Synthesis, conformational analysis and antimicrobial activity of 10-benzyl-1,2,4-triazolo[4,3-b]1,2,4-triazino[5,6-b]indole acyclo C-nucleoside analogs.

Condensation of 5-benzyl-3-hydrazino-1,2,4-triazino[5,6-b]indole with various sugar aldoses or ketoses gave the corresponding sugar hydrazones as single geometrical isomer or exist in E/Z tautomeric isomers. The hydrazones underwent heterocyclization with Fe(Ш)Cl3 to give the N2-adduct acyclo C-nucleosides: 3-(alditol-1yl)-10-benzyl-1,2,4-triazolo[4,3-b]1,2,4-triazino[5,6-b]indoles rather than the N4-adduct: 10-(alditol-1-yl)-3-benzyl-1,2,4-triazolo[3,4-c]1,2,4-triazino[5,6-b] indoles on the basis of chemical and UV spectral proofs. Conformational analysis of their polyacetates were studied. The new acyclo C-nucleosides were evaluated for antimicrobial activity.

Circularly Polarized Luminescence of Thiophene-Bridged Macrocyclic pseudo-meta [2.2]Paracyclophanes.

Chiral organic molecules possessing high quantum yields, circular dichroism, and circularly polarized luminescence values have great potential as optically active materials for future applications. Recently, the identification of a promising class of inherently chiral compounds was reported, namely macrocyclic 1,3-butadiyne-linked pseudo-meta[2.2]paracyclophanes, displaying high circular dichroism and related gabs values albeit modest quantum yields. Increasing the quantum yields in an attempt to get bright circularly polarized light emitters, the high-yielding heterocyclization of those 1,3-butadiyne bridges resulting in macrocyclic 2,5-thienyls-linked pseudo-meta [2.2]paracyclophanes is herein described. The chiroptical properties of both, the previously reported 1,3-butadiyne, and the novel 2,5-thienyl bridged macrocycles of various sizes, are experimentally recorded, and theoretically described using density-functional theory.

5+1-Heterocyclization as preparative approach for carboxy-containing triazolo[1,5-c]quinazolines with anti-inflammatory activity.

Present article is devoted to the purposeful search of novel anti-inflammatory agents among carboxyl-containing partially hydrogenated [1,2,4]triazolo[1,5-с]quinazolines and products of their tandem cyclization. It has been shown that target compound's could be obtained via interaction between [2-(3-R-1H-1,2,4-triazol-5-yl)phenyl]amines and oxo-containing carboxylic acids and their esters of various structure. The structures of synthesized compounds were verified by appropriate methods, the features of NMR-spectra patterns were discussed as well. The low predicted toxicity of obtained compounds has been estimated using in silico methods. In vivo study on the model of acute aseptic inflammation (carrageenan test) have been revealed that synthesized compounds expose anti-inflammatory activity in the range of 0.94-52.66%. 4-(2-(Ethoxycarbonyl)-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-5-yl)benzoic acid has been identified as most active compound. Additionally, the effects of some (2-R-5,6-dihydro[1,2,4]triazolo[1,5-c]quinazolin-5-yl)benzoic acids (compounds 3) on the levels of key inflammatory markers have been estimated. It has been shown that studied compounds decrease the level of neutrophils, COX-2, nitrotyrosine, IL-1b, C-reactive protein and increase level of eNOS. 4-(2-(Ethoxycarbonyl)-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-5-yl)benzoic acid (3.2) has been identified as compound with most expressed anti-inflammatory activity and significant effect on the levels of marker of inflammatory processes. Molecular docking study towards СОХ-1 and СОХ-2 has been conducted to substantiate possible mechanism of obtained compounds anti-inflammatory activity. It has been found that fixation of 4-(2-(ethoxycarbonyl)-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-5-yl)benzoic acid (3.2) molecule in active site of enzyme is outstandingly similar to the reference ligands. The essential value of carboxylic group for presence of anti-inflammatory activity has been estimated as result of SAR-analysis. It has been found that studied class of compounds is perspective for further structural modification aimed to the creation of novel anti-inflammatory agents.

6-Amino-4-aryl-7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxamides: Synthesis, Biological Activity, Quantum Chemical Studies and In Silico Docking Studies.

New [1,2]dithiolo[3,4-b]pyridine-5-carboxamides were synthesized through the reaction of dithiomalondianilide (N,N'-diphenyldithiomalondiamide) with 3-aryl-2-cyanoacrylamides or via a three-component reaction involving aromatic aldehydes, cyanoacetamide and dithiomalondianilide in the presence of morpholine. The structure of 6-amino-4-(2,4-dichloro- phenyl)-7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxamide was confirmed using X-ray crystallography. To understand the reaction mechanism in detail, density functional theory (DFT) calculations were performed with a Grimme B97-3c composite computational scheme. The results revealed that the rate-limiting step is a cyclization process leading to the closure of the 1,4-dihydropyridine ring, with an activation barrier of 28.8 kcal/mol. Some of the dithiolo[3,4-b]pyridines exhibited moderate herbicide safening effects against 2,4-D. Additionally, ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) parameters were calculated and molecular docking studies were performed to identify potential protein targets.

Advances in ß-Diketocyclisation of Curcumin Derivatives and their Antitumor Activity.

Curcumin, derived from the popular spice turmeric, is a pharmacologically active polyphenol. Curcumin's therapeutic activity has been extensively studied in recent decades, with reports implicating curcumin in many biological activities, particularly, its significant anticancer activity. However, its potential as an oral administration product is hampered by poor bioavailability, which is associated with a variety of factors, including low water solubility, poor intestinal permeability, instability, and degradation at alkaline pH. To improve its bioavailability, modifying ß-diketone curcumin with heterocycles, such as pyrazole, isoxazole and triazole is a powerful strategy. Derivatives are synthesized while maintaining the basic skeleton of curcumin. The ß-diketone cyclized curcumin derivatives are regulators of multiple molecular targets, which play vital roles in a variety of cellular pathways. In some literatures, structurally modified curcumin derivatives have been compared with curcumin, and the former has enhanced biological activity, improved water solubility and stability. Therefore, the scope of this review is to report the most recently synthesized heterocyclic derivatives and to classify them according to their chemical structures. Several of the most important and effective compounds are reviewed by introducing different active groups into the ß-diketone position to achieve better therapeutic efficacy and bioavailability.

Dihydroazolopyrimidines: Past, Present and Perspectives in Synthesis, Green Chemistry and Drug Discovery.

Dihydroazolopyrimidines are an important class of heterocycles that are isosteric to natural purines and are therefore of great interest primarily as drug-like molecules. In contrast to the heteroaromatic analogs, synthetic approaches to these compounds were developed much later, and their chemical properties and biological activity have not been studied in detail until recently. In the review, different ways to build dihydroazolopyrimidine systems from different building blocks are described - via the initial formation of a partially hydrogenated pyrimidine ring or an azole ring, as well as a one-pot assembly of azole and azine fragments. Special attention is given to modern approaches: multicomponent reactions, green chemistry, and the use of non-classical activation methods. Information on the chemical properties of dihydroazolopyrimidines and the prospects for their use in the design of drugs of various profiles are also summarized in this review.

5-Nitroisoxazoles in SNAr Reactions: A Novel Chemo- and Regioselective Approach to Isoxazole-Based Bivalent Ligands of AMPA Receptors.

An efficient regioselective approach to novel functionalized bis(isoxazoles) with a variety of aromatic and aliphatic linkers was elaborated, based on the heterocyclization reaction of electrophilic alkenes under the treatment with tetranitromethane-triethylamine complex affording 3-EWG-5-nitroisoxazoles. The subsequent SNAr reactions of 5-nitroisoxazoles with various O,O-, N,N- and S,S-bis(nucleophiles) provide a wide range of bis(isoxazole) derivatives in good isolated yields. Employing an elaborated method, a series of novel bis(3-EWG-isoxazoles) as the promising allosteric modulators of AMPA receptors were designed and synthesized. The effect of the compounds on the kainate-induced currents was studied in the patch clamp experiments, revealing modulator properties for several of them. The best positive modulator potency was found for dimethyl 5,5'-(ethane-1,2-diylbis(sulfanediyl))bis(isoxazole-3-carboxylate), which potentiated the kainate-induced currents in a wide concentration range (10-12-10-6 M) with maximum potentiation of 77% at 10-10 M. The results were rationalized using molecular docking and molecular dynamics simulations of modulator complexes with the dimeric ligand-binding domain of the GluA2 AMPA receptor. The predicted physicochemical, ADMET, and PAINS properties confirmed that the AMPA receptor modulators based on the bis(isoxazole) scaffold may serve as potential lead compounds for the development of neuroprotective drugs.

Advances in Selected Heterocyclization Methods.

This Account summarizes efforts in our group toward synthesis of heterocycles in the past decade. Selected examples of transannulative heterocyclizations, intermediate construction of reactive compounds en route to these important motifs, and newer developments of a radical approach are outlined.

Stereospecific Aminative Cyclizations Triggered by Intermolecular Aza-Prilezhaev Alkene Aziridination.

Under acidic reaction conditions (TFA), deprotection of BocNR(OSO2 R) reagents triggers intermolecular aminative cyclizations of alkenes equipped with pendant nucleophiles. The processes are predicated on a sequence of stereospecific intermolecular aza-Prilezhaev aziridination followed by stereospecific SN 2-like opening by the pendant nucleophile. The method offers broad scope with respect to the nucleophile (N-, O- or C-based), alkene and cyclization mode, allowing the installation of two contiguous stereocenters under operationally simple conditions.

Development of On-DNA Thiophene Synthesis for DEL Construction.

Thiophene and its substituted derivatives are a highly important class of heterocyclic compounds, with noteworthy applications in pharmaceutical ingredients. In this study, we leverage the unique reactivity of alkynes to generate thiophenes on-DNA, using a cascade iodination, Cadiot-Chodkiewicz coupling and heterocyclization. This approach, tackling on-DNA thiophene synthesis for the first time, generates diverse, and unprecedented structural and chemical features, which could be significant motifs in DEL screening as molecular recognition agents for drug discovery.

Revelation of contributing mechanism of reactive oxygen species in photocatalytic ozonation heterocyclization of gaseous hexane isomers.

The reactive oxygen species (ROS) involved photocatalytic ozonation of gaseous n-hexane to heterocyclic compounds has been recently reported. However, whether such heterocyclization reaction happens on other alkanes and what is the contributing mechanism of ROS to the heterocyclic compound formation are still unclear. In present study, photocatalytic ozonation of three n-hexane's isomers (i.e. 2-methypentane, 3-methylpentane and 2,3-dimethylbutane) on Cu2O-CuO/TiO2-foam ceramic was investigated. Within reaction period, 2-methylpentane and 3-methylpentane not only showed higher average degradation efficiency than 2,3-dimethylbutane, but also separately converted to interfacial heterocyclic compounds of 5,5-dimethyldihydro-2(3H)-furanone and 4,5-dimethyl-4,5-dihydro-2(3H)-furanone. Enough reaction time, optimum experimental atmosphere and shorter light wavelength benefited the formation of heterocyclization products. None of O3, 1O2, electron and hole directly contributed to the heterocyclic compound formation. While •O2- dominated the production of the heterocyclic compound under the dry reaction atmosphere and •OH showed more important role than •O2- in the heterocyclic compound formation under the moist reaction atmosphere. Theoretical calculation confirmed that •OH or •O2- induced heterocyclization reaction of alkane was exothermic, while the former reaction released 0.47 eV higher energy than the later reaction. The findings provide a comprehensive understanding of contributing roles of ROS in heterocyclization reaction of alkanes, and are helpful for effective elimination of industrial alkanes by advanced oxidation methods.

The Reactions of N,N'-Diphenyldithiomalondiamide with Arylmethylidene Meldrum's Acids.

The Michael addition reaction between dithiomalondianilide (N,N'-diphenyldithiomalondiamide) and arylmethylidene Meldrum's acids, accompanied by subsequent heterocyclization, was investigated along with factors affecting the mixture composition of the obtained products. The plausible mechanism includes the formation of stable Michael adducts which, under the studied conditions, undergo further transformations to yield corresponding N-methylmorpholinium 4-aryl-6-oxo-3-(N-phenylthio-carbamoyl)-1,4,5,6-tetrahydropyridin-2-thiolates and their oxidation derivatives, 4,5-dihydro-3H-[1,2]dithiolo[3,4-b]pyridin-6(7H)-ones. The structure of one such product, N-methylmorpholinium 2,2-dimethyl-5-(1-(2-nitrophenyl)-3-(phenylamino)-2-(N-phenylthiocarbamoyl)-3-thioxopropyl)-4-oxo-4H-1,3-dioxin-6-olate, was confirmed via X-ray crystallography.

Novel Set of Highly Substituted Bis-pyridines: Synthesis, Molecular Docking and Drug-Resistant Antibacterial Profile.

Aims: Development of antimicrobial agents having the ability to prevent bacterial biofilm formation which causes serious health problems, especially with antibiotic-resistant bacterial strains. Materials and methods: The use of 1,3-diaryl enones as structural motifs to access the pyridine core. Antimicrobial activities of the synthesized compounds against methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus and vancomycin-resistant S. aureus bacterial strains were investigated. Results: The newly synthesized bis-enones were used as building blocks to access some novel highly substituted bis-pyridine derivatives. Several novel bis-compounds showed great bacterial biofilm eradication activity. Conclusion: A new series of bis-chalcones was synthesized and their structural diversity was exploited to access the corresponding, more biologically active, pyridine core. These bis-pyridines showed respectable antibacterial activities against various drug-resistant bacterial strains: namely, methicillin-susceptible, methicillin-resistant and vancomycin-resistant S. aureus.

Synthesis, Structure and Molecular Docking of New 4,5-Dihydrothiazole Derivatives Based on 3,5-Dimethylpyrazole and Cytisine and Salsoline Alkaloids.

The interaction results of 1,2-dibromo-3-isothiocyanatopropane with some pyrazoles as well as cytisine and salsoline alkaloids were presented in this paper. It was shown that the reaction resulted in one one-step and rather mild method for the preparation of the corresponding 1,3-thiazoline bromomethyl derivatives. The yield of this reaction was affected by the presence of a base and an order in which reagents were added. Molecular docking of the synthesized 1,3-thiazoline derivatives for putative antibacterial activity was carried out using the penicillin-binding target protein (PBP4) of the bacteria E. coli "Homo sapiens" and S. aureus "Homo sapiens" as an example. Molecular docking demonstrated that the compounds had insignificant binding energies at the level of selected reference drugs (Cephalotin and Chloramphenicol). The presence of natural alkaloids in the structure of thiazoline derivatives somewhat increased the affinity of these substrates for target proteins selected.

Heterocyclization of Bis(2-chloroprop-2-en-1-yl)sulfide in Hydrazine Hydrate-KOH: Synthesis of Thiophene and Pyrrole Derivatives.

The article is devoted to heterocyclization of bis(2-chloroprop-2-en-1-yl)sulfide which proceeds in hydrazine hydrate-alkali medium and leads to formation of thiophene and pyrrole derivatives: previously described 4,5,9,10-tetrahydrocycloocta[1,2-c;5,8-c']dithiophene, as well as unknown hydrazone of 5-methylidene-3-methyldihydrothiophen-2-one and 1-amino-2-(propynylsulfanylpropenylsulfanyl)-3,5-dimethylpyrrole. Tentative mechanisms for the formation of the heterocyclic products are discussed. Obtained hydrazone of 5-methylidene-3-methyldihydrothiophen-2-one was used for the synthesis of a range of azine derivatives and in oxidation process with SeO2. The found reactions open up expedient approaches to the formation of various hardly accessible thiophene and pyrrole compounds from 2,3-dichloropropene and elemental sulfur as starting reagents.

Triflamidation of Allyl-Containing Substances:Unusual Dehydrobromination vs. Intramolecular Heterocyclization.

Allyl halides with triflamide under oxidative conditions form halogen-substituted amidines. Allyl cyanide reacts with triflamide in acetonitrile or THF solutions in the presence of NBS to give the products of bromotriflamidation with a solvent interception, whereas in CH2Cl2 two regioisomers of the bromotriflamidation product without a solvent interception were obtained. The formed products undergo base-induced dehydrobromination to give linear isomers with the new C=C bond conjugated either with the nitrile group or the amidine moiety or alkoxy group. Under the same conditions, the reaction of allyl alcohol with triflamide gives rise to amidine, which was prepared earlier by the reaction of diallyl formal with triflamide. Unlike their iodo-substituted analogs, bromo-substituted amidines successfully transform into imidazolidines under the action of potassium carbonate.

Triflamides and Triflimides: Synthesis and Applications.

Among the variety of sulfonamides, triflamides (CF3SO2NHR, TfNHR) occupy a special position in organic chemistry. Triflamides are widely used as reagents, efficient catalysts or additives in numerous reactions. The reasons for the widespread use of these compounds are their high NH-acidity, lipophilicity, catalytic activity and specific chemical properties. Their strong electron-withdrawing properties and low nucleophilicity, combined with their high NH-acidity, makes it possible to use triflamides in a vast variety of organic reactions. This review is devoted to the synthesis and use of N-trifluoromethanesulfonyl derivatives in organic chemistry, medicine, biochemistry, catalysis and agriculture. Part of the work is a review of areas and examples of the use of bis(trifluoromethanesulfonyl)imide (triflimide, (CF3SO2)2NH, Tf2NH). Being one of the strongest NH-acids, triflimide, and especially its salts, are widely used as catalysts in cycloaddition reactions, Friedel-Crafts reactions, condensation reactions, heterocyclization and many others. Triflamides act as a source of nitrogen in C-amination (sulfonamidation) reactions, the products of which are useful building blocks in organic synthesis, catalysts and ligands in metal complex catalysis, and have found applications in medicine. The addition reactions of triflamide in the presence of oxidizing agents to alkenes and dienes are considered separately.

Tandem Electrochemical Oxidative Azidation/Heterocyclization of Tryptophan-Containing Peptides under Buffer Conditions.

As the aromatic tryptophan (Trp) side chain plays a pivotal role in influencing the structure and function of peptides and proteins, it has become an attractive target for the late-stage modification of these important biomolecules. Herein, we report an electrochemical approach for late-stage functionalization of peptides containing a Trp side chain through manganese-catalyzed tandem radical azidation/heterocyclization. This electrochemical oxidative strategy provides access to azide-substituted tetrazolo[1,5-a]indole-containing peptides with broad functional group tolerance, high site selectivity, and good yields of products (up to 87 %) under mild buffer conditions. Moreover, the modified Trp-containing peptides bearing an azide functionality are promising building blocks, paving the way for the construction of various derivatives, such as "click" chemistry products.

Domino Nitro Reduction-Friedländer Heterocyclization for the Preparation of Quinolines.

The Friedländer synthesis offers efficient access to substituted quinolines from 2-aminobenzaldehydes and activated ketones in the presence of a base. The disadvantage of this procedure lies in the fact that relatively few 2-aminobenzaldehyde derivatives are readily available. To overcome this problem, we report a modification of this process involving the in situ reduction of 2-nitrobenzaldehydes with Fe/AcOH in the presence of active methylene compounds (AMCs) to produce substituted quinolines in high yields. The conditions are mild enough to tolerate a wide range of functionality in both reacting partners and promote reactions not only with phenyl and benzyl ketones, but also with ß-keto-esters, ß-keto-nitriles, ß-keto-sulfones and ß-diketones. The reaction of 2-nitroaromatic ketones with unsymmetrical AMCs is less reliable, giving a competitive formation of substituted quinolin-2(1H)-ones from the cyclization of the Z Knoevenagel intermediate which appears to be favored when certain large groups are adjacent to the AMC ketone carbonyl.

Bicyclic Isoxazoline Derivatives: Synthesis and Evaluation of Biological Activity.

The application of non-planar scaffolds in drug design allows for the enlargement of the chemical space, and for the construction of molecules that have more effective target-ligand interactions or are less prone to the development of resistance. Among the works of the last decade, a literature search revealed spirothiazamenthane, which has served as a lead in the development of derivatives active against resistant viral strains. In this work, we studied the novel molecular scaffold, which resembles spirothiazamenthane, but combines isoxazoline as a heterocycle and cyclooctane ring as a hydrophobic part of the structure. The synthesis of new 3-nitro- and 3-aminoisoxazolines containing spiro-fused or 1,2-annelated cyclooctane fragments was achieved by employing 1,3-dipolar cycloaddition of 3-nitro-4,5-dihydroisoxazol-4-ol 2-oxide or tetranitromethane-derived alkyl nitronates with non-activated alkenes. A series of spiro-sulfonamides was obtained by the reaction of 3-aminoisoxazoline containing a spiro-fused cyclooctane residue with sulfonyl chlorides. Preliminary screening of the compounds for antiviral, antibacterial, antifungal and antiproliferative properties in vitro revealed 1-oxa-2-azaspiro[4.7]dodec-2-en-3-amine and 3a,4,5,6,7,8,9,9a-octahydrocycloocta[d]isoxazol-3-amine with activity against the influenza A/Puerto Rico/8/34 (H1N1) virus in the submicromolar range, and high values of selectivity index. Further study of the mechanism of the antiviral action of these compounds, and the synthesis of their analogues, is likely to identify new agents against resistant viral strains.