Preparation and in vitro antioxidant activity of some novel flavone analogues bearing piperazine moiety.

BACKGROUND: A series of eight new flavone derivatives containing a piperazine chain with different substitution were synthesized and their structures were determined. METHODS: Their antiradical and antioxidant activities were evaluated using superoxide anion radical, hydroxyl radical, 2,2-diphenyl-1-picrylhydrazyl radical, 2,2'-azino-di(3-ethylbenzthiazoline sulphonate) radical cation (ABTS+) scavenging (as measure total antioxidant status TAS), ferric reducing antioxidant power (TAC), and hydrogen peroxide decomposition. The antioxidant activities of the synthesized compounds were compared with standard antioxidants trolox, ascorbic acid, butylated hydroxytoluene (BHT) as positive controls, reference antibiotics (doxycycline, dicloxacillin), and medicinal plants (Menthae piperita, Cistus incanus). Chemiluminescence, spectrophotometry, electron spin resonance (ESR) spectroscopy in conjunction with 5,5-dimethyl-1-pyrroline-1-oxide (DMPO) as the spin trap were the measurement techniques. RESULTS: The results show that the synthesized compounds exhibit weak, albeit a wide spectrum of antiradical and antioxidant activities. The TAS values were measured as trolox equivalents, ranging from 209.6 ± 6.1 to 391.1 ± 8.2 µM TE/g; the TAC values were in ranges from 10.8 ± 0.5 to 49.5 ± 0.5 µM TE/g being higher than that of dicloxacillin (241.0 ± 16.5 and 9.73 ± 0.8 µM TE/g, respectively), but lower than ascorbic acid, BHT, doxycycline, and medicinal plants. Best antioxidant activities were found for the piperazinyl analogues with methoxy group on phenyl piperazine ring. CONCLUSION: We suggest that the synthesized compounds may be used as lead molecules for optimization of molecular structure to maximize the antioxidant potency.

Thiazolidinedione or Rhodanine: A Study on Synthesis and Anticancer Activity Comparison of Novel Thiazole Derivatives.

PURPOSE: A new series of thiazolyl-2,4-thiazolidinedione / rhodanine compounds T1-T23 was synthesized and tested for their anticancer activities. Hepatocellular carcinoma cell lines were chosen due to their strong drug resistance to test the new compounds. METHODS: All compounds were synthesized via Knoevenagel Condensation reaction and thiazolidinedione ester compounds (T3,T9,T15,T20) were hydrolyzed for obtaining the acidic compounds (T6,T12,T17,T23). All compounds were firstly screened for their anticancer activity against two hepatocellular carcinoma (HCC) cell lines, Huh7 and Plc/Prf/5 (Plc) cell lines by sulforhodamine B assay. Further IC50 values were calculated for three candidates (T4, T15, T21) in five different HCC (Huh7, Plc, Snu449, HepG2, Hep3B) and one breast cancer (Mcf7) cell line. RESULTS: Compounds T4, T15, T21 had very strong anticancer effects even though their 10 µM concentration in Huh7 cell line. According to IC50 values, T21 was the most effective compound with IC50 values in a range from 2 to 16 µM in 6 cancer cell lines. In terms of cytotoxicity T21 mostly affected Huh7 and interestingly it was less effective against Plc. CONCLUSIONS: Considering these results it can be suggested that compounds T4, T15 and T21 may lead to the development of more potent anticancer drugs in the future. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Synthesis and in vitro antioxidant activity study of some new piperazinyl flavone compounds.

Flavones exhibit a variety of beneficial effects and are well known for their medicinal importance in several diseases, including cardiovascular, neurodegenerative and cancer. The inclusion of the piperazine ring to the flavone backbone is an important strategy in drug discovery but only a few studies have synthesized piperazinyl flavone compounds to test their biological activity. While there is a major focus on the antioxidant properties of drugs in therapy of several diseases of inflammatory origin, we synthesized a series of the novel piperazinyl flavone analogues bearing the phenyl ring with different substituents. The analogues were evaluated for in vitro antioxidant activity against superoxide anion radical, hydroxyl radical, 2,2-diphenyl-1-picrylhydrazyl radical, and hydrogen peroxide scavenging properties. The total antioxidant status based on the absorbance of the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) radical cation (ABTS+• ) and total antioxidant capacity using the Fe(III)-ferrozine complex were also monitored. The results of the above studies showed that the compounds synthesized were found possessed moderate radical scavenging potential, and that their interaction with reactive oxygen species is complex and depends on their structural conformation and the type of substituent R in the piperazine ring being attached. Best antiradical activity were found for the compounds with methoxy groups on the phenyl ring of substituent R, whereas the presence of methoxy or trifluoromethyl groups in substituent R resulted in higher ABTS+• and ion Fe(III) reduction. These compounds are promising molecules to be used for their antioxidant properties and may be regarded, after improvement of the antioxidant potential, to control diseases of free radical etiology.

Studies on the antioxidant activity of some chromonylrhodanine derivatives.

Fifteen chromonylrhodamine derivatives (CRs) were synthesized and the antioxidant activity levels were evaluated for the first time. The antioxidant activity potencies of these chromone derivatives were evaluated towards superoxide anion radicals, hydroxyl radicals and 2,2-diphenyl-1-picrylhydrazyl radicals. Also, the total antioxidant capacity of the tested compounds was measured using the ferric-ferrozine assay. The antioxidant activities were investigated using a chemiluminescence (CL) assay, spectrophotometry measurements, direct electron paramagnetic resonance (EPR) and the EPR spin-trapping technique. The 5,5-dimethyl- 1-pyrroline-1-oxide (DMPO) was applied as spin trap. Eleven of the 15 chromone compounds exhibited a decrease in the CL accompanying the superoxide anion radical produced in anhydrous dimethylsulfoxide (DMSO), ranging from 71-94% at concentration of 1 mmol /L; four of these compounds enhanced light emission in the range 231-672%. Similarly, these compounds caused 28-58% inhibition in the intensity of the DMPO-OOH radical EPR signal and the DMPO-OH radical (from 12-48%). Furthermore, three of these compounds showed very good antioxidant response towards the DPPH radical (EC50 : 0.51-0.56 µmol/L) and the high reduction potentials. These findings demonstrate that the chromone compounds tested may be considered as effective free radicals scavengers, a finding that is of great pharmacological importance.

Studies on the antioxidant activity of some thiazolidinedione, imidazolidinedione and rhodanine derivatives having a flavone core.

A series of flavonyl-2,4-thiazolidinedione, imidazolidinedione and rhodanine derivatives were tested for their antioxidant activity as scavengers of oxygen free radicals. Free radical scavenging activities, including superoxide anion radical O2•, hydroxyl radical (HO(•)) and 2,2'-diphenyl-1-picrylhydrazyl free radical have been evaluated using chemiluminescence, electron paramagnetic resonance and spin trapping with 5,5-dimethyl-1-pyrroline-1-oxide as a spin trap. Potassium superoxide in dimethylsulfoxide and 18-crown-6 ether were used for the production of O2•. Hydroxyl radical was generated using the Fenton reaction. Ten of the eleven examined compounds exhibited decrease in chemiluminescence, but there were large differences in the decrease, ranging from 16% to 89%; also, two of these compounds increased light emission by about 200%. On the contrary, all compounds tested exhibited 30-68% scavenging HO(•) and 25-96% scavenging the DPPH(•) radical respectively. Possible mechanisms are proposed to explain the results.

6-Methyl 3-chromonyl 2,4-thiazolidinedione/2,4-imidazolidinedione/2-thioxo-imidazolidine-4-one compounds: novel scavengers of reactive oxygen species.

The benefits of antioxidants on human health are usually ascribed to their potential ability to remove reactive oxygen species providing protection against oxidative stress. In this paper the free radicals scavenging activities of nine 6-methyl 3-chromonyl derivatives (CMs) were evaluated for the first time by the chemiluminescence, electron paramagnetic resonance, spin trapping and 2,2-diphenyl-1-picrylhydrazyl (DPPH(•)) methods. The total antioxidant capacity was also measured using a ferric-ferrozine reagent. Compounds having a hydrogen atom at the N3-position of the ß-ring were effective in quenching CL resulted from the KO2 /18-crown-6-ether system (a source of superoxide anion radical, O2•¯) in a dose-dependent manner over the range of 0.05-1 mmol/L [IC50 ranged from 0.353 (0.04) to 0.668 (0.05) mmol/L]. The examined compounds exhibited a significant scavenging effect towards hydroxyl radicals (HO(•) HO(•)), produced by the Fenton reaction, and this ranged from 24.0% to 61.0%, at the concentration of 2.5 mmol/L. Furthermore, the compounds examined were also found to inhibit DPPH(•) and this ranged from 51.9% to 97.4% at the same concentration. In addition, the use of the total antioxidant capacity assay confirmed that CM compounds are able to act as reductants. According to the present study, CM compounds showed effective in vitro free radical scavenging activity and may be considered as potential therapeutics to control diseases of oxidative stress-related etiology.

Antioxidant activities of some new chromonyl-2,4-thiazolidinediones and chromonyl-2,4-imidazolidinediones having chromone cores.

The antioxidant properties of 11 new synthesized chromonyl-2,4-thiazolidinediones and chromonyl-2,4-imidazolidinediones (CBs) were investigated. The antioxidant activities and mechanisms of the CBs interaction with reactive oxygen species (ROS) were clarified using various in vitro antioxidant assay methods including superoxide anion radical (O2(•-)), hydroxyl radical (HO(•)), 1,1-diphenyl-2-picryl-hydrazyl free radical (DPPH(•)) scavenging activity and the iron (II)-ferrozine complex formation. The potassium superoxide/18-crown-6 ether dissolved in dimethylsulfoxide (DMSO) was applied as a source of superoxide anion radical. Hydroxyl radicals were produced in the Fenton-like reaction Fe(II)+H2O2. Chemiluminescence, spectrophotometry, and electron paramagnetic resonance (EPR) spectroscopy using 5,5-dimethyl-1-pyrroline-1-oxide (DMPO) as spin trap were applied as the measurement techniques. The CBs examined that exhibited good free radical scavenging activity also showed strong total antioxidant power capacity. Possible mechanisms of antioxidation are proposed to explain the differences in the experimental results between the chromone derivatives with imidazolidine-2,4-dione ring and those with thiazolidine-2,4-dione ring. In conclusion, some of the new CBs are promising to be applied as inhibitors of free radicals.

Free radical scavenging activity of novel thiazolidine-2,4-dione derivatives.

Free radical activity towards superoxide anion radical (O2•¯), hydroxyl radical (HO(•)) and 2,2-diphenyl-1-picrylhydrazyl (DPPH(•)) of a series of novel thiazolidine-2,4-dione derivatives (TSs) was examined using chemiluminescence, electron paramagnetic resonance (EPR) and EPR spin trapping techniques. 5,5-Dimethyl-1-pyrroline-N-oxide (DMPO) was applied as the spin trap. Superoxide radical was produced in the potassium superoxide/18-crown-6 ether dissolved in dimethyl sulfoxide. Hydroxyl radical was generated in the Fenton reaction (Fe(II) + H2O2. It was found that TSs showed a slight scavenging effect (15-38% reduction at 2.5 mmol/L concentration) of the DPPH radical and a high scavenging effect of O2•¯ (41-88%). The tested compounds showed inhibition of HO(•)-dependent DMPO-OH spin adduct formation (the amplitude of EPR signal decrease ranged from 20 to 76% at 2.5 mmol/L concentration. Our findings present new group compounds of relatively high reactivity towards free radicals.

Free radical scavenging abilities of flavonyl-thiazolidine-2,4-dione compounds.

Free radical scavenging activity of flavonyl-thiazolidine-2,4-dione compounds has been evaluated using chemiluminescence, electron spin resonance spectroscopy with 5,5-dimethyl-1-pyrroline-1-oxide as spin trap and DPPH (2,2'-diphenyl-1-picrylhydrazyl) method. The examined compounds exhibited 28-50% scavenging superoxide anion radical O2⁻ⁱ16.7-76.7% hydroxyl radical (HO•) and 9-40% DPPH radical. Compounds containing carbonyl group in their structure can be considered as antioxidants with high relevance and great biological importance.

Scavenging of superoxide anion radical and hydroxyl radical by novel thiazolyl-thiazolidine-2,4-dione compounds.

The antioxidant behavior of a series of new synthesized substituted thiazolyl-thiazolidine-2,4-dione compounds (TZDs) was examined using chemiluminescence and electron paramagnetic resonance spin trapping techniques. 5,5-Dimethyl-1-pyrroline-N-oxide (DMPO) was used as the spin trap. The reactivity of TZDs with superoxide anion radical (O2(*-)) and hydroxyl radical (HO(*)) was evaluated using potassium superoxide/18-crown-6 ether dissolved in dimethylsulfoxide, and the Fenton-like reaction (Fe(2+) + H2O2), respectively. The results showed that TZDs efficiently inhibited light emission from the O2(*-) generating system at a concentration of 0.05-1 mmol L(-1) (5-94% reductions were found at 1 mmol L(-1) concentration). The TZD compounds showed inhibition of HO(*)-dependent DMPO-OH spin adduct formation from DMPO (the amplitude decrease ranged from 8 to 82% at 1 mmol L(-1) concentration). The findings showed that examined TZDs had effective activities as radical scavengers.

Scavenging capacities of some thiazolyl thiazolidine-2,4-dione compounds on superoxide radical, hydroxyl radical, and DPPH radical.

The scavenging effects of eighteen thiazolyl thiazolidine-2,4-dione compounds (TTCs) on superoxide radical ( (-) (*) ) (2), hydroxyl radical HO(*), and 1,1-diphenyl-2-picrylhydrazyl (DPPH(*)) radical were evaluated by the chemiluminescence technique, electron spin resonance spectrometry (ESR) and visible spectrophotometry, respectively. The examined compounds were shown to have 27-59% ( (-) (*) ) (2) scavenging ability, 19-69% HO(*) scavenging activity and 2-32% DPPH(*) scavenging ability. This property of the tested compound seems to be important in the prevention of various diseases of free radicals etiology.

Synthesis and antimicrobial activity of some novel thiazolidine-2,4-dione derivatives.

In this study, a series of phenylethylsulfanyl-1,3-thiazolo-thiazolidine-2,4-dione derivatives (VII a-f, VIII a-f) and 5-methyl-[1,2,4]triazolyl-sulfanyl-1,3-thiazolo-thiazolidine-2,4-dione derivatives (IX a-f, X a-f) were synthesized and evaluated for their antibacterial and antifungal activities against S. aureus (ATCC 25923), methicillin resistant S. aureus (MRSA ATCC 43300), B. subtilis (ATCC 6633), E. coli (ATCC 23556) and C. albicans (ATCC10145). All the compounds were found active against used bacteria.

Hydroxyl and superoxide radical scavenging abilities of chromonyl-thiazolidine-2,4-dione compounds.

The oxygen free radical scavenging activities of 15 chromonyl-thiazolidine-2,4-dione compounds (CTDs) were examined in chemical systems producing superoxide anion radicals, O2(-*) (potassium superoxide-18-crown-6 ether-DMSO), and hydroxyl radicals, HO(*) (a Fenton reaction: Fe(II)-H2O2-sodium trifluoroacetate, pH 6.15). Chemiluminescence and electron spin resonance (ESR) spectroscopy using 5,5-dimethyl-1-pyrroline-1-oxide (DMPO) as spin trap were applied to evaluate antioxidant behaviour of CTDs towards the oxygen radicals. The results indicated that 11 of the 15 tested compounds showed a significant inhibitory effect on the chemiluminescence generated from the O2(-*)-generating system, ranging from 41 to 86%, and 13 CTDs quenched the ESR signal of the DMPO-OH spin adduct by 33-86%, at a concentration of 1 mmol L(-1). Our findings demonstrate that CTDs could be good free radical scavengers.

Synthesis and biological activity of some new flavonyl-2,4-thiazolidinediones.

A new series of flavonyl-2,4-thiazolidinediones (Va-c, VIa-c) was prepared by Knoevenagel reaction. The synthesized compounds were tested for their ability to inhibit rat kidney aldose reductase (AR) and for their insulinotropic activities in INS-1 cells. Compound Vb was able to increase insulin release in the presence of 5.6mmol/l glucose. Compounds VIa-c displayed moderate to high AR inhibitory activity levels. Particularly, compound VIa showed the highest AR inhibitory activity (86.57%).

In vitro aldose reductase inhibitory activity of some flavonyl-2,4-thiazolidinediones.

Aldose reductase (AR) is implicated to play a critical role in diabetes and cardiovascular complications because of the reaction it catalyzes. AR enzyme appears to be the key factor in the reduction of glucose to sorbitol. Synthesis and accumulation of sorbitol in cells due to AR activity is the main cause of diabetic complications, such as diabetic cataract, retinopathy, neuropathy and nephropathy. Aldose reductase inhibitors have been found to prevent sorbitol accumulation in tissues. Numerous compounds have been prepared in order to improve the pharmacological prophile of inhibition of aldose reductase enzyme. In this study, seventeen flavonyl-2,4-thiazolidinediones (flavonyl-2,4-TZD) (Ia-e, IIa-e and IIIa-g) were tested for their ability to inhibit rat kidney AR. Compound Ib showed the highest inhibitory activity (88.69 +/- 1.46%) whereas Ia, IIa, IIIa, IIIb also showed significant inhibitory activity (49.26 +/- 2.85, 67.29 +/- 1.09, 71.11 +/- 1.95, 64.86 +/- 1.21%, respectively).

Synthesis and antidiabetic activity of some new thiazolyl-2,4-thiazolidinediones.

In this study, a series of thiazolyl-2,4-thiazolidinediones (VIa-f, VIHa-f and VIIa-f) was prepared by Knoevenagel reaction of substituted phenacyl-2,4-thiazolidinediones (IVa-f)/substituted benzyl-2,4-thiazolidinediones (Va-f) with chlorothiazolecarbaldehydes (II, III). The prepared compounds were tested for their insulinotropic activities in INS-1 cells. A significant insulinotropic effect was seen with compounds VIa, VIb, VIe, VIIa, VIIb and VIIId. Introducing a 2-[(phenylethyl)thio] group into the thiazole ring increased the biological effect, whereas NO2 groups in phenylacyl or benzyl groups diminished the effects.

Synthesis and aldose reductase inhibitory activity of some new chromonyl-2,4-thiazolidinediones.

As it is known that still, there were no any confident ARIs on the market and they have several side effects, we need to approve new ARIs to reduce diabetic complications especially which have effect on the cataract formation. In this study, a new series of chromonyl-2,4-thiazolidinediones (Ia-e, IIa-e, IIIa-e) were prepared by Knoevenagel reaction with substituted 3-formylchromones (3a-e) and unsubstituted (1) or substituted 2,4-thiazolidinedione (2). The synthesized compounds were tested for their ability to inhibit rat kidney AR by an in vitro spectrophotometric assay. Compound IIIe showed the highest inhibitory activity (82.43+/-0.76%). Compounds Ia-e and IIIa-d also showed significant inhibitory activity (42.40+/-5.78, 52.71+/-3.31, 49.69+/-1.55, 50.80+/-3.62, 46.70+/-2.33, 49.44+/-4.53, 61.17+/-4.74, 68.58+/-2.05, 77.28+/-0.26%, respectively).

Synthesis and antidiabetic activity of some new chromonyl-2,4-thiazolidinediones.

A series of chromonyl-2,4-thiazolidinediones (VIa-f) and chromonyl-2,4-imidazolidinediones (VIIa-f) was prepared by Knoevenagel reaction of substituted benzyl-2,4-thiazolidinediones (IVa-f) and substituted benzyl-2,4-imidazolidinediones (Va-f) with chromone-3-carboxaldehyde (I). The prepared compounds were tested for their insulinotropic activities in INS-1 cells. Compounds VIa, VIb, VId and VIIe (at lower concentration; 1 microg/ml) were able to increase insulin release in the presence of 5.6 mmol/l glucose; their effects were lower than that of glibenclamide (CAS 10238-21-8). The activity of the most potent compound (VId) was still 9% less than that of glibenclamide.

Synthesis and antimicrobial activity of some new thiazolyl thiazolidine-2,4-dione derivatives.

In this study, a series of thiazolyl thiazolidine-2,4-dione derivatives (Va-f and VIa-f) were synthesized and evaluated for their antibacterial and antifungal activities against Staphylococcus aureus (ATCC 25923), methicillin resistant S. aureus (MRSA ATCC 43300), methicillin resistant S. aureus (MRSA isolate), and Escherichia coli (ATCC 23556) and C. albicans (ATCC10145). All the compounds were found active against used microorganisms.

Synthesis and antidiabetic activity of novel 2,4-thiazolidinedione derivatives containing a thiazole ring.

A series of thiazolyl-2,4-thiazolidinediones (Ia-f, IIa-f and IIIa-f) was prepared by Knoevenagel reaction of substituted benzyl-2,4-thiazolidinediones (4a-f) with chlorothiazolecarbaldehydes (2, 3a-b). The prepared compounds were tested for their insulinotropic activities in INS-1 cells. A significant insulinotropic effect was seen with compounds If and IIa.