Ethyl 5-[(1H-benzoimidazol-2-yl)amino­carbon­yl]-4-hydr­oxy-2-methyl-6-oxo-1-propyl-1,6-dihydro­pyridine-3-carboxyl­ate–ethanol–methanol (4/2/1)

The asymmetric unit of the title compound, 4C20H22N4O5·2C2H6O·CH4O, contains two pyridine-3-carboxyl­ate mol­ecules, one ethanol mol­ecule and one methanol mol­ecule disordered about in a centre of symmetry. The pyridinone ring, the carbamide group and the bicyclic fragment in both independent mol­ecules are planar within 0.03 Å due to the formation of intra­molecular O—H⋯O and N—H⋯O hydrogen bonds. The formation of these latter inter­actions also causes the redistribution of the electron density within the hydroxy­pyridone fragment, with the result that some bonds are elongated compared with values in the literature and some others are shorter. In the crystal phase, the pyridine-3-carboxyl­ate mol­ecules form layers parallel to (010), which are inter­linked through hydrogen bonds mediated by the bridging solvate mol­ecules. A terminal ethyl group in one of the mol­ecules is disordered over two sites of equally occupancy

Пошук потенційних інгібіторів SARS-CoV-2 за допомогою in silico методів

Aim. Using in silico technologies to search for potential SARS-CoV-2 inhibitors among novel tetracyclic ring systems, which are the common core of Crinipellin.Materials and methods. The study object was new compounds previously synthesized via oxidative dearomatization of Crinipellin A. The method of the flexible molecular docking was applied in the study.Results and discussion. Using the molecular docking, the affinity of five compounds for the receptor-ACE2 SARS-CoV-2 (PDB ID: 7DF4), a spike protein SARS-CoV-2 (PDB ID: 1WNC), a PL protein SARS-CoV-2 (PDB ID: 7CJD) and a reverse transcriptase enzyme SARSCoV-2 (PDB ID: 6YYT) was studied. The results of the molecular docking obtained suggest that 8,8-dimethyl-5-(phenylsulfonyl)-3,3a,4,5,8,9-hexahydroindeno[3a,4-b]furan-2(7H)-one may be a potential SARS-CoV-2 inhibitor; it is the basis for its further experimental pharmacological study.Conclusions. The study constitutes one of the stages of searching for SARS-CoV-2 inhibitors. According to the results obtained, a way to search for potential SARS-COV-2 inhibitors based on Crinipellin A derivatives was proposed. Using the most promising compound with hexahydroindeno[3a,4-b]furan core further studies open up another direction for searching for compounds of SARS-COV-2 inhibitors and will save time and laboratory animals while conducting targeted experimental research.Мета роботи. За використання in silico технологій здійснити пошук потенційних інгібіторів SARS-CoV-2 серед нових тетрациклічних кільцевих систем, які є загальним ядром криніпеліну.Матеріали та методи. Об’єктом дослідження є п’ять нових сполук, одержаних шляхом деароматизації криніпеліну А і синтезованих у попередніх дослідженнях. В in silico дослідженнях використано метод гнучкого молекулярного докінгу.Результати та їх обговорення. Шляхом використання докінгових досліджень вивчено афінітет п’яти сполук до рецептора-ACE2 SARS-CoV-2 (PDB ID:7DF4), spike протеїну SARS-CoV-2 (PDB ID: 1WNC), PL протеїну SARS-CoV-2 (PDB ID: 7CJD) та ферменту зворотної транскриптази SARS-CoV-2 (PDB ID: 6YYT). Одержані результати докінгових досліджень дозволяють стверджувати, що 8,8-диметил-5-(фенілсульфоніл)-3,3a,4,5,8,9-гексагідроіндено[3a,4-b]фуран-2(7H)-он може бути потенційним інгібітором SARS-COV-2, що є підставою для його подальшого експериментального фармакологічного вивчення.Висновки. Подане дослідження є одним з етапів пошуку інгібіторів SARS-CoV-2. З огляду на одержані результати запропоновано шлях пошуку потенційних інгібіторів SARS-COV-2 на основі похідних крініпеліну А. Подальші дослідження з використанням найбільш перспективної похідної гексагідроіндено[3a,4-b]фурану відкривають ще один напрям пошуку сполук інгібіторів SARS-COV-2 та дають можливість заощадити час і лабораторних тварин у межах виконання цілеспрямованих експериментальних досліджень у майбутньому

Synthesis, Spatial Structure and Analgesic Activity of Sodium 3-Benzylaminocarbonyl-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazin-4-olate Solvates

In order to obtain and then test pharmocologically any possible conformers of the new feasible analgesic N-benzyl-4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide, its 4-O-sodium salt was synthesized using two methods. X-ray diffraction study made possible to determine that, depending on the chosen synthesis conditions, the above-mentioned compound forms either monosolvate with methanol or monohydrate, where organic anion exists in the form of three different conformers. Pharmacological testing of the two known pseudo-enantiomeric forms of the original N-benzylamide and of the two solvates of its sodium salt was performed simultaneously under the same conditions and in equimolar doses. Comparison of the results obtained while studying the peculiarities of the synthesized compounds spatial structure and biological properties revealed an important structure-action relationship. In particular, it was shown that the intensity of analgesic effect of different conformational isomers of N-benzyl-4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide may change considerably: while low active conformers are comparable with piroxicam, highly active conformers are more than twice as effective as meloxicam

N-Aryl-7-hydroxy-5-oxo-2,3-dihydro-1H,5H-pyrido-[3,2,1-ij]quinoline-6-carboxamides. The Synthesis and Effects on Urinary Output

Continuing a targeted search for new leading structures with diuretic action among tricyclic derivatives of hydroxyquinolines, which are of interest as potential inhibitors of aldosterone synthase, the synthesis of a series of the corresponding pyrido[3,2,1-ij]quinoline-6-carboxanilides was carried out by amidation of ethyl-7-hydroxy-5-oxo-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-6-carboxylate with aniline, aminophenols and O-alkylsubstituted analogs with high yields and purity. The optimal conditions of this reaction are proposed; they make it possible to prevent partial destruction of the original heterocyclic ester and thereby avoid formation of specific impurities of 7-hydroxy-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one. To confirm the structure of all substances obtained, elemental analysis, nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry were used. Moreover, the peculiarities of their 1H and 13C-NMR spectra, as well as their mass spectrometric behavior under conditions of electron impact ionization, were discussed. The effect of pyrido[3,2,1-ij]quinoline-6-carboxanilides on the urinary function of the kidneys was studied in white rats of both genders by the standard method of oral administration at a dose of 10 mg/kg. Testing was conducted in comparison with hydrochlorothiazide, as well as with structurally close pyrrolo[3,2,1-ij] quinoline-5-carboxanilides studied earlier with the same substituents in the anilide fragments. It was found that addition of one methylene unit to the heterocycle partially hydrogenated and annelated with the quinolone core has a positive impact on biological properties—most of the substances studied exhibit a statistically significant diuretic effect exceeding the activity of not only hydrochlorothiazide, in some cases, but also the action of the structural analogs. The important structural and biological regularities, which are common with pyrroloquinolines and introduced by a chemical modification, were revealed. The importance of the presence in the structure of terminal amide fragments of tricyclic quinoline-3-carboxamides of a 4-methoxy-substituted aromatic ring was particularly marked. The expediency of further study of pyridoquinolines as promising diuretic agents has been shown

The Study of the Structure—Diuretic Activity Relationship in a Series of New N-(Arylalkyl)-6-hydroxy-2-methyl-4-oxo-2,4-dihydro-1H-pyrrolo-[3,2,1-ij]quinoline-5-carboxamides

In accordance with the principles of “me-too” technique, the preparative method for obtaining has been proposed, and the synthesis of a large series of new N-(arylalkyl)-6-hydroxy-2-methyl-4-oxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-5-carboxamides as structurally close analogs of tricyclic pyrrolo- and pyridoquinoline diuretics has been carried out. All target compounds were obtained with high yields and purity by amidation of ethyl ester of the corresponding 2-methyl-pyrroloquinoline-5-carboxylic acid with arylalkylamines in boiling ethanol. Their structure was confirmed by the data of elemental analysis, nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry and polarimetry. Moreover, interpretations of their 1H and 13C-NMR spectra, their mass spectrometric behavior, as well as peculiarities of the polarimetric studies were discussed. The effect of N-(arylalkyl)-6-hydroxy-2-methyl-4-oxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-5-carboxamides on the urinary function of the kidneys was studied in white rats by the standard method of oral administration in the dose of 10 mg/kg compared to hydrochlorothiazide. According to the results of the primary pharmacological screening, the structural and biological regularities that were unexpected, but interesting for further studies were revealed. Among the substances studied, the samples, which by their diuretic effect are not inferior and even superior to both the known hydrochlorothiazide and the lead structure of the pyrroloquinoline group, have been found. On this basis, it can be argued that the introduction of the methyl group made by us in position 2 of pyrrolo[3,2,1-ij]quinoline nucleus can be considered as a successful and promising implementation of the “me-too” cloning of tricyclic 4-hydroxyquinoline-2-one diuretics

Molecular Conformations and Biological Activity of <i>N</i>-Hetaryl(aryl)alkyl-4-methyl-2,2-dioxo-1<i>H</i>-2λ⁶,1-benzothiazine-3-carboxamides

The analysis of our previous studies on the search for synthetic analgesics among N-R-amides of bicyclic hetaryl-3-carboxylic acids has been performed; on its basis N-hetaryl(aryl)-alkyl-4-methyl-2,2-dioxo-1H-2&#955;6,1-benzothiazine-3-carboxamides have been selected as new study objects. The &#8220;one pot synthesis&#8222; of these compounds, which is simple to perform and at the same time highly effective, has been offered. The method consists in the initial reaction of 4-methyl-2,2-dioxo-1H-2&#955;6,1-benzothiazine-3-carboxylic acid and N,N&#8242;-carbonyldiimidazole in anhydrous N,N-dimethylformamide with the subsequent amidation of imidazolide formed with hetarylalkyl- or benzylamines in the same solvent. The peculiarities of 1H- and 13C-NMR spectra of the substances obtained, as well as their electrospray ionization liquid chromato-mass spectra are discussed. According to the results of the pharmacological tests carried out on the model of carrageenan inflammation it has been found that all without exception N-hetaryl(aryl)alkyl-4-methyl-2,2-dioxo-1H-2&#955;6,1-benzothiazine-3-carboxamides demonstrate the statistically significant analgesic and anti-inflammatory properties. Among the substances presented in this article analgesics and antiphlogistics, which increase the pain threshold and suppress the inflammatory response more effectively than Lornoxicam and Diclofenac in the same doses, have been identified. The molecular and crystal structures of a large group of the substances synthesized have been studied by X-ray diffraction analysis. Comparison of these data with the results of biological tests has revealed the fact of excellent correlation between the molecular conformations of N-hetaryl(aryl)alkyl-4-methyl-2,2-dioxo-1H-2&#955;6,1-benzothiazine-3-carboxamides recorded in the crystal and the potency of their analgesic effect. N-Thiophen-2-ylmethyl- and N-4-methoxybenzyl-amides of 4-methyl-2,2-dioxo-1H-2&#955;6,1-benzothiazine-3-carboxylic acid has shown a high analgesic and anti-inflammatory effect, therefore, they deserve more careful research

Theoretical Justification of A Purposeful Search of Potential Neurotropic Drugs

A targeted search for potential drugs of neurotropic action involves the choice of a basic “pharmacophore”, which is advisable to carry out on the basis of the achieved principle among the classes of chemical compounds where active pharmaceutical substances with high targeted activity have already been identified. Therefore, the pyrrolidine core, which is the basic fragment of nootropics of the racetam group, is promising for the rational design of biologically active compounds of nootropic action. Its combination with other heterocyclic fragments, in particular, the 1,2,4-triazole ring, allows for these “hybrid” molecules to expect a permanent change in the magnitude of the pharmacological effects. Creation of a virtual library of compounds, 3D-pharmacophore screening and molecular docking is a promising way to optimize a targeted search for substances with a given pharmacological activity.The aim. To optimize targeted search for new nootropic compounds.Materials and methods. The base generation for the virtual screening was carried out using the Marvin Sketch 20.5 software. For receptor-oriented flexible docking, the Autodock 4.2 software package was used.Results. New derivatives of 1-benzyl-4-pyrrolidin-2-one were selected as the object of the study. Based on the results of the 3D pharmacophore screening and molecular docking to nootropic targets of the virtual base compounds, scoring functions were calculated. A detailed analysis of the geometrical arrangement of “hit compounds” at the active sites of nootropic receptors (PDB ID: 5UOW, 5CXV, 6PV7) made it possible to formulate hypotheses regarding possible ways of interaction of “hybrid” compounds with biotargets.The activity of promising molecules with respect to the studied receptors can be realized by creating complexes between them, the stability of which is ensured mainly due to the energetically favourable geometric arrangement of ligands in the active center of these acceptors, the formation of hydrogen bonds between them, and intermolecular electrostatic and donor-acceptor interactions.Conclusions. Structural modification of the pyrrolidine ring by combining with 1,2,4-triazole scaffold containing substituents of various electronic nature has been proposed. Using 3D-pharmacophore screening, the virtual base of 1-benzyl-4-pyrrolidin-2-one derivatives was analyzed in order to search among them for new molecules of nootropic action. Docking studies have identified a promising group of derivatives of 1-benzyl-4 (4-R-5-sulfanylidene-4,5 dihydro-1H-1,2,4-triazol-3-yl) pyrrolidin-2-one, which have affinity for nootropic biotargets and are promising for further synthetic and pharmacological studie