Differential apoptotic and redox regulatory activities of curcumin and its derivatives

We have synthesized different bioconjugates of curcumin, which were tested for their pro- and antioxidant properties. In the present study five representative derivatives of curcumin, i.e., 4,4'-di-(O-acetyl) curcumin, 4,4'-di-(O-glycinoyl) curcumin, 4,4'-di-(O-glycinoyl-di-N-piperoyl) curcumin, 4,4'-di-(O-piperoyl) curcumin, and 4,4'-(O,O-cystinoyl)-3,3'-dimethoxydiphenyl-1,6-heptadiene-3,5-dione, were used for testing their apoptotic potential on tumor cells. Dipiperoyl and diglycinoyl derivatives showed higher apoptotic activity at lower concentrations, whereas diacetyl curcumin had slightly lower apoptotic activity on tumor cells. On the other hand, diglycinoyl-dipiperoyl and cystinoyl heptadiene derivatives had lost their apoptotic potential significantly. The apoptotic activity of these derivatives correlated very well with the generation of ROS by the tumor cells, whereas GSH levels remained unaltered. Our studies also indicate downregulation of Bcl-2 and participation of caspase-3 in the apoptotic death of tumor cells.     

Syntheses of Curcumin Bioconjugates and Study of Their Antibacterial Activities against beta-Lactamase-Producing Microorganisms.

In the present study curcumin bioconjugates, viz. di-O-glycinoylcurcumin (I), di-O-glycinoyl-C(4)-glycylcurcumin (II), 5'-deoxy-5'-curcuminylthymidine (5'-cur-T) (IV), and 2'-deoxy-2'-curcuminyluridine (2'-cur-U) (V) have been synthesized and characterized by elemental analysis and (1)H NMR. The turmeric peptide (Tp) was isolated from the aqueous turmeric extract of the turmeric rhizome. The antibacterial activity of these four bioconjugates and also of the turmeric peptide and sodium salt of curcumin (III) have been tested particularly for beta-lactamase-producing microorganisms.     

Design and synthesis of curcumin-bioconjugates to improve systemic delivery.

Di-O-glycinoyl curcumin (I), di-O-glycinoyl-C4-glycyl-curcumin (II), 5'-deoxy-5'-curcuminyl thymidine (5'-cur-T) (III) and 2'-deoxy-2'-curcuminyl uridine (2'-cur-U) (IV) have been synthesized and characeterised by elemental analysis & 1H NMR. The antibacterial activities of these four bioconjugates has been tested particularly for multiresistant micro-organisms. Best results are shown by I & IV. These bioconjugates serve dual purpose of systemic delivery as well as therapeutic agents against viral diseases.     

Design, synthesis, synergistic antimicrobial activity and cytotoxicity of 4-aryl substituted 3,4-dihydropyrimidinones of curcumin

3,4-Dihydropyrimidinones of curcumin were synthesized in excellent yield by multi-component one-pot condensation of curcumin, substituted aromatic aldehydes and urea/thiourea under solvent free conditions using SnCl(2)·2H(2)O catalyst. All the synthesized compounds have been characterized by IR, (1)H NMR, (13)C NMR, Mass spectra as well as elemental analyses. The synthesized compounds 4a-n were evaluated for their synergistic antimicrobial (antibacterial and antifungal) activity against bacteria and fungi. Zone of inhibition was measured by adopting disc diffusion method. In vitro minimum inhibitory concentrations were measured using broth microdilution and food poisoning method. In addition to this in vitro cytotoxicity of synthesized compounds against three human cancer lines Hep-G2, HCT-116 and QG-56 were also evaluated. Most of the compounds showed interesting antimicrobial and cytotoxic activity as compared to curcumin, that is, the compounds derived from 2-hydroxy benzaldehyde, 4-hydroxy benzaldehyde and 4-hydroxy-3-methoxy benzaldehyde showed the highest biological activity as compared to other compounds.     

Novel role of Zn(II)-curcumin in enhancing cell proliferation and adjusting proinflammatory cytokine-mediated oxidative damage of ethanol-induced acute gastric ulcers

Alcohol consumption can induce gastric ulcers and zinc deficiency. Zinc complexes were reported to have anti-ulcer activity as it acts as an anti-inflammatory and antioxidant. Zn(II)-curcumin complex and its solid dispersions (SDs) were synthesized and evaluated for its gastroprotective activity and mechanism against ethanol-induced ulcer. The Swiss murine fibroblast cell line (3T3) was used as an alternative in vitro model to evaluate the effects of Zn(II)-curcumin on cell proliferation. Zn(II)-curcumin were administered orally for seven consecutive days prior to induction of ulcers using ethanol. Gross and microscopic lesions, immunological and biochemical parameters were taken into consideration. The results showed that solid dispersions (SDs) of Zn(II)-curcumin (2.5-20 μM) enhanced the proliferation of 3T3 cells more significantly than curcumin at the same concentrations (P<0.01). Oral administration of Zn(II)-curcumin (12, 24 and 48 mg/kg) SDs dose-dependently prevented formation of ulcer lesions induced by ethanol. The levels of proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and oxidative stress superoxide dismutase (SOD), glutathione peroxidase (GPX-Px), malonaldehyde (MDA) and H(+)-K(+)-ATPase were in the rats exposed to ethanol in ulceration have been altered. Zn(II)-curcumin prevented formation of ulcer lesions, significantly inhibited TNF-α and IL-6 mRNA expression, increased the activity of SOD and GSH-Px, reduced MDA levels and H(+)-K(+)-ATPase in mucosa of rats compared to controls (P<0.05). These findings suggest that the gastroprotective activity of Zn(II)-curcumin complex might contribute in stimulating cell proliferation and adjusting the proinflammatory cytokine-mediated oxidative damage to the gastric mucosa.     

In-vitro antibacterial, antifungal and cytotoxic activities of some coumarins and their metal complexes

A series of new antibacterial and antifungal coumarin-derived compounds and their transition metal complexes [cobalt (II), copper (II), nickel (II) and zinc (II)] have been synthesized, characterized and screened for their in vitro antibacterial activity against Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Salmonella typhi, Shigella dysenteriae, Bacillus cereus, Corynebacterium diphtheriae, Staphylococcus aureus and Streptococcus pyogenes bacterial strains and for in vitro antifungal activity against Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani, Candida glaberata. The results of these studies show the metal complexes to be more antibacterial and antifungal as compared to the uncomplexed coumarins. The brine shrimp bioassay was also carried out to study their in vitro cytotoxic properties.     

In vitro multitarget activity of sulfadiazine substituted triazenes as antimicrobial,cytotoxic, and larvicidal agents

Multidrug resistance (MDR) causes difficulties in the treatment of infections and cancer. Research and development studies have become increasingly important for the strategy of preventing MDR. There is a need for new multitarget drug research and advancement to reduce the development of drug resistance in drug-drug interactions and reduce cost and toxic effects. This study aimed to determine the effects of multi-target triazene compounds on antibacterial, antifungal, antiviral, cytotoxic, and larvicidal activities were investigated in vitro. A series of 12 novel of 1,3-diaryltriazene-substituted sulfadiazine (SDZ) derivatives were synthesized, and the obtained pure products characterized in detail by spectroscopic and analytic methods (FT-IR, ¹H-NMR, ¹³C-NMR, and melting points). The antibacterial and antifungal activities of these derivatives (AH1-12) were determined by broth microdilution method. All derivatives have been evaluated in cell-based assays for cytotoxic and antiviral activities against Modified Vaccinia Virus Ankara. The larvicidal efficacy of these chemical compounds was also investigated by using Lucilia sericata (L. sericata) larvae. Twelve 1,3-diaryltriazene-substituted SDZ derivatives (AH1-12) were designed and developed as potent multitargeted compounds. Among them, the AH1 derivative showed the most antibacterial and antifungal activity. Besides, synthesized derivatives AH2, AH3, AH5, and AH7 showed higher antiviral activity than SDZ. All synthesized derivatives showed higher cytotoxic activity than SDZ. Also, they showed larvicidal activity at 72 h of the experiment. As a result, these compounds might be great leads for the development of next-generation multitargeted agents.     

Synthesis, characterization and antimicrobial activity of new aliphatic sulfonamide

A series of novel aliphatic sulfonamide derivatives (1-7) were synthesized and characterized by elemental analyses, FT-IR, (1)H NMR, (13)C NMR and LC-MS techniques. All the synthesized compounds were evaluated in vitro as antimicrobial agents against representative strains of Gram-positive (Staphylococcus aureus ATCC 25953, Bacillus cereus ATCC 6633 and Listeria monocytogenes ATCC Li6 (isolate), Gram-negative bacteria (Escherichia coli ATCC 11230) and antifungal agent against Candida albicans (clinical isolate) by both disc diffusion and minimal inhibition concentration (MIC) methods. All these bacteria and fungus studied were screened against some antibiotics to compare with our chemicals' zone diameters. Our aliphatic sulfonamides have highest powerful antibacterial activity for Gram-negative bacteria than Gram-positive bacteria and antibacterial activity decreases as the length of the carbon chain increases.     

Synthesis of (1,4)-naphthoquinono-[3,2-c]-1H-pyrazoles and their (1,4)-naphthohydroquinone derivatives as antifungal, antibacterial, and anticancer agents

A series of (1,4)-naphthoquinono [3,2-c]-1H-pyrazoles and their (1,4)-naphthohydroquinone derivatives 2-7 were synthesized and evaluated for antifungal, antibacterial, and anticancer activities. The structure-activity relationship of these compounds was studied and the results show that the compound 2b exhibited in vitro antifungal activity against Candida albicans and Cryptococcus neoformans, and also possessed antibacterial profile against Klebsiella pneumoniae and Escherichia coli whereas 1c showed anticancer activity against Walker 256 Carcinosarcoma in rats.     

Sulfonamide-1,2,4-triazole derivatives as antifungal and antibacterial agents: synthesis, biological evaluation, lipophilicity, and conformational studies

A series of 10 new 5-[2-(substituted sulfamoyl)-4,5-dimethoxy-benzyl]-4aryl-s-triazole-3-thiones were synthesized and evaluated for in vitro antifungal and antibacterial activity. All compounds tested showed significant antifungal activity against all the micromycetes, compared to the commercial fungicide bifonazole. Differences in their activity depend on the substitution of different reactive groups. More specifically, best antifungal activity among synthetic analogues was shown with N-dimethylsulfamoyl group. All the compounds tested against bacteria showed the same activity as the commercial agent streptomycin, except for Enterobacter cloacce and Salmonella species. Chloramphenicol showed lower bactericidal effect than the synthetic compounds. Furthermore, it is apparent that different compounds reacted in different ways against bacteria. Gram (-) bacteria seem to be more sensitive to these compounds than Gram (+) species. An effort was made to correlate the above-mentioned differences in activity with lipophilicity studies. Furthermore, molecular modeling was used to obtain the main conformational features of this class of molecules for future structure-activity relationship studies.     

Synthesis and biological evaluation of novel (L)-alpha-amino acid methyl ester, heteroalkyl, and aryl substituted 1,4-naphthoquinone derivatives as antifungal and antibacterial agents

A series of (S)-N-(1,4-naphthoquinon-2-yl)-alpha-amino acid methyl esters 3-9, 2-N,N-dialkylamino-1,4-naphthoquinones 10-11 and 2-hydroxy-3-(2'-mercaptoimidazolyl)-1,4-naphthoquinones and their cyclic analogs 12-15 were synthesized and evaluated for antifungal and antibacterial activities. The structure-activity relationships of these compounds were studied and the results show that the compounds 9b and 13c exhibited in vitro antifungal activity against Candida albicans, Cryptococcus neoformans, and Sporothrix schenckii, whereas compound 6a showed in vitro antibacterial activity against Streptococcus faecalis, K. pneumoniae, Escherichia coli, and Staphylococcus aureus.     

Hydrazones of 2-aryl-quinoline-4-carboxylic acid hydrazides: synthesis and preliminary evaluation as antimicrobial agents

A new series of 2-arylquinoline-4-carboxylic acid hydrazide–hydrazones was synthesized using an appropriate synthetic route. All the target compounds were evaluated for their in vitro antimicrobial activity against Staphylococcus aureus as an example for Gram-positive bacteria, Escherichia coli as an example for Gram-negative bacteria, and Candida albicans as a representative of fungi. The minimum inhibitory concentration (MIC) was determined for test compounds as well as for reference standards. Among the compounds tested, compounds having nitro substituents at the arylidene moiety showed the most potent antifungal as well as antibacterial activities against E. coli. Compound 23 displayed an antifungal activity comparable to that of nystatin. However, none of the compounds demonstrated any antibacterial activity against S. aureus. Hydrophobicity of the target compounds correlated weakly with their antibacterial and antifungal activities. The most potent compounds namely, 7, 18, 19, 22, and 23 were assessed for hemolytic toxicity and found to be non-hemolytic up to a concentration of 100 μg/mL. In addition, the most potent compound (23) was evaluated for in vitro cytotoxic activity against various cancer cell lines. This compound was found to display no cytotoxic activity but rather it induces the proliferation rate of Hep-G2 cells.     

Inhibitory effect of curcumin on the Al(III)-induced Aβ₄₂ aggregation and neurotoxicity in vitro

The pathogenesis of Alzheimer's disease (AD) involves a key event which changes the morphology of amyloid-β 42 (Aβ)?? peptide from its soluble monomeric form into the fibrillated aggregates in the brain. Aluminum ion, Al(III), is known to act as a pathological chaperone of the Aβ?? in this process; curcumin, a natural phenolic compound, is considered capable of binding Al(III) and Aβ??; nevertheless, little is known about the combined action of curcumin and Al(III) on the Aβ?? fibrillation and neurotoxicity. Here, combinations of circular dichroism spectroscopy, thioflavin T fluorescence, atomic force microscopy, Bradford and MTT assays, it is demonstrated that although Al(III) can promote the Aβ?? fibrillation dose-dependently, leading to the high neurotoxicity to PC12 cells, curcumin can inhibit the events. Besides, we found that curcumin is able not only to inhibit the formation of Al(III)-induced Aβ?? fibrillation, but also to form the Al(III)-curcumin complexes which in turn can remold the preformed, mature, ordered Aβ?? fibrils into the low toxic amorphous aggregates. These findings suggest that curcumin could block the binding of Al(III) with Aβ?? and form the Al(III)-curcumin complexes, so as to inhibit the Al(III)-induced Aβ?? fibrillation and neurotoxicity. The Al(III)-curcumin complexes are worth potentially developing as a therapy agent against the neurodegenerative disorders in the future.     

Antialgal, antibacterial and antifungal activity of two metabolites produced and excreted by cyanobacteria during growth

The antimicrobial activity of two cyanobacterial exometabolites, norharmane (9H-pyrido(3,4-b)indole) and 4,4'-dihydroxybiphenyl, was determined in suspension assays. Good anticyanobacterial activities (concentrations of 8-80 microg ml(-1)) and moderate antibacterial (16-160 microg ml(-1)) and antifungal (32-40 microg ml(-1)) activities were found for both compounds. The natural function as allelopathic chemicals and a possible applicability as antifouling agents or leads for the development of new antifouling chemicals are discussed.     

Design, synthesis, and biological evaluation of 1,2,3-trisubstituted-1,4-dihydrobenzo[g]quinoxaline-5,10-diones and related compounds as antifungal and antibacterial agents

A series of (S)-N-(3-chloro-1,4-naphthoquinon-2-yl)-alpha-amino acid ethyl esters 3 and 1,2,3-trisubstituted-1,4-dihydrobenzo[g]quinoxaline-5,10-diones 6-23 were synthesized and evaluated for antifungal and antibacterial activities. The structure-activity relationship of these compounds was studied and the results show that the compounds 3a and 3b exhibited in vitro antifungal activity against Candida albicans, Cryptococcus neoformans, and Sporothrix schenckii whereas compounds 12 and 22 showed in vitro antibacterial activity against Klebsiella pneumoniae and Escherichia coli.     

In-vitro antibacterial, antifungal and cytotoxic activity of cobalt (II), copper (II), nickel (II) and zinc (II) complexes with furanylmethyl- and thienylmethyl-dithiolenes: [1, 3-dithiole- 2-one and 1,3-dithiole-2-thione

Some antibacterial and antifungal furanylmethyl-and thienylmethyl dithiolenes and, their Co(II), Cu(II), Ni (II) and Zn (II) complexes have been synthesized, characterized and screened for their in vitro antibacterial activity against four Gram-negative; Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi and Shigella flexeneri, and two Gram-positive; Bacillus subtilis and Staphylococcus aureus bacterial strains, and for in-vitro antifungal activity against Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani and Candida glaberata. All compounds showed significant antibacterial and antifungal activity. The metal complexes, however, were shown to possess better activity as compared to the simple ligands. The brine shrimp bioassay was also carried out to study their in-vitro cytotoxic properties.     

Design,synthesis, biological activities and DFT calculation of novel 1,2,4-triazole Schiff base derivatives

Series of 1,2,4-triazole Schiff bases (2a-2d, 2f-2h and 3a-3h) have been designed and synthesized. The structure of title compounds was confirmed on the basis of their spectral data and elemental analysis. All the target compounds were screened for their in vitro antifungal activity and antibacterial activity. Two of the tested compounds (2a and 2b) exhibited significant antifungal activity against most fungi, especially compound 2a showed better antifungal activity than triadimefon. Meanwhile, the antibacterial activity assay also indicated compound 2a exhibited excellent antibacterial activities comparable to chloramphenicol. The SAR manifested no substitution at position 5 of the triazole ring caused an increase in activity, and 3-phenoxy phenyl group introduced in 1,2,4-triazole scaffold can enhance the antibacterial activity. The DFT calculation indicated triazole ring, S atom and benzene ring in both of the 2a and 3a make a major contribution to the activity.     

Evaluation of a new copper(II)-curcumin complex as superoxide dismutase mimic and its free radical reactions

A mononuclear (1:1) copper complex of curcumin, a phytochemical from turmeric, was synthesized and examined for its superoxide dismutase (SOD) activity. The complex was characterized by elemental analysis, IR, NMR, UV-VIS, EPR, mass spectroscopic methods and TG-DTA, from which it was found that a copper atom is coordinated through the keto-enol group of curcumin along with one acetate group and one water molecule. Cyclic voltammetric studies of the complex showed a reversible Cu(2+)/Cu(+) couple with a potential of 0.402 V vs NHE. The Cu(II)-curcumin complex is soluble in lipids and DMSO, and insoluble in water. It scavenges superoxide radicals with a rate constant of 1.97 x 10(5) M(-1) s(-1) in DMSO determined by stopped-flow spectrometer. Subsequent to the reaction with superoxide radicals, the complex was found to be regenerated completely, indicating catalytic activity in neutralizing superoxide radicals. Complete regeneration of the complex was observed, even when the stoichiometry of superoxide radicals was 10 times more than that of the complex. This was further confirmed by EPR monitoring of superoxide radicals. The SOD mimicking activity of the complex was determined by xanthine/xanthine oxidase assay, from which it has been found that 5 microg of the complex is equivalent to 1 unit of SOD. The complex inhibits radiation-induced lipid peroxidation and shows radical-scavenging ability. It reacts with DPPH radicals with rate constant 10 times less than that of curcumin. Pulse radiolysis-induced one-electron oxidation of the complex by azide radicals in TX-100 micellar solutions produced strongly absorbing ( approximately 500 nm) phenoxyl radicals, indicating that the phenolic moiety of curcumin remained intact on complexation with copper. The results confirm that the new Cu(II)-curcumin complex possesses SOD activity, free radical neutralizing ability, and antioxidant potential. Quantum chemical calculations with density functional theory have been performed to support the experimental observations.