New insides into chimeric and hybrid azines derivatives with antifungal activity.

During the last decades, five or six member rings azaheterocycles compounds appear to be an extremely valuable source of antifungal agents. Their use seems to be a very attractive solution in antifungal therapy and to overcome antifungal resistance in agriculture. The present review highlights the main results obtained in the field of hybrid and chimeric azine (especially pyridine, quinoline, phenanthroline, bypyridine, naphthyridine and their fused derivatives) derivatives presented in scientific literature from the last 10 years, with emphasis on antifungal activity of the mentioned compounds. A special attention was played to hybrid and chimeric azole-azine class, having in view the high antifungal potential of azoles.

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Suberoylanilide Hydroxamic Acid Analogs with Heteroaryl Amide Group and Different Chain Length: Synthesis and Effect on Histone Deacetylase.

This review covers the last 25 years of the literature on analogs of suberoylanilide hydroxamic acid (SAHA, known also as vorinostat) acting as an HDAC inhibitor. In particular, the topic has been focused on the synthesis and biological activity of compounds where the phenyl group (the surface recognition moiety, CAP) of SAHA has been replaced by an azaheterocycle through a direct bond with amide nitrogen atom, and the methylene chain in the linker region is of variable length. Most of the compounds displayed good to excellent inhibitory activity against HDACs and in many cases showed antiproliferative activity against human cancer cell lines.

Synthesis of 5-(trifluoroacetyl)imidazoles from Bromoenones and Benzimidamides via Aza-Michael Initiated Ring Closure Reaction.

INTRODUCTION: A simple method for the preparation of 5-(trifluoroacetyl)imidazoles was elaborated. METHODS: The reaction of trifluoromethyl(α-bromoalkenyl)ketones with benzimidamides was employed to afford the target heterocycles in good yields. RESULTS: The assembly of imidazole core proceeds via aza-Michael adduct formation followed by intramolecular nucleophilic substitution and spontaneous aromatization as an oxidation sequence. CONCLUSION: The yields of target imidazoles can be improved by the use of soft oxidizing agents.

Application of Metathesis Protocols to the Stereocontrolled Synthesis of some Functionalized ß-Amino Esters and Azaheterocycles.

In this account our aim was to give an insight into the application of metathesis protocols (ROM, RCM, RCEYM, CM, RRM) for the synthesis of various azaheterocyclic frameworks. Due to the high biological potential and importance in peptide chemistry and drug design of ß-amino acids our intention is to give a highlight on the synthetic procedures and transformation of these class of compounds with the above-mentioned metathesis strategies with emphasis on selectivity, stereocontrol, substrate-directing effect or functional group tolerance.

Identification of Potential Antitubulin Agents with Anticancer Assets from a Series of Imidazo[1,2-a]quinoxaline Derivatives: In Silico and In Vitro Approaches.

Computer-aided drug design is a powerful and promising tool for drug design and development, with a reduced cost and time. In the current study, we rationally selected a library of 34 fused imidazo[1,2-a]quinoxaline derivatives and performed virtual screening, molecular docking, and molecular mechanics for a lead identification against tubulin as an anticancer molecule. The computational analysis and pharmacophoric features were represented as 1A2; this was a potential lead against tubulin, with a maximized affinity and binding score at the colchicine-binding site of tubulin. The efficiency of this lead molecule was further identified using an in vitro assay on a tubulin enzyme and the anticancer potential was established using an MTT assay. Compound 1A2 (IC50 = 4.33-6.11 µM against MCF-7, MDA-MB-231, HCT-116, and A549 cell lines) displayed encouraging results similar to the standard drug colchicine in these in vitro studies, which further confirmed the effectiveness of CADD in new drug developments. Thus, we successfully applied the utility of in silico techniques to identify the best plausible leads from the fused azaheterocycles.

A Review on the Synthesis of Fluorescent Five- and Six-Membered Ring Azaheterocycles.

Azaheterocycles rings with five and six members are important tools for the obtaining of fluorescent materials and fluorescent sensors. The relevant advances in the synthesis of azaheterocyclic derivatives and their optical properties investigation, particularly in the last ten years, was our main objective on this review. The review is organized according to the size of the azaheterocycle ring, 5-, 6-membered and fused ring azaheterocycles, as well as our recent contribution on this research field. In each case, the reaction pathways with reaction condition and obtained yield, and evaluation of the optical properties of the obtained products were briefly presented.

Selective Transformation of Norbornadiene into Functionalized Azaheterocycles and ß-Amino Esters with Stereo- and Regiocontrol.

Novel functionalized azaheterocycles with multiple chiral centers have been accessed from readily available norbornene ß-amino acids or ß-lactams across a stereocontrolled synthetic route, based on ring-opening metathesis (ROM) of the staring unsaturated bicyclic amino esters, followed by selective cyclization through ring-closing metathesis (RCM). The RCM transformations have been studied under various experimental conditions to assess the scope of conversion, catalyst, yield, and substrate influence. The structure of the starting norbornene ß-amino acids predetermined the structure of the new azaheterocycles, and the developed synthetic route took place with the conservation of the configuration of the chiral centers.

Acid-Base and Anion Binding Properties of Tetrafluorinated 1,3-Benzodiazole, 1,2,3-Benzotriazole and 2,1,3-Benzoselenadiazole.

The influence of fluorination on the acid-base properties and the capacity of structurally related 6-5 bicyclic compounds - 1,3-benzodiazole 1, 1,2,3-benzotriazole 2 and 2,1,3-benzoselenadiazole 3 to σ-hole interactions, i. e. hydrogen (1 and 2) and chalcogen (3) bondings, is studied experimentally and computationally. The tetrafluorination increases the Brønsted acidity of the diazole and triazole scaffolds and the Lewis acidity of selenadiazole scaffold decreases the basicity. Increased Brønsted acidity facilitates anion binding via the formation of hydrogen bonds; particularly, tetrafluorinated derivative of 1 (compound 4) binds Cl- . Increased Lewis acidity of tetrafluorinated derivative of 3 (compound 10), however, is not enough for binding with Cl- and F- via chalcogen bonds in contrast to previously studied Te analog of 10. It is suggested that the maximum positive values of molecular electrostatic potential at the σ-holes, VS,max , can be a reasonable metric for design and synthesis of new anion receptors with selenadiazole-diazole/triazole hybrids as a special target. Related chlorinated compounds are also discussed.

In-vitro evaluation of antioxidant and anticholinesterase activities of novel pyridine, quinoxaline and s-triazine derivatives.

Cholinesterase enzymes such as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) cause hydrolysis of acetylcholine (ACh), a neurotransmitter responsible for the cognitive functions of the brain such as acquiring knowledge and comprehension. Therefore, inhibition of these enzymes is an effective process to curb the progressive and fatal neurological Alzheimer's disease (AD). Herein, we explored the potential inhibitory activities of various pyridine, quinoxaline, and triazine derivatives (3a-k, 6a-j and 11a-h) against AChE and BuChE enzymes by following the modified Ellman's method. Further, anti-oxidant property of these libraries was monitored using DPPH (2,2'-diphenyl-1-picryl-hydrazylhydrate) radical scavenging analysis. From the studies, we identified that compounds 6e, 6f, 11b and 11f behaved as selective AChE inhibitors with IC50 values ranging from 7.23 to 10.35 µM. Further studies revealed good anti-oxidant activity by these compounds with IC50 values in the range of 14.80-27.22 µM. The kinetic studies of the active analogues demonstrated mixed-type of inhibition due to their interaction with both the catalytic active sites (CAS) and peripheral anionic sites (PAS) of the AChE. Additionally, molecular simulation in association with fluorescence and circular dichroism (CD) spectroscopic analyses explained strong affinities of inhibitors to bind with AChE enzyme at the physiological pH of 7.2. Binding constant values of 5.4 × 104, 4.3 × 104, 3.2 × 104 and 4.9 × 104 M-1 corresponding to free energy changes -5.593, -6.799, -6.605 and -8.104 KcalM-1 were obtained at 25 °C from fluorescence emission spectroscopic studies of 6e, 6f, 11b and 11f, respectively. Besides, CD spectroscopy deliberately explained the secondary structure of AChE partly unfolded upon binding with these dynamic molecules. Excellent in vitro profiles of distinct quinoxaline and triazine compounds highlighted them as the potential leads compared to pyridine derivatives, suggesting a path towards developing preventive or therapeutic targets to treat the Alzheimer's disease.

Rapid, High-Throughput Quantitation of Odor-Active 2-Acetyl Azaheterocycles in Food Products by UHPLC-MS/MS.

A rapid, high-throughput method for the quantitation of the 2-acetyl azaheterocycles, 2-acetyl-1-pyrroline, 2-acetyl-1,4,5,6-tetrahydropyridine, 2-acetylpyrazine, and 2-acetyl-2-thiazoline, in different food products, by liquid chromatography-tandem mass spectrometry (LC-MS/MS), was developed. The quick extraction by bead beater homogenization, fast derivatization by 3-nitrophenylhydrazine (40 °C, 2 h), and efficient LC separation make this method suitable for high-throughput analysis. As established in this study, the highly precise LC-MS/MS method applies to different food products or beverages without requiring further adjustment. The analysis was performed with sample amounts of 0.2-0.5 g, and limit of quantitation values of 0.6, 0.5, 0.6, and 1.0 µg/kg were obtained for 2-acetyl-1-pyrroline, 2-acetyl-1,4,5,6-tetrahydropyridine, 2-acetylpyrazine, and 2-acetyl-2-thiazoline, respectively. Thus, it was possible to quantitate the analytes in the range of their odor thresholds.

Vinyl sulfone-modified carbohydrates: Michael acceptors and 2π partners for the synthesis of functionalized sugars and enantiomerically pure carbocycles and heterocycles.

Increasing demands for molecules with skeletal complexity, including those of stereochemical diversity, require new synthetic strategies. Carbohydrates have been used extensively as chiral building blocks for the synthesis of various complex molecules. On the other hand, the vinyl sulfone group has been identified as a unique functional group, which acts either as a Michael acceptor or a 2π partner in cycloaddition reactions. A combination of the high reactivity of the vinyl sulfone group and the in-built chiralities of carbohydrates has the potential to function as a powerful tool to generate a wide variety of enantiomerically pure reactive intermediates. Since CS bond formation in carbohydrates is easily achieved with regioselectivity, further synthetic manipulations of these thiosugars has led to the generation of a wide range of vinyl sulfone-modified furanosyl, pyranosyl, acyclic, and bicyclic carbohydrates. Several approaches have been studied to standardize the preparative methods for accessing vinyl sulfone-modified carbohydrates at least on a gram scale. Reactions of these modified carbohydrates with appropriate reagents afford a large number of new chemical entities primarily via (i) Michael addition reactions, (ii) desulfostannylation, (iii) Michael-initiated ring-closure reactions, and (iv) cycloaddition reactions. A wide range of desulfonylating reagents in the context of sensitive molecules such as carbohydrates have also been extensively studied. Applications of these strategies have led to the synthesis of (a) amino sugars and branched-chain sugars, (b) C-glycosides, (c) enantiomerically pure cyclopropanes, five- and six-membered carbocycles, (d) saturated oxa-, aza-, and thio-monocyclic heterocycles, (e) bi-and tricyclic saturated oxa and aza heterocycles, (f) enantiomerically pure and trisubstituted pyrroles, (g) 1,5-disubstituted 1,2,3-triazolylated carbohydrates and the corresponding triazole-linked di- and trisaccharides, (h) divinyl sulfone-modified carbohydrates and densely functionalized S,S-dioxothiomorpholines, and (i) modified nucleosides. Details of reaction conditions were incorporated as much as possible and mechanistic discussions were included wherever necessary.

The Bestmann-Ohira Reagent and Related Diazo Compounds for the Synthesis of Azaheterocycles.

Azaheterocycles are one of the most prevalent classes of compounds present in numerous bioactive compounds, natural products, and agrochemicals, and undoubtedly, new methods to access them are always in high demand. Among the methods available, the 1,3-dipolar cycloaddition reactions involving diazo compounds are particularly attractive because of their ability to rapidly construct densely functionalized azaheterocycles in a regioselective manner. In this context, the Bestmann-Ohira reagent has become a well-known reagent for the 1,3-dipolar cycloaddition reactions to produce phosphonylated heterocycles, besides its widespread use as a homologating agent for the conversion of aldehydes to alkynes. This account details our efforts toward broadening the synthetic utility of the Bestmann-Ohira reagent and related compounds for the preparation of azaheterocycles such as pyrazoles, spirooxindoles, triazoles, triazolines, and spiropyrazolines, emphasizing on domino multicomponent reactions employing readily available feedstock reagents.

Microwave Assisted Reactions of Azaheterocycles Formedicinal Chemistry Applications.

Microwave (MW) assisted reactions have became a powerful tool in azaheterocycles chemistry during the last decades. Five and six membered ring azaheterocycles are privileged scaffolds in modern medicinal chemistry possessing a large variety of biological activity. This review is focused on the recent relevant advances in the MW assisted reactions applied to azaheterocyclic derivatives and their medicinal chemistry applications from the last five years. The review is divided according to the main series of azaheterocycles, more precisely 5- and 6-membered ring azaheterocycles (with one, two, and more heteroatoms) and their fused analogues. In each case, the reaction pathways, the advantages of using MW, and considerations concerning biological activity of the obtained products were briefly presented.

Stereocontrolled Synthesis of Functionalized Azaheterocycles from Carbocycles through Oxidative Ring Opening/Reductive Ring Closing Protocols.

Fluorine-containing organic scaffolds are of significant interest in medicinal chemistry. The incorporation of fluorine into biomolecules can lead to remarkable changes in their physical, chemical, and biological properties. There are already many drugs on the market, which contain at least one fluorine atom. Saturated functionalized azaheterocycles as bioactive substances have gained increasing attention in pharmaceutical chemistry. Due to the high biorelevance of organofluorine molecules and the importance of N-heterocyclic compounds, selective stereocontrolled procedures to the access of new fluorine-containing saturated N-heterocycles are considered to be a hot research topic. This account summarizes the synthesis of functionalized and fluorine-containing saturated azaheterocycles starting from functionalized cycloalkenes and based on oxidative ring cleavage of diol intermediates followed by ring expansion with reductive amination.

A New Synthetic Tool: The Pseudo-Intramolecular Process.

An efficient synthetic protocol based on a new concept named "the pseudo-intramolecular process" is developed. Substrates are brought closed to each other by forming a salt, and this spatial proximity facilitates an efficient reaction like an intramolecular process, despite actually proceeding via an intermolecular pathway. This concept can be widely applied in organic synthesis. For instance, α-aryl-ß-keto esters undergo a transacylation with amines accompanied by high efficiency, regioselectivity, and chemoselectivity. On the other hand, α-nitro-ß-keto nitriles react via a tandem cyclization to afford polyfunctionalized azaheterocyclic compounds, which cannot be easily prepared by alternative methods. These synthetic protocols are practically useful because each reaction can be conducted without using any special reagent under mild reaction conditions through only simple experimental manipulations.

Highly Stereoselective Synthesis of a Compound Collection Based on the Bicyclic Scaffolds of Natural Products.

Despite the great contribution of natural products in the history of successful drug discovery, there are significant limitations that persuade the pharmaceutical industry to evade natural products in drug discovery research. The extreme scarcity as well as structural complexity of natural products renders their practical synthetic access and further modifications extremely challenging. Although other alternative technologies, particularly combinatorial chemistry, were embraced by the pharmaceutical industry to get quick access to a large number of small molecules with simple frameworks that often lack three-dimensional complexity, hardly any success was achieved in the discovery of lead molecules. To acquire chemotypes beholding structural features of natural products, for instance high sp³ character, the synthesis of compound collections based on core-scaffolds of natural products presents a promising strategy. Here, we report a natural product inspired synthesis of six different chemotypes and their derivatives for drug discovery research. These bicyclic hetero- and carbocyclic scaffolds are highly novel, rich in sp³ features and with ideal physicochemical properties to display drug likeness. The functional groups on the scaffolds were exploited further to generate corresponding compound collections. Synthesis of two of these collections exemplified with ca. 350 compounds are each also presented. The whole compound library is being exposed to various biological screenings within the European Lead Factory consortium.

Crystal structures of the two epimers from the unusual thermal C6-epimerization of 5-oxo-1,2,3,5,5a,6,7,9b-octa-hydro-7,9a-ep-oxy-pyrrolo-[2,1-a]iso-indole-6-carb-oxy-lic acid, 5a(RS),6(SR),7(RS),9a(SR),9b(SR) and 5a(RS),6(RS),7(RS),9a(SR),9b(SR).

The isomeric title compounds, C12H13NO4 (Ia) and C12H13NO4 (IIa), the products of an usual thermal C6-epimerization of 5-oxo-1,2,3,5,5a,6,7,9b-octa-hydro-7,9a-ep-oxy-pyrrolo-[2,1-a]iso-indole-6-carb-oxy-lic acid, represent the two different diastereomers and have very similar mol-ecular geometries. The mol-ecules of both compounds comprise a fused tetra-cyclic system containing four five-membered rings (pyrrolidine, pyrrolidinone, di-hydro-furan and tetra-hydro-furan), all of which adopt the usual envelope conformations. The dihedral angle between the basal planes of the pyrrolidine and pyrrolidinone rings are 14.3 (2) and 16.50 (11)°, respectively, for (Ia) and (IIa). The nitro-gen atom has a slightly pyramidalized geometry [bond-angle sum = 355.9 and 355.3°, for (Ia) and (IIa)], respectively. In the crystal of (Ia), mol-ecules form zigzag-like hydrogen-bonded chains along [010] through strong O-H⋯O hydrogen bonds and are further linked by weak C-H⋯O hydrogen bonds into complex two-tier layers parallel to (100). Unlike (Ia), the crystal of (IIa) contains centrosymmetric cyclic hydrogen-bonded dimers [graph set R22(14)], formed through strong O-H⋯O hydrogen bonds and are further linked by weak C-H⋯O hydrogen bonds into ribbons extending across [101].

Crystal structure of 1-(4-meth-oxy-phen-yl)-4-(4-nitro-phen-yl)-3-phen-oxy-azetidin-2-one.

In the title compound, C22H18N2O5, the central ß-lactam ring (r.m.s. deviation = 0.002 Å) makes dihedral angles of 64.21 (14), 82.35 (12) and 20.66 (13)° with the phenyl ring and the nitro- and meth-oxy-benzene rings, respectively. The mol-ecular structure is stabilized by an intra-molecular C-H⋯O hydrogen bond. In the crystal, mol-ecules are linked via C-H⋯O hydrogen bonds, forming slabs lying parallel to (111). The slabs are linked via C-H⋯π inter-actions, forming a three-dimensional network.