Cimetna kiselina i njeni derivati

Cinnamic acid (3-phenylpropenoic or phenylacrylic acid) and its derivatives occur naturally in a number of plants. Th ey are precursors in the biosynthetic pathways of many alkaloids, aromatic amino acids, phenylpropanoids, styrenes, stilbenes, coumarins, lignins and fl avonoids, and are present in various essential oils, gums and balsams. Cinnamic acid derivatives are used in large quantities in the food, cosmetic and pharmaceutical industries. In addition, they possess a variety of pharmacological activities: antimicrobial, antitubercular, antioxidative, antimicrobial, antimalarial, antiviral, antidiabetic, hepatoprotective, antidepressant, anxiolytic, hypolipemic, anti-infl ammatory and cytostatic activities. Several drugs with cinnamic acid motifs are used in modern therapy (panobinostat, belinostat, cinanserin, tranilast, ozagrel and entacapone)

Lijekovi s fluorom

Naturally occurring organofluorine compounds are extremely rare. On the other hand, there are almost million of synthetic organofluorine compounds and their number is growing rapidly. Due to their unique physicochemical and biological characteristics, they are widely used as pharmaceuticals, materials and agrochemicals. Strategic incorporation of fluorine in drug-candidate became a common strategy in drug design and development. Organofluorine compounds have increased lipophilicity, membrane permeability, thermal and metabolic stability, and enhanced binding affinity to the targeted macromolecules compared to their nonfluorinated analogs. About 20 % of the currently marketed drugs contain fluorine. Organofluorine drugs are particularly popular among inhalation anesthetics, glucocorticoids, anticancer drugs, neuroleptics and antidepressants. Many blockbuster pharmaceuticals such as fluoxetine, rosuvastatin, atorvastatin, celecoxib, sitagliptin etc. contain fluorine. 18F-radiolabeled 2-fl uoro-2-deoxyglucose, florbetapir, florbetaben, flutemetamol and fluorodopa are used in positron emission tomography (PET) as medical diagnostics of neurodegenerative diseases and cancer. Inorganic compound sodium fluoride is used for the prevention of tooth decay. The fluoride enhances the strength of teeth by the formation of fluorapatite, a naturally occurring component of tooth enamel. Sodium fluoride, hexafluorosilicic acid and sodium hexafluorosilicate are commonly used for water fluoridation, while sodium and tin(II) fluoride are components of toothpaste

ANALYSIS OF FINANCIAL STATEMENTS ON EXAMPLE OF COMPANY ILIRIJA D.D.

Predmet ovog završnog rada je analiza temeljnih financijskih izvještaja poduzeća Ilirija d.d. na temelju koje će se ocijeniti uspješnost poslovanja istoga. Financijski izvještaji su izvještaji o financijskom stanju i prometu nekog poduzeća. Temeljna financijska izvješća u Hrvatskoj prema Zakonu o računovodstvu su: bilanca, račun dobiti i gubitka, izvještaj o ostaloj sveobuhvatnoj dobiti, izvještaj o promjenama kapitala, izvještaj o novčanim tokovima te bilješke uz financijske izvještaje. Kako bi se dobile informacije o tome posluje li ovo poduzeće uspješno ili neuspješno, analizira se bilanca, račun dobiti i gubitka te izvještaj o novčanim tokovima poduzeća Ilirija d.d. Kao metode analize financijskih izvještaja koriste se horizontalna i vertikalna analiza te analiza financijskih pokazatelja. Horizontalna analiza omogućuje uspoređivanje podataka u financijskim izvještajima kroz duže vremensko razdoblje, dok vertikalna analiza omogućuje uspoređivanje podataka u financijskim izvještajima u jednoj godini. Analiza putem financijskih pokazatelja se najčešće provodi na način da se koriste indeksi koji povezuju dva financijska podatka, a temeljni financijski pokazatelji koji će se analizirati su: pokazatelji likvidnosti, pokazatelji zaduženosti, pokazatelji aktivnosti, pokazatelji ekonomičnosti i pokazatelji profitabilnosti.The subject of this final paper is an analysis of the financial statements of Ilirija d.d. based on which will evaluate business performance. Financial statements are statements about the financial condition and business traffic of a company. The basic financial statements in Croatia according to the Accounting Act are: balance sheet, income statement, statement of other comprehensive income, statement of changes in equity, cash flow statement and notes to the financial statements. In order to get information on whether this company works successfully or unsuccessfully, it will be analyzed the balance sheet, income statement and cash flow statement of Ilirija d.d. As methods of analysis of financial statements are used horizontal and vertical analysis and analysis of financial ratios. Horizontal analysis enables the comparison of information in the financial statements for a longer period of time, while the vertical analysis enables the comparison of information in the financial statements in one year. Analysis by financial ratios are most often carried out in a way to use indexes that link two financial data, and basic financial indicators which will be analyzed are: liquidity ratios, leverage ratios, activity ratios, economy ratios and profitability ratios

Synthesis, characterization and biological activity of primaquine semicarbazides, ureas and ureidoamides

U okviru ovog doktorskog rada, koji predstavlja nastavak istraživanja o mogućnostima derivatizacije antimalarijskog lijeka primakina (PQ) u Zavodu za farmaceutsku kemiju Farmaceutsko-biokemijskog fakulteta Sveučilišta u Zagrebu, sintetizirane su bis-uree PQ 11 te uree i semikarbazoni 12 s velikim arilnim i hidroksialkilnim supstituentima, konjugati PQ i derivata cimetne kiseline (DCK) amidnog 15 i acilsemikarbazidnog tipa 16 te ureidoamidi PQ 20. Većina derivata PQ pripremljena je koristeći benzotriazolsku metodu – klorid 1-benzotriazolkarboksilne kiseline (BtcCl) s nukleofilima daje cijeli niz vrlo reaktivnih prekursora koji su upotrijebljeni u sintezi navedenih derivata PQ. Za pripremu bis-urea 11 primijenjena su dva sintetska pristupa. U prvom pristupu produkti su „rasli” sa semikarbazidne strane, a PQ je ulazio u molekulu zadnji, dok su u drugom pristupu produkti sintetizirani iz zajedničkog prekursora semikarbazida PQ 9. Drugi pristup bio je prikladniji za pripremu cijele serije bis-urea. Derivati PQ 12 sintetizirani su iz benzotriazolida 8, 2c ili 2d i odgovarajućih amina ili izravno iz PQ i izocijanata. PQ-DCK amidi 15 i acilsemikarbazidi 16 pripremljeni su iz odgovarajućih klorida 14 i PQ ili semikarbazida PQ 9. Amidi 15d,e,g pripremljeni su dodatno aminolizom benzotriazolida DCK 13 primakinom. Derivati PQ i aminokiselina ureidoamidi 20 pripravljeni su iz PQ i odgovarajućih amida N-(1-benzotriazolkarbonil)aminokiselina 19. Svi sintetizirani spojevi karakterizirani su uobičajenim analitičkim i spektroskopskim metodama te im je in vitro ispitano citostatsko djelovanje, kao i antioksidativno djelovanje na temelju sposobnosti redukcije 1,1-difenil-2-pikrilhidrazila (DPPH) te inhibicije lipidne peroksidacije linolne kiseline i lipooksigenaze. Najbolje citostatsko djelovanje na staničnu liniju MCF-7 adenokarcinoma dojke pokazao je spoj 16j, a slijedio ga je 11f s povoljnijim omjerom citostatske aktivnosti i citotoksičnosti. Najjaču sposobnost redukcije DPPH pokazali su spojevi 16d,g,i,j,k, najjači inhibitori lipidne peroksidacije bili su spojevi 20c i 12d, a najsnažniji inhibitor lipooksigenaze bio je spoj 16d. Iz dobivenih rezultata može se zaključiti da su bis-uree i acilsemikarbazidni derivati primakina aktivniji od urea i amida te mogu poslužiti kao vodeći spojevi u razvoju novih citostatika i antioksidansa.This doctoral thesis describes synthesis of various primaquine (PQ) derivatives: bis-ureas 11, ureas and semicarbazones 12 with bulky aryl or hydroxyalkyl substituents, PQ-cinnamic acid conjugates (PQ-CAD) of the amide 15 and acylsemicarbazide type 16, and ureidoamides 20, as a continuation of the previous work on the derivatization of the antimalarial drug PQ developed at the Department of Medicinal Chemistry, Faculty of Pharmacy and Biochemistry in Zagreb. Most PQ derivatives were prepared utilizing benzotriazole as a synthetic auxiliary – 1-benzotriazolecarboxylic acid chloride (BtcCl) reacts readily with nucleophiles affording a variety of highly reactive synthetic precursors for the synthesis of the title compounds. Two synthetic approaches for the preparation of the PQ bis-ureas 11 were applied. In the first approach, the products grew from the semicarbazide part, and PQ entered the molecule at the final stage. In the second approach, one common precursor PQ semicarbazide 9 was introduced, from which various PQ bis-ureas were prepared. Derivatives 12 were obtained in the reaction of benzotriazolide 8, 2c or 2d with corresponding amines or directly from PQ and isocyanate. PQ-CAD amides 15 and acylsemicarbazides 16 were prepared from the corresponding chlorides 14 and PQ or PQ semicarbazide 9, respectively. Additionally, amides 15d,e,g were obtained by aminolysis of CAD benzotriazolide 13 with PQ. Ureidoamide derivatives of PQ and amino acids 20 were synthesized in the reaction of PQ and corresponding N-(1-benzotriazolecarbonyl)amino acid amides 19. Common analytical and spectroscopic methods for the characterization of the synthesized compounds were used. Their cytostatic activity, antioxidative activity by DPPH reducing ability, and inhibition of linoleic acid lipid peroxidation and lipoxygenase were evaluated in vitro. The most prominent cytostatic activity on MCF-7 breast adenocarcinoma cell line was exerted by compound 16j, followed by 11f having more favourable ratio of antiproliferative activity and cytotoxicity. Compounds 16d,g,i,j,k had the strongest DPPH reducing ability, whereas compounds 20c and 12d showed the highest inhibition of linoleic acid lipid peroxidation. The most potent lipoxigenase inhibitor was compound 16d. The obtained results indicate that PQ bis-ureas and acylsemicarbazides are more active than ureas and amides, and therefore could be considered as lead compounds in development of novel cytostatics and antioxidants

Application of the deterministical and stochastical geostatistical methods in petrophysical modelling - a case study of Upper Pannonian reservoir in Sava Depression

Deterministic methods are still widely used for reservoir characterization and modelling. The result of such methods is only one solution. It is clear that our knowledge about the subsurface is uncertain. Since stochastic methods include uncertainty in their calculations and offer more than one solution sometimes they are the best method to use. This paper shows testing of the deterministic (Ordinary Kriging) and stochastic (Sequential Gaussian Simulations) methods of reservoir properties distribution in the Lower Pontian hydrocarbon reservoirs of the Sava Depression. Reservoirs are gas- and oil-prone sandstones. Ten realizations were obtained by Sequential Gaussian Simulation, which are sufficient for defining locations with the highest uncertainties of distributed geological variables. The results obtained were acceptable and areas with the highest uncertainties were clearly observed on the maps. However, high differences of reservoir property values in neighbouring cells caused the numerical simulation duration to be too long. For this reason, Ordinary Kriging as a deterministic method was used for modelling the same reservoirs. Smooth transitions between neighbouring cells eliminated the simulation duration problems and Ordinary Kriging maps showed channel sandstone with transitional lithofacies in some reservoirs. </span

Iron Phosphate Glass-ceramics

The crystallization of 40Fe2O3-60P2O5, 10ZnO-30Fe2O3-60P2O5 and (43.3−x)PbO–(13.7+x)Fe2O3–43P2O5, (0 < x < 30), glasses and glass-ceramic have been investigated. The structural evolution of glasses during heat treatment at various temperatures and the tendency for crystallization for series of glasses with modified composition are characterized by a dendrite-like phase separation in the early stage of crystallization. Such a behavior leads to the formation of randomly dispersed agglomerates which contain the anhedrally shaped crystallites embedded in glass matrix. Therefore, regardless of the type of crystallization, controlled or spontaneous, the formation of crystalline phases in these phosphate glasses and glass-ceramics is attributed to the disordered interfaces between crystalline grains and glassy matrix

Synthesis and Biological Evaluation of Harmirins, Novel Harmine–Coumarin Hybrids as Potential Anticancer Agents

As cancer remains one of the major health burdens worldwide, novel agents, due to the development of resistance, are needed. In this work, we designed and synthesized harmirins, which are hybrid compounds comprising harmine and coumarin scaffolds, evaluated their antiproliferative activity, and conducted cell localization and cell cycle analysis experiments. Harmirins were prepared from the corresponding alkynes and azides under mild reaction conditions using Cu(I) catalyzed azide–alkyne cycloaddition, leading to the formation of the 1H-1, 2, 3-triazole ring. Antiproliferative activity of harmirins was evaluated in vitro against four human cancer cell lines (MCF-7, HCT116, SW620, and HepG2) and one human non-cancer cell line (HEK293T). The most pronounced activities were exerted against MCF-7 and HCT116 cell lines (IC50 in the single-digit micromolar range), while the most selective harmirins were 5b and 12b, substituted at C-3 and O-7 of the β-carboline core and bearing methyl substituent at position 6 of the coumarin ring (SIs &gt; 7.2). Further experiments demonstrated that harmirin 12b is localized exclusively in the cytoplasm. In addition, it induced a strong G1 arrest and reduced the percentage of cells in the S phase, suggesting that it might exert its antiproliferative activity through inhibition of DNA synthesis, rather than DNA damage. In conclusion, harmirin 12b is a novel harmine and coumarin hybrid with significant antiproliferative activity and warrants further evaluation as a potential anticancer agent

Harmicens, Novel Harmine and Ferrocene Hybrids: Design, Synthesis and Biological Activity

Cancer and malaria are both global health threats. Due to the increase in the resistance to the known drugs, research on new active substances is a priority. Here, we present the design, synthesis, and evaluation of the biological activity of harmicens, hybrids composed of covalently bound harmine/β-carboline and ferrocene scaffolds. Structural diversity was achieved by varying the type and length of the linker between the β-carboline ring and ferrocene, as well as its position on the β-carboline ring. Triazole-type harmicens were prepared using Cu(I)-catalyzed azide-alkyne cycloaddition, while the synthesis of amide-type harmicens was carried out by applying a standard coupling reaction. The results of in vitro biological assays showed that the harmicens exerted moderate antiplasmodial activity against the erythrocytic stage of P. falciparum (IC50 in submicromolar and low micromolar range) and significant and selective antiproliferative activity against the MCF-7 and HCT116 cell lines (IC50 in the single-digit micromolar range, SI &gt; 5.9). Cell localization experiments showed different localizations of nonselective harmicene 36 and HCT116- selective compound 28, which clearly entered the nucleus. A cell cycle analysis revealed that selective harmicene 28 had already induced G1 cell cycle arrest after 24 h, followed by G2/M arrest with a concomitant drastic reduction in the percentage of cells in the S phase, whereas the effect of nonselective compound 36 on the cell cycle was much less pronounced, which agreed with their different localizations within the cell

Design, synthesis and biological evaluation of novel primaquine-cinnamic acid conjugates of the amide and acylsemicarbazide type

In this paper design and synthesis of a scaffold comprising primaquine (PQ) motif and cinnamic acid derivatives (CADs) bound directly (compounds 3a–k) or via a spacer (compounds 7a– k) are reported. In the first series of compounds, PQ and various CADs were connected by amide bonds and in the second series by acylsemicarbazide functional groups built from the PQ amino group, CONHNH spacer and the carbonyl group originating from the CADs. PQ- CAD amides 3a–k were prepared by a simple one- step condensation reaction of PQ with a series of CAD chlorides (method A) or benzotriazolides 2 (method B). The synthesis of acylsemicarbazides 7a–k included activation of PQ with benzotriazole, preparation of PQ- semicarbazide 6 and its condensation with CAD chlorides 4. All synthesized PQ-CAD conjugates were evaluated for their anticancer, antiviral and antioxidative activities. Almost all compounds from series 3 were selective towards the MCF-7 cell line and active at micromolar concentrations. The o-fluoro derivative 3h showed high activity against HeLa, MCF-7 and in particular against the SW 620 cell line, while acylsemicarbazide 7f with a benzodioxole ring and 7c, 7g and especially 7j with methoxy-, chloro- or trifluoromethyl-substituents in the para position showed high selectivity and high inhibitory activity against MCF-7 cell line at micromolar (7c, 7f, 7g) and nanomolar (7j) levels. Acylsemicarbazide derivatives with trifluoromethyl group(s) 7i, 7j and 7k showed specific activity against human coronavirus (229E) at concentrations which did not alter the normal cell morphology. The same compounds exerted the most potent reducing activity in the DPPH test, together with 7d and 7g, while methoxy (compounds 7c–e), benzodioxole (7f), p- Cl (7g) and m-CF3 (7i) acylsemicarbazides and amide 3f presented the highest LP inhibition (83%–89%). The dimethoxy derivative 7d was the most potent LOX inhibitor (IC50 = 10 μΜ). The performed biological tests gave evidence of acylsemicarbazide functional group as superior binding group in PQ-CAD conjugates

Primary and secondary prevention of cardiovascular diseases embedded in the visiting nurse services: description of the intervention model [Primarna i sekundarna prevencija kardiovaskularnih bolesti uklopljena u patronažnu djelatnost: opis modela intervencije]

The paper describes a visiting nurse led intervention model for the primary and secondary prevention of cardiovascular diseases (CVD) and specificities of its application. Although CVD burden is high in Croatia, the visiting nurse services have not been specifically focused on CVD prevention in the population until now. The intervention model described here is being implemented alongside the second cycle of the Croatian Adult Health Survey (2008 CAHS). The model includes an objective evaluation of respondents' CVD risk factors through quantitative and qualitative analyses, as well as respondents' self-evaluation of risk factors and motivation to change. At the same time, respondents are educated and intervention is evaluated. A 'health booklet' was specifically designed for documentation during one year's follow-up, where both the user and the visiting nurse keep copies of the negotiated targets and strategies set to achieve them. This intervention model has the potential to mobilize the service towards permanent incorporation of primary and secondary CVD prevention into routine care and, due to work specificities of the visiting nurse services, to cover the entire population in an organized CVD prevention