Design and synthesis of some new 1,3,4-thiadiazines with coumarin moieties and their antioxidative and antifungal activity.

A series of newly disubstituted (compounds 4a,b) and trisubstituted 1,3,4-thiadiazines 5a-l with various substituents was prepared utilizing different thiosemicarbazides and 3-α-bromoacetylcoumarins as starting compounds. The structures of the synthesized 1,3,4-thiadiazines are elucidated and confirmed utilizing the corresponding analytical and spectroscopic data. All of the new thiadiazine derivatives were tested for their antioxidant activity, employing different antioxidant assays (DPPH scavenging activity, iron chelating activity, power reducing activity). Compounds 5b, 5f, 5j and 4b were proven to be the best DPPH radical scavengers, while compounds 5h and 5j have shown the best iron chelating activity. Thiadiazine derivatives were also tested on their antifungal activity against four mycotoxicogenic fungi, Aspergillus flavus, A. ochraceus, Fusarium graminearum and F. verticillioides. The best antifungal against A. flavus was proven to be compound 5e, while compounds 4a and 5c were the best antifungals on A. ochraceus, and compound 5g showed the best antifungal activity on F. verticillioides.

4-Methyl-7-hydroxycoumarin antifungal and antioxidant activity enhancement by substitution with thiosemicarbazide and thiazolidinone moieties.

According to literature data, thiosemicarbazide and thiazolidinone moieties should enhance biological properties of coumarin. Antioxidant, metal-chelating and antifungal activities of all compounds were investigated and compared to the activity of the starting material, 7-hydroxy-4-methylcoumarin, and were proven to possess potent antioxidant and antifungal activity. In general, thiosemicarbazides showed higher scavenging activity towards DPPH and galvinoxyl radicals than did 4-thiazolidinones and some of them had the same or even better activity than had ascorbic acid itself, depending on the free radical used. In antifungal activity tests towards four foodborne mycotoxigenic fungi, Aspergillus flavus, Aspergillus ochraceus. Fusarium graminearum and Fusarium verticillioides, coumarin derivatives were proven to possess a very high activity in terms of growth inhibition, depending on the fungi investigated. In general, 4-thiazolidinones showed better antifungal activity than did thiosemicarbazides. F. graminearum was the most susceptible to the compounds investigated and F. verticillioides was proven to be the most resistant. Two compounds, both coumarinyl thiosemicarbazides, were found to possess both antifungal and antioxidant activity which could be useful for applications in medicine, food industry and agriculture.

Synthesis and antioxidant activity of some new coumarinyl-1,3-thiazolidine-4-ones.

A series of Schiff's bases (E)-N-2-aryliden-2-(4-methyl-2-oxo-2H-chromen-7-yloxy)acetohydrazides 2a-l and N-(2-(substituted phenyl)-4-oxo-thiazolidin-3-yl)-2-(4-methyl-2-oxo-2H-chromen-7-yloxy)acetamides 3a-l were synthesized and evaluated for their antioxidant activity by the phosphomolybdenum method. Most of the Schiff's bases and thiazolidine-4-ones bearing two hydroxyl groups on the phenyl ring showed excellent antioxidant activity in comparison with ascorbic acid. Preliminary investigation on cytotoxic and antifungal activity was done on some representative samples.

Design and synthesis of some thiazolidin-4-ones based on (7-hydroxy-2-oxo-2H-chromen-4-yl) acetic acid.

(7-Hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid methyl ester(1) upon reaction with ethyl bromoacetate furnishes (7-ethoxycarbonylmethoxy-2-oxo-2H-chromen-4-yl)-acetic acid methylester (2), which on treatment with 100% hydrazine hydrate yields (7-hydrazinocarbonylmethoxy-2-oxo-2H-chromen-4-yl)-acetic acid hydrazide (3). The condensation of compound 3 with different aromatic aldehydes afforded a series of [7-(arylidenehydrazinocarbonylmethoxy)-2-oxo-2H-chromen-4-yl]-acetic acid arylidene-hydrazide Schiff's bases 4a-k. Cyclo-condensation of compounds 4a-k with 2-mercapto-acetic acid in N,N-dimethylformamide in the presence of anhydrous ZnCl(2 )affordsN-(2-aryl-4-oxothiazolidin-3-yl)-2-(4-(2-aryl-4-oxothiazolidin-3-ylcarbamoyl)-methyl)-2-oxo-2H-chromen-7-yloxy)-acetamides 5a-k. Structure elucidation of the products has been accomplished on the basis of elemental analysis, IR, (1)H-NMR and (13)C-NMR data. Compounds 4a-k and 5a-k will be screened for their antibacterial activity against both Gram-positive and Gram-negative bacteria and the results reported elsewhere in due course.

Heavy metal distribution in tissues of six fish species included in human diet, inhabiting freshwaters of the Nature Park "Hutovo Blato" (Bosnia and Herzegovina).

The aim of the study was to quantify heavy metal (mercury, lead, cadmium, and arsenic) concentration in tissues (muscles, liver, kidney, gills, and gonads) of six fish species (carp: Cyprinus carpio, tench: Tinca tinca, pumpkinseed: Lepomis gibosus, prussian carp: Carassius auratus gibelio, hasselquist: Salmo dentex, eel: Anguilla anguilla) from the freshwaters of the Nature Park Hutovo Blato, Bosnia and Herzegovina, and determine whether they are potentially harmful for human health if included in the diet. Fish were angled from the Svitava Lake in the second part of August of the year 2003, and fish tissues were stored at -18 degrees C until analysis. Heavy metal concentration was determined by atomic absorption spectrophotometry in the Veterinary Institute Brno, Czech Republic, and expressed as mg.kg(-1) of wet tissue. Concentration of mercury, lead, and arsenic in most tissues of all analyzed fish types is lower than the maximal allowed concentration (MAC) in most countries. Cadmium concentration is also low in muscles and gonads, but kidney, liver, and gill concentrations exceed MAC value in most countries. Hasselquist, an endemic type for that region, differs from other fish types in the fact that it has very low cadmium concentration in liver and kidney, but the highest concentration of arsenic in most tissues, especially muscles. In muscles and gonads of all fish types analyzed, Pb is present in higher concentration than Cd, whereas in liver, gills, and particularly kidney, the situation is opposite, suggesting diverse metabolic pathways and unequal bioaccumulation of these two metals in different fish tissues. Although the region of the Nature Park Hutovo Blato in Bosnia and Herzegovina is not an agricultural territory, the intensive agricultural activities in the neighboring regions already result in high cadmium concentration in inner organs of fish species analyzed. Therefore, fish types in the freshwaters of the Park may be included in the human diet, but without inner organs and gills (or the whole head).

Heavy metal concentration in fish tissues inhabiting waters of "Busko Blato" reservoir (Bosnia and Herzegovina).

Heavy metals concentration (mercury, lead, cadmium, arsenic, copper, zinc and chromium) in tissues (muscles, liver, kidney and gonads) of Dalmatian barbelgudgeon, the nase, the souffie and brown trout, inhabiting waters of Busko Blato reservoir in Bosnia and Herzegovina, has been determined by atomic absorption spectrophotometry. The meat of the tested fish sorts does not contain elevated concentration of most analyzed heavy metals with exception of lead (higher than MAC in Italy, Germany and Denmark) and mercury (in muscles of brown trout higher than MAC in most countries). The lowest level of all heavy metals is always detected in gonads, with higher values in fry compared to milt for copper, zinc, chromium and arsenic. The highest copper concentration is observed in the liver from the souffie which is suggested as a suitable biomonitor for copper intoxication. In muscles of all fish sorts, lead was always present in much higher concentration than cadmium, while in kidneys of most fish sorts, lead and cadmium concentrations were similar. We showed that bioaccumulation of some heavy metals in the fish sorts analyzed is tissue and sex dependent. Also, we concluded that the small water exchange in reversible shallow reservoir does not induce elevated concentration of heavy metals in fish tissues inhabiting Busko Blato.

Synthesis and antimicrobial activity of some derivatives of (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid hydrazide.

(7-Hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid hydrazide (2) was prepared from (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid ethyl ester (1) and 100% hydrazine hydrate. Compound 2, is the key intermediate for the synthesis of several series of new compounds such as Schiff's bases 3a-l, formic acid N'-[2-(7-hydroxy-2-oxo-2H- chromen-4-yl)acetyl] hydrazide (4), acetic acid N'-[2-(7-hydroxy-2-oxo-2H-chromen-4- yl)-acetyl] hydrazide (5), (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid N'-[2-(4- hydroxy-2-oxo-2H-chromen-3-yl)-2-oxoethyl] hydrazide (6), 4-phenyl-1-(7-hydroxy-2- oxo-2H-chromen- 4-acetyl) thiosemicarbazide (7), ethyl 3-{2-[2-(7-hydroxy-2-oxo-2H- chromen-4-yl)-acetyl]hydrazono}butanoate (8), (7-hydroxy-2-oxo-2H-chromen-4-yl)- acetic acid N'-[(4-trifluoromethylphenylimino)methyl] hydrazide (9) and (7-hydroxy-2- oxo-2H-chromen-4-yl)acetic acid N'-[(2,3,4-trifluorophenylimino)-methyl] hydrazide (10). Cyclo- condensation of compound 2 with pentane-2,4-dione gave 4-[2-(3,5- dimethyl-1H-pyrazol-1-yl)-2-oxoethyl]-7-hydroxy-2H-chromen-2-one (11), while with carbon disulfide it afforded 7-hydroxy-4-[(5-mercapto-1,3,4-oxadiazol-2-yl)methyl]-2H- chromen-2-one (12) and with potassium isothiocyanate it gave 7-hydroxy-4-[(5- mercapto-4H-1,2,4-triazol-3-yl)methyl]-2H-chromen-2-one (14). Compound 7 was cyclized to afford 2-(7-hydroxy-2-oxo-2H-chromen-4-yl)-N -(4-oxo-2-phenylimino- thiazolidin-3-yl) acetamide (15).