RESUMEN
A series of piperine derivatives were designed and successfully synthesized. The antitumor activities of these compounds against 293 T human normal cells, as well as MDA-MB-231 (breast) and Hela (cervical) cancer cell lines, were assessed through the MTT assay. Notably, compound H7 exhibited moderate activity, displaying reduced toxicity towards non-tumor 293 T cells while potently enhancing the antiproliferative effects in Hela and MDA-MB-231 cells. The IC50 values were determined to be 147.45 ± 6.05 µM, 11.86 ± 0.32 µM, and 10.50 ± 3.74 µM for the respective cell lines. In subsequent mechanistic investigations, compound H7 demonstrated a dose-dependent inhibition of clone formation, migration, and adhesion in Hela cells. At a concentration of 15 µM, its inhibitory effect on Hela cell function surpassed that of both piperine and 5-Fu. Furthermore, compound H7 exhibited promising antitumor activity in vivo, as evidenced by significant inhibition of tumor angiogenesis and reduction in tumor weight in a chicken embryo model. These findings provide a valuable scientific foundation for the development of novel and efficacious antitumor agents, particularly highlighting the potential of compound H7 as a therapeutic candidate for cervical cancer and breast cancer.
Asunto(s)
Alcaloides , Benzodioxoles , Piperidinas , Alcamidas Poliinsaturadas , Humanos , Piperidinas/farmacología , Piperidinas/síntesis química , Piperidinas/química , Benzodioxoles/farmacología , Benzodioxoles/síntesis química , Alcamidas Poliinsaturadas/farmacología , Alcamidas Poliinsaturadas/síntesis química , Alcamidas Poliinsaturadas/química , Alcaloides/farmacología , Alcaloides/síntesis química , Alcaloides/química , Animales , Estructura Molecular , Línea Celular Tumoral , Células HeLa , Embrión de Pollo , Movimiento Celular/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Diseño de Fármacos , Proliferación Celular/efectos de los fármacosRESUMEN
Inhibition of human dihydroorotate dehydrogenase (hDHODH) represents a promising strategy for suppressing the proliferation of cancer cells. To identify novel and potent hDHODH inhibitors, a total of 28 piperine derivatives were designed and synthesized. Their cytotoxicities against three human cancer cell lines (NCI-H226, HCT-116, and MDA-MB-231) and hDHODH inhibitory activities were also evaluated. Among them, compound H19, exhibited the strongest inhibitory activities (NCI-H226 IC50 = 0.95 µM, hDHODH IC50 = 0.21 µM). Further pharmacological investigations revealed that H19 exerted anticancer effects by inducing ferroptosis in NCI-H226 cells, with its cytotoxicity being reversed by ferroptosis inhibitors. This was supported by the intracellular growth or decline of ferroptosis markers, including lipid peroxidation, Fe2+, GSH, and 4-HNE. Overall, H19 emerges as a promising hDHODH inhibitor with potential anticancer properties warranting development.
Asunto(s)
Alcaloides , Antineoplásicos , Benzodioxoles , Proliferación Celular , Dihidroorotato Deshidrogenasa , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos , Ferroptosis , Piperidinas , Alcamidas Poliinsaturadas , Humanos , Alcaloides/farmacología , Alcaloides/química , Alcaloides/síntesis química , Dihidroorotato Deshidrogenasa/antagonistas & inhibidores , Piperidinas/farmacología , Piperidinas/química , Piperidinas/síntesis química , Benzodioxoles/farmacología , Benzodioxoles/síntesis química , Benzodioxoles/química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Relación Estructura-Actividad , Ferroptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Alcamidas Poliinsaturadas/farmacología , Alcamidas Poliinsaturadas/química , Alcamidas Poliinsaturadas/síntesis química , Estructura Molecular , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Línea Celular TumoralRESUMEN
A set of 12 analogues of piperine was designed, replacing the amide functional group of the molecule with different aliphatic and aromatic ester functional groups. Molecular docking studies of these molecules with FDA-approved target proteins for anti-bacterial drugs were done. The binding energy of the proteins and the ligands were low and the analogues were found to be drug-like based on the ADME results; hence, the molecules were synthesized. The synthesized compounds were tested for their anti-bacterial property against six bacterial species via Agar well-diffusion method. Acinetobacter baumannii, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis and Staphylococcus epidermidis were the strains tested. The overall susceptibility is higher in gram-positive. The analogues showed better activity than piperine. The analogues, propyl piperic ester (P3) and 2-fluorophenyl piperic ester (P9) and 4-fluorophenyl piperic ester (P10) showed comparatively bigger inhibition zones for all the strains.
Asunto(s)
Alcaloides/síntesis química , Antibacterianos/síntesis química , Benzodioxoles/síntesis química , Ácidos Grasos Insaturados/síntesis química , Piperidinas/síntesis química , Alcamidas Poliinsaturadas/síntesis química , Alcaloides/farmacología , Antibacterianos/farmacología , Benzodioxoles/farmacología , Ácidos Grasos Insaturados/farmacología , Humanos , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Molecular , Piperidinas/farmacología , Alcamidas Poliinsaturadas/farmacología , Relación Estructura-ActividadRESUMEN
Cancer stem cells (CSCs) are involved in recurrent hepatocellular carcinoma (HCC), yet there is a lack of effective treatment that targets these CSCs. CD44+ and CD133+ CSCs are markedly expressed in HepG2 cells and were isolated and characterized using fluorescence-activated cell sorting (FACS) analysis. Since piperine is known as an effective molecule against metastasis, we thought to investigate the effect of piperine against CD44+/CD133+ CSCs. Herein, piperine was found to be active against these CSCs. Also, it was found appropriate to respite at the 'subG0/G1 and G0/G1' phase of the cell cycle analysis, respectively. TGF-ß activated epithelial-mesenchymal transition (EMT) has been involved in the invasion and metastasis of HepG2 cells in hepatocellular carcinoma. Therefore, we next investigated the effect of piperine on different biomarkers that remarkably takes part in the process of EMT using flow cytometric analysis. Piperine was found able to repress the epithelial marker (E-cadherin) but was unable to restore the level of Vimentin (mesenchymal marker) and SNAIL (EMT-inducing transcription factor). Therefore, the findings of this study revealed that piperine could be an effective treatment strategy for recurrent hepatocarcinogenesis.
Asunto(s)
Alcaloides/farmacología , Antineoplásicos/farmacología , Benzodioxoles/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Piperidinas/farmacología , Alcamidas Poliinsaturadas/farmacología , Alcaloides/síntesis química , Alcaloides/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Benzodioxoles/síntesis química , Benzodioxoles/química , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Simulación de Dinámica Molecular , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Alcamidas Poliinsaturadas/síntesis química , Alcamidas Poliinsaturadas/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Piper species is one of the most widely consumed spices for culinary purposes. Piperine (PIP) present in Piper species has a wide range of therapeutic activity including hepatoprotection. However, the major biological limitation of PIP is its low bioavailability after oral administration. Purpose of the study was to prepare an optimized and adequately characterized PIP-phospholipid complex (PPC) as a delivery system to overcome these limitations and to investigate the pharmacokinetics and hepato-protectivity of the formulation in the animal model. Response surface methodology was adopted to optimize the process parameters for PPC preparation. FT-IR, DTA, PXRD, SEM, molecular docking etc. were used for characterization. Solubility, log P, dissolution efficiency and in vivo pharmacokinetics were also investigated. PPC showed enhanced hepatoprotective potential as compared to pure PIP at the same dose level (25 and 50 mg/kg). PPC restored the levels of serum marker and antioxidant enzymes. PPC also increased the bioavailability of PIP in rat serum by 10.40-fold in comparison with pure PIP at the same dose level and enhanced the elimination half-life (t1/2 el) from 0.477 ± 1.76 to 9.80 ± 1.98 h. Results concluded that PPC enhanced the hepatoprotection of PIP which may be due to the improved bioavailability and pharmacokinetics of PIP in rats.
Asunto(s)
Alcaloides/administración & dosificación , Alcaloides/metabolismo , Benzodioxoles/administración & dosificación , Benzodioxoles/metabolismo , Hígado/metabolismo , Fosfolípidos/administración & dosificación , Fosfolípidos/metabolismo , Piperidinas/administración & dosificación , Piperidinas/metabolismo , Alcamidas Poliinsaturadas/administración & dosificación , Alcamidas Poliinsaturadas/metabolismo , Alcaloides/síntesis química , Animales , Benzodioxoles/síntesis química , Disponibilidad Biológica , Hígado/efectos de los fármacos , Masculino , Simulación del Acoplamiento Molecular/métodos , Fosfolípidos/síntesis química , Piperidinas/síntesis química , Alcamidas Poliinsaturadas/síntesis química , Sustancias Protectoras/administración & dosificación , Sustancias Protectoras/síntesis química , Sustancias Protectoras/metabolismo , Ratas , Ratas WistarRESUMEN
The natural products piperlongumine and piperine have been shown to inhibit cancer cell proliferation through elevation of reactive oxidative species (ROS) and eventually cell death, but only have modest cytotoxic potencies. A series of 14 novel phenylallylidenecyclohexenone analogues based on piperlongumine and piperine therefore were designed and synthesized, and their pharmacological properties were evaluated. Most of the compounds produced antiproliferative activities against five human cancer cells with IC50 values lower than those of piperlongumine and piperine. Among these, compound 9m exerted the most potent antiproliferative activity against drug-resistant Bel-7402/5-FU human liver cancer 5-FU resistant cells (IC50 = 0.8 µM), which was approximately 10-fold lower than piperlongumine (IC50 = 8.4 µM). Further, 9m showed considerably lower cytotoxicity against LO2 human normal liver epithelial cells compared to Bel-7402/5-FU. Mechanistically, compound 9m inhibited thioredoxin reductase (TrxR) activity, increased ROS levels, reduced mitochondrial transmembrane potential (MTP), and induced autophagy in Bel-7402/5-FU cells via regulation of autophagy-related proteins LC3, p62, and beclin-1. Finally, 9m activated significantly the p38 signaling pathways and suppressed the Akt/mTOR signaling pathways. In conclusion, 9m could be a promising candidate for the treatment of drug-resistant cancer cells and, as such, warrants further investigation.
Asunto(s)
Alcaloides/farmacología , Antineoplásicos Fitogénicos/farmacología , Autofagia/efectos de los fármacos , Benzodioxoles/farmacología , Dioxolanos/farmacología , Proteína Oncogénica v-akt/efectos de los fármacos , Piperidinas/farmacología , Alcamidas Poliinsaturadas/farmacología , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/efectos de los fármacos , Tiorredoxina Reductasa 1/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/efectos de los fármacos , Alcaloides/síntesis química , Alcaloides/química , Antimetabolitos Antineoplásicos/farmacología , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/química , Benzodioxoles/síntesis química , Benzodioxoles/química , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Dioxolanos/síntesis química , Dioxolanos/química , Resistencia a Antineoplásicos/efectos de los fármacos , Fluorouracilo/farmacología , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Alcamidas Poliinsaturadas/síntesis química , Alcamidas Poliinsaturadas/química , Especies Reactivas de OxígenoRESUMEN
INTRODUCTION: Peroxisome proliferator-activated receptor γ (PPARγ) plays a key role in glucose, which is a ligand-mediated transcription factor. The lipid homeostasis often serves as a pharmacological target for new drug discovery and development. MATERIALS AND METHODS: In the research, we synthesized a series of piperine derivatives and then used a fluorescence polarization-based PPARγ ligand screening assay to evaluate the agonistic activity of PPARγ. Then, we cultured human normal hepatocytes, which were treated with 100µM compounds 2a, 2t or 3d. Then, the levels of PPARγ gene were determined so as to show whether the compounds could activate or inhibit the expression of PPARγ. RESULTS: A total of 30 piperine derivatives were synthesized and evaluated. Compound 2a was identified as a potential PPARγ agonist with IC50 at 2.43 µM, which is 2 times more potent than the positive control rosiglitazone with IC50 at 5.61µM. The human hepatocytes cells were cultured and treated with compounds 2a, 2t or 3d as described in the "Materials and Methods" section. We found that compounds 2a, 2t and 3d could activate PPARγ by 11.8, 1.9 and 7.0 times compared with the "blank", with compound 2a activation being the most significant. Molecular docking studies indicated that the piperine derivative 2a stably interacts with the amino acid residues of the PPARγ complex active site, which is consistent with the results of the in vitro PPARγ ligand screening assay.
Asunto(s)
Alcaloides/farmacología , Benzodioxoles/farmacología , PPAR gamma/agonistas , Piperidinas/farmacología , Alcamidas Poliinsaturadas/farmacología , Alcaloides/síntesis química , Alcaloides/química , Benzodioxoles/síntesis química , Benzodioxoles/química , Células Cultivadas , Relación Dosis-Respuesta a Droga , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Estructura Molecular , PPAR gamma/genética , PPAR gamma/metabolismo , Piperidinas/síntesis química , Piperidinas/química , Alcamidas Poliinsaturadas/síntesis química , Alcamidas Poliinsaturadas/química , Relación Estructura-ActividadRESUMEN
Parkinson's disease (PD) is a slowly progressive and complex neurodegenerative disorder. Up to date, there are no approved drugs that could slow or reverse the neurodegenerative process of PD. Here, we reported the synthesis of series of piperine analogues and the evaluation of their neuroprotective effects against hydrogen peroxide (H2O2) induced damage in the neuron-like PC12 cells. Among these analogues, 3b exhibited the most potent protection effect and its underlying mechanism was further investigated. Further results indicated that the ROS scavenging and cytoprotection effect of 3b might be related to the Nrf2 activation and upregulation of related phase II antioxidant enzymes, such as HO-1 and NQO1. In in vivo study, oral administration (100 mg/kg) of 3b significantly attenuated PD-associated behavioral deficits in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD and protected tyrosine hydroxylase-immunopositive dopaminergic neurons. Our results provided evidence that 3b might be a promising candidate for Parkinson's disease treatment.
Asunto(s)
Alcaloides/farmacología , Benzodioxoles/farmacología , Proteína 1 Asociada A ECH Tipo Kelch/antagonistas & inhibidores , Factor 2 Relacionado con NF-E2/antagonistas & inhibidores , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Piperidinas/farmacología , Alcamidas Poliinsaturadas/farmacología , Alcaloides/síntesis química , Alcaloides/química , Animales , Apoptosis/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Benzodioxoles/síntesis química , Benzodioxoles/química , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Estructura Molecular , Factor 2 Relacionado con NF-E2/metabolismo , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Células PC12 , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Piperidinas/síntesis química , Piperidinas/química , Alcamidas Poliinsaturadas/síntesis química , Alcamidas Poliinsaturadas/química , Ratas , Relación Estructura-ActividadRESUMEN
Kelch-like ECH-associated protein (Keap1)-nuclear factor erythroid-2-related factor 2 (Nrf2) protein-protein interaction has become an important drug target for the treatment of Alzheimer's disease. In this study, we found a novel piperine derivative (HJ22) synthesized by our group with great ability to bind to Keap-1 and activate Keap1-Nrf2-ARE signaling pathway in vitro, driving us to investigate the beneficial effects of HJ22 on ibotenic acid (IBO)-induced neurological disorders in rats and underlying mechanisms. Interestingly, HJ22 significantly ameliorated IBO-induced cognitive impairment in Morris water maze, Y-maze and passive avoidance tests. Moreover, HJ22 significantly attenuated cholinergic dysfunction and neuronal morphological changes via inhibiting apoptotic cell death induced by IBO. Notably, HJ22 inhibited the interaction between Keap1 and Nrf2, and subsequently up-regulated nuclear Nrf2 expression, thereby inhibiting oxidative stress and Thioredoxin-interacting protein (TXNIP)-mediated Nod-like receptor protein 3 (NLRP3) inflammasome activation. These findings demonstrated that HJ22 exhibited potent therapeutic effects against IBO-induced cognitive impairment by alleviating cholinergic damage, oxidative stress, apoptosis and neuroinflammation, which might be partly attributed to its inhibitory activity on Keap1-Nrf2 protein-protein interaction.
Asunto(s)
Alcaloides , Benzodioxoles , Disfunción Cognitiva , Inflamasomas , Proteína 1 Asociada A ECH Tipo Kelch , Factor 2 Relacionado con NF-E2 , Neuronas , Piperidinas , Alcamidas Poliinsaturadas , Animales , Humanos , Ratas , Alcaloides/síntesis química , Alcaloides/uso terapéutico , Apoptosis , Benzodioxoles/síntesis química , Benzodioxoles/uso terapéutico , Células Cultivadas , Disfunción Cognitiva/tratamiento farmacológico , Modelos Animales de Enfermedad , Ácido Iboténico , Inflamasomas/metabolismo , Inflamación , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Neuronas/fisiología , Estrés Oxidativo , Piperidinas/síntesis química , Piperidinas/uso terapéutico , Alcamidas Poliinsaturadas/síntesis química , Alcamidas Poliinsaturadas/uso terapéutico , Unión Proteica , Dominios y Motivos de Interacción de Proteínas/genética , Ratas Sprague-Dawley , Factor 2 Relacionado con NF-E2/metabolismoRESUMEN
Piperine has been associated with neuroprotective effects and monoamine oxidase (MAO) inhibition, thus being an attractive scaffold to develop new antiparkinsonian agents. Accordingly, we prepared a small library of piperine derivatives and screened the inhibitory activities towards human MAO isoforms (hMAO-A and hMAO-B). Structure-activity relationship (SAR) studies pointed out that the combination of α-cyano and benzyl ester groups increased both potency and selectivity towards hMAO-B. Kinetic experiments with compounds 7, 10 and 15 indicated a competitive hMAO-B inhibition mechanism. Compounds 15 and 16, at 10⯵M, caused a small but significant decrease in P-gp efflux activity in Caco-2â¯cells. Compound 15 stands out as the most potent piperine-based hMAO-B inhibitor (IC50â¯=â¯47.4â¯nM), displaying favourable drug-like properties and a broad safety window. Compound 15 is thus a suitable candidate for lead optimization and the development of multitarget-directed ligands.
Asunto(s)
Alcaloides/farmacología , Benzodioxoles/farmacología , Diseño de Fármacos , Inhibidores de la Monoaminooxidasa/farmacología , Monoaminooxidasa/metabolismo , Fármacos Neuroprotectores/farmacología , Piperidinas/farmacología , Alcamidas Poliinsaturadas/farmacología , Alcaloides/síntesis química , Alcaloides/química , Benzodioxoles/síntesis química , Benzodioxoles/química , Células CACO-2 , Diferenciación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Ligandos , Estructura Molecular , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/química , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Estrés Oxidativo/efectos de los fármacos , Piperidinas/síntesis química , Piperidinas/química , Alcamidas Poliinsaturadas/síntesis química , Alcamidas Poliinsaturadas/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Plants are vital for the wellbeing of humankind in a variety of ways. Some plant extracts contain antimicrobial properties that can treat different pathogens. Most of the world's population relies on medicinal plants and natural products for their primary health care needs. Therefore, there is a growing interest in natural products, medicinal plants, and traditional medicine along with a desire to design and develop novel plant-based pharmaceuticals. These plant-based pharmaceuticals may address the concerns of reduced efficacy of synthetic antibiotics due to the emergence of drug-resistant pathogens. In this regard, some plant extracts from black pepper (Piper nigrum) with antimicrobial properties, including piperine, have the potential to be used as natural dietary supplements together with modern therapeutic approaches. This review highlights possible applications of piperine as the active compound in the fields of rational drug design and discovery, pharmaceutical chemistry, and biomedicine. We discuss different extraction methods and pharmacological effects of the analyzed substance to pave the way for further research strategies and perspectives towards the development of novel herbal products for better healthcare solutions.
Asunto(s)
Alcaloides/farmacología , Benzodioxoles/farmacología , Piper nigrum/química , Piperidinas/farmacología , Alcamidas Poliinsaturadas/farmacología , Alcaloides/análisis , Alcaloides/síntesis química , Alcaloides/aislamiento & purificación , Animales , Benzodioxoles/análisis , Benzodioxoles/síntesis química , Benzodioxoles/aislamiento & purificación , Línea Celular Tumoral , Humanos , Piperidinas/análisis , Piperidinas/síntesis química , Piperidinas/aislamiento & purificación , Alcamidas Poliinsaturadas/análisis , Alcamidas Poliinsaturadas/síntesis química , Alcamidas Poliinsaturadas/aislamiento & purificaciónRESUMEN
In continuation of our program to discover new potential pesticidal agents, thirty-one piperine analogs containing isoxazoline/pyrazoline scaffold were prepared, and confirmed by infrared spectra, proton/carbon-13 nuclear magnetic resonance spectra, and high-resolution mass spectra. The structures of compounds VIIb and VIIIc were further determined by 1H-1H COSY spectra. Especially the configuration of compound VIIIc was unambiguously confirmed by single-crystal X-ray diffraction. Their pesticidal activities were evaluated against three serious and typically crop-threatening agricultural pests, Tetranychus cinnabarinus Boisduval (spider mite), Mythimna separata Walker (Oriental armyworm), and Plutella xylostella Linnaeus (diamondback moth). Compounds VIIIb and VIIIc exhibited greater than 40-fold more potent acaricidal activity than the lead compound piperine against T. cinnabarinus. Notably, compounds VIa-c exhibited more pronounced oral toxicity against P. xylostella than toosendanin; compounds VIb and VIc displayed more promising growth inhibitory activity against M. separata than toosendanin. It demonstrated that the methylenedioxy and isoxazoline scaffolds were important for the oral toxicity and growth inhibitory activity against P. xylostella and M. separata, respectively; the ethylenedioxy and isoxazoline scaffolds were vital for the acaricidal activity against T. cinnabarinus. Moreover, compounds VIb, VIIf, and VIIIc showed very low toxicity against NRK-52E cells.
Asunto(s)
Alcaloides/química , Benzodioxoles/química , Isoxazoles/química , Plaguicidas/química , Piperidinas/química , Alcamidas Poliinsaturadas/química , Pirazoles/química , Alcaloides/síntesis química , Animales , Benzodioxoles/síntesis química , Línea Celular , Lepidópteros , Estructura Molecular , Plaguicidas/síntesis química , Piperidinas/síntesis química , Alcamidas Poliinsaturadas/síntesis química , Ratas , Tetranychidae , Pruebas de ToxicidadRESUMEN
Piperine amide analogs are synthesized by replacement of the piperidine moiety with different types of cyclic amines, including adamantyl and monoterpene-derived fragments. The compounds are screened for activity against Mycobacterium tuberculosis H37Rv. The most potent compounds are the 1-adamantyl and the monoterpene-derived hybrids, which combine nanomolar antimycobacterial activity with low cytotoxicity against human cells. The presence of quaternary carbon atom as main structural requirement for anti-TB activity is pointed out by a QSAR study. The most promising compound is the (+)-isopinocampheylamine-derived amide which is characterized with selectivity index of 1387.8.
Asunto(s)
Alcaloides , Antituberculosos , Benzodioxoles , Mycobacterium tuberculosis/crecimiento & desarrollo , Piperidinas , Alcamidas Poliinsaturadas , Alcaloides/síntesis química , Alcaloides/química , Alcaloides/farmacología , Antituberculosos/síntesis química , Antituberculosos/química , Antituberculosos/farmacología , Benzodioxoles/síntesis química , Benzodioxoles/química , Benzodioxoles/farmacología , Piperidinas/síntesis química , Piperidinas/química , Piperidinas/farmacología , Alcamidas Poliinsaturadas/síntesis química , Alcamidas Poliinsaturadas/química , Alcamidas Poliinsaturadas/farmacologíaRESUMEN
NO donor drugs showed a significant therapeutic effect in the treatment of many diseases, such as arteriopathies, various acute and chronic inflammatory conditions, and several degenerative diseases. NO-releasing anti-inflammatory drugs are the prototypes of a novel class of compounds, combining the pharmacological activities of anti-inflammatory and anti-nociceptive of drugs with those of NO, thus possessing potential therapeutic applications in a great variety of diseases. In this study, we designed and predicted biological activity by targeting cyclooxygenase type 2 (COX-2) and NF-κB subunits and pharmacological profiling along with toxicity predictions of various N-aryl piperamides linked via an ester bond to a spacer that is bound to a NO-releasing moiety (-ONO2). The result of absorption, distribution, metabolism and excretion and Docking studies indicated that among 51 designed molecules PA-3'K showed the best binding potential in both the substrate and inhibitory binding pocket of the COX-2 enzyme with affinity values of -9.33 and -5.12 for PDB ID 1CVU and 3LN1, respectively, thereby having the potential to be developed as a therapeutic agent. The results of cell viabilities indicated that PA-3'k possesses the best cell viability property with respect to its dose (17.33 ng/ml), with 67.76% and 67.93% viable cells for CHME3 and SVG cell lines, respectively.
Asunto(s)
Alcaloides/farmacología , Benzodioxoles/farmacología , FN-kappa B/metabolismo , Neuritis/metabolismo , Donantes de Óxido Nítrico/farmacología , Piperidinas/farmacología , Alcamidas Poliinsaturadas/farmacología , Transporte de Proteínas/efectos de los fármacos , Alcaloides/síntesis química , Alcaloides/farmacocinética , Animales , Benzodioxoles/síntesis química , Benzodioxoles/farmacocinética , Disponibilidad Biológica , Línea Celular , Simulación por Computador , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/farmacocinética , Inhibidores de la Ciclooxigenasa 2/farmacología , Diseño de Fármacos , Humanos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Piperidinas/síntesis química , Piperidinas/farmacocinética , Alcamidas Poliinsaturadas/síntesis química , Alcamidas Poliinsaturadas/farmacocinética , Relación Estructura-Actividad , Distribución TisularRESUMEN
BACKGROUND: Serious side effects such as gastric intestinal ulcer, bleeding etc. are associated with most of the antiinflammatory and analgesic drugs. So, there is a need to search novel, potent, and safer antiinflammatory and analgesic drug. METHOD: Based on "biology-oriented synthesis approach", piperine alkaloid was isolated from Piper nigrum L. and some derivatives of piperine having azomethine, sulfamoyl, propanoyl, acetamoyl and heterocyclic oxadiazole were synthesized. The structures of synthetic derivatives were confirmed by using different spectroscopic techniques such as 1H-, 13C-NMR, EI-MS, and IR. Melting points were also determined for all compounds. Piperine and its all the synthetic derivatives were subjected to comparative in vivo evaluation of analgesic and antiinflammatory activities at the oral dose of 6 mg/kg/day. Analgesic activity was evaluated by tail immersion, hot plate and acetic acid writhing methods. While, antiinflammatory activity was evaluated by carrageenan-induced paw inflammation. In silico studies of all synthetic compounds was also conducted on COX-2 and adenosine kinase enzymes. RESULTS: A number of derivatives showed enhanced antiinflammatory and analgesic activities as compared to piperine and standard drug diclofenac. CONCLUSION: The newly identified molecules may serve as lead for the future research in connection of potent and safer antiinflammatory and analgesic drug candidate.
Asunto(s)
Alcaloides/farmacología , Analgésicos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Benzodioxoles/farmacología , Piperidinas/farmacología , Alcamidas Poliinsaturadas/farmacología , Adenosina Quinasa/antagonistas & inhibidores , Alcaloides/síntesis química , Alcaloides/química , Alcaloides/aislamiento & purificación , Analgésicos/síntesis química , Analgésicos/química , Analgésicos/aislamiento & purificación , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/aislamiento & purificación , Benzodioxoles/síntesis química , Benzodioxoles/química , Benzodioxoles/aislamiento & purificación , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/aislamiento & purificación , Inhibidores de la Ciclooxigenasa 2/farmacología , Femenino , Humanos , Masculino , Ratones , Simulación del Acoplamiento Molecular , Piper nigrum , Piperidinas/síntesis química , Piperidinas/química , Piperidinas/aislamiento & purificación , Alcamidas Poliinsaturadas/síntesis química , Alcamidas Poliinsaturadas/química , Alcamidas Poliinsaturadas/aislamiento & purificaciónRESUMEN
Endoplasmic reticulum (ER) is the key organelle involved in protein folding and maturation. Emerging studies implicate the role of ER stress in the development of chronic kidney disease. Thus, there is an urgent need for compounds that could ameliorate ER stress and prevent CKD. Piperine and its analogs have been reported to exhibit multiple pharmacological activities; however, their efficacy against ER stress in kidney cells has not been studied yet. Hence, the goal of this study was to synthesize amide-substituted piperine analogs and screen them for pharmacological activity to relieve ER stress using an in vitro model of tunicamycin-induced ER stress using normal rat kidney (NRK-52E) cells. Five amide-substituted piperine analogs were synthesized and their chemical structures were elucidated by pertinent spectroscopic techniques. An in vitro model of ER stress was developed using tunicamycin, and the compounds of interest were screened for their effect on cell viability, and the expression of ER chaperone GRP78, the pro-apoptotic ER stress marker CHOP, and apoptotic caspases 3 and 12 (via western blotting). Our findings indicate that exposure to tunicamycin (0.5 µg/mL) for 2 h induces the expression of GRP78 and CHOP, and apoptotic markers (caspase-3 and caspase-12) and causes a significant reduction in renal cell viability. Pre-treatment of cells with piperine and its cyclohexylamino analog decreased the tunicamycin-induced upregulation of GRP78 and CHOP and cell death. Taken together, our findings demonstrate that piperine and its analogs differentially regulate ER stress, and thus represent potential therapeutic agents to treat ER stress-related renal disorders. Graphical Abstract Piperine (PIP) reduces the expression of ER stress markers (GRP78 and CHOP) induced by pathologic stimuli and consequently decreases the activation of apoptotic caspase-12 and caspase-3; all of which contributes to its chemical chaperone and cytoprotective properties to protect renal cells against ER stress and ER stress-induced cell death, and would ultimately prevent the development of chronic kidney disease.
Asunto(s)
Alcaloides/farmacología , Amidas/química , Benzodioxoles/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Piperidinas/farmacología , Alcamidas Poliinsaturadas/farmacología , Alcaloides/síntesis química , Alcaloides/química , Amidas/síntesis química , Animales , Apoptosis/efectos de los fármacos , Benzodioxoles/síntesis química , Benzodioxoles/química , Caspasa 12/metabolismo , Caspasa 3/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Chaperón BiP del Retículo Endoplásmico , Ácidos Grasos Insaturados/síntesis química , Ácidos Grasos Insaturados/química , Ácidos Grasos Insaturados/farmacología , Proteínas de Choque Térmico/metabolismo , Piperidinas/síntesis química , Piperidinas/química , Alcamidas Poliinsaturadas/síntesis química , Alcamidas Poliinsaturadas/química , Ratas , Relación Estructura-Actividad , Factor de Transcripción CHOP/metabolismo , Tunicamicina/farmacología , Regulación hacia Arriba/efectos de los fármacosAsunto(s)
Alanina/química , Alcaloides/farmacología , Benzodioxoles/farmacología , Proteínas Inhibidoras de la Apoptosis/química , Neoplasias/tratamiento farmacológico , Piperidinas/farmacología , Alcamidas Poliinsaturadas/farmacología , Alcaloides/síntesis química , Alcaloides/química , Benzodioxoles/síntesis química , Benzodioxoles/química , Humanos , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Neoplasias/patología , Piperidinas/síntesis química , Piperidinas/química , Alcamidas Poliinsaturadas/síntesis química , Alcamidas Poliinsaturadas/química , Unión Proteica , Survivin , Interfaz Usuario-ComputadorRESUMEN
Twelve methylenedioxy-containing compounds including piperine and 10 piperine-like synthetic compounds were assessed to determine their antifungal and antiaflatoxigenic activities against Aspergillus flavus ATCC 22546 in terms of their structure-activity relationships. Piperonal and 1,3-benzodioxole had inhibitory effects against A. flavus mycelial growth and aflatoxin B1 production up to a concentration of 1000 µg/mL. Ten piperine-like synthetic compounds were synthesized that differed in terms of the carbon length in the hydrocarbon backbone and the presence of the methylenedioxy moiety. In particular, 1-(2-methylpiperidin-1-yl)-3-phenylprop-2-en-1-one had potent antifungal and antiaflatoxigenic effects against A. flavus up to a concentration of 1 µg/mL. This synthetic compound was remarkable because the positive control thiabendazole had no inhibitory effect at this concentration. Reverse transcription-PCR analysis showed that five genes involved in aflatoxin biosynthesis pathways were down-regulated in A. flavus, i.e., aflD, aflK, aflQ, aflR, and aflS; therefore, the synthetic compound inhibited aflatoxin production by down-regulating these genes.
Asunto(s)
Aflatoxina B1/biosíntesis , Alcaloides/farmacología , Aspergillus flavus/efectos de los fármacos , Benzodioxoles/farmacología , Fungicidas Industriales/farmacología , Piperidinas/farmacología , Alcamidas Poliinsaturadas/farmacología , Alcaloides/síntesis química , Aspergillus flavus/genética , Aspergillus flavus/crecimiento & desarrollo , Aspergillus flavus/metabolismo , Benzodioxoles/síntesis química , Relación Dosis-Respuesta a Droga , Fungicidas Industriales/síntesis química , Regulación Fúngica de la Expresión Génica/efectos de los fármacos , Estructura Molecular , Piperidinas/síntesis química , Alcamidas Poliinsaturadas/síntesis química , Relación Estructura-ActividadRESUMEN
The combination of antiestrogens and histone deacetylase inhibitors (HDACi) has been found to be antiproliferative in breast cancer models. We designed and synthesized hybrid structures which combined structural features of the pure antiestrogen ICI-164,384 and HDACi's SAHA and entinostat in a single bifunctional molecule. The hybrids retained antiestrogenic and HDACi activity and, in the case of benzamide hybrids, were selective for Class I HDAC3 over Class II HDAC6. The hybrids possessed low micromolar to high nanomolar activity against both ER+ MCF-7 and ER- MDA-MB-231 breast cancer cell models.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Moduladores de los Receptores de Estrógeno/química , Moduladores de los Receptores de Estrógeno/farmacología , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Antineoplásicos/síntesis química , Benzamidas/síntesis química , Benzamidas/química , Benzamidas/farmacología , Mama/efectos de los fármacos , Mama/metabolismo , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Estradiol/análogos & derivados , Estradiol/síntesis química , Estradiol/química , Estradiol/farmacología , Moduladores de los Receptores de Estrógeno/síntesis química , Femenino , Inhibidores de Histona Desacetilasas/síntesis química , Histona Desacetilasas/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Alcamidas Poliinsaturadas/síntesis química , Alcamidas Poliinsaturadas/química , Alcamidas Poliinsaturadas/farmacología , Piridinas/síntesis química , Piridinas/química , Piridinas/farmacologíaRESUMEN
By structural modification of piperine, some piperine-based phenylsulfonylhydrazone derivatives exhibited an unprecedented and potent narcotic activity against the oriental armyworm, Mythimna separata (Walker). The ND50 values of compounds 6c and 6e against the third-instar larvae of M. separata, which were more potent than those of wilfortrine and wilforgine, were 0.0074 µmol (after 3.5 h), and 0.0075 µmol (after 7 h) per larvae, respectively. By transmission electron microscope, it demonstrated that mitochondria were vacuolated and swollen in the ganglion cell of M. separata after treatment with 6c. More importantly, 6c selectively displayed the inhibition activity on acetylcholine esterase (AchE) of M. separata. This work paved the way for further studying the insecticidal mechanism of 6c as a new and promising botanical narcotic agent.