Mykhailo V. Vovk

Novel Potent Orthosteric Antagonist of ASIC1a Prevents NMDAR-Dependent LTP Induction.

Acid sensing ion channels 1a (ASIC1a) are of crucial importance in numerous physiological and pathological processes in the brain. Here we demonstrate that novel 2-oxo-2H-chromene-3-carboxamidine derivative 5b, designed with molecular modeling approach, inhibits ASIC1a currents with an apparent IC50 of 27 nM when measured at pH 6.7. Acidification to 5.0 decreases the inhibition efficacy by up to 3 orders of magnitude. The 5b molecule not only shifts pH dependence of ASIC1a activation but also inhibits its maximal evoked response. These findings suggest that compound 5b binds to pH sensor of ASIC1a acting as orthosteric noncompetitive antagonist. At 100 nM, compound 5b completely inhibits induction of long-term potentiation (LTP) in CA3-CA1 but not in MF-CA3 synapses. These findings support the knockout data indicating the crucial modulatory role of ASIC1a channels in the NMDAR-dependent LTP and introduce a novel type of ASIC1a antagonists.

Synthesis and investigation of antioxidant activity of the dithiocarbamate derivatives of 9,10-anthracenedione

A variety of new derivatives of 9,10-anthracenedione with mono- and bisdithiocarbamate moiety in the non-catalytic conditions have been synthesized. The obtained compounds were screened for their antioxidant capacity using the cupric-reducing antioxidant capacity (CUPRAC) method. Three of the compounds showed CUPRAC-Trolox equivalent antioxidant capacity (TEAC) coefficients higher than trolox. Scavenging effects on reactive oxygen species (ROS), hydroxyl radical scavenging (HRS), hydrogen peroxide scavenging (HPS), and superoxide anion radical scavenging (SARS) of all synthesized compounds were determined. It was established that the results of HRS-, HPS-, and SARS-CUPRAC methods for three compounds are in accordance with TEAC-CUPRAC assay data.Graphical abstract

Synthesis of (1H-pyrrol-1-yl)anthracene-9,10-diones

A method for the preparation of (1H-pyrrol-1-yl)anthracene-9,10-diones under the conditions of an iodine-catalyzed Clauson–Kaas reaction is proposed.

Trifluoromethyl-containing 3,4-dihydropyrimidine-2-ones and their condensed analogs

В огляді систематизовані та проаналізовані літературні джерела, які стосуються методів одержання 4- та 6-трифторометил-3,4-дигідропіримідин-2-онів та їх конденсованих похідних як перспективних молекулярних платформ для синтезу біоактивних сполук. Відзначена роль міжмолекулярних та внутрішньомолекулярних циклоконденсацій CF3-вмісних субстратів, а також реакцій приєднання С-нуклеофілів до C=N зв’язку CF3-вмісних 3,4-дигідропіримідонів як ключових методологічних підходів до конструювання 4-трифторометильованих похідних. Важливе місце відведене способу побудови трифторометилдигідропіримідонів високої оптичної чистоти та їх тіоаналогів, в основі якого лежить конденсація хіральних сечовин або тіосечовин. Значна увага приділена опису асиметричних реакцій, які приводять до синтезу хіральних аналогів анти-ВІЛ препарату Ефавіренц. Констатовано, що найбільш розповсюдженим варіантом отримання 6-трифторометилпіримідонів є реакція Біджинеллі відповідних фторовмісних кетоестерів. Метод дозволяє отримати цільові продукти в одну стадію, хоча і має обмеження, обумовлені потребою виділення проміжних циклічних продуктів, які в подальшому необхідно піддавати процесу дегідратації. Проаналізовано вплив природи каталізатора на перебіг реакції Біджинеллі за участю CF3-вмісних кетоестерних субстратів. Показана перспективність використання реакції 3,6-приєднання до 4-CF3-дигідропіримідонів для синтезу похідних дигідрооротової кислоти.

Synthesis and investigation of antimicrobial and antioxidant activity of anthraquinonylhydrazones

The new anthraquinonylhydrazones were obtained by the interaction of 9,10-dioxoanthracene-1-diazonium sulfates with a number of α- and β-carbonyl-containing compounds under modified conditions of the Japp–Klingemann reaction, and a probable mechanism of the formation has been proposed. It was found that hydrazones, unsaturated in the second position of the anthraquinone ring, containing acetyl or ethoxycarbonyl moieties in the ylidene part of the molecule, are capable of eliminating these fragments. It has been experimentally established that hydrazones, free rotation around the N=C bond of which is possible, exist as one isomer due to the presence of an intramolecular hydrogen bond in the molecule. The anthraquinonylhydrazone of dimedone with action against the bacteria strains of Staphylococcus aureus 209-P, Mycobacterium luteum B-917, and fungus Candida tenuis VKM Y-70 was found. The hydrazones of dimedone and barbituric acid with a higher trolox equivalent antioxidant coefficients of antioxidant action were found using CUPRAC assay. In addition, the hydrazones of dimedone and barbituric acid exhibited better activity against catalase enzyme. Correlations between the structure of the synthesized hydrazones and their antioxidant activity have been defined.Graphical abstract

Synthesis of benzofuro[3,2-b]furo[2,3-d]pyridin-4(5H)-ones, derivatives of a novel heterocyclic system

Abstract Methyl 2-[(cyanophenoxy)methyl]-3-furoates obtained from methyl 2-(chloromethyl)-3-furoate and salicylonitriles undergo tandem cyclization in the presence of excess t-BuOK in N,N-dimethylformamide (DMF) solution at 65°C to give substituted benzofuro[3,2-b]furo[2,3-d]pyridin-4(5H)-ones, derivatives of a novel heterocyclic system.

Synthesis and functionalization of 2-alkylidene-5-(bromomethyl)-2,3-dihydro-1,3-thiazole derivatives

2-Alkylidene-5-methylidene-1,3-thiazolidin-2-ylidenes react with N-bromosuccinimide to form 2-alkylidene-5-(bromomethyl)-2,3-dihydro-1,3-thiazoles, the reaction of which with S,O,N-nucleophiles is used for the selective synthesis of the corresponding 5-methylfunctionalized derivatives.

The addition of β-ketoacids to 4-(trifluoromethyl)pyrimidin- 2(1 Н )-ones with decarboxylation: an effective method for the synthesis of 4-(2-oxoalkyl)-6-(trifluoromethyl)-3,4-dihydropyrimidin-2-ones

β-Ketoacids reacted with 4-(trifluoromethyl)pyrimidin-2(1Н)-ones according to the mechanism of Michael addition–decarboxylation, forming 4-(2-oxoalkyl)-6-(trifluoromethyl)-3,4-dihydropyrimidin-2-ones.

Polyfunctional pyrazoles 11*. Synthesis of 5-aroylpyrano[3,4- c ]pyrazol-7(2 H )-ones

Aroylmethyl esters of 4-formylpyrazole-3-carboxylic acids underwent intramolecular cyclocondensation in the presence of sodium acetate in refluxing acetic anhydride, giving moderate yields of 5-aroylpyrano[3,4-с]pyrazol-7(2Н)-ones.

The New 1,2,3-Triazolylantracene-9,10-Diones: Synthesis and ComputerBioactivity Screening

The reactions of 1,4(1,5)-diazido-9,10anthracenediones with phenylacetylene and methyl propiolate under copper(I)-catalyzed reaction of the azidealkyne cycloaddition conditions have been studied and a series of new 1,2,3-triazole derivatives of 9,10anthracendione have been obtained. The computer screening of synthesized compounds was carried out using the PASS Online software to identify areas of experimental biomedical researches. Compounds with high affinity to the receptors family of tyrosine kinases of the epidermal growth factor EGFR have been found among the newly synthesized 1,2,3-triazoles of 9,10anthracenedione using molecular docking. The results of molecular docking indicate a probable mechanism for the realization of antitumor activity.