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Thiazolidinediones are heterocyclic compounds, also known as glitazones, which possess thiazolidine core. This class of compounds is used in the production of drugs for the treatment of diabetes mellitus type 2. Depending on the substituents, the thiazolidinedione derivatives may possess different biological activities such as anti-diabetic, anti-cancer, anti-arthritic, anti-inflammatory, anti-microbial and anti- melanoma. Various studies have been performed showing different biological activities of thiazolidinediones associated with enzymes like aldose reductase (ALR2), histone deacetylase (HDAC), phosphoinositide 3-kinases (PI3Ks), pim kinase, mitogen activated protein kinase (MEK), protein tyrosine phosphatase 1B (PTP1B), tyrosinases, cyclooxygenase-2 (COX-2), UDP-N- acetylmuramoylalanine D-glutamate ligase (MurD ligase). Due to different biological activities, numerous methods for the synthesis of thiazolidinedione derivatives have been developed. Many methods for the synthesis of these compounds are conventional and are not environmentally acceptable due to utilization of various catalysts and organic solvents. In order to reduce the formation of harmful substances during the synthesis, deep eutectic solvents can be used. Deep eutectic solvents are considered green solvents according to their properties like low toxicity, low inflammability, high recyclability and low volatility. The aim of this work was to synthesize thiazolidinedione derivatives by an environmentally acceptable method. Thiazolidinediones were obtained via Knoevenagel condensation in deep eutectic solvent (choline chloride:N-methylurea) at 80 °C in reactions between substituted benzaldehydes and thiazolidine-2, 4-dione. Synthesized thiazolidinediones are obtained in yields from 21.49 % to 90.90 % and compounds showed lipoxygenase inhibition in the range from 7.7 % to 76.3 %.

I ncreasing need in drug consumption during last few decades, lead to the development of the pharmaceutical industry, thus increasing the synthesis of compounds with positive effects on human health. Mass production leads to the increased waste production and environmental pollution. Therefore, emphasis is placed on the green production methods and technologies. In organic synthesis, pollutants can be various solvents as well as catalysts. It is also important to reduce the energy consumption that can be achieved by using ultrasound and microwave irradiation. One of the green approaches in the synthesis is utilization of deep eutectic solvents (DESs), which can be used both as solvents and catalysts. DESs are composed of biodegradable and environmentally benign components. The advantages of the deep eutectic solvents are low toxicity, low inflammability, high availability, high recyclability, low volatility and low price. Among the many desired compounds that are synthesized today, rhodanine derivatives are compounds that have been increasingly synthesized due their significant biological activities such as antibacterial, antimalarial, herbicidal, antifungal, antitumor, insecticidal, antiviral, anti- inflammatory and cardiotonic activities. It has been reported that rhodanine derivatives can potentially be used in the treatment of obesity, cystic fibrosis, diabetes, Alzheimer’s disease, thrombocytopenia, cancer, sleep, mood and central nervous system disorders as well as chronic inflammation. In this work Knoevenagel condensation of salicylaldehydes and rhodanine was conducted under different conditions. Initially, reaction was performed in 20 different DESs at 80 °C in order to find the suitable reaction media. Choline chloride based DESs are synthesized from choline chloride as a hydrogen bond acceptor and 20 different hydrogen bond donors (carboxylic acids, sugars, ureas or amides). The best reaction media was proven to be ChCl:acetamide DES, with the highest product yield of 96.3 %, followed by ChCl:malonic acid, ChCl:levulinic acidand 1, 3- dimethylurea with the yields of 91.1 %, 85.8 % and 80.1 %, respectively. Reaction of rhodanine and salicylaldehyde was performed in four mentioned DESs under microwave and ultrasound irradiation, and with DES as a catalyst in order to find the best reaction conditions.

Due to the growing use of bioactive components in the food and in the pharmaceutical industry, rapid development of various methods for their extraction and separation is required. In the last few years, deep eutectic solvents (DESs), composed of a hydrogen bond acceptor (HBA) and hydrogen bond donor (HBD) components, stand out as an appropriate substitution to conventional solvents due to their properties, with emphasis on non- toxicity, thermal stability and biodegradability, with easy preparation and low price of components. Alchemilla vulgaris L. is a plant that is often used in folk medicine as it possesses numerous health-promoting benefits due to its specific chemical composition with emphasis on phenolic acids and elagitannins. The most important components with antioxidant activity in sage are phenolic acids, such as gallic and ellagic acid as well as elagitannins which can be extracted by various extraction techniques, most commonly solid-liquid extraction. The aim of this paper was to select the most suitable choline chloride based deep eutectic solvent for the extraction of gallic and ellagic acid as well as elagitannins from lady's mantle (Alchemilla vulgaris L.) and then optimize extraction conditions for extraction with stirring and heating, ultrasound-assisted extraction and mechanoextraction. Seventeen different choline chloride-based DESs with different volumes of water (10%, 30%, and 50% (v/v)) were used for the extraction at different temperatures (30, 50, and 70 °C) to investigate the influence on this extraction parameters on yield of desired components. The results obtained were compared with the results obtained by extraction with conventional solvents. Gallic and ellagic acid content was obtained by high- performance liquid chromatography with diode-array detector (HPLC- DAD) and total ellagitannins were determined spectrophotometrically in the obtained extracts. Screening revealed that among 17 different DESs, the most suitable solvent is choline chloride: urea (1:2) and the most suitable extraction technique is extraction with stirring and heating. According to the results, the prepared solvents prove to be a good substitute for organic solvents in the extraction of bioactive components from lady's mantle plant.

Environmental pollution has led to the development of numerous methods in organic synthesis that are considered as green and environmental friendly. The application of deep eutectic solvents (DESs) in organic synthesis is considered a green method due to avoidance of organic solvents and toxic catalysts. Recently, DESs, due to their properties (thermal stability, low vapor pressure, biodegradability, nonflammability and component for their preparation are very cheap and easily available), are increasingly replacing conventional solvents. Many compounds are synthesized for the purposes of the pharmaceutical, food and many others industries. In this work three groups of compounds are synthesized, namely coumarins, rhodanines and thiazolidinediones. All compounds are synthesized in DESs via Knoevenagel condensation. Initially, model reaction was performed in 20 various DESs at 80 °C in order to find the best reaction media for each compound group. DESs are based on choline chloride (ChCl) as hydrogen bond acceptor and 20 other components in role of hydrogen bond donors. According to the highest yields obtained, it turned out that ChCl:urea, ChCl:acetamide and ChCl:N-methylurea are the best reaction medias for synthesis of coumarine, rhodanine and thiazolidinedione derivatives, respectively. Coumarine, rhodanine and thiazolidinedione derivatives (Scheme 1) were successfully synthesized and isolated. Coumarins are obtained in the yields from 6 to 98 %. The yields of synthesized rhodanine and thiazolidinedione derivatives were in the range 51 – 99 % and 21 – 90 %, respectively.

Marine algae are known for their numerous benefits and pharmacological effect due to the presence of various bioactive compounds such as terpenoids, meroterpenoids, lipids, phlorotannins and phenolic compounds. Phlorotannins usually serve as a plant defense system against different adverse conditions and are often associated with different biological activities of macroalgae extracts, such as antifungal against Candida sp., antibacterial, anti-inflammatory, antioxidant, antitumor and neuroprotective. Phlorotannins possess numerous - OH groups in their structure, making them a highly hydrophilic molecules which can be extracted using polar deep eutectic solvents (DES).Fifteen different choline chloride based DESs were used for extraction of phlorotannins from Padina pavonica and Cytoseira compressa. Phlorotanin content and antioxidant activity (DPPH method) were determined spectrophotometrically in obtained extracts. Phlorotannines content is much higher in most of the C. compressa extracts compared to P. pavonica. For C. compressa, choline chloride:lactic acid (1:2) showed the best results, considering both phlorotannin yield and DPPH scavenging activity. In the case of P. pavonica extracts, choline chloride:urea (1:2) was the most efficient for the extraction of phlorotannins and the best DPPH scavenging activity was obtained with choline chloride:thiourea (1:2).

The mandarin peels are most valuable by- products due to their content of bioactive compounds which have shown health-related properties including antioxidant, anticancer and anti-inflammatory. The extraction of bioactive compounds can be performed in deep eutectic solvents (DESs), which are composed of a hydrogen bond acceptor and hydrogen bond donor components. The advantages of using DESs as extraction media are their non-toxicity, thermal stability, biodegradability and easy preparation. The peels of Citrus reticulata Blanco cultivars of a different variety (Zorica rana, Chahara, Okitsu, Kuno) from the Opuzen were extracted in 15 different choline chloride based DESs at 50 °C for 30 min and with the 20% of added water. The extracts were analysed by high performance liquid chromatography (HPLC) to found the most suitable choline chloride based DES for the extraction of the highest amount of hesperidin. Screening showed that the best solvent was choline chloride:acetamide (1:2) and the highest amount of hesperidin was found in variety Zorica rana. The results showed that the amounts of extracted hesperidin were completely different according to the used mandarin variety. Furthermore, the application of deep eutectic solvents for the extraction exhibited strong potential for the production of the extracts rich in bioactive compounds.

1, 2, 3-Triazole and 1, 2, 4-triazole are two isomers of five-membered nitrogen containing heterocyclic compound. 1, 2, 4-Triazole derivatives are biologically active components with many human health positive effects (antibacterial, antifungal, antitumor, anticonvulsant, anti-inflammatory, antimicrobial). There are many methods for 1, 2, 4-triazole synthesis, but most of them include organic solvents and catalyst which are toxic [1]. In this research deep eutectic solvents (DESs) are used as tunable media for chemical synthesis of desired compounds. DESs are environmental-friendly solvents due to their properties (non-toxic, low vapor pressure, biodegradability, chemical stability) [2]. A reaction of 2-((4-methyl-2-oxo-2H-chromen-7-yl)oxy)acetohydrazide and phenyl isothiocyanate (Sheme 1) was performed in 14 different choline chloride based DESs and at two different temperatures (40 °C and 80 °C). In choline chloride:urea (1:2) and choline chloride:N-methyl urea (1:3) DESs at 80 °C pure 1, 2, 4-triazole was obtained. At 40 °C, in choline chloride:ethane-1, 2-diol (1:2), choline chloride:malic acid (1:1), choline chloride:malonic acid (1:1), choline chloride:butane-1, 4-diol (1:3) and choline chloride:glycerole (1:2) pure thiosemicarbazide was obtained. The temperature as well as deep eutectic solvent significantly affected compound formation.

Nowadays, the biologically active compounds attract considerable attention due to their various biological and pharmaceutical properties. Many of these compounds can be extracted from plants, but due to their increased use for medical purposes, they are increasingly synthesized in laboratories. Coumarins are an important class of biologically active compounds and play an important role in nature, acting as the plant growth hormones and growth regulators, participating in a respiration control, photosynthesis, and defense against infections. Coumarins are also attributed to a range of medical applications, such as the anticancerogenic, antioxidant, and anti‐HIV one, acting as an enzyme inhibitor, vasorelaxant, anticoagulant, an antibacterial agent, and much more. Among many reactions for coumarin synthesis (the Pechmann condensation reaction, Witting, Claisen, Reformatsky, and Kontanecki‐Robinson reaction), the most used reaction is the Knoevenagel condensation. An important factor in chemical synthesis is a usage of the environment‐friendly solvents. One of the green approaches in synthesis is a usage of the deep eutectic solvents (DESs) as the reaction media. The DESs possess many desired properties, such as a low toxicity, high availability, low inflammability, high recyclability, low volatility and low price. The aim of this work was to synthesize the coumarin derivatives via Knoevenagel condensation using the green solvents (DESs) under conditions established to be the best ones by a previously performed screening. A model reaction of salicylaldehyde and dimethyl malonate was performed in 20 different DESs at 80 °C. Choline chloride was used as a hydrogen bond acceptor, and 20 other components like urea, carboxylic acids, sugars or amides were the hydrogen bond donors. ChCl:Urea (ChCl:U, 1:2) is proven to be the best solvent, which afforded a yield of 50.5%, followed by the ChCl:N-methylurea (1:3) with a yield of 45.1%. Based on the obtained results, a series of coumarin derivatives was synthesized from the substituted salicylaldehydes and dimethyl malonate, diethyl malonate, or ethyl benzoylacetate.

The development of pharmaceuticals and drug production has led to an increase in synthesis of compounds that have a positive effect on human health. Nowadays, attention is increasingly being drawn to the green synthesis technologies. One of the green approaches in synthesis is usage of deep eutectic solvents (DESs) since those solvents are easily synthesized from biodegradable and environmentally benign components. Also DESs have low toxicity, high availability, low inflammability, high recyclability, low volatility and low price [1]. In this research deep eutectic solvents (DESs) are used as reaction media and catalyst. Among the many desired compounds that are synthesizing today, rhodanine derivatives are compounds that have been increasingly synthesized due their significant biological activities such as antibacterial, antifungal, antiviral, antimalarial, insecticidal, herbicidal, antitumor, anti-inflammatory and cardiotonic activities. It has been reported that rhodanine derivatives can potentially be used in the treatment of diabetes, obesity, Alzheimer’s disease, cystic fibrosis, thrombocytopenia, cancer, sleep, mood and central nervous system disorders as well as chronic inflammation [2]. In this work Knoevenagel condensation of salicylaldehyde and rhodanine in 20 different DESs at 80°C is performed in order to find the best reaction media. DESs are based on choline chloride (ChCl) as hydrogen bond acceptor and 20 other components in role of hydrogen bond donors like urea, carboxylic acids, sugars or amides. Product was obtained in all reaction media, but in different yields. The best reaction media was proven to be ChCl:acetamide (ChCl:A, 1:2) with highest yield of 96.3 % followed by ChCl:malonic acid (ChCl:MA, 1:1) with yield of 91.1 %.

A study of 1, 2, 4‐triazoles synthesis from 2‐ ((4‐methyl‐2‐oxo‐2H‐chromen‐7‐ yl)oxy)acetohydrazide (1) or 2‐(7‐hydroxy‐2‐ oxo‐ 2H‐chromen‐4‐yl)acetohydrazide (2) and various isothiocyanates, in deep eutectic solvents was performed. In order to find the best conditions for 1, 2, 4‐triazole formation, a model reaction on 1 and phenylisothiocyanate was performed in 14 different choline chloride based deep eutectic solvents, at two different temperatures (40°C and 80°C). Pure 1, 2, 4‐ triazoles were obtained in choline chloride:urea (1:2) and choline chloride:N‐ methyl urea (1:3) deep eutectic solvents at 80°C. Pure thiosemicarbazides were obtained in choline chloride:ethane‐1, 2‐diol (1:2), choline chloride:malic acid (1:1), choline chloride:malonic acid (1:1), choline chloride:butane‐1, 4‐diol (1:3) and choline chloride:glycerole (1:2) at 40°C. The ratio of 1, 2, 4‐triazoles and thiosemicarbazides in reaction mixtures was determined by HPLC and 1H NMR. After the best conditions for 1, 2, 4‐ triazole synthesis were found, a some coumarinyl 1, 2, 4‐ triazoles were synthesized from two different coumarinyl hydrazides (1 and 2) and various alkyl and aryl isothiocyanates in one step reaction.

Introduction: A synthesis of biologically active compounds for potential application in medicine, pharmacy, cosmetic industry, have been intensified in the last few decades. Not only it became desirable to find a new synthetic paths for the synthesis of such heterocyclic compounds, the focus has been put on finding the synthetic routes with the minimal adverse impact on the environment. When utilizing a green chemistry procedures and methods in the synthesis, one can be guided by the green chemistry principles. Deep eutectic solvents (DES), as a green solvents, fit these green chemistry principles, since they are synthesized from non-toxic and cheap biodegradable components, with 100% atom economy. They are formed from the hydrogen bond acceptor (HBA) and hydrogen bond donor (HBD), mixed together in various ratios, to form a eutectic mixture. DES have been extensively used in a wide range of synthetic transformations, both as the solvents and catalysts. Our work is focus on choline chloride based DES which were successfully applied for the synthesis of different heterocyclic compounds. Materials and methods DES synthesis: an equimolar amount of choline chloride and corresponding HBD is mixed together and heated to 80 °C until a clear liquid is formed. Thus synthesized DES is used in the synthesis of desired compounds without further purification. N-Acetylation of different amines: Amines and acetic anhydride are mixed together (1:1.2 molar ratio) and added to choline chloride:urea (1:2) DES. The reaction was monitored by TLC, yielding acetylated amines in good to excellent yields. Synthesis of mercapto quinazolinones: An equimolar amount of anthranilic acid and various isothiocyanates was added to corresponding DES and stirred until the completion of reaction monitored on TLC. Synthesis of coumarinyl Schiff bases: an equimolar amount of coumarinyl hydrazide and substituted aldehydes was mixed together and stirred until all reactatns were consumed. A solid product precipitated upon addition of water. One-pot synthesis of 1, 2, 4-triazoles: Coumarinyl hydrazides and substituted isothiocyanates were mixed and stirred in DES until the completion of reaction. Water was added and the solid product precipitated. Results and discussion Since DES can be synthesized from different HBA and HBD, their physical and chemical properties vary greatly, depending on the components mixed together, so they can be referred to as tunable solvents. Their ability to be recycled for several times without adverse effect on the reaction products makes them even more desirable in synthetic chemistry. They have been successfully applied for the synthesis of different heterocyclic compounds with no need for catalysts. N-Acetylated amines were successfully synthesized in good to excellent yields in this improved reaction, since the amount of acetic anhydride which is often used in these kind of reactions, was drastically reduced. Mercapto quinazolinones were successfully synthesized in choline chloride:urea DES with no need for catalysts, which are usually utilized in this kind of reaction. Obviously, DES can serve as a solvent and as catalyst as well. Coumarinyl Schiff bases were also synthesized in good to excellent yields, with no need for addition of acetic acid as a catalyst. One-pot synthesis of 1, 2, 4-triazoles was also performed, with no catalysts needed, form corresponding hydrazide and isothiocyanates. Deep eutectic solvents were proven to be an excellent reaction media for all these reactions, while the isolation of the products was very easy, and included only the addition of water and filtration.

Extraction of rutin from Ruta graveolens L. leaves was performed in choline chloride based deep eutectic solvents (DESs). Firstly, rutin extraction was performed in five different DESs ; pure DESs and with different amounts of water added (25% and 50% v/v), for different times (1h, 3h and 6h) in order to find the best DES for further optimization. Choline chloride plus citric acid (1:1) was shown to be best DES and optimization of rutin extraction was performed using response surface methodology (RSM) based on the selected solvent and applying different extraction parameters: extraction time, temperature and water content. The rutin content was determined by HPLC and varied from 0.55 g/100 g of plant to 1.81 g/100 g of plant depending on the applied conditions. The best conditions for rutin extraction were found to be: a temperature of 70°C, an extraction time of 52 min and a water content of 27% for the extraction of 1.88g /100 g plant.

Coumarins are a class of compounds widely distributed in plant kingdom, but lots of synthetic work has been done on them in the last few decades as well. Most synthetic routes utilize various toxic solvents and catalysts, leaving a significant environmental impact and tendency today is to reduce such negative impact whenever possible. For such purpose, deep eutectic solvents are often used. Deep eutectic are often used as green media for many synthetic routes and are often characterized as environmentally friendly [1-3]. Their application in organic synthesis and extraction, as well as an extensive analysis of their properties were described in some recent reviews [1-6]. The aim of our work was to synthesize a novel coumarinyl Schiff bases utilizing choline chloride/malonic acid based deep eutectic solvent as reaction media. Previously, a series of Schiff bases was synthesized [7] in our laboratory conventionally, but we have noticed their formation when deep eutectic solvents are applied. No need for specific catalyst, like acetic acid which is often used in these kinds of reactions, was noticed, since this eutectic solvent acted as a catalyst as well. Not only did we get a novel compounds, we applied an environmentally friendly approach, utilizing a solvent made of biodegradable components, with low toxicity and vapor pressure which can be easily recycled and reused.

Smeđe alge roda Cystoseira sadrže mnoštvo različitih bioaktivnih spojeva, od kojih su posebno zanimljivi florotanini zbog svojih različitih bioloških svojstava. U ovom radu je stoga fokus bio na ekstrakciji florotanina, koja je provedena s 15 različitih niskotemperaturnih eutektičkih otapala na bazi kolin-klorida. Ocjena učinkovitosti otapala donesena je na osnovu koncentracije florotanina i aktivnosti hvatanja \(DPPH^{*}\) radikala. Koncentracija florotanina u ekstraktu određena je spektrofotometrijskim mjerenjem pri valnoj duljini od 510 nm, a aktivnost hvatanja \(DPPH^{*}\) radikala mjerenjem apsorbancije pri 517 nm. Otapalo kolin-klorid:mliječna kiselina (1:2) pokazalo se kao najučinkovitije otapalo za ekstrakciju florotanina iz alge Cystoseira compressa. Brown algae from Cystoseira genus contain numerous bioactive compounds, such as phlorotannins, which are subject of interest in this study because of their various bioactive activities. Therefore, an extraction of phlorotannins in 15 different choline-chloride based deep eutectic solvents (DESs) was performed. The efficiency was assessed considering phlorotannin concentration and \(DPPH^{*}\) scavenging activity. Phlorotannin concentration in extracts was determined by spectrophotometric measurement at 510 nm and the \(DPPH^{*}\) activity by measuring absorbance at 517 nm. Choline chloride:lactic acid (1:2) DES proved to be the most effective solvent for the extraction of phlorotannins from the alga Cystoseira compressa.

Cilj ovog rada bilo je odrediti koja metoda i uvjeti ekstrakcije su najbolji za ekstrakciju bioaktivnih komponenti prisutnih u vrkuti ili gospinom plaštu (Alchemilla vulgaris) pomoću niskotemperaturnih eutektičkih otapala. Vrkuta je višegodišnja zeljasta biljka koja se koristi za liječenje kožnih bolesti, probavnih problema i slično. Bogata je bioaktivnim komponentama zbog čega ima antivirusno, antibakterijsko, antioksidativno i antiproliferativno djelovanje. Niskotemperaturna eutektička otapala se koriste kao nova održiva, sigurnija i zelenija alternativa komercijalnim otapalima, te pokazuju različitu funkcionalnost i topljivost za komponente koje se nalaze u biljci. Ekstrakcija niskotemperaturnim eutektičkim otapalima je provedena miješanjem i na ultrazvučnoj (UZV) kupelji. Bioaktivne komponente s naglaskom na hidrolizirane tanine, flavonoide i fenolne kiseline, identificirane su spektrofotometrijski odnosno tekućinskom kromatografijom visoke djelotvornosti (HPLC). Nakon identifikacije i kvantifikacije može se zaključiti da je ekstrakcija miješanjem na magnetskoj miješalici učinkovitija u odnosu na ekstrakciju potpomognutu ultrazvukom, te da prilikom ekstrakcije na visokoj temperaturi i kroz duže vrijeme dolazi do degradacije komponenti i smanjenog prinosa. The aim of this work was to determine which extraction method and conditions are best for the extraction of bioactive components present in lady's mantle (Alchemilla vulgarisI) using deep eutectic solvents. Lady’s mantle is a perennial herb that is used to treat skin diseases, digestive problems and similar conditions. It is rich in bioactive components, possessing antiviral, antibacterial, antioxidant and antiproliferative effects. Deep eutectic solvents are used as a new, sustainable, safer and greener alternative to commercial solvents and they show different functionality and solubility for components found in the plant. Extraction with deep eutectic solvents was performed using by stirring on magnetic stirrer and in ultrasonic (UZV) bath. Bioactive components, with an emphasis on hydrolyzed tannins, flavonoids and phenolic acids, were identified spectrophotometricaly or by high performance liquid chromatography (HPLC). After identification and quantification, it can be concluded that the extraction using a magnetic stirrer is more efficient compared to the ultrasound-assisted extraction and that high temperature and long extraction time cause degradation of components and a yield decrease.

Cilj ovog rada bio je razviti zelenu metodu za sintezu derivata kumarina, rodanina i tiazolidindiona primjenom niskotemperaturnih eutektičkih otapala na bazi kolin-klorida te ispitati njihovu biološku aktivnost. Za svaku grupu spojeva odabrana je modelna reakcija koja je provedena u 20 različitih niskotemperaturnih eutektičkih otapala, te je na temelju najvišeg iskorištenja odabrano najpogodnije otapalo za daljnju sintezu. Za sintezu derivata kumarina najpogodnijim otapalom pokazao se kolin-klorid : urea, za sintezu derivata rodanina kolin-klorid : acetamid, a za sintezu taizolidindiona kolin-klorid : N-metilurea. Sinteza serije ciljanih derivata provedena je na temelju odabira odgovarajućeg otapala, konvencionalnom metodom uz miješanje, reakcijom potpomognutom mikrovalovima, te ultrazvukom. Nadalje, u radu je ispitana inhibicija aktivnosti enzima lipooksigenaze iz soje te inhibicija lipidne peroksidacije sintetiziranim spojevima. Spojevima je također određena antioksidacijska aktivnost ABTS i DPPH metodom. Aktivnost lipooksigenaze uspješno je inhibirana 7,1 – 96,9 % derivatima kumarina, 3,7 – 100,0 % derivatima rodanina i 7,3 – 76,3 % derivatima tiazolidindiona. Dobiveni rezultati upućuju da sintetizirani spojevi imaju potencijala za sprječavanje dioksigenacije kod višestruko nezasićenih masnih kiselina i nastajanja konjugiranih dienskih hidroperoksida u prehrambenim proizvodima. The aim of this study was to develop a green method for the synthesis of coumarin, rhodanine and thiazolidinedione derivatives and to examine their biological activity. For each group of compounds, a model reaction was selected and performed in 20 different deep eutectic solvents in order to find the most suitable solvent for further synthesis based on the highest yield. The most suitable solvents for the synthesis of coumarin, rhodanine and thiazolidinedione derivatives were choline chloride : urea, choline chloride : acetamide and choline chloride : N-methylurea, respectively. After selecting the most suitable solvent, synthesis with stirring, microwave synthesis and ultrasound-assisted synthesis were performed. The synthesized compounds were tested for inhibition of lipid peroxidation as well as for inhibition of soybean lipoxygenase enzyme activity. The antioxidant activity of the compounds was also determined by the ABTS and DPPH method. Coumarin, rhodanine and thiazolidinedione derivatives successfully inhibited lipoxygenase activity with inhibition ranging 7.1 - 96.9%, 3.7 - 100.0% and 7.3 - 76.3%, respectively. According to the obtained results, it can be concluded that the synthesized compounds have the potential to prevent dioxygenation in polyunsaturated fatty acids and the formation of conjugated diene hydroperoxides in food products.

Primjena eutektičkih otapala u kemijskim sintezama predstavlja prihvatljivu alternativu najčešće korištenim organskim otapalima koja mogu biti štetna po zdravlje i okoliš. Ovom radu cilj je ispitati i dokazati mogućnost korištenja takvih dvokomponentnih otapala u sintezi Schiffovih baza. Schiffove baze su spojevi koji nastaju kondenzacijom aldehida ili ketona i primarnih amina. Takvi se spojevi smatraju podgrupom imina i predmet su brojnih istraživanja jer pokazuju potencijalna antimikrobna, antiviralna i antikancerogena svojstva. Prvi dio rada obuhvaća optimizaciju modelne reakcije u 20 eutektičkih otapala na bazi kolin-klorida, nakon čega slijedi sinteza 20 Schiffovih baza s kinazolinonskom jezgrom pri optimalnim uvjetima. The use of deep eutectic solvents in chemical syntheses is an acceptable alternative to the most commonly used organic solvents that can be harmful to human health and environment. The aim of this research was to investigate and prove the possibility of using such two - component solvents in the synthesis of Schiff bases. Schiff bases are compounds formed by the condensation of aldehydes or ketones and primary amines. Such compounds are considered a subgroup of imines and are the subject of many research because they show potential antimicrobial, antiviral and anticancer properties. The first part of the paper includes the optimization of the model reaction in 20 choline chloride based eutectic solvents, followed by the synthesis of 20 Schiff bases with quinazolinone nucleus under optimal conditions.

U okviru doktorskog rada sintezirani su 2,3-disupstituirani (1 – 130) i 3-supstituirani derivati kinazolin-4(3H)-ona (131 – 136) u niskotemperaturnim eutektičkim otapalima s ciljem njihove primjene u sintezi heterocikala. Sinteze derivata kinazolin-4(3H)-ona provedene su konvencionalno, potpomognute mikrovalovima i ultrazvukom te mehanokemijskim reakcijama. Niskotemperaturna eutektička otapala za sintezu novih spojeva priređena su miješanjem kolin-klorida (ChCl) i različitih amida, karboksilnih kiselina, ugljikohidrata i alkohola u određenom molarnom omjeru. Optimiranje reakcijskih uvjeta za svaku klasu spojeva provedeno je na odabranoj modelnoj reakciji izborom najpovoljnijeg niskotemperaturnog eutektičkog otapala, volumena otapala, temperature i vremena trajanja reakcije. Pri optimiranju mehanokemijske sinteze ispitan je dodatno i utjecaj količine kuglica. Derivati 2-merkapto-3-supstituiranih kinazolin-4(3H)-ona (1 – 50) sintetizirani su u otapalu ChCl : urea reakcijom antranilne kiseline i alifatskih te aromatskih izotiocijanata konvencionalno s iskorištenjima 19 – 76 %, sintezom potpomognutom mikrovalovima u iskorištenjima 10 – 49 %, sintezom potpomognutom ultrazvukom u iskorištenjima 17 – 64 % i mehanokemijskom sintezom s iskorištenjima 48 – 88 %. 2-metil-3-supstituirani kinazolin-4(3H)-oni (51 – 87) sintetizirani su reakcijom 2-metilbenzoksazin-4-ona i aromatskih amina te hidrazida kumarina i piridin-2,6-dikarbohidrazida u otapalu ChCl : urea konvencionalno s iskorištenjima 17 – 77 %, sintezom potpomognutom mikrovalovima (10 – 41 %), sintezom potpomognutom ultrazvukom (15 – 56 %) i mehanokemijskom sintezom (45 – 87 %). Schiffove baze kinazolin-4(3H)-ona (88 – 130) sintetizirane su u otapalu ChCl : malonska kiselina reakcijom 3-amino-2-metilkinazolin-4(3H)-ona i aromatskih aldehida konvencionalno u iskorištenjima 63 – 97 %, sintezom potpomognutom mikrovalovima (39 – 68 %), sintezom potpomognutom ultrazvukom (40 – 80 %) te mehanokemijskom sintezom u visokim iskorištenjima 79 – 97 %. Trokomponentnim reakcijama antranilnih kiselina, trimetilortoformijata i aromatskih amina u otapalu ChCl : urea detektirani su 3-supstituirani derivati kinazolin-4(3H)-ona (130 – 136) u tragovima. Najbolja iskorištenja reakcija u sintezi 2,3-disupstituiranih derivata kinazolin-4(3H)-ona (1 – 130) dobivena su mehanokemijskom sintezom koju karakteriziraju najkraće vrijeme reakcije i čistoća izoliranih produkata. Zatim slijedi konvencionalna sinteza, sinteza potpomognuta ultrazvukom i s najmanjim iskorištenjem sinteza potpomognuta mikrovalovima. Korištenjem niskotemperaturnih eutektičkih otapala u sintezi smanjen je štetan utjecaj na okoliš organskih otapala i katalizatora, skraćeno je vrijeme trajanja reakcija, jednostavna je izolacija i pročišćavanje produkata te omogućeno recikliranje otapala. Strukture svih sintetiziranih spojeva potvrđene su 1H- i 13C-NMR spektroskopijom te masenom spektrometrijom. In the doctoral thesis 2,3-disubstituted (1 – 130) and 3-substituted quinazolin-4(3H)-one derivatives (130 – 136) are synthesized in deep eutectic solvents to investigate their application in the synthesis of heterocycles. Syntheses of quinazolin-4(3H)-one derivatives were performed conventionally, by microwave-assisted and ultrasound-assisted synthesis and mechanochemical reactions as well. Deep eutectic solvents for the synthesis of new compounds were prepared by mixing of choline chloride (ChCl) with various amides, carboxylic acids, carbohydrates and alcohols in a specific molar ratio. The optimization of the reaction conditions for each class of compounds was carried out on the selected model reaction by choosing the most favourable deep eutectic solvents, volume, temperature and reaction time. The influence of the amount of balls in mechanochemical synthesis was also optimized. 2-mercapto-3-substituted quinazolin-4(3H)-one derivatives (1 – 50) were synthesized in ChCl: urea deep eutectic solvent by reaction of anthranilic acids and aliphatic and aromatic isothiocyanates conventionally with yields 19 – 76%, by microwave-assisted synthesis (10 – 49%), by ultrasound-assisted synthesis (17 – 64%) and by mechanochemical synthesis (48 – 88%). 2-methyl-3-substituted quinazolin-4(3H)-one derivatives (51 – 87) were synthesized by the reaction of 2-methylbenzoxazin-4-one and aromatic amines and coumarinyl hydrazides and pyridine-2,6-dicarbohydrazide in ChCl: urea conventionally with yields 17 – 77%, by microwave-assisted synthesis (10 – 47%), by ultrasound-assisted synthesis (15 – 56%) and by mechanochemical synthesis (45 – 87%). Quinazolin-4(3H)-one Schiff bases (88 – 130) were synthesized in ChCl: malonic acid from 3-amino-2-methylquinazolin-4(3H)-ones and aromatic aldehydes conventionally with yields 63 – 97%, by microwave-assisted synthesis (39 – 68%), by ultrasound-assisted synthesis (40 – 80%) and by mechanochemical synthesis with high yields 79 – 97%. 3-substituted quinazolin-4(3H)-one derivatives (130 – 136) were detected in traces obtained by a three-component reaction of anthranilic acids, trimethyl orthoformate and aromatic amines. The best yields of the reactions in the synthesis of 2,3-disubstituted quinazolin-4(3H)-one derivatives (1 – 130) were obtained by mechanochemical synthesis, which is characterized by the shortest reaction time and the purity of the isolated products. Lower yields were obtained with conventional synthesis, ultrasound-assisted synthesis, and the lowest yields were achieved by microwave-assisted synthesis. With the use of deep eutectic solvents in the synthesis, the harmful impact of organic solvents and catalysts on the environment is reduced, the reaction time is shorter, the isolation and purification of products are simple, and the recycling of solvents is enabled. The structures of all synthesized compounds were confirmed by 1H- and 13C-NMR spectroscopy and mass spectrometry.

Cystoseira compressa je jedna od najrasprostanjenijih algi na području Jadranskog mora. Riječ je o smeđoj algi koja sintetizira širok spektar sekundarnih metabolita koji su biološki aktivni. Takvi spojevi imaju pozitivan utjecaj na zdravlje ljudi te zbog toga navedena alga ima velik farmakološki potencijal. U budućnosti, značajna može biti i u pogledu funkcionalne hrane. Za ekstrakciju bioaktivnih komponenti, sve je češća primjena tzv. niskotemperaturnih eutektičkih otapala koja su i dalje u fazi istraživanja. Problem kod eutektičkih otapala pojavljuje se prilikom analize ekstrahiranih spojeva prvenstveno zbog viskoznosti samih otapala. U ovom radu, kao potencijalno rješenje izolacije i kvantificiranja ekstrahiranih spojeva u niskotemperaturnim eutektičkim otapalima, ispitana je metoda izolacije s makroporoznim smolama koje imaju ulogu adsorbensa. Izolacijom su biološki aktivni spojevi desorbirani iz niskotemperaturnog eutektičkog otapala (ekstrakta alge) u otapalo pogodno za daljnje analize (etanol). Izolirani spojevi ispitivani su primjenom spektrofotometrijskih i kromatografskih tehnika kako bi se ispitala prisutnost florotanina, ukupnih fenola, pigmenata i lakohlapljivih komponenata u etanolnom pripravku. Na temelju dobivenih rezultata, utvrđeno je da se makroporoznim smolama mogu izolirati samo pojedine komponente iz niskotemperaturnih eutektičkih otapala, točnije florotanini i ukupni fenoli, a kao najpogodnije eutektičko otapalo iz kojeg su se mogle izolirati iste, pokazalo se otapalo sastava fruktoza:mliječna kiselina u molarnom omjeru 1:5. Cystoseira compressa is one of the most widespread algae in the Adriatic Sea. It is a brown alga that synthesizes a broad spectrum of biologically active secondary metabolites. Such compounds positively affect human health, which is why the mentioned alga has an excellent pharmacological potential. In the future, it may also be significant in terms of functional food. For the extraction of bioactive compounds, the usage of the so-called deep eutectic solvents, which are still being examined, is getting more pronounced. The main dissadvantage of deep eutectic solvents appears during the analysis of extracted compounds and is due to the viscosity of the solvents. In this paper, the isolation method with macroporous resins that act as adsorbents was examined as a potential solution for isolation and quantification of extracted compounds in deep eutectic solvents. Biologically active compounds were desorbed from deep eutectic solvent (alga extract) to a solvent suitable for further analysis (ethanol). The isolated compounds were examined using spectrophotometric and chromatographic techniques to examine the presence of phlorotannins, total phenols, pigments, and volatile components in the ethanol preparation. The results showed that macroporous resins could isolate only specific compounds from deep eutectic solvents, phlorotannins and total phenols namely. The most suitable eutectic solvent for their isolation was found to be a solvent composed of fructose:lactic acid in a molar ratio of 1:5.

Padina pavonica smeđa je alga, koju pronalazimo i u Jadranskom moru. Ova alga je pronašla široku primjenu u proizvodnji biodizela, biosorpciji teških metala, kao biomonitor metala u tragovima, bioindikator zagađenja, antioksidans, bioinsekticid te kao antibakterijsko sredstvo. U ovom završnom radu provedena je ekstrakcija na navedenoj algi sa 15 niskotemperaturnih eutektičkih otapala na bazi kolin-klorida. Ekstraktima je određen sadržaj florotanina, te antioksidacijska aktivnost određivanjem hvatanja slobodnog DPPH radikala. Na temelju dobivenih rezultata određeno je najpogodnije otapalo za dobivanje ekstrakta alge P. Pavonicas najvišim udjelom florotanina, te s najvišom antiradikalnom aktivnošću. Padina pavonica is a brown algae, which is also found in the Adriatic Sea. This algae has wide usage in the production of biodiesel, biosorption of heavy metals, as a biomonitor of trace metals, bioindicator of pollution, antioxidant, bioinsecticide and as an antibacterial agent. In this final work, extraction was performed on said algae with 15 low-temperature eutectic solvents based on choline chloride. The extracts determined the content of florotanin and antioxidant activity by determining the capture of free DPPH radicals. Based on the obtained results, the most suitable solvent for obtaining P. Pavonica algae extract with the highest content of florotanin and with the highest antiradical activity was determined.

U zadnjih se nekoliko godina pojavila nova generacija otapala, eutektičkih otapala (DES) i pokazala su se kao pogodna i vrlo učinkovita u ekstrakciji različitih visokovrijednih bioaktivnih komponenti iz biljnih materijala. Ove vrste otapala predstavljaju zelene i održive smjese netoksičnih jeftinih komponenata kombiniranih zajedno u obliku eutektičke smjese. S ciljem odabira idealnog DES-a za određenu ekstrakciju, veliki broj karakteristika otapala se mora uzeti u obzir, uključujući njegov sastav, viskoznost, polarnost itd. U ovom radu korišteno je 15 različitih eutektičkih otapala na bazi kolin klorida za ekstrakciju hesperidina iz kora mandarina različitih sorti (Zorica rana, Chahara, Okitsu i Kuno). U tako dobivenim ekstraktima određivao se udio hesperidina tekućinskom kromatografijom visoke djelotvornosti (HPLC). Otapalo kolin klorid:acetamid (1:2) pokazalo se kao najučinkovitije u procesu ekstrakcije ciljane komponente. Nadalje, provedena je optimizacija postupka ekstrakcije za svaku pojedinu sortu mandarina, a vezano za udio hesperidina u ekstraktima, primjenom metode odzivnih površina na osnovi eksperimentalnih podataka dobivenih prema Box-Behnken-ovom planu pokusa. Dobiveni rezultati pokazuju da sadržaj hesperidina u korama mandarina razlikuje se u ovisnosti o odabranoj sorti mandarina In the last couple of years, a new generation of solvents has emerged-deep eutectic solvents (DES). They showed to be an appropriate and effective solvents in the extraction of various bioactive components from plant-based materials. These types of solvents represent eco-friendly and sustainable mixtures of non-toxic, cheap components mixed in form of eutectic blend. When picking the right DES for certain kind of extraction, many characteristics of solvent must be considered (composition, viscosity, polarity etc.). In this thesis, 15 different choline chloride based DES were used for the extraction of hesperidin from mandarin peels of different varieties (Zorica rana, Chahara, Okitsu and Kuno). The obtained extracts were analysed by high performance liquid chromatography (HPLC) to determine the hesperidin amounts. Choline chloride:acetamide (1:2) provided the most efficient hesperidin extraction. Furthermore, extraction process was optimized for each variety of mandarin peel. Optimized set of parameters and their impact on hesperidin yield were determined using response surface methodology. These parameters were obtained according to the Box-Behnken experiment design. The results indicated that hesperidin content in mandarin peels was completely variety-dependent.

Kumarin i njegovi derivati su važna skupina bioaktivnih heterocikličkih spojeva koji su prisutni u različitim biljnim vrstama. Upravo je biološka aktivnost razlog iznalaženja novih puteva i metoda njihove sinteze. U posljednje vrijeme osobito su značajna otkrića na području zelene kemije i sinteze pa je stoga u ovom radu za sintezu spojeva korišteno „zeleno otapalo“, odnosno eutektičko otapalo (kolin-klorid:urea), koje predstavlja ekološki prihvatljivu verziju organskim otapalima. U ovom je radu opisan postupak alkiliranja derivata rodanina s 3-(bromacetil)-2H-kromen-2-onom u navedenom eutektičkom otapalu, uz K2CO3 kao katalizator. Svi su spojevi potvrđeni LC-MS/MS spektroskopijom te okarakterizirani Rf vrijednostima i temperaturama tališta. Coumarin and its derivates are an important group of heterocylic compounds which are found in various plants exhibiting a wide variety of biological activities. Their potent biological activity is the main reason for finding new methods for their synthesis. In the last few decades, many achievements have been made in the field of green chemistry. Therefore, in this work coumarin derivates were synthesized using deep eutectic solvent (choline-chloride:urea), which are ecologically acceptable compared to conventional organic solvents. This work describes alkylation of rhodanine derivates with 3-(bromoacetyl)-2H-chromen-2-one in solvent with K2CO3 as a catalyst. Structures of all compounds were confirmed by LC-MS/MS spectroscopy and compounds were characterized by Rf values and melting points.

Primjena eutektičkih otapala u kemijskim sintezama predstavlja prihvatljivu alternativu konvencionalnim organskim otapalima koja mogu biti štetna po zdravlje i okoliš. U ovom radu cilj je ispitati mogućnost primjene takvih dvokomponentnih otapala u sintezama različitih derivata kinazolin-4(3H)-ona. Prvo će se kroz teorijski dio opisati svojstva i primjena eutektičkih otapala te kinazolinona, a nakon toga proći će se kroz eksperimentalni dio završnog rada u kojem se dvama metodama pokušalo dobiti tražene spojeve. Application of deep eutectic solvents in chemical synthesis presents acceptable alternative to conventional organic solvents which are often harmful to human health and environment. The goal in this work is to examine a potential usage of such two-component solvents in synthesis of quinazolin-4(3H)-one derivates. Firstly, the theoretical part on properties and application of deep eutectic solvents and quinazolinones will be described. Furthermore, an experimental part explains a synthesis of desired compounds by using two different methods.

Eutektička otapala predstavljaju ekološki prihvatljivu zamjenu konvencionalno korištenim organskim otapalima. U ovom radu nastojala se ispitati mogućnost sinteze derivata kinazolin-4(3H)-ona upotrebom eutektičkog otapala na bazi kolin-klorida i uree. Prvo su uspješno sintetizirani 3-supstituirani-2-tiokso-2,3-dihidrokinazolin-4(1H)-oni. Isto eutektičko otapalo pokazao se kao pogodan medij i za sintezu derivata 6-jod-2-tiokso-2,3-dihidrokinazolin-4(1H)-ona. Reakcije su uspješno provedene bez upotrebe katalizatora i nije bilo potrebe za pročišćavanjem dobivenih spojeva. Eutektičko otapalo na bazi kolin-klorida i uree je jednostavno za pripremu i lako se upotrebljava. Deep eutectic solvents are environmentally friendly substitution for conventional organic solvents. In this paper we investigated suitability of choline chloride/urea based deep eutectic solvent for synthesis some quinazolin-4(3H)-ones. 3-Substitued-2-thioxo-2,3-dihydroquinazolin-4(1H)-ones were successfully synthesized. Therefore, the same deep eutectic solvent was used for synthesis of 6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1H)-ones derivatives. All chemical reactions were performed without use of catalysts and without further purification of products. Choline chloride/urea based deep eutectic solvent is environmentally acceptable, available, cheap and easily used.