Background: Due to the increase of multidrug-resistant microorganisms, the search for biologically active molecules does not stop. In the present study, we developed the effective QSAR model which allows a quick search of new potential Staphylococcus aureus inhibitors in the series of quaternary phosphonium salts. A number of the most promising 1,3-oxazol-4-yltriphenylphosphonium derivatives with predicted activities were synthesized and examined to confirm their antibacterial properties and the accuracy of the forecast. Furthermore, the toxicity of the investigated compounds was evaluated. Methods: The predictive QSAR model was developed using Artificial Neural Network approach. Antibacterial properties of the investigated compounds were performed using standard disk diffusion method. The toxicity of the compounds was determined in vivo using zebrafish (Danio rerio) and in vitro on acetylcholinesterase (AChE) enzyme as the test models. Results: The predictive ability of the regression model was tested by cross-validation, giving the cross-validated coefficient q2=0.82. Derivatives of 1,3-oxazol-4-yltriphenylphosphonium salts predicted as active were synthesized and screened for their antibacterial activities. All compounds demonstrated antibacterial activity according to the prediction. The toxicity tests indicated that all investigated samples were less toxic than well-known cationic surfactants. Conclusion: The most promising compound 2b exhibited strong antibacterial activity together with low toxicity and can be considered as a new efficient biocidal agent for future investigation. In addition, the proposed QSAR model can be used for predicting and designing novel potential S. aureus inhibitors among ionic liquids/salts.

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Inhibition of acetylcholinesterase is considered as a promising approach for treatment of neurodegenerative disorders including Alzheimer's disease. In this study, we demonstrated that 5-substituted N-phenacylthiazolium derivatives are capable of inhibiting acetylcholinesterase and butyrylcholinesterase activities with IC50 values in the micromolar range. Some of the new thiazolium-based inhibitiors showed more than 10-fold selectivity for butyrylcholinesterase. Kinetic experiments and molecular docking were performed for understanding the inhibition mechanisms.________________________________________________________________________________

Cholinesterase inhibitors can be used for treatment of neuropsychiatric symptoms and functional impairments in neurodegenerative pathologies such as Alzheimer's and Parkinson's diseases.Aim. To synthesize and assess the inhibitory activity of adamantyl-containing 5-substituted N-benzyl and N-phenacylthiazolium salts against butyrylcholinesterase and acetylcholinesterase.Results and discussion. The synthesis of 3-aroylmethyl-and 3-arylmethyl-5-(2-acyloxyethyl)-4-methylthiazolium salts included preparation of 5-acyloxyethyl thiazole derivatives by the reaction of 5-(2-hydroxyethyl)-4-methyl-1,3-thiazole with the corresponding adamantoyl-or adamantylacetyl chlorides. The derivatives of 5-acyloxyethyl thiazole were quaternized in the reaction with benzyl or phenacyl halides. The studies in vitro have shown that the compounds synthesized inhibit butyrylcholinesterase with IC 50 values in the micromolar range. Some of them exhibited selectivity over acetylcholinesterase. The molecular docking was performed for understanding the mechanisms of the enzyme-inhibitor complex formation.Experimental part. The synthesis of the intermediate and target compounds was carried out by the classical methods. The structures of compounds were proven by NMR 1 H-spectroscopy and elemental analysis. The methods of enzymatic kinetics were used for determination of the inhibitory effects of the compounds synthesized. Calculations by molecular docking were carried out using Autodock 4.2 program.Conclusions. 3-Aroylmethyl-and 3-arylmethyl-5-(2-acyloxyethyl)-4-methylthiazolium salts with adamantylcontaining substituents in position 5 can selectively inhibit butyrylcholinesterase compared to their effect on acetylcholinesterase.Key words: butyrylcholinesterase; acetylcholinesterase; adamantan; inhibitor; thiazolium salt; molecular docking А. Д. Очеретнюк, О. Л. Кобзар, О. П. Козаченко, В. С. Броварець, А. І. Вовк Синтез та оцінка активності адамантиловмісних тіазолієвих інгібіторів бутирилхолінестеразиВідомо, що інгібітори холінестераз можуть використовуватись для лікування нейродегенеративних захво-рювань, таких як хвороба Альцгеймера і хвороба Паркінсона.Мета роботи. Метою роботи був синтез та оцінка активності адамантиловмісних 5-заміщених N-бензильних та N-фенацильних солей тіазолію як інгібіторів бутирилхолінестерази і ацетилхолінестерази.Результати та їх обговорення. Синтези 3-ароїлметил-і 3-арилметил-5-(2-ацилоксіетил)-4-метилтіазолієвих солей включали одержання 5-ацилоксіетильних похідних тіазолу при взаємодії 5-(2-гідроксіетил)-4-метил-1,3-тіазолу з відповідними адамантоїл-чи адамантилацетилхлоридами, які надалі кватернізували в реак-ції з бензил-або фенацилгалогенідами. Результати дослідження in vitro показали, що синтезовані сполуки інгібують бутирилхолінестеразу зі значеннями ІС 50 в мікромолярному діапазоні. Деякі з них демонструва-ли селективність дії у порівнянні з інгібуванням ацетилхолінестерази. Для з'ясування механізмів форму-вання комплексів інгібіторів з бутирилхолінестеразою було проведено молекулярний докінг.Експеримента...

This paper describes QSAR studies by using the Online Chemical Modeling Environment, synthesis, in vitro antifungal activity of 1,3-oxazolylphosphonium derivatives and their acetylcholinesterase inhibitory potential. Three classification QSAR models were created using Random Forests (WEKA-RF), k-Nearest Neighbors and Associative Neural Networks methods and different combinations of descriptors. The predictive ability of the models was tested through cross-validation, giving a balanced accuracy BA=80-91%. All compounds demonstrated good antifungal properties and slight inhibition of acetylcholinesterase activity. The high percentage of coincidence between the QSAR predictions and the experimental results confirmed the high predictive power of the developed QSAR models that can be applied as tools for finding new potential inhibitors against of Candida spp. Furthermore, 1,3-oxazol-4-yl(triphenyl)phosphonium salts could be considered as promising candidates for the treatment of candidiasis and the disinfection of medical equipment.