RESUMO
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
BACKGROUND & PURPOSE: The constant emergence and broad toxicological effects of synthetic cannabinoids create a discernible public health threat. The synthetic cannabinoid AMB-FUBINACA (AMB-FUB) is a potent agonist at the CB1 receptor and has been associated with numerous fatalities. Synthetic cannabinoids are commonly abused alongside other drugs and medications, including a "party pill" drug, para-fluorophenylpiperazine (pFPP), and the antipsychotic risperidone. This research aimed to investigate the mechanisms underpinning AMB-FUB toxicity and the impact of clinically relevant co-exposures in vivo. EXPERIMENTAL APPROACH: Male and female C57Bl/6 mice received a single dose of AMB-FUB (3 or 6 mg kg-1), pFPP (10 or 20 mg kg-1) or vehicle intraperitoneally. Mice were co-exposed to AMB-FUB (3 mg kg-1) and pFPP (10 mg kg-1) or risperidone (0.5 mg kg-1) to investigate these drug combinations. To study receptor-dependency and potential rescue of AMB-FUB toxicity, rimonabant (3 mg kg-1) was administered both pre- and post-AMB-FUB. Adverse effects caused by drug administration, including hypothermia and convulsions, were recorded. KEY RESULTS: AMB-FUB induced CB1-dependent hypothermia and convulsions in mice. The combination of AMB-FUB and pFPP significantly potentiated hypothermia, as did risperidone pre-treatment. Interestingly, risperidone provided significant protection from AMB-FUB-induced convulsions in female mice. Pre- and post-treatment with rimonabant was able to significantly attenuate both hypothermia and convulsions in mice administered AMB-FUB. CONCLUSION & IMPLICATIONS: Factors such as dose, CB1 signalling, and substance co-exposure significantly contribute to the toxicity of AMB-FUBINACA. Mechanistic understanding of synthetic cannabinoid toxicity and fatality can help inform overdose treatment strategies and identify vulnerable populations of synthetic cannabinoid users.
Assuntos
Antipsicóticos , Camundongos Endogâmicos C57BL , Piperazinas , Receptor CB1 de Canabinoide , Animais , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/metabolismo , Receptor CB1 de Canabinoide/agonistas , Feminino , Masculino , Camundongos , Antipsicóticos/farmacologia , Antipsicóticos/efeitos adversos , Antipsicóticos/toxicidade , Piperazinas/farmacologia , Canabinoides/farmacologia , Risperidona/farmacologia , Piperazina/farmacologia , Rimonabanto/farmacologiaRESUMO
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
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
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 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
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.
Assuntos
Anfotericina B , Apoptose , Doença Hepática Induzida por Substâncias e Drogas , Ácido Glicirrízico , Fármacos Neuroprotetores , Animais , Apoptose/efeitos dos fármacos , Camundongos , Ácido Glicirrízico/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Anfotericina B/toxicidade , Masculino , Fígado/efeitos dos fármacos , Fígado/patologia , Rim/efeitos dos fármacos , Rim/patologia , Estresse Oxidativo/efeitos dos fármacos , Piperazinas/farmacologia , Piperazina/farmacologia , Substâncias Protetoras/farmacologiaRESUMO
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
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
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
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
Serotonin reuptake inhibition combined with the action targeting 5-hydroxytryptamine receptor subtypes can serve as a potential target for the development of antidepressant drugs. Herein a series of new aralkyl piperazines and piperidines were designed and synthesized by the structural modifications of the previously discovered aralkyl piperidine compound 1, targeting SSRI/5-HT1A/5-HT7. The results exhibited that compound 5a showed strong binding to 5-HT1A and 5-HT7 (Ki of 0.46 nM, 2.7 nM, respectively) and a high level of serotonin reuptake inhibition (IC50 of 1.9 nM), all of which were significantly elevated compared to 1. In particular, compound 5a showed weaker inhibitory activity against hERG than 1, and demonstrated good stability in liver microsomes in vitro. The preliminary screening using FST indicated that orally administered 5a, at a high dose, could reduce immobility time in mice markedly, indicating potential antidepressant activity.
Assuntos
Inibidores Seletivos de Recaptação de Serotonina , Serotonina , Camundongos , Animais , Piperazina/farmacologia , Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Piperidinas/farmacologia , Piperazinas/química , Receptor 5-HT1A de SerotoninaRESUMO
Chronic kidney disease (CKD) is a type of chronic disease in which multiple factors are responsible for the structural and functional disorders of the kidney. Piperazine ferulate (PF) has anti-platelet and anti-fibrotic effects, and its mechanism of action remains to be elucidated. This study aimed to investigate the protective effect of PF against CKD in rats and to determine its mechanism of action. Network pharmacology was used to predict potential PF action targets in the treatment of CKD and to further validate them. A rat model of CKD was established; blood was collected, etc., for the assessment of the renal function; renal pathologic damage was examined using hematoxylin and eosin (HE) staining and Masson staining; changes in the levels of TGF-ß1 and α-SMA were determined with ELISA; EPOR, FN, and COL I expression were detected utilizing immunohistochemistry; and HIF-1α, HIF-2α, and EPO protein molecules were analyzed deploying western blotting. PF reduces Scr, BUN, and 24 h UP levels; decreases FN and COL I expression; and attenuates renal injury. Additionally, PF inhibited TGF-ß1 and stimulated the production of HIF-1α and HIF-2α, which downregulated α-SMA and upregulated EPO. PF attenuated the progression of the CKD pathology, and the mechanism of its action is possibly associated with the promotion of HIF-1α/HIF-2α/EPO production and TGF-ß1 reduction.
Assuntos
Nefrectomia , Ratos Sprague-Dawley , Insuficiência Renal Crônica , Fator de Crescimento Transformador beta1 , Animais , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/prevenção & controle , Masculino , Fator de Crescimento Transformador beta1/metabolismo , Ratos , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Eritropoetina/farmacologia , Piperazinas/farmacologia , Piperazina/farmacologia , Modelos Animais de Doenças , Ácidos Cumáricos/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismoRESUMO
An innovative series of N-substituted piperazine-linked imidazothiazole derivatives 7(a-x) were synthesized, and their antitubercular effectiveness was evaluated. A three-step reaction sequence involving the condensation of 1,3-dichloroacetone and thiourea, coupling with substituted piperazines to give the intermediates 5(a-d) and cyclization with substituted α-bromoacetophenones produced the desired imidazothiazole derivatives 7(a-x) in excellent yields. In vitro screening of new derivatives against Mycobacterium tuberculosis H37Rv resulted in 7k (minimum inhibitory concentration [MIC]: 0.78 µg/mL) and 7g and 7h (MIC: 1.56 µg/mL) as potent hit compounds. Further, the docking studies of the promising compounds 7k, 7g, and 7h revealed that the best molecular interactions are with the DprE1 in complex with sulfonyl PBTZ of M. tuberculosis as the target protein (PDB ID: 6G83).
Assuntos
Mycobacterium tuberculosis , Piperazina/farmacologia , Piperazinas/farmacologia , Antituberculosos/farmacologia , Tiazóis/farmacologiaRESUMO
The multi-target directed ligand (MTDL) discovery has been gaining immense attention in the development of therapeutics for Alzheimer's disease (AD). The strategy has been evolved as an auspicious approach suitable to combat the heterogeneity and the multifactorial nature of AD. Therefore, multi-targetable chalcone derivatives bearing N-aryl piperazine moiety were designed, synthesized, and evaluated for the treatment of AD. All the synthesized compounds were screened for thein vitro activityagainst acetylcholinesterase (AChE), butylcholinesterase (BuChE), ß-secretase-1 (BACE-1), and inhibition of amyloid ß (Aß) aggregation. Amongst all the tested derivatives, compound 41bearing unsubstituted benzylpiperazine fragment and para-bromo substitution at the chalcone scaffold exhibited balanced inhibitory profile against the selected targets. Compound 41 elicited favourable permeation across the blood-brain barrier in the PAMPA assay. The molecular docking and dynamics simulation studies revealed the binding mode analysis and protein-ligand stability ofthe compound with AChE and BACE-1. Furthermore,itameliorated cognitive dysfunctions and signified memory improvement in thein-vivobehavioural studies (scopolamine-induced amnesia model). Theex vivobiochemical analysis of mice brain homogenates established the reduced AChE and increased ACh levels. The antioxidant activity of compound 41 was accessed with the determination of catalase (CAT) and malondialdehyde (MDA) levels. The findings suggested thatcompound 41, containing a privileged chalcone scaffold, can act as a lead molecule for developing AD therapeutics.