Селективные ингибиторы карбоксилэстеразы для повышения эффективности, безопасности и рационального применения лекарственных препаратов, содержащих сложноэфирные группы

In clinical practice, a large number of prodrugs and active drugs containing an ester, carbamate or amide moiety are used. Carboxylesterase (CaE, EC 3.1.1.1) is the key enzyme of hydrolytic metabolism of such drugs in the body, it largely determines their pharmacokinetics, bioavailability, efficacy and possible toxic effects. Using CaE selective inhibitors as components of combined drug therapy it is possible us to regulate the rate of hydrolytic transformation of ester-containing drugs and opens the possibility of their rational use. The development of effective and selective CaE inhibitors suitable for in vivo application is a new promising approach in medicinal chemistry and pharmacology that allows to improve the efficacy, bioavailability and reduce the side effects of ester-containing drugs.В клинической практике применяется большое число пролекарств и активных лекарственных средств, содержащих сложноэфирную, карбаматную или амидную группировку. Ключевым ферментом гидролитического метаболизма таких препаратов в организме являются карбоксилэстеразы (КЭ, КФ 3.1.1.1), которые в значительной степени определяют их фармакокинетику, эффективность и возможные токсические эффекты этих лекарственных средств. Использование селективных ингибиторов КЭ в качестве компонентов комбинированной лекарственной терапии позволяет регулировать скорость гидролитического превращения лекарственных препаратов со сложноэфирной группой и открывает возможность их рационального использования. Создание эффективных и селективных ингибиторов КЭ для применения in vivo, является новым перспективным подходом в медицинской химии и фармакологии, позволяющим повысить эффективность, биодоступность и снизить побочные эффекты многочисленных лекарственных средств, содержащих сложноэфирные группировки

Влияние размера цикла и структуры спейсера конъюгатов такрина и его циклопентильного гомолога с 5-(4-трифторметил-фениламино)-1,2,4-тиадиазолом на спектр биологической активности

The conjugates of tacrine and its cyclopentyl analogue with 5-(4-trifluoromethyl-phenylamino)-1,2,4-thiadiazole, combined with two different spacers, pentylaminopropane and pentylaminopropene, were synthesized. Their esterase profile, the ability to displace propidium from the peripheral anionic site (PAS) of acetylcholinesterase (AChE) and antioxidant activity in the ABTS test were investigated. The compounds obtained effectively inhibit cholinesterases with a predominant effect on butyrylcholinesterase, displace propidium from the PAS of Electrophorus electricus AChE (EeAChE) and exhibit a high radical-scavenging capacity. It is shown that, depending on the spacer structure, particulary, the presence of a propenamine or propanamine fragment, the spectrum of biological activity of the conjugates changes.Синтезированы конъюгаты такрина и его циклопентильного аналога с 5-(4-трифторметил-фениламино)-1,2,4- тиадиазолом, объединённые двумя разными спейсерами – пентиламинопропановым и пентиламинопропеновым, исследован их эстеразный профиль, способность вытеснять пропидий из периферического анионного сайта (ПАС) ацетилхолинэстеразы (АХЭ) и антиоксидантная активность в тесте АБТС. Полученные соединения эффективно ингибируют холинэстеразы с преимущественным действием на бутирилхолинэстеразу, вытесняют пропидий из ПАС АХЭ из Electrophorus electricus (EeАХЭ) и обладают высокой радикал-связывающей способностью. Показано, что в зависимости от строения спейсера, а именно наличия в нем пропенаминового или пропанаминового фрагмента, меняется спектр биологической активности конъюгатов

POLYFLUOROALKYL-2-(HET)ARYLHYDRAZONO-1,3-DICARBONYL COMPOUNDS IN INTRAMOLECULAR CYCLIZATION REACTIONS

This work was financially supported by the Program UB RAS (Grant number 18-3-3-13)

Derivatives of 9-phosphorylated acridine as butyrylcholinesterase inhibitors with antioxidant activity and the ability to inhibit β-amyloid self-aggregation: potential therapeutic agents for Alzheimer’s disease

We investigated the inhibitory activities of novel 9-phosphoryl-9,10-dihydroacridines and 9-phosphorylacridines against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carboxylesterase (CES). We also studied the abilities of the new compounds to interfere with the self-aggregation of β-amyloid (Aβ42) in the thioflavin test as well as their antioxidant activities in the ABTS and FRAP assays. We used molecular docking, molecular dynamics simulations, and quantum-chemical calculations to explain experimental results. All new compounds weakly inhibited AChE and off-target CES. Dihydroacridines with aryl substituents in the phosphoryl moiety inhibited BChE; the most active were the dibenzyloxy derivative 1d and its diphenethyl bioisostere 1e (IC50 = 2.90 ± 0.23 µM and 3.22 ± 0.25 µM, respectively). Only one acridine, 2d, an analog of dihydroacridine, 1d, was an effective BChE inhibitor (IC50 = 6.90 ± 0.55 μM), consistent with docking results. Dihydroacridines inhibited Aβ42 self-aggregation; 1d and 1e were the most active (58.9% ± 4.7% and 46.9% ± 4.2%, respectively). All dihydroacridines 1 demonstrated high ABTS•+-scavenging and iron-reducing activities comparable to Trolox, but acridines 2 were almost inactive. Observed features were well explained by quantum-chemical calculations. ADMET parameters calculated for all compounds predicted favorable intestinal absorption, good blood–brain barrier permeability, and low cardiac toxicity. Overall, the best results were obtained for two dihydroacridine derivatives 1d and 1e with dibenzyloxy and diphenethyl substituents in the phosphoryl moiety. These compounds displayed high inhibition of BChE activity and Aβ42 self-aggregation, high antioxidant activity, and favorable predicted ADMET profiles. Therefore, we consider 1d and 1e as lead compounds for further in-depth studies as potential anti-AD preparations

Influence of complicating factors on a rod pump productivity

Relevance. In the Russian Federation rod screw pumps installations are widely used in the Ural-Volga region and first of all in the Republic of Tatarstan as they allow extracting reservoir liquid of the increased viscosity with the content of mechanical impurity and gas. The main aim of the research is to determine the effect of complicating factors, such as the presence of mechanical impurities, increased viscosity, water cut of formation fluid, on operational efficiency of rod screw pumps; determine the regularities in reducing the operating time of the rod column and the elastomer of the pump. Objects. The main number of rod screw pumps is in wells, which have opened the layers of the Bashkirian stage and the Verean horizon. They are distinguished by high viscosity of oil and presence of water-oil emulsion. The analysis of the chemical properties of oil samples from 188 wells in Sheshmaoyl, Kondurchaneft and Ideoloyl, operated by rod screw pumps, showed that the average viscosity of oil wells is 610 mPas. At the same time, a significant proportion falls on the wells producing reservoir fluid with a viscosity of more than 500 mPass. Methods. The accumulated volume of operational data on Bashkirian and Vereisk horizon wells equipped with rod screw pumps allows determining the operating time of the rod pumps reduction with an increase in viscosity of the fluid caused by a significant growth in hydraulic resistance to rotary motion of the rod string. The carried out statistical analysis of the rod screw pumps repair determined the regularity of wearout degree of the elastomer depending on a number of accumulated rotor speed, water content, content of mechanical impurities in the produced fluid, saturation pressure, fluid level in the well and with favorable conditions. Results. We defined the main complicating factors which influence the efficiency of rod pump operation. The analysis of the rod screw pumps repair causes shown that low quality of polished rods produced by the manufacturer, rod deviation from geometric parameters of different structures, hardness, chemical composition of rods (factory defect) are often the causes of breaks. Open threaded rod or polished rod was primarily due to insufficient torque screwing the threaded connection or a bend in the rod head. The breackage of polished rods mainly occur in the oil seal and due to fatigue voltage. The fatigue fracture occurs as a result of permanent deformation forces and temperature action. One of the main causes of the elastomer swelling is the maintenance with pressure at the reception of rod screw pumps below the saturation pressure. It leads to saturation of elastomer material with gases and rotor jamming in the stator which can turn into breakages of the rod string and polished rod

Synthesis, molecular docking, and biological activity of 2-vinyl chromones: Toward selective butyrylcholinesterase inhibitors for potential Alzheimer's disease therapeutics

We investigated the biological activity of a series of substituted chromeno[3,2-c]pyridines, including compounds previously synthesized by our group and novel compounds whose syntheses are reported here. Tandem transformation of their tetrahydropyridine ring under the action of activated alkynes yielding 2-vinylsubstituted chromones was used to prepare nitrogen-containing derivatives of a biologically active chromone system. The inhibitory activity of these chromone derivatives against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and carboxylesterase (CaE) was investigated using the methods of enzyme kinetics and molecular docking. Antioxidant (antiradical) activity of the compounds was assessed in the ABTS assay. The results demonstrated that a subset of the studied chromone derivatives selectively inhibit BChE but do not exhibit antiradical activity. In addition, the results of molecular docking effectively explained the observed features in the efficacy, selectivity, and mechanism of BChE inhibition by the chromone derivatives. © 2018 Elsevier Lt