperidinas/química , Piperidinas/farmacologia , Piperidinas/síntese química , Humanos , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/química , Animais , HIV-1/efeitos dos fármacos , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/síntese química , Camundongos , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/metabolismo , Estrutura Molecular , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/síntese química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Piperazinas/química , Piperazinas/farmacologia , Piperazinas/síntese química , Piperazina/química , Piperazina/farmacologiaRESUMO
Recently, pharmaceutical research has been focused on the design of new antibacterial drugs with higher selectivity towards several strains. Major issues concern the possibility to obtain compounds with fewer side effects, at the same time effectively overcoming the problem of antimicrobial resistance. Several solutions include the synthesis of new pharmacophores starting from piperazine or morpholine core units. Mass spectrometry-based techniques offer important support for the structural characterization of newly synthesized compounds to design safer and more effective drugs for various medical conditions. Here, two new piperazine derivatives and four new morpholine derivatives were synthesized and structurally characterized through a combined approach of Fourier transform-ion cyclotron resonance (FT-ICR) and Linear Trap Quadrupole (LTQ) mass spectrometry. The support of both high-resolution and low-resolution mass spectrometric data namely accurate mass measurements, isotopic distribution and MSn spectra, was crucial to confirm the success of the synthesis. These compounds were further evaluated for inhibitory activity against a total of twenty-nine Gram-positive and Gram-negative bacteria to determine the action spectrum and the antimicrobial effectiveness. Results demonstrated compounds' antimicrobial activity against many tested bacterial species, providing an inhibitory effect linked to different chemical structure and suggesting that the new-synthesized derivatives could be considered as promising antimicrobial agents.
Assuntos
Antibacterianos , Bactérias Gram-Negativas , Espectrometria de Massas , Testes de Sensibilidade Microbiana , Morfolinas , Piperazinas , Morfolinas/farmacologia , Morfolinas/química , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/análise , Antibacterianos/síntese química , Testes de Sensibilidade Microbiana/métodos , Piperazinas/farmacologia , Piperazinas/química , Bactérias Gram-Negativas/efeitos dos fármacos , Espectrometria de Massas/métodos , Bactérias Gram-Positivas/efeitos dos fármacos , Relação Estrutura-Atividade , Piperazina/farmacologia , Piperazina/químicaRESUMO
In this study, a series of acrylamide derivatives containing trifluoromethylpyridine or piperazine fragments were rationally designed and synthesized. Subsequently, the in vitro antifungal activities of all of the synthesized compounds were evaluated. The findings revealed that compounds 6b, 6c, and 7e exhibited >80% antifungal activity against Phomopsis sp. (Ps) at the concentration of 50 µg/mL. Furthermore, the EC50 values for compounds 6b, 6c, and 7e against Ps were determined to be 4.49, 6.47, and 8.68 µg/mL, respectively, which were better than the positive control with azoxystrobin (24.83 µg/mL). At the concentration of 200 µg/mL, the protective activity of compound 6b against Ps reached 65%, which was comparable to that of azoxystrobin (60.9%). Comprehensive mechanistic studies, including morphological studies with fluorescence microscopy (FM), cytoplasmic leakage, and enzyme activity assays, indicated that compound 6b disrupts cell membrane integrity and induces the accumulation of defense enzyme activity, thereby inhibiting mycelial growth. Therefore, compound 6b serves as a valuable candidate for the development of novel fungicides for plant protection.
Assuntos
Acrilamida , Desenho de Fármacos , Fungicidas Industriais , Piridinas , Fungicidas Industriais/farmacologia , Fungicidas Industriais/síntese química , Fungicidas Industriais/química , Acrilamida/química , Piridinas/química , Piridinas/farmacologia , Piridinas/síntese química , Relação Estrutura-Atividade , Ascomicetos/efeitos dos fármacos , Ascomicetos/crescimento & desenvolvimento , Piperazina/química , Piperazina/farmacologia , Piperazinas/farmacologia , Piperazinas/química , Piperazinas/síntese química , Estrutura Molecular , Testes de Sensibilidade Microbiana , Doenças das Plantas/microbiologiaRESUMO
A series of combretastatin A-4 (CA-4) derivatives were designed and synthesized, which contain stilbene core structure with different linker, predominantly piperazine derivatives. These compounds were evaluated for their cytotoxic activities against four cancer cell lines, HCT116, A549, AGS, and SK-MES-1. Among them, compound 13 displayed the best effectiveness with IC50 values of 0.227 µM and 0.253 µM against HCT116 and A549 cells, respectively, showing low toxicity to normal cells. Mechanistic studies showed that 13 inhibited HCT116 proliferation via arresting cell cycle at the G2/M phase through disrupting the microtubule network and inducing autophagy in HCT116 cells by regulating the expression levels of autophagy-related proteins. In addition, 13 displayed antiproliferative activities against A549 cells through blocking the cell cycle and inducing A549 cells apoptosis. Because of the poor water solubility of 13, four carbohydrate conjugates were synthesized which exhibited better water solubility. Further investigations revealed that 13 showed positive effects in vivo anticancer study with HCT116 xenograft models. These data suggest that 13 could be served as a promising lead compound for further development of anti-colon carcinoma agent.
Assuntos
Antineoplásicos , Autofagia , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Polimerização , Estilbenos , Tubulina (Proteína) , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Autofagia/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Estilbenos/farmacologia , Estilbenos/química , Estilbenos/síntese química , Tubulina (Proteína)/metabolismo , Animais , Polimerização/efeitos dos fármacos , Estrutura Molecular , Células HCT116 , Piperazinas/farmacologia , Piperazinas/química , Piperazinas/síntese química , Camundongos , Relação Dose-Resposta a Droga , Apoptose/efeitos dos fármacos , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Camundongos Nus , Piperazina/química , Piperazina/farmacologia , Piperazina/síntese química , Camundongos Endogâmicos BALB CRESUMO
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 was also highlighted to provide a good understanding to researchers for future research on piperazines.
Assuntos
Piperazinas , Relação Estrutura-Atividade , Piperazinas/química , Piperazinas/síntese química , Piperazinas/farmacologia , Humanos , Piperazina/química , Piperazina/farmacologia , Piperazina/síntese química , Estrutura Molecular , AnimaisRESUMO
INTRODUCTION: In this study, a series of novel piperazine derivatives were synthesised with high-to-good yields, and their structural analogies were confirmed using FTIR, 1H-NMR, and LC-MS techniques. METHODS: The synthesised compounds were evaluated for antioxidant and antimicrobial activities. Among the four synthesised piperazine derivatives, compound PD-2 exhibited relatively good antioxidant activity, with an IC50 value of 2.396 µg/mL, while the other three derivatives showed moderate to low antioxidant activity. Furthermore, compound PD-2 displayed antimicrobial activity against Pseudomonas aeruginosa, a gram-negative bacterium, and Candida albicans, a fungus. However, all four compounds showed strong resistance against grampositive bacteria, Staphylococcus aureus. RESULTS: Additionally, compound PD-1 exhibited significant antihistamine activity, eliciting an 18.22% reduction in histamine levels. Both PD-1 and PD-2 demonstrated noteworthy anti-inflammatory activity in a dosedependent manner (5-10 µM), leading to the inhibition of nitrite production up to 39.42% and 33.7% at higher concentrations (10 µM) and inhibition of tumour necrosis factor-alpha (TNF-α) generation up to 56.97% and 44.73% at 10 µM, respectively. Additionally, both novel molecules PD-1 and PD-2 effectively restrained the growth of HepG2 cells in a manner that is dependent on the dosage up to 55.44% and 90.45% at the highest concentrations (100 µg/mL), respectively. CONCLUSION: These findings substantiate the rationale for further investigation into the novel series of persuasive piperazine analogues as potential agents with anti-inflammatory, antihistamine and anticancer properties.
Assuntos
Antineoplásicos , Candida albicans , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Testes de Sensibilidade Microbiana , Piperazinas , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Humanos , Relação Estrutura-Atividade , Piperazinas/farmacologia , Piperazinas/química , Piperazinas/síntese química , Estrutura Molecular , Candida albicans/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/síntese química , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Animais , Staphylococcus aureus/efeitos dos fármacos , Antioxidantes/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Pseudomonas aeruginosa/efeitos dos fármacos , Piperazina/química , Piperazina/farmacologia , Piperazina/síntese química , Sobrevivência Celular/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , CamundongosRESUMO
A novel small molecule based on benzothiazole-piperazine has been identified as an effective multi-target-directed ligand (MTDL) against Alzheimer's disease (AD). Employing a medicinal chemistry approach, combined with molecular docking, MD simulation, and binding free energy estimation, compound 1 emerged as a potent MTDL against AD. Notably, compound 1 demonstrated efficient binding to both AChE and Aß1-42, involving crucial molecular interactions within their active sites. It displayed a binding free energy (ΔGbind) -18.64± 0.16 and -16.10 ± 0.18â¯kcal/mol against AChE and Aß1-42, respectively. In-silico findings were substantiated through rigorous in vitro and in vivo studies. In vitro analysis confirmed compound 1 (IC50=0.42⯵M) as an effective, mixed-type, and selective AChE inhibitor, binding at both the enzyme's catalytic and peripheral anionic sites. Furthermore, compound 1 demonstrated a remarkable ability to reduce the aggregation propensity of Aß, as evidenced by Confocal laser scanning microscopy and TEM studies. Remarkably, in vivo studies exhibited the promising therapeutic potential of compound 1. In a scopolamine-induced memory deficit mouse model of AD, compound 1 showed significantly improved spatial memory and cognition. These findings collectively underscore the potential of compound 1 as a promising therapeutic candidate for the treatment of AD.
Assuntos
Acetilcolinesterase , Doença de Alzheimer , Peptídeos beta-Amiloides , Benzotiazóis , Inibidores da Colinesterase , Simulação de Acoplamento Molecular , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Benzotiazóis/farmacologia , Benzotiazóis/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Peptídeos beta-Amiloides/metabolismo , Acetilcolinesterase/metabolismo , Camundongos , Masculino , Humanos , Piperazinas/farmacologia , Piperazinas/química , Escopolamina , Piperazina/farmacologia , Piperazina/química , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacologia , Simulação de Dinâmica Molecular , Simulação por Computador , Modelos Animais de Doenças , Aprendizagem em Labirinto/efeitos dos fármacosRESUMO
It is well known that daidzein has various significant medicinal values and health benefits, such as anti-oxidant, anti-inflammatory, anti-cancer, anti-diabetic, cholesterol lowering, neuroprotective, cardioprotective and so on. To our disappointment, poor solubility, low permeability and inferior bioavailability seriously limit its clinical application and market development. To optimize the solubility, permeability and bioavailability of daidzein, the cocrystal of daidzein and piperazine was prepared through a scientific and reasonable design, which was thoroughly characterized by single-crystal X-ray diffraction, powder X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry and thermogravimetric analysis. Combining single-crystal X-ray diffraction analysis with theoretical calculation, detailed structural information on the cocrystal was clarified and validated. In addition, a series of evaluations on the pharmacogenetic properties of the cocrystal were investigated. The results indicated that the cocrystal of daidzein and piperazine possessed the favorable stability, increased solubility, improved permeability and optimized bioavailability of daidzein. Compared with the parent drug, the formation of cocrystal, respectively, resulted in 3.9-, 3.1-, 4.9- and 60.8-fold enhancement in the solubility in four different media, 4.8-fold elevation in the permeability and 3.2-fold in the bioavailability of daidzein. Targeting the pharmaceutical defects of daidzein, the surprising elevation in the solubility, permeability and bioavailability of daidzein was realized by a clever cocrystal strategy, which not only devoted assistance to the market development and clinical application of daidzein but also paved a new path to address the drug-forming defects of insoluble drugs.
Assuntos
Disponibilidade Biológica , Isoflavonas , Permeabilidade , Piperazina , Solubilidade , Isoflavonas/química , Isoflavonas/farmacocinética , Piperazina/química , Cristalização , Difração de Raios X , Espectroscopia de Infravermelho com Transformada de Fourier , Animais , Cristalografia por Raios X , Varredura Diferencial de Calorimetria , HumanosRESUMO
We report the discovery and biosynthesis of new piperazine alkaloids-arizonamides, and their derived compounds-arizolidines, featuring heterobicyclic and spirocyclic isoquinolone skeletons, respectively. Their biosynthetic pathway involves two crucial non-heme iron enzymes, ParF and ParG, for core skeleton construction. ParF has a dual function facilitating 2,3-alkene formation of helvamide, as a substrate for ParG, and oxidative cleavage of piperazine. Notably, ParG exhibits catalytic versatility in multiple oxidative reactions, including cyclization and ring reconstruction. A key amino acid residue Phe67 was characterized to control the formation of the constrained arizonamide B backbone by ParG.
Assuntos
Alcaloides , Alcaloides/química , Alcaloides/metabolismo , Alcaloides/biossíntese , Piperazinas/química , Piperazinas/metabolismo , Ferro/química , Ferro/metabolismo , Ciclização , Biocatálise , Estrutura Molecular , Compostos de Espiro/química , Compostos de Espiro/metabolismo , Oxirredução , Piperazina/química , Piperazina/metabolismoRESUMO
Breast cancer is the most common type of cancer in women. Although current treatments can increase patient survival, they are rarely curative when the disease is advanced (metastasis). Therefore, there is an urgent need to develop new cytotoxic drugs with a high selectivity toward cancer cells. Since repurposing approved drugs for cancer therapy has been a successful strategy in recent years, in this study, we screened a library of antiviral piperazine-derived compounds as anticancer agents. The compounds included a piperazine ring and aryl urea functions, which are privileged structures present in several anti-breast cancer drugs. The selective cytotoxic activity of a set of thirty-four 4-acyl-2-substituted piperazine urea derivatives against MCF7 breast cancer cells and MCF 10A normal breast cells was determined. Compounds 31, 32, 35, and 37 showed high selective anticancer activity against breast cancer cells and were also tested against another common type of cancer, non-small cell lung cancer (A549 lung cancer cells versus MRC-5 lung normal cells). Compounds 35 and 37 also showed selectivity against lung cancer cells. These results suggest that compounds 35 and 37 may be promising hit compounds for the development of new anticancer agents.
Assuntos
Antineoplásicos , Neoplasias da Mama , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Feminino , Humanos , Neoplasias da Mama/tratamento farmacológico , Reposicionamento de Medicamentos , Antineoplásicos/farmacologia , Antineoplásicos/química , Piperazina/farmacologia , Piperazina/química , Ureia/farmacologia , Relação Estrutura-Atividade , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células , Estrutura Molecular , Células MCF-7RESUMO
Piperazine and homopiperazine are well-studied heterocycles in drug design that have found gainful application as scaffolds and terminal elements and for enhancing the aqueous solubility of a molecule. The optimization of drug candidates that incorporate these heterocycles in an effort to refine potency, selectivity, and developability properties has stimulated the design and evaluation of a wide range of bioisosteres that can offer advantage. In this review, we summarize the design and application of bioisosteres of piperazine and homopiperazine that have almost exclusively been in the drug design arena. While there are â¼100 approved drugs that incorporate a piperazine ring, only a single marketed agricultural product is built on this heterocycle. As part of the review, we discuss some of the potential reasons underlying the relatively low level of importance of this heterocycle to the design of agrochemicals and highlight the potential opportunities for their use in contemporary research programs.