7 research outputs found

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

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    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

    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

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    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

    Исследование эстеразного статуса организма как комплексного биомаркера воздействия фосфорорганических соединений

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    Development of biomarkers of human exposures to organophosphorus compounds OPCs and their quantification is a vital component of a system of prediction and early diagnostics of OPC-induced diseases. Our study was focused on investigation of esterase status as a complex biomarker of exposure to OPCs and an aid in accurate diagnosis. We suggest that this complex biomarker should be more effective and informative than standard assays of plasma butyrylcholinesterase (BChE), erythrocyte acetylcholinesterase (RBC AChE), and lymphocyte neuropathy target esterase (NTE). It will help: 1) to assess an exposure as such and to confirm the nonexposure of individuals suspected to have been exposed; 2) to determine if the exposure was to agents expected to produce acute and/or delayed neurotoxicity; 3) to perform dosimetry of the exposure, which provides valuable information for medical treatment. To confirm this hypothesis, we have examined the changes in activity of blood AChE, NTE, BChE and carboxylesterase (CaE) 1 h after i.p. administration of increasing doses of three OPCs with different esterase profiles: the known neuropathic compound O,O-dipropyl-O-dichlorovinyl phosphate (C3H 7O)2P(O)OCH=CCl2 (diPr-DClVP) as the control compound and two model dialkylphosphates (C2H5O)2P(O)OCH(CF3)2 (diEt-PFP) and (C4H9O)2P(O)OCH(CF3)2 (diBu-PFP). The esterases assay was performed in hemolysed blood by spectrophotometric (AChE, BChE, CaE) and biosensor (NTE) methods. Analysis of the obtained dose-dependences for blood esterases inhibition showed that blood BChE and CaE were the most sensitive biomarkers, allowing detection of low doses. Inhibition of blood NTE and AChE can be used to assess the likelihood that an exposure to OPC would produce cholinergic and/or delayed neuropathic effects.Разработка системы биомаркеров воздействия фосфорорганических соединений (ФОС) на человека и их количественная оценка являются важным компонентом предсказания и ранней диагностики заболеваний, вызываемых антихолинэстеразными соединениями. Целью нашей работы было исследование эстеразного статуса организма как комплексного биомаркера воздействия ФОС для диагностики воздействия и последующей терапии такого рода интоксикаций. Мы полагаем, что этот комплексный биомаркер будет более эффективным и информативным по сравнению со стандартным определением бутирилхолинэстеразы плазмы крови (БХЭ), ацетилхолинэстеразы эритроцитов (АХЭ) и нейротоксичной эстеразы лимфоцитов (НТЭ). Он позволит: 1) подтвердить или опровергнуть сам факт воздействия ФОС; 2) определить, обусловлено ли воздействие агентами, вызывающими острую и/или отставленную нейротоксичность; 3) провести дозиметрию воздействия, которая даст ценную информацию для последующей терапии отравления. Для подтверждения этой гипотезы мы провели исследование изменения активности АХЭ, НТЭ, БХЭ и карбоксиэстеразы (КЭ) крови мышей через 1 ч после внутрибрюшинного введения возрастающих доз трёх ФОС с различным эстеразным профилем: известного нейропатичного соединения O,O-дипропил-O-дихлорвинилфосфата (C3H 7O)2P(O)OCH=CCl2 (diPr-DClVP) в качестве контрольного соединения и двух модельных диалкилфосфатов – (C2H5O)2P(O)OCH(CF3)2 (diEt-PFP) и (C4H9O)2P(O)OCH(CF3)2 (diBu-PFP). Измерение активности эстераз проводили в препаратах гемолизованной крови спектрофотометрическим (АХЭ, БХЭ, КЭ) и биосенсорным (НТЭ) методами. Анализ полученных дозозависимостей для ингибирования эстераз крови показал, что БХЭ и КЭ являются наиболее чувствительными биомаркерами, позволяющими детектировать низкие дозы ФОС токсикантов. Одновременное определение активности АХЭ и НТЭ в крови может быть использовано для оценки вероятности воздействия острых и/или отставленных нейротоксикантов

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

    No full text
    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

    The impact of collaborative instruction of language learning strategies on language learning beliefs and learner autonomy

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    Research on the relationship among language learning strategy, language learning beliefs and autonomy abounds in the literature. However, few studies have explored the possibility of promoting learners’ autonomy and changing their beliefs through instructing language learning strategies in a collaborative manner. In addition, most of the earlier investigations have been carried out through purely cognitive or sociocultural perspectives employing solely quantitative or qualitative methods. Using a socio-cognitive framework, the present study aimed at first, identifying the relationships among language learning beliefs, language learning strategies, and learner autonomy; and second, investigating the role of collaboration in using language learning strategies that would eventually lead to autonomy and change of beliefs. To collect data, a mixed-method design was applied. An autonomy questionnaire, Horwitz's BALLI (Beliefs about Language Learning Inventory, 1987) and Oxford's SILL (Strategy Inventory for Language Learning, 1990) were given to177 EFL learners at the University of Mazandaran in Iran. To supplement the quantitative data with qualitative data, negotiated interviews and the learners' self-reflection notes were used. The analysis was done using paired sample T-tests, SEM and also content analysis. The findings revealed that language learning beliefs affected the learners' autonomy through the mediation of language learning strategies. However, the instruction of the strategies did not have any effects on the learners' autonomy but it helped in changing their language learning beliefs. The qualitative analysis also led to identifying some categories, subcategories and their relationships to and effects on each other. © 2020, Slovenska Vzdelavacia Obstaravacia. All rights reserved
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