Synthesis and Anticancer Activity of New Thiopyrano[2,3-d]thiazoles Based on Cinnamic Acid Amides

Novel rel-(5R,6S,7S)-2-oxo-5-phenyl-7-aryl(hetaryl)-3,7-dihydro-2H-thiopyrano [2,3-d]thiazole-6-carboxylic acid amides were synthesized in a hetero-Diels-Alder reaction with a series of cinnamic acid amides. The synthesized compounds were tested for their anticancer activity in vitro in the standard National Cancer Institute 60 cancer cell line assay. Promising compounds 3e, 3g, and 3h with moderate antitumor activity were identified among the synthesized series

Огляд похідних 1,2,4-триазолу та 1,3,4-тіадіазолу як потенційних знеболювальних та протизапальних засобів

The aim. The purpose of this review is to summarize data on the synthesis and structural modification of heterocyclic systems with triazole and thiadiazole fragments in molecules as promising objects in bioorganic and medicinal chemistry. Materials and methods. The research based on bibliosemantic and analytical methods using bibliographic and abstract databases, as well as databases of chemical compounds. Results. Modern medicinal chemistry faces many challenges, one of which is the determination of the activity and specificity of therapeutic agents. Recent scientific data showed that triazoles and/or thiadiazoles have broad spectrum of biological activities, in particular antimicrobial, antifungal, antiviral, anticancer and anticonvulsant. Synthetic research allows to propose a whole number of new molecular design directions of biological active triazole and/or thiadiazole derivatives, as well as to obtain directed library that include hundreds of new compounds. This review is an effort to summarize data of its analgesic and anti-inflammatory activity over the last decade. We summarized and analyzed the series of triazole and/or thiadiazole derivatives and provided data of their structure-activity relationship. For optimization and rational design of highly active molecules with optimal «drug-like» characteristics and discovering of possible mechanism of action SAR, QSAR analysis and molecular docking were summarized. Conclusions. It has been shown that heterocyclic systems containing fragments of triazole and / or thiadiazole are a significant source of promising analgesic and/or anti-inflammatory agents. It has been established that the mentioned heterocyclic derivatives have a high selectivity of action, low toxicity and an effect commensurate with standard drugsМета. Метою даного огляду є узагальнення даних про синтез та структурну модифікацію гетероциклічних систем з тріазольним та тіадіазольним фрагментами в молекулах як перспективних об’єктів у біоорганічній та медичній хімії. Матеріали та методи. У дослідженні застосовано бібліосемантичний та аналітичний методи використовуючи бібліографічні і реферативні бази даних, а також бази даних хімічних сполук. Результати. Сучасна медична хімія стикається з багатьма проблемами, одна з яких – необхідність визначення активності та специфічності потенційного терапевтичного агента. Останні наукові дані вказують на те, що похідним тріазолу та/чи тіадіазолу притаманний широкий спектр біологічної дії, зокрема протимікробна, протигрибкова, противірусна, протиракова та антиконвульсантна. Синтетичні дослідження, дозволили запропонувати низку нових спрямувань молекулярного дизайну біологічно активних похідних тріазолу та/чи тіадіазолу, а також одержати сфокусовані бібліотеки, що нараховують сотні нових сполук. Ця оглядова стаття є спробою узагальнити дані щодо їх анальгезуючої та протизапальної активності за останнє десятиліття. У роботі проаналізовано ряди похідних тріазолу та/чи тіадіазолу, та наведено залежності «структура-активність». Для оптимізації і раціонального дизайну високоактивних молекул з оптимальними «лікоподібними» характеристиками та визначення можливого механізму біологічної дії проведено узагальнення даних щодо SAR- і QSAR-аналізу і молекулярного докінгу серед даного класу гетероциклічних сполук. Висновки. Показано, що гетероциклічні системи, що містять фрагменти тріазолу та/чи тіадіазолу, є суттєвим джерелом перспективних анальгетичних та/чи протизапальних засобів. Встановлено, що згадані гетероциклічні похідні володіють високою селективністю дії, малою токсичністю та ефектом, що співмірний з існуючими лікарськими засобам

Thiopyrano[2,3-d]Thiazoles as New Efficient Scaffolds in Medicinal Chemistry

This review presents the up to date development of fused thiopyranothiazoles that comprise one of the thiazolidine derivatives classes. Thiazolidine and thiazolidinone-related compounds belong to the widely studied heterocycles from a medicinal chemistry perspective. From the chemical point of view, they are perfect heterodienes to undergo hetero-Diels–Alder reaction with a variety of dienophiles, yielding regio- and diastereoselectively thiopyranothiazole scaffolds. The annealing of thiazole and thiopyran cycles in condensed heterosystem is a precondition for the “centers conservative” creation of the ligand-target binding complex and can promote a potential selectivity to biotargets. The review covers possible therapeutic applications of thiopyrano[2,3-d]thiazoles, such as anti-inflammatory, antibacterial, anticancer as well as aniparasitic activities. Thus, thiopyrano[2,3-d]thiazoles may be used as powerful tools in the development of biologically active agents and drug-like molecules

5-[4-(<i>tert</i>-Butyl)cyclohexylidene]-2-thioxothiazolidin-4-one

The Knoevenagel reaction is an essential synthetic tool in the organic and medicinal chemistry of thiazolidin-4-one derivatives. In the present work, the application of ethylenediamine diacetate (EDDA) as an effective catalyst for the interaction of 2-thioxothiazolidin-4-one with 4-(tert-butyl)cyclohexanone is proposed. The structure of novel synthesized 5-[4-(tert-butyl)cyclohexylidene]-2-thioxothiazolidin-4-one (yield 61%) was confirmed by 1H-, 13C-NMR, LC-MS, IR, and UV spectra. Drug-like properties of the synthesized compound were evaluated in silico using the SwissAdme, and their potential antimicrobial activity against 15 strains of Gram-positive and Gram-negative bacteria as well as yeasts was evaluated in vitro. The synthesized compound possesses satisfactory drug-like parameters and promising antimicrobial properties and presents interest as a prospective intermediate for the forthcoming design of biologically active small molecules

5-[4-(tert-Butyl)cyclohexylidene]-2-thioxothiazolidin-4-one

The Knoevenagel reaction is an essential synthetic tool in the organic and medicinal chemistry of thiazolidin-4-one derivatives. In the present work, the application of ethylenediamine diacetate (EDDA) as an effective catalyst for the interaction of 2-thioxothiazolidin-4-one with 4-(tert-butyl)cyclohexanone is proposed. The structure of novel synthesized 5-[4-(tert-butyl)cyclohexylidene]-2-thioxothiazolidin-4-one (yield 61%) was confirmed by 1H-, 13C-NMR, LC-MS, IR, and UV spectra. Drug-like properties of the synthesized compound were evaluated in silico using the SwissAdme, and their potential antimicrobial activity against 15 strains of Gram-positive and Gram-negative bacteria as well as yeasts was evaluated in vitro. The synthesized compound possesses satisfactory drug-like parameters and promising antimicrobial properties and presents interest as a prospective intermediate for the forthcoming design of biologically active small molecules

An Overview on 1,2,4-triazole and 1,3,4-thiadiazole Derivatives as Potential Anesthesic and Anti-inflammatory Agents

The aim. The purpose of this review is to summarize data on the synthesis and structural modification of heterocyclic systems with triazole and thiadiazole fragments in molecules as promising objects in bioorganic and medicinal chemistry. Materials and methods. The research based on bibliosemantic and analytical methods using bibliographic and abstract databases, as well as databases of chemical compounds. Results. Modern medicinal chemistry faces many challenges, one of which is the determination of the activity and specificity of therapeutic agents. Recent scientific data showed that triazoles and/or thiadiazoles have broad spectrum of biological activities, in particular antimicrobial, antifungal, antiviral, anticancer and anticonvulsant. Synthetic research allows to propose a whole number of new molecular design directions of biological active triazole and/or thiadiazole derivatives, as well as to obtain directed library that include hundreds of new compounds. This review is an effort to summarize data of its analgesic and anti-inflammatory activity over the last decade. We summarized and analyzed the series of triazole and/or thiadiazole derivatives and provided data of their structure-activity relationship. For optimization and rational design of highly active molecules with optimal «drug-like» characteristics and discovering of possible mechanism of action SAR, QSAR analysis and molecular docking were summarized. Conclusions. It has been shown that heterocyclic systems containing fragments of triazole and / or thiadiazole are a significant source of promising analgesic and/or anti-inflammatory agents. It has been established that the mentioned heterocyclic derivatives have a high selectivity of action, low toxicity and an effect commensurate with standard drug

Hydrogen Sulfide Releasing 2-Mercaptoacrylic Acid-Based Derivative Possesses Cytoprotective Activity in a Small Intestine of Rats with Medication-Induced Enteropathy

Small intestinal injury is known to be one of the most commonly appearing pathologies, resulting in the use of medications such as: nonsteroidal anti-inflammatory drugs (NSAIDs), antitumor drugs and angiotensin-converting enzyme (ACE) inhibitors. The principal objective of this study is to evaluate the action of a novel mercaptoacrylic acid derivative able to release H2S on parameters of NO-synthase system and oxidative stress. Inducing enteropathy, three types of medications were used: indomethacin, an NSAID (35 mg/kg); methotrexate, an antitumor drug (10 mg/kg); and enalapril, an ACE inhibitor (2 mg/kg/day). 2-[(4-chlorophenyl-carbamoyl)-methyl]-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-acrylic acid (2C3DHTA) was introduced based on the background of medication-induced enteropathy (10 mg/kg/day). The survey showed that malondialdehyde (MDA) concentration, myeloperoxidase (MPO) activity, superoxide dismutase (SOD), catalase, and NO-synthases (NOS) were determined in the small intestinal mucosa. The increase in inducible NO-synthase (iNOS) activity was due to indomethacin and methotrexate administration. Constitutive NO-synthase (cNOS) activity was decreased by an ACE-inhibitor. The cytoprotective effect was demonstrated by 2C3DHTA, which returned iNOS activity to its control level and increased cNOS activity. The enterotoxic action of studied medication was accompanied by the development of oxidative stress manifested, activity of MPO was increased. MPO activity and manifestations of oxidative stress were decreased by 2C3DHTA. Effects of 2C3DHTA can be explained by the action of H2S, released from this compound in the gastrointestinal (GI) system

A Technology of Hydrocarbon Fluid Production Intensification by Productive Stratum Drainage Zone Reaming

The paper proposes a new technology for fluid production intensification, in particular hydrocarbons, which is implemented via significant increasing of the local wellbore diameter in the interval, where the productive stratum is present. The proposed technology improves the well productivity by increasing the filtration surface area and opening new channels for filtering fluids into the well. The innovative, technical idea is to drill large diameter circular recesses in planes perpendicular to the well axis. After that, the rock mass located between the circular recesses are destroyed by applying static or dynamic axial loads. The required value of the axial force is provided by the weight of the standard drilling tool. As a result of the study, the analytical relations to specify the admissible radius of circular recesses and admissible thickness of rock mass between two adjacent circular recesses from the condition of safe operation are obtained. The numerical analysis carried out for typical reservoir rocks substantiated the possibility of well diameter local reaming twenty times. A special tool for circular recess drilling is developed and the principle of its operation is described. The advantage of the proposed approaches is the low energy consumption for well diameter reaming. Our technology will have special economic expediency for the intensification of production from hydrodynamically imperfect wells and under the condition of fluid filtration according to the expressed nonlinear law

Evaluation of 5-[(Z)-(4-nitrobenzylidene)]-2-(thiazol-2-ylimino)-4-thiazolidinone (Les-6222) as Potential Anticonvulsant Agent

It was determined that the studied 5-[(Z)-(4-nitrobenzylidene)]-2-(thiazol-2-ylimino)-4-thiazolidinone (Les-6222) affects the cyclooxygenase pathway of the arachidonic acid cascade, the markers of damage to neurons on models of PTZ kindling. In the model of chronic epileptogenesis in mice (pentylenetetrazole kindling), a 4-thiazolidinone derivative showed high anticonvulsant activity, which is weaker than the effect of sodium valproate and higher than Celecoxib. The mentioned compound has a pronounced anti-inflammatory effect in the brain on the background of the PTZ kindling, reliably inhibiting COX-1 and COX-2. The predominant inhibition of COX-2 by 44.5% indicates this enzyme&rsquo;s high selectivity of Les-6222. According to the molecular docking study results, the studied compound revealed the properties of COX-1/COX-2 inhibitor and especially 5-LOX/FLAP. The decreasing content of 8-isoprostane in the brain of mice of the Les-6222 group indicates a beneficial effect on cell membranes in the background of oxidative stress during the long-term administration of PTZ. In addition, Les-6222 significantly decreased the content of neuron-specific enolase, indicating neuroprotective properties in the background of chronic epileptogenesis. The obtained results experimentally substantiate the feasibility of further developing Les-6222 as a promising anticonvulsant agent

Evaluation of 5-[(<i>Z</i>)-(4-nitrobenzylidene)]-2-(thiazol-2-ylimino)-4-thiazolidinone (Les-6222) as Potential Anticonvulsant Agent

It was determined that the studied 5-[(Z)-(4-nitrobenzylidene)]-2-(thiazol-2-ylimino)-4-thiazolidinone (Les-6222) affects the cyclooxygenase pathway of the arachidonic acid cascade, the markers of damage to neurons on models of PTZ kindling. In the model of chronic epileptogenesis in mice (pentylenetetrazole kindling), a 4-thiazolidinone derivative showed high anticonvulsant activity, which is weaker than the effect of sodium valproate and higher than Celecoxib. The mentioned compound has a pronounced anti-inflammatory effect in the brain on the background of the PTZ kindling, reliably inhibiting COX-1 and COX-2. The predominant inhibition of COX-2 by 44.5% indicates this enzyme’s high selectivity of Les-6222. According to the molecular docking study results, the studied compound revealed the properties of COX-1/COX-2 inhibitor and especially 5-LOX/FLAP. The decreasing content of 8-isoprostane in the brain of mice of the Les-6222 group indicates a beneficial effect on cell membranes in the background of oxidative stress during the long-term administration of PTZ. In addition, Les-6222 significantly decreased the content of neuron-specific enolase, indicating neuroprotective properties in the background of chronic epileptogenesis. The obtained results experimentally substantiate the feasibility of further developing Les-6222 as a promising anticonvulsant agent