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The prepared oxazolopyrimidine derivatives exhibited high anti-breast-cancer activity and ADK suppression, indicating their potential as candidates in the targeted search for new, highly effective antitumor drugs.

The oxazole and pyrimidine rings are widely displayed in natural products and synthetic molecules. They are known as the prime skeletons for drug discovery. On the account of structural and chemical diversity, oxazole and pyrimidine-based molecules, as central scaffolds, not only provide different types of interactions with various receptors and enzymes, showing broad biological activities, but also occupy a core position in medicinal chemistry, showing their importance for development and discovery of newer potential therapeutic agents (Curr Top Med Chem, 16, 2016, 3133; Int J Pharm Pharm Sci, 8, 2016, 8; BMC Chem, 13, 2019, 44). For a long time, relatively little attention has been paid to their fused rings that are oxazolopyrimidines, whose chemical structure is similar to that of natural purines because probably none of these compounds were found in natural products or their biological activities turned out to be unexpressed (Bull Chem Soc Jpn, 43, 1970, 187). Recently, however, a significant number of studies have been published on the biological properties of oxazolo[5,4-d]pyrimidines, showing their significant activity as agonists and antagonists of signaling pathways involved in the regulation of the cell life cycle, whereas oxazolo[4,5-d]pyrimidines, on the contrary, represent a poorly studied class of compounds. Limited access to this scaffold has resulted in a corresponding lack of biological research (Eur J Organ Chem, 18, 2018, 2148). Actually, oxazolo[5,4-d]pyrimidine is a versatile scaffold used for the design of bioactive ligands against enzymes and receptors. This review focuses on biological targets and associated pathogenetic mechanisms, as well as pathological disorders that can be modified by well-known oxazolopyrimidines that have been proven to date. Many molecular details of these processes are omitted here, which the interested reader will find in the cited literature. This work also does not cover the methods for the synthesis of the oxazolopyrimidines, which are exhaustively described by De Coen et al. (Eur J Organ Chem, 18, 2018, 2148). The review as well does not discuss the structure-activity relationship, which is described in detail in the original works and deliberately, whenever possible, cites not primary sources, but mostly relevant review articles, so that the reader who wants to delve into a particular problem will immediately receive more complete information. It is expected that the information presented in this review will help readers better understand the purpose of the development of oxazolopyrimidines and the possibility of their development as drugs for the treatment of a wide range of diseases.

A novel series of 1,3-oxazol-4-yltriphenylphosphonium salts has been synthesized and functionalized. Oxazole derivatives were subjected to NCI in vitro assessment. Seven most active derivatives have been selected for five-dose assay. Among them, compounds 9 ([2-(4-methylphenyl)-5-[(4-methylphenyl)sulfanyl]-1,3-oxazol-4-yl]triphenylphosphonium perchlorate), 1 ([5-(4-methylphenyl)amino]-2-phenyl-1,3-oxazol-4-yl]triphenylphosphonium perchlorate) and 4 ([5-phenyl-2-[(4-methylphenyl)amino]-1,3-oxazol-4-yl]triphenylphosphonium perchlorate) were the most active against all tested cancer subpanels. Statistical analysis of the total panel data showed average values of parameters of anticancer activity in the range of 0.3-1.1 μM (GIsub50/sub), 1.2-2.5 μM (TGI) and 5-6 μM (LCsub50/sub). It was found that the presence of phenyl or 4-methylphenyl groups at C(2) and C(5) in the oxazole ring is of critical importance for the manifestation of the anticancer activity. Matrix COMPARE analysis using LCsub50/subvector showed a high positive correlation of compound 9 with standard anticancer agents that can directly disrupt mitochondrial function, causing programmed death of cancer cells. The obtained results indicate the anticancer activity of 1,3-oxazol-4-ylphosphonium salts, which could be useful for developing new anticancer drugs. The most active of them can be recommended for further in-depth studies and synthesis of new derivatives with antitumor activity on their basis.

2-Aryl-2-(2-aryl-2-oxoethyl)-1H,2H,3H-imidazo[1,2-a]pyridin-4-ium bromides were obtained in the reaction of (2Z)-4-bromo-1,3-diphenylbut-2-en-1-one derivatives with 2-aminopyridines in benzene. The effect of the structure of the starting reagents on the results of the reactions was studied. Antitumor activity of 2-(4-chlorophenyl)-2-[2-(4-chlorophenyl)-2-oxoethyl]-1H,2H,3H-imidazo[1,2-a]pyridin-4-ium bromide was determined, which showed high antitumor potential of the test compound on 60 human cancer cell lines.

We propose a new method for assembling the imidazo[2,1-b][1,3]thiazole system, based on the reaction of (2Z)-1,3-diaryl-4-bromobut-2-en-1-one derivatives with 2-aminothiazoles. The outcome of this reaction depends on the structure of the starting bromo ketone: when electron-withdrawing substituents are present in the structure of the ketone, a competing reaction occurs, which leads to the formation of 2,5-diarylfurans. Screening for antitumor activity has been performed in the case of 1-phenyl-2-(6-phenyl-5,6-dihydroimidazo[2,1-b]- thiazol-6-yl)ethanone and this compound has shown moderate ability to suppress the growth of kidney cancer cells, with a weaker effect on the cell lines of prostate cancer, colon cancer, and leukemia.

A convenient method was developed for the synthesis of novel isoquinolin-1(2H)-ones, 1-chloroisoquinolines, and 1-aminoisoquinolines with a heterocyclic substituent in position 3 via a recyclization of 3-hetarylisocoumarins with (NH4)2CO3. 1-Aminoisoquinolines were efficiently obtained from corresponding 1-chloro-3-hetarylisoquinolines (obtained by interaction of isoquinolin-1(2H)-ones with POCl3) and cyclic secondary amines (morpholine or 1-methylpiperazine). Literature data and preliminary results of biological assays allow to consider 1-amino-3-hetarylisoquinolines a promising family of anticancer compounds.

A series of 2,2-disubstituted 8-azachromanones, including spirocyclic compounds, have been synthesized via Horner–Wadsworth– Emmons reaction. Dimethyl methylphosphonate was acylated with methyl 2-methoxypyridine-3-carboxylate to afford the key intermediate – dimethyl [2-(2-methoxypyridin-3-yl)-2-oxoethyl]phosphonate. Further reaction of this phosphonate and ketones followed by treatment with TMSCl–NaI provided the target 8-azachromanones. Scope and limitations of the developed synthetic method have been investigated.

Method of quantitative estimation of the π-electron affinity for conjugated molecules, which is directly related to donor/acceptor properties is presented. The index φ0 is proposed, it is determine...

A series of benzenesulfonamides incorporating pyrazole- and pyridazinecarboxamides decorated with several bulky moieties has been obtained by original procedures. The new derivatives were investigated for the inhibition of four physiologically crucial human carbonic anhydrase (hCA, EC 4.2.2.1.1) isoforms, hCA I and II (cytosolic enzymes) as well as hCA IX and XII (transmembrane, tumor-associated isoforms). Examples of isoform-selective inhibitors were obtained for all four enzymes investigated here, and a computational approach was employed for explaining the observed selectivity, which may be useful in drug design approaches for obtaining inhibitors with pharmacological applications useful as antiglaucoma, diuretic, antitumor or anti-cerebral ischemia drugs.

This minireview highlights known methods for the synthesis of azachromones and azachromanones, including the earliest and the latest examples of their synthesis. Methods considered for constructing azachromone or azachromanone system include intramolecular heterocyclization, deprotection–cyclization, spirocyclization, cyclization–aromatization, Ullman-type O-arylation, and C–H activation of pyridine N-oxides.

New coumarin-4-ylmethylphosphonates and coumarin-4-ylmethylphosphonic acids were synthesized and tested for antiviral activity.

Ten 5-functionalized derivatives of 1,3-oxazole-4-carboxylate and 1,3-oxazole-4-carbonitrile were synthesized and their antiviral activities against the human cytomegalovirus (HCMV) were evaluated in vitro. Bioassays showed that seven compounds exhibited considerably higher antiviral activity (EC50: 150 µM, and SI50 = 3125) towards the resistant isolate compared to standard drugs Cidofovir (EC50 = 0.10 µM, CC50: >30 µM and SI50

For the estimation of donor/acceptor character of conjugated heterocyclic compounds, the φ0 index is used. This parameter is determined by the relative positions of the frontier molecular orbital energy levels. It is shown that φ0 value of 0.5 means that the donor and acceptor properties in the conjugated molecule are balanced, while an increase of the index (φ0 > 0.5) corresponds to increasing of the donor strength, and, conversely, its lowered value (φ0 < 0.5) points to increased acceptor strength. In this work, a series of widely known heterocyclic compounds, as well as derivatives of oxazole and nucleobases are analyzed in detail. It is shown that change in φ0 index is connected to the biological activity. As an example, the influence of the conjugated substituents is studied and it is found that the oxazole derivatives with acceptor substituents inhibit cancer cells.

The quantum-chemical analysis of donor–acceptor properties of the conjugated heterocyclic compounds is performed. For quantitative estimation of donor/acceptor ability, the topological index φ0 is ...

Graphic abstract An efficient and practical synthetic procedure for libraries of diversified 1,2-dihydrochromeno[2,3-c]pyrrole-3,9-diones using a multicomponent process is presented. A convenient synthetic procedure for obtaining functionalized 3-(2-hydroxyphenyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-ones via ring-opening strategy has also been developed. This protocol was found to be compatible with a wide range of substituents and paves the way for the practical synthesis of title compounds with a broad range of substituents under mild condition. The products can be easily isolated by crystallization without the use of chromatography. Supplementary Information The online version contains supplementary material available at 10.1007/s11030-021-10234-2.

Natural products as well as their derivatives play a significant role in the discovery of new biologically active compounds in the different areas of our life especially in the field of medicine. The synthesis of compounds produced from natural products including cytisine is one approach for the wider use of natural substances in the development of new drugs. QSAR modeling was used to predict and select of biologically active cytisine-containing 1,3-oxazoles. The eleven most promising compounds were identified, synthesized and tested. The activity of the synthesized compounds was evaluated using the disc diffusion method against C. albicans M 885 (ATCC 10,231) strain and clinical fluconazole-resistant Candida krusei strain. Molecular docking of the most active compounds as potential inhibitors of the Candida spp. glutathione reductase was performed using the AutoDock Vina. The built classification models demonstrated good stability, robustness and predictive power. The eleven cytisine-containing 1,3-oxazoles were synthesized and their activity against Candida spp. was evaluated. Compounds 10, 11 as potential inhibitors of the Candida spp. glutathione reductase demonstrated the high activity against C. albicans M 885 (ATCC 10,231) strain and clinical fluconazole-resistant Candida krusei strain. The studied compounds 10, 11 present the interesting scaffold for further investigation as potential inhibitors of the Candida spp. glutathione reductase with the promising antifungal properties. The developed models are publicly available online at http://ochem.eu/article/120720 and could be used by scientists for design of new more effective drugs.

QSAR analysis of a set of previously synthesized phosphonium ionic liquids (PILs) tested against Gram-negative multidrug-resistant clinical isolate Acinetobacter baumannii was done using the Online Chemical Modeling Environment (OCHEM). To overcome the problem of overfitting due to descriptor selection, fivefold cross-validation with variable selection in each step of the model development was applied. The predictive ability of the classification models was tested by cross-validation, giving balanced accuracies (BA) of 76%-82%. The validation of the models using an external test set proved that the models can be used to predict the activity of newly designed compounds with a reasonable accuracy within the applicability domain (BA = 83%-89%). The models were applied to screen a virtual chemical library with expected activity of compounds against MDR Acinetobacter baumannii. The eighteen most promising compounds were identified, synthesized, and tested. Biological testing of compounds was performed using the disk diffusion method in Mueller-Hinton agar. All tested molecules demonstrated high anti-A. baumannii activity and different toxicity levels. The developed classification SAR models are freely available online at http://ochem.eu/article/113921 and could be used by scientists for design of new more effective antibiotics.

In this series, six new 2-substituted 5-arylsulfonyl-1,3-oxazole-4-carbonitriles were synthesized and characterized by IR, 1H NMR, 13C NMR spectroscopy, elemental analysis and chromato-mass-spectrometry. The anticancer activities of the compounds were evaluated via single high dose (10−5M) against 60 cancer cell lines by the National Cancer Institute according to its own screening protocol. In the next phase, the compounds have been selected for five-dose assay. All synthesized compounds displayed growth inhibitory (GI50) and cytostatic activities (TGI) against the most sensitive cell lines at submicromolar (0.2–0.6 μM) and micromolar concentrations (1–3 μM), respectively. Cytotoxic activity (LC50) of these compounds, with the exception of 4d, against the most sensitive cell lines was also high (5–6 μM). All compounds exhibit high selectivity towards leukemia cell lines, and among them, 4e and 4f showed the best antiproliferative and cytostatic selectivity. Compounds 4c and 4f displayed considerable cytotoxic selectivity towards the renal and breast cancer subpanels. Our results provided evidence for anticancer activities of novel 2-substituted 5-arylsulfonyl-1,3-oxazole-4-carbonitriles which could be useful for developing new anticancer drugs. These substances could also be used as an excellent framework in anticancer research that may lead to discovery of potent antitumor agents.

The problem of designing new antitubercular drugs against multiple drug‐resistant tuberculosis (MDR‐TB) was addressed using advanced machine learning methods. As there are only few published measurements against MDR‐TB, we collected a large literature data set and developed models against the non‐resistant H37Rv strain. The predictive accuracy of these models had a coefficient of determination q2=.7–.8 (regression models) and balanced accuracies of about 80% (classification models) with cross‐validation and independent test sets. The models were applied to screen a virtual chemical library, which was designed to have MDR‐TB activity. The seven most promising compounds were identified, synthesized and tested. All of them showed activity against the H37Rv strain, and three molecules demonstrated activity against the MDR‐TB strain. The docking analysis indicated that the discovered molecules could bind enoyl reductase, InhA, which is required in mycobacterial cell wall development. The models are freely available online (http://ochem.eu/article/103868) and can be used to predict potential anti‐TB activity of new chemicals.

A preparative method for the synthesis of 1-alkyl-3-methyl-1,4-dihydropyrazolo[4,3-c]pyrazoles was developed. The alkylation of the obtained compounds with halocarboxylic acid esters was also investigated. A principal possibility of creating libraries of compounds based on pyrazolo[4,3-c]pyrazole derivatives was shown.

Reactions of 1-acylamino-2,2-dichloroacrylonitriles, diethyl 1-acylamino-2,2,2-trichloroethyl-phosphonates and 1-acylamino-2,2-dichloroethenylphosphonium salts with natural alkaloid cytisine have been studied. A series of novel multifunctional cytisine derivatives containing pharmacophore 1,3-oxazole moiety have been obtained. Composition and structure of the synthesized compounds have been confirmed by mass spectrometry and NMR spectroscopy data.

Alkylation of 4-(phenylthio)-1H-pyrazol-5-ols with methyl bromoacetate has afforded a series of phenyl pyrazolyl sulfides which have been oxidized into sulfones. The resulting esters have been hydrolyzed into the corresponding acids. The synthesized compounds potentially exhibit biological activity.

In this study, the synthesis, in vitro anti-Candida activity and molecular modeling of 4-phosphorylated derivatives of 1,3-oxazole as inhibitors of Candida albicans fructose-1,6-bisphosphate aldolase (FBA-II) are demonstrated and discussed. Significant similarity of the primary and secondary structure, binding sites and active sites of FBA-II C. albicans and Mycobacterium tuberculosis are established. FBA-II C. albicans inhibitors contained 1,3-oxazole-4-phosphonates moiety are created by analogy to inhibitors FBA-II M. tuberculosis. The experimental studies of the anti-Candida activity of the designed and synthesized compounds have shown their high activity against standard strain and its C. albicans fluconazole resistant clinical isolate. It was hypothesized that the growth suppression of fluconazole-resistant С. albicans strain may be due to the inhibition of aldolase fructose-1,6-bisphosphate. A qualitative homology 3D model of the C. albicans FBA-II was created using SWISS-MODEL server. The probable mechanism of FBA-II inhibition by studied 4-phosphorylated derivatives was shown using molecular docking. The main role of amino acid residues His110, His226, Gly227, Leu248, Val238, Asp144, Lys230, Glu147, Gly227, Ala112, Leu145 and catalytic zinc atom in the formation of stable ligand-protein complexes with ΔG = –6.89, –7.2, –7.16, –7.5, –8.0, –7.9 kcal/mol was shown. Thus, the positive results obtained in the work were demonstrated the promise of using the proposed homology 3D model of the C. albicans FBA-II as the target for the search and development of new anti-Candida agents against azole-resistant fungal pathogens. Designed and studied 4-phosphorylated derivatives of 1,3-oxazole having a direct inhibiting FBA-II molecular mechanism of action can be used as perspective drug-candidates against resistant C. albicans strains.

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho/physiological conditions. A series of chromene-based sulfonamides were synthesized and tested as possible CA inhibitors. Their inhibitory activity was assessed against the cytosolic human isoforms hCA I, hCA II and the transmembrane hCA IX and XII. Several of the investigated derivatives showed interesting inhibition activity towards the tumor associate isoforms hCA IX and hCA XII. Furthermore, computational procedures were used to investigate the binding mode of this class of compounds, within the active site of hCA IX.

Reactions of substituted 2-hydroxyalkyl-1,3-thiazole-5-carbaldehydes and 5-hydroxyalkyl-1,3-thiazole-2-carbaldehydes with phenylhydrazine, isoniazid, N-substituted rhodanines were performed as well as Biginelli reaction with acetoacetic ester and urea. As a result, new 1,3-thiazole derivatives were obtained. They are of interest as potential bioactive substances.

Based on modern literature data about biological activity of E7010 derivatives, a series of new sulfonamides as potential anticancer drugs were rationally designed by QSAR modeling methods Сlassification learning QSAR models to predict the tubulin polymerization inhibition activity of novel sulfonamides as potential anticancer agents were created using the Online Chemical Modeling Environment (OCHEM) and are freely available online on OCHEM server at https://ochem.eu/article/107790 . A series of sulfonamides with predicted activity were synthesized and tested against 60 human cancer cell lines with growth inhibition percent values. The highest antiproliferative activity against leukemia (cell lines K-562 and MOLT-4), non-small cell lung cancer (cell line NCI-H522), colon cancer (cell lines NT29 and SW-620), melanoma (cell lines MALME-3M and UACC-257), ovarian cancer (cell lines IGROV1 and OVCAR-3), renal cancer (cell lines ACHN and UO-31), breast cancer (cell line T-47D) was found for compounds 4–9. According to the docking results the compounds 4–9 induce cytotoxicity by the disruption of the microtubule dynamics by inhibiting tubulin polymerization via effective binding into colchicine domain, similar the E7010.

A general approach towards synthesis of 2(5)-hydroxyalkyl-substituted 1,3-thiazole derivatives has been proposed. The method includes lithiation of 1,3-thiazole ring followed by reacting the formed thiazole lithium derivatives with electrophiles.

5-Morpholino-1,3-oxazole-4-carbonitriles bearing 4-phthalimidobutyl or 5-phthalimidopentyl substi-tuent at position 2 of the oxazole ring were synthesized. Upon reaction with hydrazine hydrate, 5-(morpholin-4-yl)-2-(4-phthalimidobutyl)-1,3-oxazole-4-carbonitrile formed the recyclization product (3-amino-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(morpholin-4-yl)methanone, whereas for 5-(morpholin-4-yl)-2-(5-phthalimidopentyl)-1,3-oxazole-4-carbonitrile, the reaction stops at the stage of 2-(5-aminopentyl)-5-(morpholin-4-yl)-1,3-oxazole-4-carbonitrile after removal of the phthalimido protecting group.

Starting from phthalimidoalkanoylamines 1 (amino-protected derivatives of L-alanine, L-valine, and L-leucine), we have suggested a straightforward synthetic route to 5-amino-1,3-oxazol-4-ylphosphonic acid derivatives 5 containing a chiral aminoalkyl substituent on the 2-position of the oxazole ring. Compounds 5 have been further used to obtain phosphonodipeptides 8, 9, and 10 with the original optical purity retained.

Chlorination of readily available 2-methyl-5-methylsulfanyl-4-tosyl-1,3-thiazole has afforded 2-methyl-4-tosyl-1,3-thiazole-5-sulfonyl chloride. The latter can react with amines to build sulfonamides, efficient electrophilic reagents capable of undergoing nucleophilic substitution reactions. Regiochemistry of the described reactions depends strongly on the nature of nucleophiles, used for regioselective synthesis of some previously unknown trisubstituted 1,3-thiazoles.

Previously unknown methyl 2-aryl-5-chlorosulfonyl-1,3-oxazole-4-carboxylates have been synthesized. Their reactions with amines and amidines have yielded the corresponding sulfonamides and 6H,7H-[1,3]oxazolo-[5,4-d]pyrimidin-7-ones.

Studies have been conducted of the reactions of 7-phenyl-3,7-dihydro-4H-pyrazolo[3,4-d]-[1,2,3]triazin-4-one with alkyl halides and formaldehyde, that occurred with retention of the pyrazolotriazine structure. Ethyl 2-(4-oxo-7-phenyl-4,7-dihydro-3H-pyrazolo[3,4-d][1,2,3]triazin-3-yl)-acetate was prepared by the reaction of 7-phenyl-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one with ethyl chloroacetate. It was used to synthesize the corresponding hydrazide with the aim of introducing the pyrazole or 1,3,4-oxadiazole fragments in the side chain of a bicyclic system.

Chlorination of 2-aryl-5-benzylsulfanyl-1,3-oxazole-4-carbonitrile in aqueous acetic acid at 50–60°C afforded new 2-aryl-5-chloro-1,3-oxazole-4-carboxamides. The reactivity of the chlorine atom with respect to the N-, O-, and S-nucleophiles was investigated.

Derivatives of 4-benzylsulfanyl-1,3-oxazole and 4-benzylsulfanyl-1,3-thiazole were synthesized using available amidophenacylating reagents. By the oxidative chlorination compounds obtained were converted to 1,3-oxazole-4-sulfonyl and 1,3-thiazol-4-sulfonyl chlorides. The latter were used to prepare the corresponding sulfonamides.

The reaction of 2-aryl-4-cyano-1,3-oxazole-5-sulfonyl chlorides with 5-amino-3-R-1H-pyrazoles and 5-amino-1H-1,2,4-triazole gave 5-[(3-R-5-amino-1H-pyrazol-1-yl)sulfonyl]-2-aryl-1,3-oxazole-4-carbo- nitriles and 5-[(5-amino-1H-1,2,4-triazol-1-yl)sulfonyl]-2-aryl-1,3-oxazole-4-carbonitriles. The action of sodium hydride on these carbonitriles leads to the elimination of sulfur dioxide and cyclocondensation to give new heterocyclic systems, namely, [1,3]oxazolo[5,4-d]pyrazolo[1,5-a]-pyrimidine and [1,3]oxazolo[5,4-d][1,2,4]triazolo[1,5-a]pyrimidine.

Reaction of 2-methoxy-5-morpholino-1,3-oxazole-4-carbonitrile with benzylamine, phenethylamine and phenylhydrazine results in the new substituted 5-amino-2,3-dihydro-1H-imidazol-2-ones.

Starting from phthalimidoalkanoylamines 1 (amino-protected derivatives of glycine, β-alanine, γ-amino butyric, δ-amino valeric, and e-amino caproic acids), a facile synthetic method has been developed to obtain diethyl 5-alkyl(dialkyl)amino-2-aminoalkyl-1,3-oxazol-4-ylphosphonates 7, which have been further used in the preparation of phosphorylated peptidomimetics 10 and 12.

N-Alkyl(aryl)-3-amino-5H,6H,7H-pyrrolo[1,2-a]imidazole-2-carboxamides were obtained by the interaction of 5-alkyl(aryl)amino-2-(3-phthalimidopropyl)-1,3-oxazole-4-carbonitriles with hydrazine hydrate and have been used for the synthesis of substituted 3H,4H,6H,7H,8H-pyrrolo[2,1-h]purin-4-ones, their thione analogs, and also 1,2,3,6,7,8-hexahydro-4H-pyrrolo[2′,1′:2,3]imidazo[4,5-d]-[1,3,2]diazaphosphinine derivatives.

Display Omitted A series of new predictive QSAR models is presented.Artificial Neural Networks used to build QSAR models.The models demonstrated good predictive ability.Cytotoxic activity of 3 compounds against Hep-2 cell line was the highest.Docking studies of 3 compounds predict their binding to the colchicine binding site of tubulin. Microtubules play a significant role in cell growth and functioning. Therefore inhibition of the microtubule assemblies has emerged as one of the most promising cancer treatment strategies. Predictive QSAR models were built on a series of selective inhibitors of the tubulin were performed by using Associative Neural Networks (ANN). To overcome the problem of data overfitting due to the descriptor selection, a 5-fold cross-validation with variable selection in each step of the analysis was used. All developed QSAR models showed excellent statistics on the training (total accuracy: 0.960.97) and test sets (total accuracy: 0.9597). The models were further validated by 11 synthesized 1,3-oxazole derivatives and all of them showed inhibitory effect on the Hep-2 cancer cell line. The most promising compound showed inhibitory activity IC50=60.2M. In order to hypothesize their mechanism of action the top three compounds were docked in the colchicine binding site of tubulin and showed reasonable docking scores as well as favorable interactions with the protein.

The reactions of diethyl 5-hydrazino-2-(4-methylphenyl)-1,3-oxazol-4-ylphosphonate with acetyl, benzoyl, and ethoxycarbonyl isothiocyanates result in the previously unknown (1,3,4-thiadiazol-2-yl)-substituted aminomethylphosphonic acids.

The interaction of 7-aryl-7H-pyrazolo[3,4-d][1,2,3]triazin-4-ols with phosphorus pentoxide or pentasulfide leads to the formation of 6-(5-amino-1-aryl-1H-pyrazol-4-yl)-1-aryl-1H,4H-pyrazolo[3,4-d][1,3]oxazin-4-ones and 6-(5-amino-1-aryl-1H-pyrazol-4-yl)-1-aryl-1H,4H-pyrazolo[3,4-d][1,3]thiazine-4-thiones, respectively. Reaction with phosphorus oxychloride leads to 1-aryl-5-chloro-1H-pyrazole-4-carbonyl chlorides, from which the corresponding amides, hydrazides, and substituted 1,3,4-oxadiazoles were synthesized.

The reaction of 2-acylamino-3,3-dichloroacrylonitriles with arylhydrazines in tetrahydrofuran upon heating was investigated. It led to previously unknown 3-acylamino-2-arylhydrazono-3-cyano-2,3-di-hydro-1H-indoles.

The reaction of substituted 2-oxo-2,3-dihydro-1H-imidazole-4-carbonitriles with Lawesson’s reagent gave new compounds of the fused imidazo[4,5-d][1,3,2]diazaphosphinine system.

Reactions of N-aroyltrichloroethaneimines CCl3C(R)=NCOAr (II, R = COOMe, CN) with phosphorus nucleophiles were studied. The reaction of imines II with o-phenylenediethylamidophosphite proceeded as [4+1]-cycloaddition leading to formation of stable spirocyclic phosphoranes. The structure of one of them was proved by the XRD analysis. The reaction of imine II with acyclic P(III) derivatives [Ph3P, Ph2POEt, (PhO)3P] also includes the formation of labile monocyclic phosphoranes which eliminate phosphine oxide and undergo chlorotropic transfer leading to trichloroazadienes CCl2=C(R)N=C(Cl)Ar. The reaction of imines II with (EtO)2POH in the presence of triethylamine leads to the formation of (EtO)2P(O)Cl and the corresponding dichlorovinylamides CCl2=C(R)NHCOAr.