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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

The substantial increase in pest’s resistance to commonly used pesticides as well as the concern of growing environmental pollution have been the biggest challenges agricultural industry had to face in recent years. Large efforts have been made to produce a variety of novel and environmentally sustainable compounds to be used as an alternative to commercially available pesticides. [1] A set of 36 newly synthesized triazole derivatives have been assayed as potential acetylcholinesterase inhibitors by utilizing the Ellman’s protocol. [2] The highest inhibition percentages were obtained with compounds 7h (68.32%), KM35 (49.77%), KM16 (48.04%), KM18 (47.82%), and KM19 (39.89%). In vivo study was performed on two species of nematodes ; Heterorhabditis bacteriophora and Steinernema feltiae. The nematodes were exposed to aforementioned compounds in the period of 72 h. The highest mortality rate of Heterorhabditis bacteriophora species was observed with the compound KM16 with the value of 75.0% after 48 h of incubation, while he highest mortality rate of Steinernema feltiae was observed with the compound KM18 with the value of 50.0% after 48 and 72 h of incubation. The inhibition percentages do not seem to correlate with the in vivo results, as the compound 7h had one of the lowest mortality rates within the tested group of compounds among the both nematode species.

Prema organizaciji Alzheimer’s Disease International, oko 55 milijuna ljudi na svijetu boluje od Alzheimerove bolesti ili drugih oblika demencije u 2020. godini. Najčešći način liječenja spomenutih stanja je inhibicija acetilkolinesteraze (AChE) i amiloid beta enzima u ljudskom mozgu korištenjem komercijalnih farmaceutika kao što su donepezil i aducanumab [1]. Prethodna istraživanju upućuju da propolis ima značajna inhibicijska svojstva AChE prvenstveno zbog visokog sadržaja fenola koji čine čak 60% ukupnog udjela komponenti u propolisu [2]. Test inhibicije AChE proveden je provođenjem Ellmanove metode [3]. Uzorci propolisa osigurani su od strane obiteljskog poljoprivrednog gospodarstva Boris Buratović sa otoka Hvara. Uz ostale cvjetne vrste, lokalitet sa kojeg je prikupljen propolis obiluje ružmarinom (Salvia rosmarinus), lavandom (Lavandula angustifolia) i vrijesom (Calluna vulgaris), biljkama koje mogu značajno utjecati na sadržaj fenola u usporedbi s propolisom prikupljenim u kontinentalnim krajevima. Volumni postotci propolisa u reakcijskoj smjesi iznosili su 5%, 3, 5% i 2, 5%. Najviši postotak inhibicije od 67, 14% postignut je s volumnim postotkom propolisa od 5%.

In silico methods are used for a rational approach in screening, optimization, and the design of newly synthesized compounds as potential agents in plant protection. The tested compounds are quinazolinone-based Schiff bases synthesized by the means of the green chemistry procedures, such as microwave-assisted, ultrasound-assisted, and mechanochemical synthesis. The aim of the study is to evaluate the inhibitory activity of mentioned compounds on enzymes that have a crucial role in the growth and spreading of plant pathogenic fungi, such as Macrophomina phaseolina, Sclerotinia sclerotiorum, Fusarium oxysporum f. sp. Lycopersici and F. culmorum. In silico study was performed by the use of molecular docking on enzymes responsible for the fungal growth: demethylase ((CYP51), pdb ID: 5eah), chitinase (pdb ID: 4txe), transferase (Nmyristoyltransferase, pdb ID: 2p6g), as well as enzymes responsible for the degradation of the plant cell-wall: endoglucanase I (pdb ID: 4ovw), proteinase K (pdb ID: 2pwb), pectinase (endopolygalacturonase, pdb ID: 1czf). The binding affinity and interactions with the active sites of enzymes was determined the mode of action of the most active compounds against fungi.

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.

Novel derivates of benzothiazoles and benzimidazoles have been evaluated on T-cell lymphoma (HuT78), as well as on normal Madin-Darby canine kidney cells (MDCK-1). Cytotoxic effects of 77 benzothiazoles and benzimidazoles against non-tumour MDCK-1 cells were ranked by activities, and 17 compounds were chosen for the test set. The best QSAR model expressed by multiple linear regression equation was generated by five molecular descriptors calculated by DRAGON program: SIC1, GATS4p, BEHv6, BELp1, and R7m. Williams plot of the applicability domain, detected one molecule as a border outlier and no molecule out of the warning leverage. After removing outlier, the new model has the model achieved better statistical performance of internal and external validation: R2train = 0.74 ; F = 30.76 ; ΔK = 0.08 ; CCCtr = 0.85 ; Q2loo = 0.68 ; CCCcv = 0.81 ; R2Yscr = 0.09 ; Q2Yscr = -0.13 ; R2ext = 0.83 ; CCCext = 0.85 ; Δr2m = 0.25. Molecules without atoms with higher atomic mass as substituents (Cl, F) and more equal neighbor atoms have higher activity. QSAR study for antiproliferative activity on T-cell lymphoma (HuT78) cell was performed on a total of 59 molecules (47 training, 12 test set). The best-obtained model includes three descriptors: MATS8v, Mor09p, Mor30m, and E2u. After exclusion of three outliers from data set, relived by Williams plot (Figure 1) resulted on the predictive model: R2train = 0.87 ; F = 66.48 ; ΔK = 0.12 ; CCCtr = 0.93 ; Q2loo = 0.83 ; CCCcv = 0.91 ; R2Yscr = 0.09 ; Q2Yscr = -0.15 ; R2ext = 0.87 ; CCCext = 0.85 ; Δr2m = 0.13. An increasing number of atomic van der Waals volumes, such as in sulphur atom in benzothiazoles, as molecules without atoms, have higher atomic mass as substituents (Cl, F) enhancing antiproliferative activity on MDCK-1 cells.

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.

The control of fungal pathogens, pests and weeds has made a crucial contribution to food provision worldwide by ensuring the harvested yield of the world’s crops. The appearance of drug resistance, environmental and health hazards indicates the urgent need for new active components in plant protection products. These compounds must be highly specific be environmentally and toxicologically acceptable. Computational design of future compounds and their synthesis, evaluation of their effectiveness on harmful and beneficial organisms in soil, as well as detail research mechanism of action at the molecular level, represents an initial stage in the long-lasting and expensive process of plant protection products. Quantitative structure-activity relationship study (QSAR) has the potential to estimate the risks of chemicals for environment and human health, reducing the time, monetary cost, and necessary animal testing. QSAR models serve for prediction of biological activities of new and untested compounds. Binding modes of the compounds on the target enzymes related to the specific biological activity are elucidate by the methods of molecular modelling. The quantitative structure-toxicity relationship (QSTR) technique allows prediction of toxicity effects for new compounds with proven biological activity related to plant protection. This lecture describes the procedure of design new compounds that represent potential active components of plant protection products from harmful fungi, nematodes and bacteria but without any adverse environmental and human health effects.

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.

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.