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Predictive QSAR models for the search of new adenosine A2A receptor antagonists were developed by using OCHEM platform. The predictive ability of the regression models has coefficient of determination q2 = 0.65-0.71 with cross-validation and independent test set. The inhibition activities of novel fused 7-deazaxanthine compounds were predicted by the developed QSAR models. A preparative method for the synthesis of pyrimido[5',4':4,5]pyrrolo[1,2-a][1,4]diazepine derivatives was developed, and 11 new adenosine A2A receptor antagonists were obtained. Preliminary investigations into the toxicology of fused 7-deazaxanthine compounds toward commonly used model organism to assess toxicity invertebrate cladoceran D. magna were also described.

A convenient method for the synthesis of methyl 8-oxo-3H,8H-2a,5a,7-triazaacenaphthylene-2-carboxylate by iodination of 7-allyl-4-methoxypyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester followed by elimination of hydrogen iodide has been developed. The use of 4-methoxypyrrolo[2,3-d]pyrimidine-6-carboxylic acid as the starting compound led to the formation of iodomethylpyrimido[5',4':4,5]-pyrrolo[2,1-c][1,4]oxazine, a promising precursor for the synthesis of a new tricyclic system based on pyrrolo[2,3-d]pyrimidine.

The marine sponges of the order Verongiida (Demospongiae: Porifera) have survived on our planet for more than 500 million years due to the presence of a unique strategy of chemical protection by biosynthesis of more than 300 derivatives of biologically active bromotyrosines as secondary metabolites. These compounds are synthesized within spherulocytes, highly specialized cells located within chitinous skeletal fibers of these sponges from where they can be extruded in the sea water and form protective space against pathogenic viruses, bacteria and other predators. This chitin is an example of unique biomaterial as source of substances with antibiotic properties. Traditionally, the attention of researchers was exclusively drawn to lipophilic bromotyrosines, the extraction methods of which were based on the use of organic solvents only. Alternatively, we have used in this work a biomimetic water-based approach, because in natural conditions, sponges actively extrude bromotyrosines that are miscible with the watery environment. This allowed us to isolate 3,5-dibromoquinolacetic acid from an aqueous extract of the dried demosponge Aplysina aerophoba and compare its antimicrobial activity with the same compound obtained by the chemical synthesis. Both synthetic and natural compounds have shown antimicrobial properties against clinical strains of Staphylococcus aureus, Enterococcus faecalis and Propionibacterium acnes. Supplementary Information The online version contains supplementary material available at 10.1007/s00339-020-04167-0.

Aim. To study the interaction of 4,6-dichloropyrimidine-5-carbaldehyde with methyl- and with tert-butylglycinate depending on the reaction conditions. Results and discussion. It has been found that the reaction of 4,6-dichloro-5-formylpyrimidine with hydrochlorides of glycine esters in the presence of triethylamine leads to obtaining derivatives of N-(5-formylpyrimidin-4-yl)glycinate and cyclization products: pyrrolo[2,3-d]pyrimidine and pyrido[2,3-d]pyrimidine. Experimental part. The interaction of 4,6-dichloropyrimidine-5-carbaldehyde with methyl or tert-butyl glycinate in methanol in the presence of triethylamine depending on the molar ratio gives the mixture of 5-hydroxy-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine and 6-amino-4-chloro-7-oxopyrido[2,3-d]pyrimidine-8(7H)-yl)acetate. The composition and structure of the compounds synthesized have been confirmed by NMR-spectroscopy, chromatography mass-spectrometry and elemental analysis. Conclusions. The previously unknown derivatives of pyrrolo[2,3-d]pyrimidine and pyrido[2,3-d]pyrimidine have been obtained as a result of the interaction of 4,6-dichloro-5-formylpyrimidine with methyl and tert-butylglycinate. The reaction features depending on the reactants ratio have been studied. The prospects for the synthesis of potential biologically active compounds from 6-amino-4-chloro-7-oxopyrido[2,3-d]pyrimidine-8(7H)-yl)acetate have been described.

Aim. A search for human protein kinase CK2 inhibitors in a series of new amino-substituted pyrido[2,3-d]pyrimidine derivatives. Methods. Organic synthesis, analytical and spectral methods, molecular docking, in vitro biochemical testing. Results. Synthesis of new pyrido[2,3-d]pyrimidine derivatives with various aminogroups in positions 4 and 6 of the heterocycle was developed. Two compounds inhibiting kinase CK2 in micromolar concentrations were found among these derivatives. Conclusion. New pyrido[2,3-d]pyrimidin-7-ones containing aminogroups in positions 4 and 6 of heterocyclic system and new 4-amino-substituted pyrido[2,3-d]pyrimidin-7-amine derivatives have been synthesized. The inhibition activity of new pyrido[2,3-d]pyrimidines has been examined and the optimization modes have been suggested. Methyl-2-[(7-aminopyrido[2,3-d]pyrimidine-6-yl)amino]benzoate and N-(4-anilino-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-3,4-dimethoxy- benzamide were found to inhibit protein kinase CK2 at IC50 of 6 and 19.5 μM, respectively. Мета. Пошук нових інгібіторів протеїнкінази СК2 людини в ряду нових амінозаміщених похідних піридо[2,3-d]піримідину. Методи. Органічний синтез, аналітичні та спектральні методи, молекулярний докінг, біохімічне тестування in vitro. Результати. Розроблено методи синтезу нових похідних піридо[2,3-d]піримідину з різноманітними аміногрупами в положеннях 4, 6, 7 гетероциклу. Серед синтезованих похідних піридо[2,3-d]піримідину виявлено дві сполуки, що інгібують кіназу СК2 в мікромолярних концентраціях. Висновки. Синтезовано нові піридо[2,3-d]піримідин-7-они, що містять аміногрупи в положеннях 4, 6 гетероциклічної системи, а також 4-амінозаміщені похідні піридо[2,3-d]піримідин-7-аміну. Досліджено інгібувальну активність похідних піридо[2,3-d]піримідину та запропоновано напрями хімічної оптимізації. Встановлено, що метил 2-[(7-амінопіридо[2,3-d]піримідин-4-іл)aмінo]бензоат та N-(4-aнілінo-7-oксo-7,8-дигідропіридо [2,3-d]піримідин-6-іл)-3,4-диметоксибензамід інгібують протеїнкіназу СК2 з ІС50 6 та 19,5 μМ відповідно. Цель. Поиск новых ингибиторов протеинкиназы СК2 человека в ряде новых аминозамещенных производных пиридо[2,3-d]пиримидина. Методы. Органический синтез, аналитические и спектральные методы, молекулярный докинг, биохимическое тестирование in vitro. Результаты. Разработаны методы синтеза новых производных пиридо[2,3-d]пиримидина с различными аминогруппами в положениях 4, 6, 7 гетероцикла. Среди синтезированных производных пиридо[2,3-d]пиримидина обнаружено два соединения, ингибирующие киназу СК2 в микромолярных концентрациях. Выводы. Синтезированы новые пиридо[2,3-d]пиримидин-7-оны, содержащие аминогруппы в положениях 4, 6 гетероциклической системы, а также 4-аминозамещенные производные пиридо[2,3-d]пиримидин-7-амина. Исследована ингибирующая активность производных пиридо[2,3-d]пиримидина и предложены направления химической оптимизации. Установлено, что метил-2-[(7-аминопиридо[2,3-d]пиримидин-4-ил)амин]бензоат и N-(4-анилин-7-оксо-7,8-дигидропиридо[2,3-d]пиримидин-6-ил)-3,4-диметоксибензамид ингибируют протеинкиназу СК2 с IC50 6 и 19,5 μМ соответственно.

The reaction of 4,6-dichloropyrimidine-5-carbaldehyde with cyanomethyltriphenylphosphonium chloride gave (2Е)-3-(4,6-dichloropyrimidin-5-yl)acrylonitrile, which was further used for the preparation of 4,6-diamino-substituted pyrimidinylacrylonitrile derivatives, capable of intramolecular cyclization with the formation of new 4-amino-substituted 7-iminopyrido[2,3-d]pyrimidines. Performing the reaction with 4-amino-6-chloropyrimidine-5-carbaldehyde led to 7-amino-4-chloropyrido[2,3-d]pyrimidine, a promising intermediate for the synthesis of pyrido[2,3-d]pyrimidine-4,7-diamines.

Marine demosponges of the Verongiida order are considered a gold-mine for bioinspired materials science and marine pharmacology. The aim of this work was to simultaneously isolate selected bromotyrosines and unique chitinous structures from A. aerophoba and to propose these molecules and biomaterials for possible application as antibacterial and antitumor compounds and as ready-to-use scaffolds for cultivation of cardiomyocytes, respectively. Among the extracted bromotyrosines, the attention has been focused on aeroplysinin-1 that showed interesting unexpected growth inhibition properties for some Gram-negative clinical multi-resistant bacterial strains, such as A. baumannii and K. pneumoniae, and on aeroplysinin-1 and on isofistularin-3 for their anti-tumorigenic activity. For both compounds, the effects are cell line dependent, with significant growth inhibition activity on the neuroblastoma cell line SH-SY5Y by aeroplysinin-1 and on breast cancer cell line MCF-7 by isofistularin-3. In this study, we also compared the cultivation of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) on the A. aerophoba chitinous scaffolds, in comparison to chitin structures that were pre-coated with Geltrex™, an extracellular matrix mimetic which is used to enhance iPSC-CM adhesion. The iPSC-CMs on uncoated and pure chitin structures started contracting 24 h after seeding, with comparable behaviour observed on Geltrex-coated cell culture plates, confirming the biocompatibility of the sponge biomaterial with this cell type. The advantage of A. aerophoba is that this source organism does not need to be collected in large quantities to supply the necessary amount for further pre-clinical studies before chemical synthesis of the active compounds will be available. A preliminary analysis of marine sponge bioeconomy as a perspective direction for application of biomaterials and secondary bioactive metabolites has been finally performed for the first time.

Naturally occurring three-dimensional (3D) biopolymer-based matrices that can be used in different biomedical applications are sustainable alternatives to various artificial 3D materials. For this purpose, chitin-based structures from marine sponges are very promising substitutes. Marine sponges from the order Verongiida (class Demospongiae) are typical examples of demosponges with well-developed chitinous skeletons. In particular, species belonging to the family Ianthellidae possess chitinous, flat, fan-like fibrous skeletons with a unique, microporous 3D architecture that makes them particularly interesting for applications. In this work, we focus our attention on the demosponge Ianthella flabelliformis (Linnaeus, 1759) for simultaneous extraction of both naturally occurring (&ldquo, ready-to-use&rdquo, ) chitin scaffolds, and biologically active bromotyrosines which are recognized as potential antibiotic, antitumor, and marine antifouling substances. We show that selected bromotyrosines are located within pigmental cells which, however, are localized within chitinous skeletal fibers of I. flabelliformis. A two-step reaction provides two products: treatment with methanol extracts the bromotyrosine compounds bastadin 25 and araplysillin-I N20 sulfamate, and a subsequent treatment with acetic acid and sodium hydroxide exposes the 3D chitinous scaffold. This scaffold is a mesh-like structure, which retains its capillary network, and its use as a potential drug delivery biomaterial was examined for the first time. The results demonstrate that sponge-derived chitin scaffolds, impregnated with decamethoxine, effectively inhibit growth of the human pathogen Staphylococcus aureus in an agar diffusion assay.

The iodolactonization product obtained from methyl 7-allylpyrrolo[2,3-d]pyrimidine-6-carboxylate was used for the synthesis of novel 1,2-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one derivatives, containing carboxamide- and methylamine-groups on the pyrrole ring of the heterocycle.

Marine sponges remain representative of a unique source of renewable biological materials. The demosponges of the family Ianthellidae possess chitin-based skeletons with high biomimetic potential. These three-dimensional (3D) constructs can potentially be used in tissue engineering and regenerative medicine. In this study, we focus our attention, for the first time, on the marine sponge Ianthella labyrinthus Bergquist &amp, Kelly-Borges, 1995 (Demospongiae: Verongida: Ianthellidae) as a novel potential source of naturally prestructured bandage-like 3D scaffolds which can be isolated simultaneously with biologically active bromotyrosines. Specifically, translucent and elastic flat chitinous scaffolds have been obtained after bromotyrosine extraction and chemical treatments of the sponge skeleton with alternate alkaline and acidic solutions. For the first time, cardiomyocytes differentiated from human induced pluripotent stem cells (iPSC-CMs) have been used to test the suitability of I. labyrinthus chitinous skeleton as ready-to-use scaffold for their cell culture. Results reveal a comparable attachment and growth on isolated chitin-skeleton, compared to scaffolds coated with extracellular matrix mimetic Geltrex&reg, Thus, the natural, unmodified I. labyrinthus cleaned sponge skeleton can be used to culture iPSC-CMs and 3D tissue engineering. In addition, I. labyrinthus chitin-based scaffolds demonstrate strong and efficient capability to absorb blood deep into the microtubes due to their excellent capillary effect. These findings are suggestive of the future development of new sponge chitin-based absorbable hemostats as alternatives to already well recognized cellulose-based fabrics.

Two variants are discussed for the synthesis of ethyl N-alkyl-N-(6-amino-5-formylpyrimidin-4-yl)-glycinate derivatives, which are converted by intramolecular cyclization under the influence of sodium methoxide to give methyl 7H-pyrrolo[2,3-d]pyrimidine-6-carboxylates. New derivatives of pyrimido- [5',4':4,5]pyrrolo[2,1-c][1,4]oxazines containing 3-chloropropyl groups at position 8 have been prepared.

A novel route has been found for the synthesis of pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazines. They are promising reagents for the preparation of pyrrolo[2,3-d]pyrimidine-6-carboxylic acid amides which contain a 3-amino-2-hydroxypropyl substituent in position 7 of the heterocyclic ring.

The bioactive bromotyrosine-derived alkaloids and unique morphologically-defined fibrous skeleton of chitin origin have been found recently in marine demosponges of the order Verongiida. The sophisticated three-dimensional (3D) structure of skeletal chitinous scaffolds supported their use in biomedicine, tissue engineering as well as in diverse modern technologies. The goal of this study was the screening of new species of the order Verongiida to find another renewable source of naturally prefabricated 3D chitinous scaffolds. Special attention was paid to demosponge species, which could be farmed on large scale using marine aquaculture methods. In this study, the demosponge Pseudoceratina arabica collected in the coastal waters of the Egyptian Red Sea was examined as a potential source of chitin for the first time. Various bioanalytical tools including scanning electron microscopy (SEM), fluorescence microscopy, FTIR analysis, Calcofluor white staining, electrospray ionization mass spectrometry (ESI-MS), as well as a chitinase digestion assay were successfully used to confirm the discovery of &alpha, chitin within the skeleton of P. arabica. The current finding should make an important contribution to the field of application of this verongiid sponge as a novel renewable source of biologically-active metabolites and chitin, which are important for development of the blue biotechnology especially in marine oriented biomedicine.

Робота присвячена синтезу нових похідних 2-(метиламіно)хінолін-3-карбоксамідів шляхом гідролітич- ного розщеплення піримідинового циклу в піримідо[4,5-b]хінолін-2,4(1Н,3Н)-діонах. В основі даного підхо- ду лежить взаємодія доступного 1,3-диметил-6-піперидиніл-5-формілурацилу з ароматичними аміна- ми, в результаті чого було синтезовано ряд заміщених похідних піримідо[4,5-b]хінолін-2,4(1Н,3Н)-діонів з високими виходами. Реакція 1,3-диметил-6-піперидиніл-5-формілурацилу з орто- та пара-заміщеними ароматичними амінами перебігає регіоселективно з утворенням похідних 1,3-диметилпіримідо[4,5-b] хінолін-2,4(1Н,3Н)-діонів з замісниками в положеннях 7 та 9 гетероциклу. Використання в реакції ме- та-метокси- чи мета-фтороаніліну приводить до суміші 6- та 8-заміщених 1,3-диметилпіримідо[4,5-b] хінолін-2,4(1Н,3Н)-діонів, які при дії лугу розщеплюються до відповідних амідів хінолін-3-карбонової кис- лоти. Отриману суміш 2-(метиламіно)хінолін-3-карбоксамідів вдалося розділити за допомогою хрома- тографії на колонці. Застосування методики кореляційної спектроскопії ЯМР (NOESY, COSY, HSQC, HMBC) дозволило достовірно встановити будову продуктів реакції конденсаціїї похідних 1,3-диметил- 5-формілурацилу з ароматичними амінами. При нагріванні до ~120°C можлива аміно-імінна прототро- пія, яка полегшує син-анти-таутомерію в положенні 6 піримідинового кільця, що приводить до циклізації в 1,3-диметилпіримідо[4,5-b]хінолін-2,4(1Н,3Н)-діон. Структура отриманих сполук чітко доведена з ви- користанням методів ЯМР 1 Н, 13С-спектроскопії, хроматомас-спектрометрії та елементного аналізу, The paper is devoted to the synthesis of new 2-(methylamino)quinoline-3-carboxamide derivatives by the pyrimidine cycle hydrolytic cleavage of pyrimido[4,5-b]quinoline-2,4(1H,3H)-diones. These later were synthetized in high yields by interaction of available 1,3-dimethyl-6-piperidinyl-5-formyluracil with aromatic amines. The reactions with participation of ortho- and para-substituted aromatic amines proceed regioselectively to give 1,3-dimethylpyrimido[4,5-b] quinoline-2,4(1H,3H)-diones with substituents in positions 7 and 9 of the heterocycle. The use of metha-methoxyand metha-fluoroaniline leads to the mixture of 6- and 8-substituted 1,3-dimethylpyrimido[4,5-b]quinoline-2,4(1H,3H)- diones, which under basic conditions were cleaved into amides of quinoline-3-carboxylic acid. The mixture of 2-(methylamino)quinoline-3-carboxamides obtained was separated by column chromatography. Application of the correlation NMR spectroscopy method (NOESY, COSY, HSQC, HMBC) has allowed to reliably determine the structures of 1,3-dimethyl-5-formyluracil derivatives with aromatic amines condensation products. The amino-imino prototropic tautomerism occurs at 120°C. It facilitates syn-anti-isomerization promoted cyclization and leads to 1,3-dimethylpyrimido[4,5-b]quinoline-2,4(1H,3H)-dione. The structure of the compounds obtained has been proven using the methods of NMR 1 Н, 13C-spectroscopy, mass-spectra and elemental analysis., Работа посвящена синтезу новых производных 2-(метиламино)хинолин-3-карбоксамидов путем гидроли- тического расщепления пиримидинового цикла в пиримидо[4,5-b]хинолин-2,4(1Н,3Н)-дионах. В основе дан- ного подхода лежит взаимодействие доступного 1,3-диметил-6-пиперидинил-5-формилурацила с арома- тическими аминами, в результате чего было синтезировано ряд замещенных производных пиримидо[4,5-b] хинолин-2,4(1Н,3Н)-дионов с высокими выходами. Реакция 1,3-диметил-6-пиперидинил-5-формилурацила с орто- и пара-замещенными ароматическими аминами протекает региоселективно с образованием произ- водных 1,3-диметилпиримидо[4,5-b]хинолин-2,4(1Н,3Н)-дионов с заместителями в положениях 7 и 9 гете- роцикла. Использование в реакции мета-метокси- или мета-фторанилина приводит к смеси 6- и 8-заме- щенных 1,3-диметилпиримидо[4,5-b]хинолин-2,4(1Н,3Н)-дионов, которые при действии щелочи расщепляют- ся до соответствующих амидов хинолин-3-карбоновой кислоты. Полученную смесь 2-(метиламино)хинолин- 3-карбоксамидов удалось разделить с помощью хроматографии на колонке. Использование методики кор- реляционной спектроскопии ЯМР (NOESY, COSY, HSQC, HMBC) позволило однозначно установить строение продуктов реакции конденсации производных 1,3-диметил-5-формилурацила с ароматическими аминами. При нагревании до ~120°C возможна амино-иминная прототропия, которая облегчает син-анти-таутомерию в положении 6 пиримидинового кольца, что приводит к циклизации в 1,3-диметилпиримидо[4,5-b]хинолин- 2,4(1Н,3Н)-дион. Структура полученных соединений строго доказана с использованием методов ЯМР 1 Н, 13С-спектроскопии, хроматомасс-спектрометрии и элементного анализа.

The substituted vinylphosphonium salt (E)-MeSCH=C(CN)P+Ph3I− readily cyclizes under the action of benzamidine and 3-amino-s-triazole, but it does not enter cyclocondensation with 2-aminopyridine. The structure of the cyclization product with 3-amino-s-triazole was confirmed by its transformation to 7-imino-6-(triphenylphosphoranylidene)-6,7-dihydro-s-triazolo[1,5]pyrimidine which was identified by X-ray diffraction. This stabilized ylide and its analogs proved useful starting materials for regioselective syntheses of 2-R-4-alkyl-4,7-dihydro-s-triazolo[1,5-a]pyrimidin-7-ones.

The products of addition of accessible phosphorus-containing ylide Ph3 $${\mathop P\limits^+}$$ - $${\mathop C\limits^\_}$$ HCN to acyl and alkoxycarbonyl isocyanates readily cyclize under the action of methanolic HCl. This reaction was used for preparing a broad range of new 5-phosphonium derivatives of di- and trifunctionalized pyrimidine bases. Among them, the corresponding tertiary phosphonium salts containing no labile hydrogen atoms are especially important. Under mild conditions, they undergo dephosphorylation in the presence of alkalis to give 4-mercapto, 4,6-dimercapto-, and 2,4,6-trimercaptopyrimidine derivatives which are difficult or impossible to prepare by traditional routes.

The reaction of readily accessible (benzimidazol-2-ylmethyl)triphenylphosphonium chloride with acyl isothiocyanates in the presence of triethylamine, as well as consecutive treatment of the above phosphonium salt first with N,N-dimethylformamide dimethyl acetal and then with phenyl or allyl isothiocyanate gives two types of phosphorus-containing derivatives of pyrimido[1,6-a]benzimidazole with the thione group in position 3 or 1 of the condensed system. The structure of one of compounds of the first type, 3-thioxo-1-p-tolyl-3,4-dihydropyrimido[1,6-a]benzimidazol-4-ylidenetriphenylphosphorane, was determined by single crystal X-ray diffraction.

12 Title compounds of type (V) are prepared and screened for their potential biological activity.