Curcumin Pyrazole Research Articles

Bis-Mannich Base derivatives of Curcumin Pyrazole: Synthesis and its Anti-inflammatory Study In-vitro and In-Silico

A series of bis-Mannich base derivatives of curcumin pyrazole (CP) have been synthesized and investigated for the potential of its anti-inflammatory activity in-vitro and in-silico. The synthesis was performed by aminomethylation of CP obtained from the cyclization of the 1,3-diketone chain of curcumin with hydrazine hydrate. The potential as an anti-inflammatory was accessed by the protein denaturation inhibition technique, and an in-silico study was performed against cyclooxygenase-1 and cyclooxygenase-2 via molecular docking. All the compounds showed better protein denaturation inhibitory activity than diclofenac sodium, curcumin, and CP used as standard and comparable compounds. Compound 2a exhibited the best active compound. The docking study found that the binding energy to COX-2 of all the compounds was lower than that of COX-1. The selectivity score (S) indicated that the compounds were very selective against COX-2. So, all the compounds possess high potential as anti-inflammatory agents, and further study is necessary to identify these compounds' safety and activity in- vivo.

An Efficient Synthesis of Curcumin Pyrazole Analogues and their Biological Activities

An Efficient Synthesis of Curcumin Pyrazole Analogues and their Biological Activities

Curcumin-Triterpene Type Hybrid as Effective Sonosensitizers for Sonodynamic Therapy in Oral Squamous Cell Carcinoma.

Sonodynamic therapy (SDT) is a non-invasive therapeutic modality in cancer treatment that combines low-intensity ultrasound (US) and sonosensitizers. Tumor cells are destroyed through the synergistic effects of ultrasound and a chemical sonosensitizer. This study focused on the synthesis and in vitro evaluation of the sonodynamic effect of natural curcumin, triterpene oleanolic acid, and their semi-synthetic derivatives on tongue cancer SCC-25 and hypopharyngeal FaDu cell lines. The combination of the tested compounds with sonication showed a synergistic increase in cytotoxicity. In the group of oleanolic acid derivatives, oleanoyl hydrogen succinate (6) showed the strongest cytotoxic effect both in the SCC-25 and FaDu cell lines. Comparing curcumin (4) and its pyrazole derivative (5), curcumin showed a better cytotoxic effect on SCC-25 cells, while curcumin pyrazole was more potent on FaDu cells. The highest sonotherapeutic activity, compared to its individual components, was demonstrated by a structural linker mode hybrid containing both curcumin pyrazole-oleanoyl hydrogen succinate units within one complex molecule (7). This study can be beneficial in the context of new perspectives in the search for effective sonosensitizers among derivatives of natural organic compounds.

Improved bioactivities of curcumin pyrazole and its HP$$\beta$$CD inclusion complex compared to curcumin

Improved bioactivities of curcumin pyrazole and its HP$$\beta$$CD inclusion complex compared to curcumin

Pyrazole-Curcumin Suppresses Cardiomyocyte Hypertrophy by Disrupting the CDK9/CyclinT1 Complex.

The intrinsic histone acetyltransferase (HAT), p300, has an important role in the development and progression of heart failure. Curcumin (CUR), a natural p300-specific HAT inhibitor, suppresses hypertrophic responses and prevents deterioration of left-ventricular systolic function in heart-failure models. However, few structure–activity relationship studies on cardiomyocyte hypertrophy using CUR have been conducted. To evaluate if prenylated pyrazolo curcumin (PPC) and curcumin pyrazole (PyrC) can suppress cardiomyocyte hypertrophy, cultured cardiomyocytes were treated with CUR, PPC, or PyrC and then stimulated with phenylephrine (PE). PE-induced cardiomyocyte hypertrophy was inhibited by PyrC but not PPC at a lower concentration than CUR. Western blotting showed that PyrC suppressed PE-induced histone acetylation. However, an in vitro HAT assay showed that PyrC did not directly inhibit p300-HAT activity. As Cdk9 phosphorylates both RNA polymerase II and p300 and increases p300-HAT activity, the effects of CUR and PyrC on the kinase activity of Cdk9 were examined. Phosphorylation of p300 by Cdk9 was suppressed by PyrC. Immunoprecipitation-WB showed that PyrC inhibits Cdk9 binding to CyclinT1 in cultured cardiomyocytes. PyrC may prevent cardiomyocyte hypertrophic responses by indirectly suppressing both p300-HAT activity and RNA polymerase II transcription elongation activity via inhibition of Cdk9 kinase activity.

Synthesis and cytotoxicity of nitrogen‐containing curcuminoids against cancer cell lines

AbstractIn a previous study, we performed the structural modification of the curcumin skeleton by varying substituents in phenyl rings. In continuation of that work, we now focus on the synthesis of nitrogen‐containing curcuminoids by a pyrazole cyclization between the free β‐diketone curcuminoids bearing ‐OCH3/‐OH/‐F substituents in aromatic rings and phenyl hydrazine hydrochloride. Seven N‐phenyl pyrazole curcuminoids (1a‐7a) were synthesized in yields of 39‐73 % and derivative (7a) was reported for the first time. Synthesized compounds were evaluated for their cytotoxicities against HepG2, LU‐1 and KB cancer cell lines. Compared to the pristine compound, i.e., curcumin, compound (1a) demonstrated better inhibitory activities toward three cell lines. Derivative (2a) exhibited higher anti‐cancer capacity against HepG2 and LU‐1 than curcumin. Analogues (4a‐7a) bearing pyrazole ring and ‐OCH3/‐F groups in aromatic rings displayed low/inactive anti‐cancer activities. In addition, compared to pyrazole curcumin (PC), derivative (1a) containing N‐phenyl substituent displayed lower cytotoxicities toward HepG2 and KB cell lines.

Solvent dependent photophysical study of stable and medicinally active diketone modified pyrazole derivatives of curcumin: A spectroscopic study

Curcumin pyrazole derivatives have already been extensively studied as potent drugs in various biological fields but the information about their fundamental physical parameters is still somewhat limited. Therefore, the study of the photophysical behaviour of pyrazole derivatives of curcumin in various solvents is a very interesting and an important research area that necessarily needs to be explored in order to understand its biological efficacy. Herein, the photophysics of stable and pharmaceutically active curcumin pyrazole derivative (CPD) and curcumin phenyl pyrazole derivative (CPPD) has been studied in various solvent environments. For the investigation of photophysical properties, various spectroscopic techniques have been utilized. Steady state spectroscopic results have revealed that the excited state of both the derivatives is largely affected by changing the polarity of the medium. The molar extinction coefficient (ε) for CPD and CPPD has also been determined in various solvents. From the measurement of Stokes shift values for wide range of solvents, it could be concluded that there is difference in the dipole moment of the excited state and the ground state of both the molecules. The Stokes shift values for both the derivatives were found to be correlated linearly with the normalized molar transition energy (ETN) of solvents with exceptions in case of polar protic solvents. This indicates that H- bonding might play a major role in the solution phase. The difference in the dipole moment of ground state and excited state of CPD and CPPD were calculated as around 5.23 D and 5.41 D. Further, using multiple regression analysis, the solute -solvent interactions were characterized as specific and non-specific. The low quantum yields obtained in polar protic solvents revealed that the positive solvatokinetic effect could take place in these solvents. The results of TCSPC study showed that the process of deactivation of the excited state of these derivatives is very slow in the presence of acetonitrile, DCM and non-polar solvents. A very fast decay of excited state of both the derivatives has been observed in the case of polar protic solvents. This could be due to the presence of strong H-bonding between the derivatives and these solvents which could result in the deactivation of excited states via non-radiative pathway.

In Silico Analysis and Comparative Molecular Docking Study of FDA Approved Drugs with Transforming Growth Factor Beta Receptors in Oral Submucous Fibrosis.

Oral sub-mucous fibrosis (OSMF) is a severe crippling malignant disorder which affects the oral mucosa. The transforming growth factor beta (TGF-β) is one of the cytokines involved with the cell proliferation, cell growth and apoptosis. Several traditional and synthetic medications have been tried in OSMF. This study attempts to identify the FDA approved drugs (including both synthetic and herbal medications) with least side effects, highest efficacy and robust dynamic mechanism for the treatment of OSMF. A ligand library comprising of FDA approved drug compounds was prepared using ChEMBL database. Molecular docking was carried out using GOLD suite 5.2.2. The docked complexes which had the highest binding affinities and lowest energy were deployed to a molecular dynamic simulation using MDweb server. Further, SwissADME was used to study ADME, physicochemistry, drug-likeness, pharmacokinetics and medicinal chemistry friendliness properties. Our docking results suggest that ligands-Curcumin, Curcumin Pyrazole and Demethoxycurcumin, which are all herbal in nature, have a better binding affinity and the best docking scores for both TGF-β type Iand TGF-β type II receptors. The molecular dynamics study discerns that the structures have become more stable with less energy. The pharmacokinetics and pharmacodynamics analysis, physicochemical properties and toxicity prediction suggest that Curcumin is the optimal lead compound and holds the potential to be used as an effective drug for the treatment of OSMF. Curcumin, a FDA approved herbal compound, can be used as an effective drug for the treatment of OSMF.

Synthesis, Characterization and Luminescence Properties of Pr3+, Nd3+, Eu3+ and Gd3+ Complexes with Curcumin Pyrazole

A series of new lanthanide complexes [LnCl 3 . xH 2 O:(L) 3 ] (where; L = curcumin pyrazole and Ln = Pr 3+ , Nd 3+ , Eu 3+ and Gd 3+ have been synthesized in ethanol under reflux conditions for 24 h. The synthesized complexes were characterised by elemental analysis, IR, UV-Vis, fluorescence and TGA. The formations of the nona-coordinated lanthanide complexes have been detected through elemental analysis. In IR-spectra, the formation of the new band at 460 cm -1 could convey the mode of co-ordination of nitrogen atom to the lanthanide. Absorption intensity as well as luminescence properties of the synthesised complexes were analysed through UV-Vis and fluorescence spectra to reveal the formation of complexes. The percentage weight loss of the complexes was studied with TGA analysis to check the thermal stability of the complexes. Further the quantum yields of the ligand and lanthanide complexes have been analyzed to study their comparative luminescence properties.

Study of the complexation of structurally modified curcumin with hydroxypropyl beta cyclodextrin and its effect on anticancer activity

This study aims at modifying curcumin to curcumin pyrazole and complexing it with HPβCD employing a simple protocol to improve curcumin's chemical–physical properties and biological activities.

Activation of anti-oxidant of curcumin pyrazole derivatives through preservation of mitochondria function and Nrf2 signaling pathway

Oxidative stress is an important cause of neurodegenerative diseases. Antioxidant is an potential important method to treat such diseases. The aim of this study is to discover new and effective antioxidants and their mechanism. The neuroprotective effect of six curcumin pyrozole compounds were first evaluated on sodium nitroprusside (SNP) - induced PC12 cell injury by testing cell viability and LDH release. The results showed that four compounds (C1-C4) have more significant protective effects compared to curcumin and edaravone. Furthermore, compounds C1-C4 can attenuate the intracellular ROS, and compound C3 is the most effective one which can preservate the mitochondria function by inhibiting the mitochondrial membrane potential loss and enhance nuclear translocation of Nrf2 in PC12 cell. These results indicated that C3 may be a potential candidate drug for treating neurodegenerative diseases.

Recent Updates in Curcumin Pyrazole and Isoxazole Derivatives: Synthesis and Biological Application.

Curcumin is an admired, plant-derived compound that has been extensively investigated for diverse range of biological activities, but the use of this polyphenol is limited due to its instability. Chemical modifications in curcumin are reported to seize this limitation; such efforts are intensively performed to discover molecules with similar but improved stability and better properties. Focal points of these reviews are synthesis of stable pyrazole and isoxazole analogs of curcumin and application in various biological systems. This review aims to emphasize the latest evidence of curcumin pyrazole analogs as a privileged scaffold in medicinal chemistry. Manifold features of curcumin pyrazole analogs will be summarized herein, including the synthesis of novel curcumin pyrazole analogs and the evaluation of their biological properties. This review is expected to be a complete, trustworthy and critical review of the curcumin pyrazole analogs template to the medicinal chemistry community.

Diketo modification of curcumin affects its interaction with human serum albumin

Curcumin isoxazole (CI) and Curcumin pyrazole (CP), the diketo modified derivatives of Curcumin (CU) are metabolically more stable and are being explored for pharmacological properties. One of the requirements in such activities is their interaction with circulatory proteins like human serum albumin (HSA). To understand this, the interactions of CI and CP with HSA have been investigated employing absorption and fluorescence spectroscopy and the results are compared with that of CU. The respective binding constants of CP, CI and CU with HSA were estimated to be 9.3×105, 8.4×105 and 2.5×105M−1, which decreased with increasing salt concentration in the medium. The extent of decrease in the binding constant was the highest in CP followed by CI and CU. This revealed that along with hydrophobic interaction other binding modes like electrostatic interactions operate between CP/CI/CU with HSA. Fluorescence quenching studies of HSA with these compounds suggested that both static and dynamic quenching mechanisms operate, where the contribution of static quenching is higher for CP and CI than that for CU. From fluorescence resonance energy transfer studies, the binding site of CU, CI and CP was found to be in domain IIA of HSA. CU was found to bind in closer proximity with Trp214 as compared to CI and CP and the same was responsible for efficient energy transfer and the same was also established by fluorescence anisotropy measurements. Furthermore docking simulation complemented the experimental observation, where both electrostatic as well as hydrophobic interactions were indicated between HSA and CP, CI and CU. This study is useful in designing more stable CU derivatives having suitable binding properties with proteins like HSA.

Biological evaluation of novel curcumin-pyrazole-mannich derivative active against drug-resistant Mycobacterium tuberculosis.

Our objective was to identify a more potent curcumin derivative with specific activity against Mycobacterium tuberculosis. A total of21 curcumin derivatives were synthesized and detailed bio-evaluation was carried out including determination of static/cidality, synergy with front-line antituberculosis drugs and determination of efficacy in the murine model of M. tuberculosis infection. We identified CPMD-6d dihydrochloride exhibiting concentration-dependent bactericidal activity against M. tuberculosis (MIC 2μg/ml), even against drug-resistant strains. In addition, it synergizes with front-line antituberculosis drugs as well as significantly reduces bacterial load in mice lungs and spleen at 25mg/kg as compared with ethambutol at 100mg/kg. Taken together, CPMD-6d dihydrochloride exhibits all properties to be positioned as a novel molecule of interest for treatment of tuberculosis. Graphical abstract: [Formula: see text].

Evaluation of Antioxidant, Anti-Inflammatory, Antibacterial Activity and In Silico Molecular Docking Study of Pyrazole Curcumin Bisacetamide Analogs

A series of pyrazole curcumin bisacetamides (4 a-l) were synthesized with excellent yield and in vitro antioxidant, anti-inflammatory and antibacterial activities were studied. These compounds have shown marvelous antioxidant and anti-inflammatory activities towards curcumin and standard drug. The compounds 4 d, 4 j, 4 l, have shown better antibacterial activity than ciprofloxacin and parent curcumin in both gram-positive and gram-negative bacterias. The compounds 4 j, 4 k, and 4 l have exhibited very good activity on methicillin-resistant staphylococcus aureus when compared to standard oxacillin and parent curcumin. Further, the molecular docking studies revealed that the compounds 4 d and 4 l have shown better binding interaction with penicillin binding protein via five hydrogen bond interactions.

2-[(2,6-Dimethylmorpholin-4-yl)methyl]-4-[(E)-2-{3-[(E)-2-{3-[(2,6-dimethylmorpholin-4-yl)methyl]-4-hydroxy-5-methoxyphenyl}ethenyl]-1H-pyrazol-5-yl}ethenyl]-6-methoxyphenol

A novel di-Mannich derivative of curcumin pyrazole, 2-[(2,6-dimethyl morpholin-4-yl)methyl]-4-[(E)-2-{3-[(E)-2-{3-[(2,6-dimethylmorpholin-4-yl)methyl]-4-hydroxy-5-methoxyphenyl}ethenyl]-1H-pyrazol-5-yl}ethenyl]-6-methoxyphenol (2), has been synthesized through a Mannich reaction of curcumin pyrazole (1), formaldehyde, and 2,6-dimethylmorpholine. The structure of the synthesized compound was confirmed on the basis of FTIR, 1H-NMR, 13C-NMR, 2D Heteronuclear Single-Quantum Correlation (HSQC) and 2D Heteronuclear Multiple Bond Correlation (HMBC), and mass spectral data. The water solubility was evaluated and the result showed that compound 2 was three times more soluble than that of curcumin pyrazole (1) and curcumin.

Synthesis of a Water‐Soluble Pyrazole Curcumin Derivative: In Vitro and In Vivo AGE Inhibitory Activity and Its Mechanism

AbstractThe new chemical entity, water‐soluble pyrazole curcumin derivative (PyCurOAc) was designed, synthesized and characterized for the purpose of inhibition of AGE formation. The compound showed an excellent in vitro AGEs inhibition activity than curcumin itself as well as the standard. Further, the AGE inhibition activity was substantiated in vivo using C.elegans as an animal model. The mechanistic investigation for the inhibition of AGEs with PyCurOAc was studied with glod‐4 expressions in C.elegans and glucose trapping method. This study suggests that the synthesized compound could be used to treat the formation of AGEs in hyperglycemic nematodes and higher animals.

Curcumin pyrazole blocks lipopolysaccharide-induced inflammation via suppression of JNK activation in RAW 264.7 macrophages.

Targeting inflammatory macrophages and their products is an effective method for controlling inflammation. The pyrazole analog of curcumin (curcumin pyrazole, PYR) has been reported to possess superior anti-inflammatory activity to curcumin (CUR). However, the role of PYR anti-inflammatory activity in macrophages has not yet been elucidated. To examine the anti-inflammatory effects of PYR and CUR in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages and determine the role of mitogen-activated protein kinases (MAPK) in their activity. Nitrite level was investigated by the Griess assay. The expression of inducible nitric oxide (NO) synthase, cyclooxygenase-2 (COX-2), and MAPK proteins were analyzed by western blot analysis. The pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay. LPS-induced NO secretion in RAW 264.7 macrophages was potently inhibited by PYR (IC50 = 3.7 ± 0.16 μM), at a higher efficacy than CUR (IC50 = 11.0 ± 0.59 μM). Treatment with identical concentrations of PYR and CUR demonstrated that PYR drastically inhibited iNOS and COX-2 expression, whereas CUR only blocked COX-2. PYR reduced the LPS-induced secretion of TNF-α to a greater extent than CUR and both similarly reduced IL-1β and IL-6 levels. Activation of c-Jun N-terminal kinase (JNK) MAPK was significantly decreased in LPS-activated RAW 264.7 macrophages upon PYR but not CUR treatment. PYR exhibited a more potent anti-inflammatory activity than CUR. This activity is partly mediated by PYR-depended inhibition of the JNK signaling pathway and underscores the utility of PYR as an anti-inflammatory agent in macrophages.

Synthesis and antiproliferative studies of curcumin pyrazole derivatives

A series of curcumin pyrazole derivatives (3a–e) were synthesized. The chemical structures were determined by 1H and 13C NMR spectroscopic techniques and their purity was confirmed by LC–MS and melting point determination. The compounds were screened for anticancer effects on different cancer cell lines by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay. The analogs demonstrated growth inhibitory effect on MCF-7, HeLa, and K562 cell lines with significant IC50 values. Compound 3b exhibited a high degree of cytotoxicity against cancer cells and minimum growth inhibitory effects against normal cells HEK293T and hence further, cell cycle analysis and mitochondrial membrane potential studies (JC-1 assay) were conducted by utilizing flow cytometry against K562 cells. This compound effectively arrested cell cycle progression at SubG1 phase and cells exhibited decreased membrane potential in a concentration-dependent manner with fluorescence shifting from red to green. Our findings suggest that compound 3b could be a promising anticancer agent since it effectively inhibited cell proliferation and can be selected for further in vitro and in vivo investigations.

Hypolipidemic Activities of a Series of Pyrazoles of Curcumin

A series of curcumin pyrazole derivatives (3a-3e) were investigated for in-vitro hypolipidemic activity. The compounds were screened for the inhibition studies of the enzymes such as pancreatic lipase, glucose 6 phosphate dehydrogenase and malate dehydrogenase which are actively involved in lipid metabolism. Curcumin and all the other compounds in the series showed differential enzyme inhibitory activity. Curcumin and compound 3b showed prominent pancreatic lipase inhibitory activity showing IC50 17.39 and 16 µM respectively. Curcumin, compound 3a and compound 3b exhibited considerable malic dehydrogenase inhibitory activity and the IC50 was found to be 23.42, 18.54 and 22.82 µM respectively. Glucose 6 phosphate dehydrogenase activity was inhibited significantly by curcumin, compounds 3a, 3b and 3e and IC50 was 17.41, 17.11, 14.02 and 18.7 µM respectively. Our results suggest that among the curcumin pyrazole derivatives (3a- 3e), compound 3a and 3b could be potential hypolipidemic agents and can be promoted for further in-vitro and in vivo investigations. Keywords: Pancreatic lipase, enzyme inhibition, glucose 6 phosphate dehydrogenase, malate dehydrogenase, in-vitro.