Синтез гетерилопохідних 2,5-дизаміщених 1,3,4-оксадіазолів

At the present stage of development of organic chemistry there are a lot of basic synthetic approaches to synthesis of 1,3,4-oksadiazole derivatives with a wide spectrum of biological activity. The heterocyclic systems which contain 1,3,4-oksadiazole nucleus have a rich synthetic history and they are characterized by a wide range of methods of synthesis. In the review for the first time have been systematized and summarized literature sources for the chemistry of heteryl derivatives of 2,5-disubstituted 1,3,4-oxadiazole as important synthetic substrates and precursors for the design of biologically active substances. There have been considered the main approaches to synthesis of this series of compounds, which consist in the intramolecular dehydration of 1,2-diacylhydrazine, in the interaction of hydrazides of heterylcarbonic acids with carbonyl dichloride, orthoethers, carbon (IV) sulfide and in the formation of an oxadiazole nucleus based on functional acylthiosemicarbazide and hydrazone. A significant emphasis is concentrated on the cyclodehydration reaction of N,N’-diacylhydrazide using dehydrating agents, which are a powerful tool for constructing their synthetically and biologically attractive derivatives.There have been analyzed in detail the methods for the preparation of acridone derivatives which contain the 1,3,4-oxadiazole fragment, have been delineated their preparative boundaries and has been revealed the biological potential. It is important to note that the processes of heteryl functionalization are new in the chemistry of 1,3,4-oxadiazole and they allow us to obtain new bioperspective hybrid structures. Analysis of literature data shows that the derivatives of 2,5-disubstituted 1,3,4-oxadiazole are considered as promising substances with antibacterial, fungicidal, anti-inflammatory, hypoglycemic, antimalarial activity. The search for biologically active substances in this series of compounds is expedient and has practical and theoretical significance.На современном этапе развития органической химии известно много основных синтетических подходов к синтезу производных 1,3,4-оксадиазолов с широким спектром биологической активности. Гетероциклические системы, содержащие 1,3,4-оксадиазольное ядро, имеют богатую синтетическую историю и характеризуются наличием широкого набора методов синтеза. В обзорной статье впервые систематизированы и обобщены литературные источники, касающиеся химии гетерилпроизводных 2,5-дизамещенных 1,3,4-оксадиазолов как важных синтетических субстратов и предшественников для конструирования биологически активных веществ. Рассмотрены основные подходы к синтезу данного ряда соединений, которые заключаются во внутримолекулярной дегидратации 1,2-диацилгидразинов, взаимодействии гидразидов гетерилкарбоновых кислот с карбонилдихлоридом, ортоэфирами, карбон (IV) сульфидом и формированием оксадиазольного ядра на базе функциональных ацилтиосемикарбазидов и гидразонов. Весомые акценты сосредоточены на реакции циклодегидратации N,N’-диацилгидразидов с использованием дегидратирующих агентов, которые являются мощным инструментом конструирования их синтетически и биологически привлекательных производных. Подробно проанализированы методы получения производных акридона, содержащих 1,3,4-оксадиазольный фрагмент, очерчены их препаративные границы и раскрыт биологический потенциал. Уместно отметить, что процессы гетерилфункционализации являются новыми в химии 1,3,4-оксадиазолов и позволяют получать новые биоперспективные гибридные структуры. Анализ данных литературы показывает, что производные 2,5-дизамещенных 1,3,4-оксадиазолов рассматриваются как перспективные вещества с антибактериальной, фунгицидной, противовоспалительной, гипогликемической, противомалярийной активностью. Поиск биологически активных веществ в данном ряду соединений целесообразен и имеет практическую и теоретическую значимость.На сучасному етапі розвитку органічної хімії відомо багато основних синтетичних підходів до синтезу похідних 1,3,4-оксадіазолів з широким спектром біологічної активності. Гетероциклічні системи, що містять 1,3,4-оксадіазольне ядро, мають багату синтетичну історію і характеризуються наявністю широкого набору методів синтезу. В оглядовій статті вперше систематизовані та узагальнені літературні джерела, які стосуються хімії гетерилопохідних 2,5-дизаміщених 1,3,4-оксадіазолів як важливих синтетичних субстратів та попередників для конструювання біологічно активних речовин. Розглянуті основні підходи до синтезу даного ряду сполук, які полягають у внутрішньомолекулярній дегідратації 1,2-діацилгідразинів, взаємодії гідразидів гетерилкарбонових кислот з карбонілдихлоридом, ортоетерами, карбону (IV) сульфідом та формуванням оксадіазольного ядра на базі функціональних ацилтіосемікарбазидів та гідразонів. Вагомі акценти зосереджені на реакції циклодегідратації N,N’-діацилгідразидів з використанням дегідратуючих агентів, яка є потужним інструментом конструювання їх синтетично та біологічно привабливих похідних. Детально проаналізовані методи одержання похідних акридону, що містять 1,3,4-оксадіазольний фрагмент, окреслені їх препаративні межі та розкрито біологічний потенціал. Доречно відзначити, що процеси гетерилфункціоналізації є новими в хімії 1,3,4-оксадіазолів і дають змогу отримувати нові біоперспективні гібридні структури. Аналіз даних літератури показує, що похідні 2,5-дизаміщених 1,3,4-оксадіазолів розглядаються як перспективні речовини з антибактеріальною, фунгіцидною, протизапальною, гіпоглікемічною, протималярійною активністю. Пошук біологічно активних речовин у даному ряду сполук є доцільним, має практичну і теоретичну значимість

VARIOUS BIOLOGICAL ACTIVITIES OF COUMARIN AND OXADIAZOLE DERIVATIVES

In this review article data is collected regarding the various derivatives of coumarin and oxadiazole as both these have wide range of biological activities and they can be further modified to synthesize more effective and potent drugs. Coumarin class of organic compounds consists of 1,2-benzopyrone ring system as a basic parent scaffold. These benzopyrones are subdivided into alpha-benzopyrones and gamma benzopyrones; with coumarin class of compounds belonging to alpha-benzopyrones. Since the last few years, coumarins were synthesized in many of their derivative forms. Their pharmacological, therapeutic and biochemical properties depend upon their pattern of substitution. Coumarins exhibit a wide range of pharmacological activities, which includes anti-diabetic, anti-viral, anti-microbial, anticancer, anti-oxidant, anti-parasitic, anti-helminthic, anti-proliferative, anti-convulsant, anti-inflammatory and antihypertensive activities. 1,3,4-Oxadiazole is a heterocyclic compound containing an oxygen atom and two nitrogen atoms in a five-membered ring. It is derived from furan by substitution of two methylene groups (=CH) with two pyridine type nitrogens (-N=). There are three known isomers: 1,2,4-oxadiazole, 1,2,3-oxadiazole and 1,2,5- oxadiazole. Oxadiazole moiety shows antimicrobial, anticancer and anti-inflammatory activity and suitably substituted 1,3,4-oxadiazole having biological activities like antimicrobial, anticancer and other biological activities

Synthesis and characterization of 1,3,4-oxadiazoles bearing an indole ring

1,3,4-oxadiazoles are important in various fields and have been involved in many studies by researchers. 1,3,4-oxadiazoles have many biological activities, for example, antifungal, antibacterial and anti-oxidant activities. A carboxylic acid hydrazide was synthesized from the reaction between an indole ester and a hydrazine hydrate and used as a starting material of 1,3,4-oxadiazole derivatives. There were four 1,3,4-oxadiazoles being synthesized in this project. The 1,3,4-oxadiazole derivatives were synthesized from carboxylic acid hydrazide reacted with different benzoic acid derivatives with the presence of POCl3. The percentage yields for the synthesized 1,3,4-oxadizoles were between 8% to 70%. For the characterization of the carboxylic acid hydrazide and the 1,3,4-oxadiazoles were using various instruments such as melting point apparatus, FT-IR, 1H NMR,13C NMR , DEPT, HMQC, and HMBC

2,4-SUBSTITUTED QUINAZOLINE AS JAK2 INHIBITOR: DOCKING AND MOLECULAR DYNAMICS STUDY

Objective: The involvement of Janus kinase2/signal transducer and activator of transcription (JAK2/STAT3) pathway reported in various solid tumors made authors study the conformational changes of JAK2-3e complex which was previously reported with a moderate percentage of In-vitro JAK2 inhibition. Methods: In this present study Compound 3e was reported with a moderate percentage of inhibition of JAK2 protein selected for performing molecular docking and molecular dynamics studies to elucidate the conformational changes with JAK2-3e complex. Docking studies were performed using ChemSketch to draw the structure of the compound and optimized/energy minimized using the Ligprep module of Schrodinger suite, employing optimized potentials for liquid simulations (OPLS-2005) force field. Molecular dynamics simulations were performed for 10 ns for complex using TIP4PEW water solvent model and neutralized by adding sodium ions. Results: Docking studies of Compound 3e which has been reported as one of the effective cytotoxic agents and a moderate percentage of In-vitro JAK2 inhibition among the series, showed H-bond interaction with leucine 855, serine936, aspartine994. Dock score and Ligand binding energy with protein suggested compound 3e has shown-4.049,-66.003 kcal/mol respectively. Molecular dynamics simulations elucidated the mechanistic insight of JAK-2 inhibition. The Root means square deviation (RMSD) pattern of both protein and ligands in the JAK2-3e complex observed to be different over 10 ns simulation. In the JAK2-3e complex, an exponential increase in RMSD of Cα and side-chain amino acids is observed during the first 1-3 ns simulation and is stabilized till 10 ns. During the 10 ns simulation, ligand 3e seems to be stable in the complex with an overall deviation<1 Å, despite a drastic increase between 1-3 ns. The ligand RMSD plot suggests that the ligand 3e remained intact within the binding site of the protein and longer time period simulation may elucidate the binding pattern and fate of ligand 3e. Conclusion: Results from molecular dynamics simulations elucidated the mechanistic insight of JAK-2 inhibition by 2, 4 disubstituted quinazoline compound that is N’(2-(4-nitrophenyl)quinazoline-4-yl) isonicotinohydrazide) and their binding phenomenon. Molecular docking studies further supported the elucidation of binding patterns of the molecules in the JAK-2 protein environment. Further simulations with a longer time period may provide deeper insights into ligand interactions in the protein environment. It is noteworthy to use compound 3e as a new scaffold for further development of multifunctional compounds

Studies on Some Bioactive Heterocyclic Moieties

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An overview of coumarin as a versatile and readily accessible scaffold with broad-ranging biological activities

Privileged structures have been widely used as an effective template for the research and discovery of high value chemicals. Coumarin is a simple scaffold widespread in Nature and it can be found in a considerable number of plants as well as in some fungi and bacteria. In the last years, these natural compounds have been gaining an increasing attention from the scientific community for their wide range of biological activities, mainly due to their ability to interact with diverse enzymes and receptors in living organisms. In addition, coumarin nucleus has proved to be easily synthetized and decorated, giving the possibility of designing new coumarin-based compounds and investigating their potential in the treatment of various diseases. The versatility of coumarin scaffold finds applications not only in medicinal chemistry but also in the agrochemical field as well as in the cosmetic and fragrances industry. This review is intended to be a critical overview on coumarins, comprehensive of natural sources, metabolites, biological evaluations and synthetic approaches

Synthesis and evaluation of acridine and acridone based compound as anti-Cancer and anti-bacterial agents

University of Minnesota Ph.D. dissertation. December 2013. Major: Medicinal Chemistry. Advisor: David M. Ferguson. 1 computer file (PDF); v, 109 pages.After the discovery of acridine in the late 1800's, the acridine class of molecules attracted much synthetic interest due to their usefulness as dyestuffs and the discovery that certain acridine derivatives possessed anti-bacterial properties. It was this discovery that lead aminoacridines to be used heavily as anti-bacterial agents until they were supplanted by the use of sulfonamides and the discovery of the penicillin's. Despite falling out of favor as anti-bacterial agents, acridine derivatives were still used in the treatment of other diseases such as malaria and cancer.Despite falling out of use as anti-bacterial agents, one area where the acridine class of compounds may find a new use is in the treatment of drug-resistant bacterial infections, namely MRSA. Infections caused by numerous drug-resistant bacteria have become a major health issue in the world today which has led to a pressing need for the development of novel agents to treat these infections.We report within this thesis the synthesis and evaluation of numerous acridine and acridone based compounds that possess activity against a number of strains of MRSA. In an attempt to elucidate a potential mechanism of action, the active compounds were also tested in DNA intercalation assays and screens against other known bacterial targets. Despite our best efforts, the mechanism of these novel acridine compounds was not elucidated and is hypothesized to be an interaction with the bacterial cell membrane

Studies on some new Heterocyclic Entities of Medicinal Interest

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A New, Extremely Sensitive, Turn-Off Optical Sensor Utilizing Schiff Base for Fast Detection of Cu(II)

Throughout this research, a unique optical sensor for detecting one of the most dangerous heavy metal ions, Cu(II), was designed and developed. The (4-mercaptophenyl) iminomethylphenyl naphthalenyl carbamate (MNC) sensor probe was effectively prepared. The Schiff base of the sensor shows a turn-off state with excellent sensitivity to Cu(II) ions. This innovative fluorescent chemosensor possesses distinctive optical features with a substantial Stocks shift (about 114 nm). In addition, MNC has remarkable selectivity for Cu(II) relative to other cations. Density functional theory (DFT) and the time-dependent DFT (TDDFT) theoretical calculations were performed to examine Cu(II) chelation structures and associated electronic properties in solution, and the results indicate that the luminescence quenching in this complex is due to ICT. Chelation-quenched fluorescence is responsible for the internal charge transfer (ICT)-based selectivity of the MNC sensing molecule for Cu(II) ions. In a 1:9 (v/v) DMSO-HEPES buffer (20 mM, pH = 7.4) solution, Fluorescence and UV-Vis absorption of the MNC probe and Cu(II) ions were investigated. By utilizing a solution containing several metal ions, the interference of other metal ions was studied. This MNC molecule has outstanding selectivity and sensitivity, as well as a low LOD (1.45 nM). Consequently, these distinctive properties enable it to find the copper metal ions across an actual narrow dynamic range (0-1.2 M Cu(II)). The reversibility of the sensor was obtained by employing an EDTA as a powerful chelating agent

Repositioning of astemizole for malaria

Malaria remains one of the most important parasitic infectious diseases as far as human suffering is concerned. With almost half of the world's population at risk, its burden is felt worldwide as seen by the high number of deaths recorded each year (405,000 in 2018: WHO World Malaria Report 2019). Unfortunately, over 90% of this mortality rate is recorded in Africa alone, with the highest risk being in children under the age of five (5) and pregnant women. Partly, this is due to the unfortunate spread of resistance to most drugs that were once effective and safe, including Artemisinins which form the basis of the current first-line regimen in the treatment of malaria. For this reason, it is crucial to invest research efforts using various approaches in the drug discovery arsenal to develop novel, and structurally diverse antimalarials with different modes of action. These new antimalarials should not only be able to circumvent resistance but need to be efficacious at different life cycle stages of the parasite (multi-stage activity). This Ph.D. project pursued a drug repositioning approach on Astemizole (AST, Figure 1), a second-generation antihistamine drug which was previously identified as an antimalarial agent by Chong et al., at the Johns Hopkins University School of Medicine through via a high-throughput screening (HTS) of diverse marketed drugs. AST was active against chloroquine-sensitive (CQ-S) and multi-drug resistant (MDR) laboratory strains of the human malaria parasite Plasmodium falciparum (P. falciparum) and demonstrated in vivo efficacy in two mouse infection models of malaria namely, P. Vinckei and P. Yoelii. However, in addition to its low solubility, AST possesses a serious and fatal cardiotoxicity risk, evidenced by its ability to potently inhibit the human ether-á-go-go-related gene (hERG) encoded potassium (K+) channels. This liability led to the withdrawal of AST in most countries during the late 1970's and it is still being discontinued for use in some countries to date