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Pyrazoline derivatives exhibit a variety of biological activities, such as antifungal, antiviral, and antibacterial. Biological effects depend on the type of substituents and their position in the ring. [1] The aim of this study was to evaluate the inhibitory effects of fluorinated pyrazole aldehydes against plant pathogenic fungi (Fusarium oxysporum f. sp. lycopersici, Fusarium culmorum, Macrophomina phaseolina and Sclerotinia sclerotiourum). The compounds demonstrated moderate activity against phytopathogenic fungi. The highest efficiency has shown 2-chlorophenyl derivative (H9) against F. culmorum (46.75%). In order to determine the binding affinity and interactions of the most active compounds with three enzymes responsible for the fungal growth and the three plant cell wall-degrading enzymes, molecular docking was performed. In order to determine the possible mechanism of action of derivatives against pathogenic fungi, molecular docking study has been performed on three enzymes responsible for the fungal growth: demethylase (sterol 14α-demethylase (CYP51), PDB: 5EAH) ; chitinase (PDB: 4TXE) ; transferase (N-myristoyltransferase, PDB: 2P6G) ; and the three plant cell wall-degrading enzymes: endoglucanase I (PDB: 2OVW) ; proteinase K (PDB: 2PWB) ; pectinase (endopolygalacturonase, PDB: 1CZF). The future derivatives should be designed to be more effective against pathogenic fungi without negative effects on beneficial organisms, environment pollution, and human health

Coumarins and triazoles are two interesting groups of heterocyclic compounds, both exhibiting a wide range of biological activities. The joining of these two scaffolds into a hybrid compound with the improved activities has already been reported. [1] In this research, 11 new hybrid compounds were synthesized, utilizing a deep eutectic solvent as an environmentally sustainable method of organic synthesis. Compounds were obtained in good yields through a one-step reaction of coumarinyl hydrazides and various substituted isothiocyanates, without the use of catalysts. [2] Since many commercially available fungicides are based on triazole derivatives, antifungal activity of 1, 2, 4-triazolyl coumarins was evaluated in vitro on two pathogenic fungi, Fusarium oxysporum and Fusarium culmorum. The tested compounds moderately inhibited the mycelial growth of F. oxysporum (35.0-57.5%), but were mostly ineffective against F. culmorum. Compound 1b, as the most potent growth inhibitor, was further analyzed computationally. A molecular docking analysis was performed to evaluate the binding mode of compound 1b with sterol 14 α-demethylase, the target enzyme of triazole based fungicides

Tyrosinases are enzymes belonging to the type-3 copper protein family which contains two copper ions in the active site. These oxidoreductases perform two sequential enzymatic reactions: hydroxylation of monophenols followed by oxidation of diphenols forming quinones which polymerize spontaneously to melanin. Tyrosinases are found in different prokaryotes as well as in plants, fungi, arthropods, and mammals. Besides its positive role in various organisms, like wound healing, sclerotization and pigmentation of insect cuticles, defence against herbivores and pathogens in plants, tyrosinases also can have negative impacts on humans (senile lentigo, melisma, freckles and pigmented ace scars) and plants (browning in fruit and vegetables following cell damage). Therefore, development of new potent tyrosinase inhibitors in medicine and cosmetic industry, as well in the food industry, is of interest. In this research 30 differently substituted rhodanine derivatives as possible mushroom tyrosinase inhibitors were tested with both, L-tyrosine and L-DOPA as substrates. Rhodanine derivatives were synthesized with green method in deep eutectic solvents without usage of organic solvents or harmful catalysts. Synthesised rhodanines inhibited tyrosinase in the range 4.2 - 100.0 % and 1.1 - 100.0 % with L-DOPA and L- tyrosine as substrates, respectively. Compound 3- allyl-5-(3-hydroxy-4-methoxybenzylidene)-2- thioxothiazolidin-4-one showed 100.0 % of tyrosinase inhibition when using both substrates. Tyrosinase inhibition of 100.0 % was also achieved with compounds 3-allyl-5-(4-(benzyloxy)-2- hydroxybenzylidene)-2-thioxothiazolidin-4-one and 3-amino-5-(3-hydroxy-4-methoxybenzylidene)-2- thioxothiazolidin-4-one but with L-tyrosine as substrate. The lowest IC50 values of 0.30 µM in case of L-DOPA and 0.23 µM in case of L-tyrosine were determined for compounds 3-allyl-5-((E)-3- phenylallylidene)-2-thioxothiazolidin-4-one and 3- amino-5-(3-hydroxy-4-methoxybenzylidene)-2- thioxothiazolidin-4-one, respectively.

Recently, nanoparticles have aroused great interest among researchers around the world due to their specific characteristics that allow them to be used in various fields with an emphasis on medicine and pharmacy where they act as catalysts or biosensors. Common methods of nanoparticle synthesis involve the use of long-term chemical and physical methods involving complicated processes, so the method of synthesis using green solvents and plant extracts appears to be more environmentally friendly and safer to use. For the synthesis of nanoparticles from different iron salts, plant extracts of five different plants prepared using GRAS (generally recognized as safe) solvents will be used to examine their effect on the possibility of nanoparticle synthesis. The prepared extracts were tested for antiradical activity (DPPH method) and total phenol content. The obtained nanoparticles were characterized by the application of appropriate techniques. According to the obtained results, the influence of different synthesis methods was shown, with emphasis on the influence of different solvents, plants, and compositions of extracts.

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.

Rhodanines have been reported to possess antibacterial, antiviral, antimalarial, antifungal, and antitumor activity. A series of novels rhodanine derivatives were assayed for their cytotoxic activity against a panel of human cancer cell lines. Quantitative structure-activity relationship (QSAR) analysis was performed on the anticancer activity against cutaneous T lymphocyte (cell line Hut-78) since 98 % of compounds have achieved the concentration achieving 50% cell growth inhibition (GI50) 100 μM. QSAR study of the anticancer activity against HUT-78 achieved the model that satisfies the fitting and internal cross-validation criteria (N = 28 ; R2 = 0.75 ; Q2 LOO = 0.64): logGI50 = 2.51 – 3.46 MATS2e – 1.05 MATs7e – 0.15 RDF060p Descriptors included in the model revealed the importance of the presence of atoms with higher polarizability in the outer region of molecules. Molecules that possess 3- methoxy group (ALR9) and 3-bromine (ALR16) at the benzene ring proved to be potential drug candidates against human T cell lymphoma since inhibited 50% growth of cells Hut-78 at the very low concentration (3 and 7.5 μmol dm-3, respectively). Also, the presence of electronegative atoms at the topological distances 2 and 7, such as hydroxyl and ethoxy groups as substituents of the benzylidene group decreases the activity. A molecular docking study confirmed the findings of the QSAR study regarding the structural features related to the inhibition of nonreceptor proteintyrosine kinase (c-Src) (PDB ID: G6H) and indicated importance of the oxygen atoms from phenoxy and rhodanine groups, and rhodanine sulphur atoms as hydrogen bond acceptors in key interactions with binding site residues, as well as benzene rings in generations of van der Waals interactions. Our study suggests that rhodanine derivatives could be developed as novel tyrosine kinase inhibitors in the treatment of leukemia.

In last 20 years, iron-based nanoparticles have gained attention due their specific properties such as special magnetic properties, availability, versatility, multivalent oxidation states. The most common iron nanoparticles in nature are magnetite (Fe3O4), maghemite (γ-Fe2O3) and hematite (α-Fe2O3). Conventional methods have been shown as a successful in synthesis of magnetic nanoparticles but they are expensive, complex, take a lot of time and create a lot of side products. In order to prevent that, scientists try novel green synthesis models which are rapid, eco- friendly with less waste products and more simple [1]. The aim of this research was to synthesize iron oxide nanoparticles, mainly magnetite, using plant extracts obtained by GRAS (generally recognized as safe) solvents and deep eutectic solvents (DESs). Total phenolic content and antiradical acitivity using DPPH method was measured for prepared extracts. Nanoparticles were synthesized from different iron salts and afterwards characterized by application of appropriate techniques.

Cannabis sativa L., commonly called hemp represents a herbaceous anemophilous plant that belongs to the Cannabinaceae family with a long history of use as food, feed, fiber, oil, and medicine. Throughout its long history of use, from around 12 000 years ago to the present day, the Cannabinaceae family of plants has gone through many ups and downs, especially through the 20th century which included bans on the use of hemp in various areas. However, today, due to better knowing the composition of hemp, its effects on the body and the endocannabinoid system (ECS) hemp is increasingly used as an ingredient in food preparation, as well as a dietary supplement for the prevention and treatment of inflammatory and chronic degenerative diseases. Cannabinoids include more than 100 components of various positive health effects, the most famous of which are cannabidiol (CBD) and delta-9- tetrahydrocannabinol (THC), as the most psychoactive component that is one of the "culprits" for the bad reputation of cannabis. In addition to that, it is important to note that Cannabis sativa L. has a high nutritional content, which is why all parts of the plant, including the stem, seeds, roots and flowers, have been used for food, feed, and therapeutic purposes for a long time. In today's market, hemp is used in a variety of food items, including bakery, confectionery, beverages and dairy, most often as plant or seeds. Due to a high market growth for hemp-containing products where bioactive components can be concentrated during production, it is important to optimize the possibility of positive health effects while at the same time reduce the possibility of safety hazards. The benefits but also possible disadvantages of such developed products must be examined using well-designed, randomized, placebo-controlled, double-blind research studies on which regulatory authorities should make decisions about products available on the market as well as their health claims.

Natural products are increasingly in demand in dermatology and cosmetology for reasons of sustainability and environmental protection. They are also a potential means of improving treatment outcomes for chronic skin diseases and skin care. Industrial hemp (Cannabis sativa L.) contains many medicinal properties that are slowly being discovered. Industrial hemp in its natural form, contain very small amounts of CBD, but therefore contain its acid form, which is CBDA. Once this acid form is activated by increasing the temperature, the desired effect and the corresponding decarboxylated analogue (CBD) is formed. This study is a good example for obtaining highly valuable natural extracts of industrial hemp with green technique - supercritical CO2 (sCO2) extraction. Terpenes in the extracts were determined by gas chromatography and mass spectrometry (GC-MS) while high performance liquid chromatography (HPLC) was used to identify and quantify present cannabinoids. GC-MS analysis indicated β-myrcene chemotype, with abundant α- pinene and β-pinene and variety of other monoterpenes as minor constituents, while the most abundant sesquiterpene was β-caryophyllene. Extracts rich in cannabidiol (CBD) as predominant compound were obtained at higher pressure with decarboxylation as pretreatment before sCO2 extraction.

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.

Coumarin and its derivatives are well-known phytochemicals that have shown great potential in acetylcholinesterase (AChE) inhibition [1]. Novel coumarin derivatives have been tested as acethylcholinesterase (AChE) inhibitors by utilizing the Ellman's method [2]. Inhibition data were expressed as a logarithm of inhibition percentages. Molecular structures were optimized by PM3 method using Hyperchem software. Molecular descriptors have been calculated by ADMEWORKS ModelBuilder software. QSAR analysis for inhibition of AChE was performed on the 34 compounds in the training set. Due to the small number of compounds, they were not split in training and test sets. The best QSAR model obtained is: log inh.% = - 1.09 – 0.11 MATS7m + 1.84 MCB + 0.17 DIPZ (1) where MATS7m is Moran autocorrelation of lag 7, weighted by atomic masses ; MCB is Balabans topological index, and DIPZ is dipole moment on Z axes. The model has achieved the following statistical performance of the internal validation: R2 = 0.78 ; F = 37.26 ; Δk = 0.23 ; CCCtr = 0.88 ; CCCcv = 0.84 ; Q2loo = 0.71 ; Q2γscr = -0.18. Williams plot for applicability domain of model (1) is shown in Figure 1. Molecular descriptors in model (1) revealed that effect of inhibition of molecules decreased with: lower number of atoms higher mass at spatial lag 7, increasing branching, and small difference in electronegativity between two bonded atoms at the Z axes.

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.

Ubrzani rast populacije koji prati povećana potrošnja i proizvodnja dobara uzrokuje i sve veće ekološko opterećenje okoliša. U težnji da zadovolje apetite populacije, proizvodni procesi povećavaju svoje kapacitete, što posredno ima negativne učinke na okoliš. U jeku takvog brzorastućeg fenomena ubrzane proizvodnje, danas se naglasak sve više stavlja na zaštitu okoliša i zelene proizvodne i ostale procese. Uz ostale, kemijska i farmaceutska industrija primijenjuju velike količine štetnih organskih lakohlapljivih otapala, koja se na kraju procesa odlažu u otpad. Osim otapala, nastoji se racionalizirati i upotreba štetnih toksičnih katalizatora i reagenasa općenito, te dizajn samog kemijskog procesa. Današnji pristup smanjenja štetnih utjecaja u kemijskim procesima se uvelike temelji na načelima zelene kemije objavljenim od strane Paul T. Anastasa i Johna C. Warnera 1998. g. Prema načelima zelene kemije i sinteza heterocikličih spojeva se nastoji što više prilagoditi navedenim principima, a radovi mnogih autora svjedoče vrlo efikasnoj primjeni i izvrsnim rezultatima. Mnoštvo autora dokazalo je da su neki procesi zelene sinteze heterocikličkih spojeva efikasniji od konvencionalnog pristupa, što zaista utire put novoj generaciji procesa s većom efikasnošću i manjim negativnim utjecajem na okoliš.