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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.

One of the main advantages of green chemistry is the tendency to develop procedures and techniques with low environmental impact. Deep eutectic solvents (DESs) have become an important part of organic synthesis due to their properties. Different quinazolinones were synthesized in choline chloride: urea (1: 2) DES using microwave-assisted and ultrasound-assisted synthesis. First, optimization was performed to find the appropriate DES, time of reaction and temperature. Starting compounds for the quinazolinone synthesis were differently substituted anthranilic acids, anilines and trimethyl orthoformate. The most appropriate method for synthesis was microwave-assisted synthesis using ethanol as a solvent. The antibacterial activity of quinazolinone derivatives was studied by minimal inhibitory concentration. All derivatives have shown antibacterial activity.

Plant diseases and pests are responsible for many losses in agricultural production worldwide, proving that their control is crucial for crop farming today. The use of plant protection products has effectively limited these losses. However, some of the active ingredients of these products are toxic for humans and fauna or cause groundwater and soil pollution. Therefore, there is an urgent need to find new, environmentally and toxicologically acceptable active ingredients for plant protection. In this study, we have tested the antifungal activity of 19 quinazolinone based Schiff bases against Sclerotinia sclerotiorum (Lib.) de Bary, a necrotrophic fungal pathogen causing disease in a variety of plants. Most of the tested compounds showed very good fungal growth inhibition at 0.8 μmol/mL, with 8 compounds inhibiting mycelial growth by more than 80 %. QSAR techniques provide an insight into the relationship between structure and biological activity of compounds, presenting an alternative path for the design and development of new active ingredients for plant protection. To elucidate important structural and physicochemical characteristics of tested quinazolinone Schiff bases related to their increased antifungal activity, a QSAR analysis was performed.

Currently, there is a growing market demand for products derived from industrial hemp for food, recreational and medical use. This plant is widely known to be the major source of cannabinoids, including cannabidiol (CBD), cannabidiolic acid (CBDA), tetrahydrocannabinol (THC), cannabichromene (CBC), cannabigerol (CBG), and cannabinol (CBN). Cannabinoids are very significant group with strong remedial potential against inflammation, depression, nausea and epilepsy. On the other hand, THC is mostly responsible for psychotropic activities, so it is a controlled substance. Given that, cannabinoids are carriers of biological activity of industrial hemp, which is increasingly used in various forms (food, cosmetics or tinctures), it is important not just to develop a fast and reliable method of quantification of cannabinoids in hemp samples but to find the most suitable solvent and extraction conditions. The aim of this paper was to select the most suitable solvent and conditions among conventional (aqueous ethanol solutions (30-70% (v/v)), ethanol, methanol, acetonitrile) and hydrophobic deep eutectic solvents (hDESs), as well as the development of HPLC method for the detection of cannabinoids in prepared extracts. Depending on the conditions used and the solvent, different cannabinoids were extracted. The solvents show different ability to extract cannabinoids, so the conclusion about a universal solvent for all cannabinoids cannot be made. However, in terms of CBD, as the best known cannabinoid and its precursor, CBDA, the most suitable solvent is ethanol when extracted at 70 °C for 30 min. On the other hand, the most suitable hDES is a menthol:acetic acid (1: 1) for 60 min at 70 °C. Using ethanol as solvent 7.57 ug/mg of plant CBD and 100.25 ug/mg of plant CBDA was extracted, while by using menthol: acetic acid(1:1) 10.0 ug/mg of plant CBD and 128.67 ug/mg of plant CBDA was extracted proving that hDES can be a good substitute in the extraction of bioactive components from industrial hemp.

Phytopathogenic fungi are one of the leading causes of plant diseases that reduce crop quality and cause huge yield losses. The control of fungal plant diseases is important for reducing or preventing these losses. The excessive use of available fungicides over a long period of time has increased the fungal resistance and become a major ecological issue, giving the incentive to find new antifungal agents. Quinazolinone is a common heterocyclic nitrogen scaffold, widely present in natural products. Its derivatives exert a variety of biological activities, such as antitumor, antiviral, antibacterial and antifungal. The aim of this study was to examine a potential antifungal activity of several structurally different, recently synthesized new quinazolinone derivatives using a computational approach. A molecular docking analysis has been performed on two fungal chitinases, type A (PDB ID: 2XUC) and B (PDB ID: 2IUZ), involved in chitin decomposition, cell wall degradation and remodeling. Molecular docking has shown that all tested compounds bind near the enzyme active sites. The most promissing compounds were N2, N6- bis(2-methyl-4- oxoquinazolin-3(4H)-yl)pyridine-2, 6-dicarboxamide for chitinase A, and 3-(4- methoxyphenyl)-2- methyl-6-nitroquinazolin-4(3H)- one for chitinase B.

Schiff base derivatives were synthesized by utilizing the green chemistry methods such as microwave-assisted, ultrasound-assisted and mechanochemical synthesis. [1] Acetylcholinesterase inhibitors are widely recognised as potential drugs for treating symptoms of the Alzheimer's disease. Inhibitory properties of AChE inhibitors have been used for the developmet of active compounds in plant protection treatments. Twenty-four Schiff base derivatives were tested as potential acetylcholinesterase inhibitors. In vitro experiment has been conducted on a 96-well microplate UV-Vis reader by utilizing the modified Elmann's method. [2] Absorbance readings were obtained by measuring at the wavelenght of 412 nm. Donepezil was used as a standard acetylcholinesterase inhibitor. The highest percentage of inhibition was obtained with the compound 10 (Fig. 1), 34.58%, while the lowest inhibition percentage was obtained with compound 26 (3.88%).

Sclerotinia sclerotiorum (Lib.) de Bary is a necrotrophic plant pathogen responsible for the reduction of the crop quality and yield. One of the most efficient ways to prevent and control diseases caused by S. sclerotiorum is the use of chemical fungicides. However, their use led to the accumulation of residual fungicides in the soil, water, and agricultural products, as well as the appearance of fungicide-resistant forms of this phytopathogen. Therefore, there is a need for new, environmentally friendly compounds that would prove effective against S. sclerotiorum. This study aimed to derive a Quantitative Structure- Activity Relationship (QSAR) for the antifungal activity of 18 quinazolinone derivatives. Antifungal test against S. sclerotiorum was carried out according to the method of Siber et al. Antifungal activities of tested compounds, expressed as % inhibition, were converted in the form of the logarithm values (log % inhibition). The optimized 3D strictures of quinazolinone derivatives were used for the descriptor calculation. Considering the limited number of compounds, splitting into test and training set was not performed. The multiple linear regression QSAR models were obtained with a genetic algorithm (GA) using QSARINS 2.2.4. (University of Insubria, Varese, Italy). The best QSAR model was generated with three DRAGON descriptors: Mv, Mor09e and R6e. The model satisfied the fitting and internal validation criteria, confirming its stability and robustness: R2 = 0.91 ; R2adj = 0.89 ; F = 45.17 ; ΔK = 0.12 ; CCCtr = 0.95 ; Q2loo = 0.85 ; R2-Q2loo = 0.06 ; CCCcv = 0.92 ; R2Yscr = 0.18 ; Q2Yscr = -0.43. Molecular descriptors in obtained QSAR model revealed that quinazolinones of higher molecular weight (Mv), higher contribution of 3D distribution of electronegativity at 8 Å (Mor09e), and enhanced interactions of electronegative atoms at a topological distance 6 (R6e), have lower antifungal effects.

Quaternization of pyridine with alkyl halides or related compounds is an example of the Menshutkin reaction, the most common rute to create quaternary salts. The most organic solvents used in conventional synthesis of pyridinium quaternary salts are volatile, hazardous, toxic like anhydrous benzene [1], acetonitrile and acetone [2-3]. Also, a lots of these solvents are considered a hazardous waste when are discarded. Reducing toxicity is one of the most challenging aspects of designing chemical syntheses. Deep eutectic solvents (DESs) have emerged recently as new and green solvents in organic synthesis. After we successfully quaternized pyridine derivatives in DESs in our previous study Bušić et al. [4], we continue to perform syntheses of pyridoxal oxime quaternary salts in eutectic solvents. In this study it was performed quaternization reaction of pyridoxal oxime and substituted phenacyl bromides in 16 choline chloride-based DESs by three synthetic approaches: conventional, microwave and ultrasound (Scheme). The purpose of this work was to investigate which eutectic solvent is most effective for the quaternization reaction. After the performed syntheses, the results show that the conventional method, with a long reaction time, generally gave low product yields in eutectic solvents. In the conventional method, the most effective eutectic solvents were: choline chloride: thiourea, choline chloride: oxalic acid, and choline chloride: levulinic acid. The highest yields of reactions in DESs were obtained using microwave irradiation where the most effective eutectic solvents were: choline chloride: oxalic acid, and choline chloride: levulinic acid. Choline chloride: malic acid, Choline chloride: malonic acid and choline chloride : trans-cinnamic acid gave approximately equal yields. In the ultrasound method the most effective eutectic solvents for the quaternization of pyridoxal oxime with substituted phenacyl bromides were choline chloride: oxalic acid, and choline chloride: levulinic acid and choline chloride : trans- cinnamic acid and reactions were carried outwith yields higher than in the conventional method. The obtained results for quaternization reaction of of pyridoxal oxime show that methods under influence of microwave and ultrasound irradiation were the most effective for quaternization in eutectic solvents.

Human dipeptidyl peptidase III (hDPP III) is a zinc‐hydrolase that cleaves dipeptides sequentially from the N‐ terminal of different bioactive peptides. Although the physiological role of hDPP III is not yet fully elucidated, its involvement in pathophysiological processes such as mammalian pain modulation and blood pressure regulation emphasizes the need to find new hDPP III inhibitors. Coumarins exhibit a variety of biological activities, and Schiff bases bearing coumarin moiety in conjunction with the imino group (-C=N-) form significant compounds in medicinal and pharmaceutical chemistry. To find new potential inhibitors of hDPP III, in this research we selected 6 coumarinyl Schiff bases to investigate their interactions with hDPP III, combining experimental and computational approaches. hDPP III activity was determined using the spectrophotometric assay, while molecular docking was performed by AutoDock Vina software to obtain information regarding the possible interactions of the strongest inhibitor and hDPP III binding site. The experimental results showed that all analyzed compounds have an inhibitory effect against hDPP III activity at the physiological concentration i.e., 100 μM. The strongest inhibition (87.9 %) has been obtained with compound 5. Docking predicts that 5 interacts with amino acid residues of hDPP III mostly in the region of inter-domain cleft by forming hydrogen bonds with Ile386, His568 and Arg572, π – interactions with Phe109, Pro387 and Ala388, and numerous van der Waals interactions. Most of these residues are found to be constituents of the hDPP III substrate binding subsites S1, S1’, S2, S2’ and S3’. The results of this study provide an insight into the coumarinyl Schiff bases inhibitory activity and interactions toward hDPP III.

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.

Acetylcholinesterase (AChE) is an enzyme responsible for the metabolism of acetylcholine (ACh), the neurotransmitter controlling motor activities in nematodes. Inhibition of AChE results in accumulation of ACh at neuromuscular junctions and leads to paralysis, which makes AChE a good target enzyme for the control of parasitic nematodes. AChE inhibitors used to control parasitic nematodes are mainly organophosphates and carbamates, however, due to their toxicity, they have been withdrawn or have restricted usage. Halogenated pyrazoline derivatives exhibit various biological activities, among them antibacterial, antifungal, and antimicrobial. A series of fluorinated pyrazolines was chosen for the investigation of possible AChE inhibition, using Ellman’s protocol modified for microplate reader. All tested compounds exhibited moderate to good inhibitory effect against AChE at 50 μM concentration, with compound 9 (Fig. 1) having the highest inhibition of 79.5 %. A molecular docking study was performed to gain insight into the binding interaction of compound 9 with AChE (PDB: 2c5g). Results show that compound 9 interacts with amino acid residues located in the peripheral active site of AChE, blocking the narrow passage to the catalytic site. The effect of fluorinated pyrazolines was also tested on two entomopathogenic nematodes, Heterorhabditis bacteriophora, and Steinernema feltiae. Entomopathogenic nematodes are beneficial nematodes used in insect pest management programs because of their resilience to pesticide exposure. Since these nematodes mostly have been unaffected by tested compounds, it indicates their potential use as plant protection agents.

Human dipeptidyl peptidase III (hDPP III) is a zinc‐hydrolase that cleaves dipeptides from the N‐ terminal of different bioactive peptides. Quinazolinones belong to a diverse class of nitrogen-containing heterocyclic compounds, derivatives of which exhibit a wide range of biological activities. In this research, we selected 10 previously synthesized [1] structuraly different quinazolinone derivatives (QDs) to investigate their potential to inactivate hDPP III activity combining in vitro and in silico approach. The experimental results showed that all analyzed QDs (at the physiological concentration i.e., 100 μM) have inhibitory effect against hDPP III activity. The strongest inhibition (% inh. = 81.9) has been obtained with compound QD8. Molecular docking revealed that hDPP III interacts mostly by hydrogen bonds and hydrophobic interactions with QD8. Among important intermolecular interactions are those with amino acid residues F443, Q446, V447, H568 and R572 that are constituents of hDPP III substrate binding subsites S1, S1’, S2’, and S3’.

Coumarin and its derivatives as highly bioactive heterocycles possess a wide range of biological, pharmacological, biochemical and therapeutic properties, which are strongly structure dependent. Schiff bases bearing coumarin moiety in conjunction with imino group (-C=N-), form a significant compounds in medicinal and pharmaceutical chemistry [1]. Deep eutectic solvents (DESs) have proven to be a suitable media for many synthetic pathways. DESs are often described as green mixtures, whose properties can be adjusted for various applications using different molar ratios of initial components [2]. The aim of this study was to synthesize coumarinyl Schiff bases utilizing ChCl-based DES as a reaction media and a catalyst, as well. Hereby, 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 [3]. DESs are proven the excellent media for all these reactions, while the isolation of the final product was easy, and included the addition of water and filtration.

1, 2, 4-triazoles, heterocyclic compounds with a wide range of biological activities such as antibacterial, antifungal, antitumor, anticolvulsant, antiinflammatory and antimicrobial, exists in two tautomeric forms, 1H and 4H. Until recently, these heterocycles are usually prepared from 1, 2, 4-oxadiazoles in reaction with hydrazine, 1, 3, 4-oxadiazoles and hydrazides or thiosemicarbazides in basic conditions or triethylamine. A model reaction between 2-((4-methyl-2-oxo-2H-chromen-7-yl)oxy)acetohydrazide and phenyl isothiocyanate was carried out on two different temperatures (40 °C and 80 °C) in 14 choline chloride based deep eutectic solvents (DESs). DES is a mixture of a salt, usually chloline chloride wich is hydrogen bond acceptor (HBA) and a hydrogen bond donor (HBD) such as alcohols, sugars, amides and carboxyl acids and mostly exist as liquid at or below 100 °C. Pure thiosemicarbazide was formed in choline chloride:malonic acid (1:1), choline chloride:malic acid (1:1) and DESs with different alcohols as HBDs. The best conversion to 1, 2, 4-triazole derivatives was obtained in choline chloride:urea (1:2) at 80 °C, so this DES was used for next synthesis of 1, 2, 4-triazoles with various isothiocyanates and hydrazides.

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.

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.

Over the last few years, deep eutectic solvents (DESs) have been proven to be an excellent green reaction media for various heterocycles. DESs are a mixture of two or three components which mixed together form a low melting-point mixtures. DESs in regards to organic solvents have more advantages such as non-toxicity, thermal stability, biodegradability, low vapour pressure and price. DESs are composed of a hydrogen bond acceptor (HBA) (usually choline chloride) and a hydrogen bond donor (HBD) components, such as sugars, amides, alcohols and carboxylic acids. Mixing of these species forms strong hydrogen bond interactions. Quinazolinones are heterocycles with a wide range of biological activities. Herein, we peformed a condensation of anthranilic acid, p- chloroaniline and trimethyl orthoformate into 3-(4-chlorophenyl)quinazolin-4(3H)-one. A screening of different choline chloride based deep eutectic solvents has been carried out to determine a favorable solvent for this synthesis as environmentally friendly procedure without hazardous solvents and catalysts.

Environmentally procedure for the synthesis of 5-arylidenerhodanines by Knoevenagel condensation of rhodanine with aromatic aldehydes using deep eutectic solvent choline chloride:urea is described. This environmentally friendly and catalyst free approach was shown to be effective in above-mentioned condensation. The procedure includes short reaction times for a few minutes, mild conditions, simple experimental work and high product yields.

Deep eutectic solvents(DESs)are novel generation of green solvents which have proven to be a convenient media for many synthetic routes. They are often characterized as environmentally friendly and sustainable mixtures of nontoxic and cheap components which are combined together from a eutectic mixture. Hydrogen bond acceptors (HBAs ; quaternary ammonium or metal salt) are often combined with hydrogen bond donors (HBDs ; amides, carboxylic acids, alcohols and sugars) in different ratios to obtain DES with desirable physical and chemical characteristics. Hereby, we describe our achievements in the field of heterocycle synthesis in DESs. So far, we have found DESs to be very effective in synthesis of novel coumarinyl Schiff bases, Knoevenagel condensation of rhodanine with aromatic aldehydes, synthesis of thiosemicarbazides and triazoles from isothiocyanates and coumarinyl hydrazide, synthesis of 2-mercaptoquinazolinones from anthranilic acid and isothiocyanates. At present, a screening of 20 different deep eutectic solvents has been carried out to determine a convenient DES and temperature for the synthesis of quinazoline derivatives from anthranilic or substituted anthranilic acid.

Over the last few years, deep eutectic solvents (DESs) have been extensively investigated as green solvents in organic synthesis. DESs are mixtures of two or three components which combined together form a low melting-point mixtures. In regards to organic solvents, DESs show advantages such as non-toxicity, thermal stability, biodegradability, low vapour pressure and low price. They are composed of a hydrogen bond acceptor (HBA) (usually choline chloride) and a hydrogen bond donor (HBD) components, such as sugars, amides, alcohols and carboxylic acids. Mixing of these species together at elevated temperatures forms a strong hydrogen bond interactions. DESs have been successfully employed as a green reaction media in organic synthesis, as well as green extraction solvents of bioactive compounds from various plant material. The Knoevenagel condensation of 1, 3- thiazolidin-2, 4-dione with various aromatic aldehydes, in choline chloride based deep eutectic solvent was studied. Choline chloride:urea (1:2) DES was proven to be an excellent media for this kind of reactions, yielding products in 2-3 h, without any catalyst added. This is environmentally friendly, green, simple work procedure with good to excellent yields of final products.

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.

Redukcijom aldehida nastaju primarni alkoholi, a redukcijom ketona sekundarni alkoholi. Uobičajeno se redukcija provodi s pomoću metalnih hidrida, natrijevog tetrahidroborata (NaBH4) i litijevog tetrahidroaluminata (LiAlH4). U ovom su radu provedene reakcije redukcije aldehida (cinamaldehid, benzaldehid, 4-hidroksibenzaldehid i 4-N, N-dimetilbenzaldehid) i ketona (acetofenon, 4-metilacetofenon, 4-kloracetofenon i 4-nitroacetofenon) uporabom dijelova biljaka mrkve (Daucus carota), jabuke (Malus pumila) i korabe (Brassica oleracea L gongylodes)). Usporedno su napravljene redukcije acetofenona i njegovih derivata natrijevim tetrahidroboratom (NaBH4). U metodičkom dijelu ovog rada obrađena je nastavna jedinica Aldehidi. Dva nastavna sata osmišljena su kao obrada novog gradiva s dva pokusa i radnim listićima.

Plants have been considered as a potential source for catalytic biotransformation, and it is well established that crude preparations of certain common vegetables can serve as selective, high-yield reducing agents in organic synthesis. Several samples of whole plants were reported as sources of reductase activity with alcohol dehydrogenase systems such as apple (Malus pumila), carrot (Daucus carota), cucumber (Cucumis sativus), onion (Allium cepa), potato (Solanum tuberosum), radish (Raphanus sativus). Experiments of biotransformations were carried using the aromatic carbonyl compounds 1-8 following previously described procedures, treating aldehydes and ketones with freshly slices of carrot (Daucus carota), apple (Malus pumila), kohlrabi (Brassica oleracea L gongylodes) in aqueous solution. The products were analyzed by LC-MS. All tested carbonylic compounds were bioreduced yielding the corresponding alcohols with low to moderate yields. This is the first time that the biotransformation of carbonyl compounds have been successfully achieved using Brassica oleracea L gongylodes

Reakcijama 1, 3-dipolarne cikloadicije reagiraju dipol i dipolarofil uz nastanak peteročlanog prstena kao produkta. Oksidacijom benzo(b)tiofena, uz ledenu octenu kiselinu i vodikov peroksid, priređen je benzo(b)tiofen 1, 1-dioksid, koji u 1, 3-dipolarnim cikloadicijama reagira kao dipolarofil. (E)-Benzaldoksim se dobio iz benzaldehida, natrijeva hidroksida i hidroksilamin hidroklorida, a u reakcijama 1, 3-dipolarne cikloadicije se koristi kao prekursor 1, 3-dipola. U ovom se radu pokušala provesti 1, 3-dipolarna cikloadicija korištenjem benzo(b)tiofen 1, 1-dioksida kao dipolarofila te benzaldoksima iz kojeg smo očekivali stvaranje 1, 3-dipola (benzonitril-oksida). Cilj je bio i usporediti odvijanje ove poznate reakcije u klasičnim uvjetima s onima u mikrovalnoj pećnici. Neočekivano, glavni produkt ovih reakcija je najvjerojatnije nastao konjugiranom adicijom umjesto 1, 3-dipolarnom cikloadicijom. U radu su ponuđena objašnjenja za dobivene rezultate.