Azole Heterocycles Research Articles

Palladium-Catalyzed Regio- and Stereoselective Glycosylation of Azole Heterocycles Enables Access to Diverse Heterocyclic N-Glycosides.

An efficient and practical glycosylation platform for synthesizing N-glycosides by leveraging palladium catalysis is disclosed. This approach enables facile access to diverse heterocyclic N-glycosides with excellent regio- and stereoselectivities and high site selectivity of multiple N atoms. The reaction exhibits a broad substrate scope (65 examples), high functional group tolerance, and easy scalability. Its synthetic utility is demonstrated through late-stage functionalization of pharmaceutically relevant molecules and various diastereoselective transformations of the glycoside products. Overall, our method provides a handy tool for efficient and stereocontrolled synthesis of valuable N-glycosylated heterocycles.

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The acylhydrazonyl hybridization of aloe emodin and azole heterocycles afforded a new unique type of framework with multitargeting antibacterial potential. The highly active compound demonstrated strong antibacterial efficacy with broad antibacterial spectrum, low hemolysis and cytotoxicity, and favorable bioavailability. The active molecule could not only cause bacterial membrane depolarization and damage the cell membrane, resulting in nucleic acid leakage, but also intercalate into DNA to impede its replication and form DNA gyrase complex to disturb the function of DNA gyrase. More details are discussed in the article by Zhou et al. on page 1741—1758.image

Boronic Acid-Catalyzed Regio- and Stereoselective N-Glycosylations of Purines and Other Azole Heterocycles: Access to Nucleoside Analogues.

In the presence of an arylboronic acid catalyst, azole-type heterocycles, including purines, tetrazoles, triazoles, indazoles, and benzo-fused congeners, undergo regio- and stereoselective N-glycosylations with furanosyl and pyranosyl trichloroacetimidate donors. The protocol, which does not require stoichiometric activators, specialized leaving groups, or drying agents, provides access to nucleoside analogues and enables late-stage N-glycosylation of azole-containing pharmaceutical agents. A mechanism involving simultaneous activation of the glycosyl donor and acceptor by the organoboron catalyst has been proposed, supported by kinetic analysis and computational modeling.

Isoflavonoids Modified with Azole Heterocycles with Three Heteroatoms

Heterocycle modified chromones are attracting increasing attention as novel potential therapeutic agents due to their effective bioactivities and low toxicity. This review describes all strategies and versatile synthons that have been developed for the synthesis of isoflavone heterocyclic analogs containing isolated 5-member heterocyclic rings with three identical or different heteroatoms. Their biological activity is also presented.

An Insight into the Biological Properties of Imidazole‐Based Schiff Bases: A Review

AbstractImidazole is an azole heterocycle containing two non‐adjacent nitrogen atoms added greatly to natural products and synthetic compounds. The planar ring system associated with electron‐rich nitrogen donors are essential for the greater affinity of imidazole derivatives to bind with various bio receptors and enzymes via weak interactions. It improves the pharmacokinetic properties of the pilot molecules consequently utilized as a solution for aqueous solubility, bioavailability, and toxicity parameters since it is a polar compound. An organic molecule with imidazole derivatives has acquired a sustainable place in medical and clinical fields. The consolidation of the imidazole unit is a significant synthetic technique in drug development. The imidazole‐based Schiff bases with enormous therapeutic properties has encouraged the scientists to focus on recently initiated novel chemotherapeutic agents such as anticancer, antimicrobial, antioxidant, antiviral, antileishmanial, etc. Imidazole drugs have expanded the degree of curing different dispositions in clinical medications. Herein, we have reported the structural feature of imidazole, design, synthesis of imidazole derivatives, and its significance. This review aims to describe the reported materials of imidazole‐based Schiff bases and their derivatives which offer fruitful scope in the field of medicinal chemistry.

Photocatalytic C-H Azolation of Arenes Using Heterogeneous Carbon Nitride in Batch and Flow.

The functionalization of aryl C(sp2)−H bonds is a useful strategy for the late‐stage modification of biologically active molecules, especially for the regioselective introduction of azole heterocycles to prepare medicinally‐relevant compounds. Herein, we describe a practical photocatalytic transformation using a mesoporous carbon nitride (mpg‐CN x ) photocatalyst, which enables the efficient azolation of various arenes through direct oxidation. The method exhibits a broad substrate scope and is amenable to the late‐stage functionalization of several pharmaceuticals. Due to the heterogeneous nature and high photocatalytic stability of mpg‐CN x , the catalyst can be easily recovered and reused leading to greener and more sustainable routes, using either batch or flow processing, to prepare these important compounds of interest in pharmaceutical and agrochemical research.

Intramolecular Diels–Alder Reactions of Oxazoles, Imidazoles, and Thiazoles

AbstractThe development of the intramolecular Diels–Alder cycloaddition­ of azole heterocycles, i.e. oxazoles (IMDAO), imidazoles (IMDAI), and thiazoles (IMDAT), has had a significant impact on the efficient preparation of heterocyclic intermediates and natural products. In particular, highly efficient and versatile IMDAO reactions have been utilized as a key step in several synthetic schemes to provide alkaloids and terpenoid target molecules. More limited studies have been performed on IMDAI and IMDAT cycloadditions. Some drawbacks, such as the occasionally­ challenging preparation of IMDA precursors, are also highlighted in this review. Perspectives are provided on how IMDAI and IMDAT­ transformations can be further expanded for target-directed syntheses.1 Introduction2 Oxazoles2.1 IMDAO Approaches to Furanosesquiterpenes and Furanosteroids2.1.1 Syntheses of Highly Oxygenated Sesquiterpenes2.1.2 Syntheses of (±)-Gnididione and (±)-Isognididione2.1.3 Synthesis of (±)-Stemoamide2.1.4 Synthesis of (±)-Paniculide A2.1.5 Syntheses of (+)- and (–)-Norsecurinine2.1.6 Synthesis of Evodone2.1.7 Syntheses of (±)-Ligularone and (±)-Petasalbine2.1.8 Syntheses of Imerubrine, Isoimerubrine, and Grandirubrine2.1.9 Syntheses of Furanosteroids2.1.10 Syntheses of Substituted Indolines and Tetrahydroquinolines2.2 IMDAO Approaches to Pyridines: the Kondrat’eva Reaction2.2.1 Syntheses of Suaveoline and Norsuaveoline2.2.2 Synthesis of Eupolauramine2.2.3 Syntheses of (–)-Plectrodorine and (+)-Oxerine2.2.4 Synthesis of Amphimedine2.2.5 Synthetic Approach to the Western Segment of Haplophytine2.2.6 Synthesis of Marinoquinoline A2.2.6.1 IMDAO Approach to Marinoquinoline A2.2.6.2 Scope of Allenyl IMDAO Cycloaddition2.3 Lewis Acid Catalysis in IMDAO Reactions2.3.1 Effects of Europium Catalysts on IMDAO Reactions2.3.2 Effects of Copper Catalysts on IMDAO Reactions3 Imidazoles4 Thiazoles4.1 Syntheses of Menthane and Eremophilane4.2 Further Comments on the Intramolecular Cycloadditions of Thiocarbonyl Ylides5 Conclusions and Outlook

Versatile approaches to a library of building blocks based on 5-acylthiazole skeleton

Thiazole derivatives represent an important class of azole heterocycles with a broad spectrum of biological activity and, therefore, the synthesis of these compounds is of remarkable concern. We present here practical and reliable protocol for synthesis of some 5-acylthiazoles and demonstrate their utility in the preparation of several new series of thiazole-containing building blocks through transformation of 5-acyl function. Specifically, thiazole-based alcohols, oximes, primary, and secondary amines were successively synthesized in good to excellent yields. The chemical structures of obtained compounds were confirmed by 1H and 13C NMR-spectroscopy, elemental analysis, and mass-spectrometry.

A Heterotrimeric Dehydrogenase Complex Functions with 2 Distinct YcaO Proteins to Install 5 Azole Heterocycles into 35-Membered Sulfomycin Thiopeptides.

Sulfomycins are sulfur-rich, ribosomally synthesized, and post-translationally modified peptides (RiPPs) that are characterized by a 35-membered macrocyclic ring system with a pyridine domain central to five azoles and additional dehydroamino acids. The pathway through which these large thiopeptide antibiotics are formed in Streptomyces viridochromogene remains elusive. Starting with the cloning of the biosynthetic gene cluster of sulfomycins, we here dissect a two-stage process in which an unusual dehydrogenase heterotrimer functions with two distinct YcaO proteins to installfive azole heterocycles into the core peptide sequence of the precursor peptide. The first stage involves the activity of a typical cyclodehydratase complex composed of a didomain E1-YcaO protein and an F-protein partner to heterocyclize distant residues l-Cys2 and l-Thr9 and then the activity of the heterotrimeric dehydrogenase complex that converts the resulting azolines to azoles. In the second stage, this dehydrogenase complex associates with a discrete YcaO protein to form an atypical, four-component azole synthase complex, which is capable of sequentially converting residues l-Cys7, l-Thr5, and l-Ser12 to azoles in a distinct manner. During this process, an E1-like partner protein plays a critical role and functions through the two stages to mediate a variety of specific protein-protein interactions. This partner protein participates in the formation of the active dehydrogenase heterotrimer and the engagement of discrete YcaO activity to form the azole synthase heterotetramer. The findings in this study advance the understanding in the biosynthesis of different azole-containing RiPPs and set the stage for the discovery, engineering, and creation of new thiopeptides using genome mining and synthetic biology approaches.

Synthesis and Plant Growth Stimulating Action of 2-Amino-6-methylpyrimidine-4(3H)-thione Derivatives

A series of new pyrimidine derivatives, including those containing an azole or azine heterocycle linked through a sulfur atom or a thiomethylene group, was synthesized based on 2-amino-6-methylpyrimidine-4(3H)-thione. The synthesized compounds exhibited a pronounced stimulating effect on plants growth in the range of 43–96% compared to heteroauxin.

Heterocycle amide isosteres: An approach to overcoming resistance for HIV-1 integrase strand transfer inhibitors

A series of heterocyclic pyrimidinedione-based HIV-1 integrase inhibitors was prepared and screened for activity against purified integrase enzyme and/or viruses modified with the following mutations within integrase: Q148R, Q148H/G140S and N155H. These are mutations that result in resistance to the first generation integrase inhibitors raltegravir and elvitegravir. Based on consideration of drug-target interactions, an approach was undertaken to replace the amide moiety of the first generation pyrimidinedione inhibitor with azole heterocycles that could retain potency against these key resistance mutations. An imidazole moiety was found to be the optimal amide substitute and the observed activity was rationalized with the use of calculated properties and modeling. Rat pharmacokinetic (PK) studies of the lead imidazole compounds demonstrated moderate clearance and moderate exposure.

Oxidation of imidazole- and pyrazole-derived aldehydes by plant aldehyde dehydrogenases from the family 2 and 10

Plant cytosolic aldehyde dehydrogenases from family 2 (ALDH2s, EC 1.2.1.3) are non-specific enzymes and participate for example in the metabolism of acetaldehyde or biosynthesis of phenylpropanoids. Plant aminoaldehyde dehydrogenases (AMADHs, ALDH10 family, EC 1.2.1.19) are broadly specific and play an important role in polyamine degradation or production of osmoprotectants. We have tested imidazole and pyrazole carbaldehydes and their alkyl-, allyl-, benzyl-, phenyl-, pyrimidinyl- or thienyl-derivatives as possible substrates of plant ALDH2 and ALDH10 enzymes. Imidazole represents a building block of histidine, histamine as well as certain alkaloids. It also appears in synthetic pharmaceuticals such as imidazole antifungals. Biological compounds containing pyrazole are rare (e.g. pyrazole-1-alanine and pyrazofurin antibiotics) but the ring is often found as a constituent of many synthetic drugs and pesticides. The aim was to evaluate whether aldehyde compounds based on azole heterocycles are oxidized by the enzymes, which would further support their expected role as detoxifying aldehyde scavengers. The analyzed imidazole and pyrazole carbaldehydes were only slowly converted by ALDH10s but well oxidized by cytosolic maize ALDH2 isoforms (particularly by ALDH2C1). In the latter case, the respective Km values were in the range of 10–2000 μmol l−1; the kcat values appeared mostly between 0.1 and 1.0 s−1. The carbaldehyde group at the position 4 of imidazole was oxidized faster than that at the position 2. Such a difference was not observed for pyrazole carbaldehydes. Aldehydes with an aromatic substituent on their heterocyclic ring were oxidized faster than those with an aliphatic substituent. The most efficient of the tested substrates were comparable to benzaldehyde and p-anisaldehyde known as the best aromatic aldehyde substrates of plant cytosolic ALDH2s in vitro.

Architecture of Microcin B17 Synthetase: An Octameric Protein Complex Converting a Ribosomally Synthesized Peptide into a DNA Gyrase Poison

SummaryThe introduction of azole heterocycles into a peptide backbone is the principal step in the biosynthesis of numerous compounds with therapeutic potential. One of them is microcin B17, a bacterial topoisomerase inhibitor whose activity depends on the conversion of selected serine and cysteine residues of the precursor peptide to oxazoles and thiazoles by the McbBCD synthetase complex. Crystal structures of McbBCD reveal an octameric B4C2D2 complex with two bound substrate peptides. Each McbB dimer clamps the N-terminal recognition sequence, while the C-terminal heterocycle of the modified peptide is trapped in the active site of McbC. The McbD and McbC active sites are distant from each other, which necessitates alternate shuttling of the peptide substrate between them, while remaining tethered to the McbB dimer. An atomic-level view of the azole synthetase is a starting point for deeper understanding and control of biosynthesis of a large group of ribosomally synthesized natural products.

Regioselective Synthesis of Fluorosulfonyl 1,2,3-Triazoles from Bromovinylsulfonyl Fluoride.

A regioselective metal-free preparation of 4-fluorosulfonyl 1,2,3-triazoles from organic azides and a hitherto underexplored bromovinylsulfonyl fluoride building block is described. This reaction is very general and was extended to the synthesis of various sulfonates, sulfonamides, and sulfonic acid derivatives of triazoles and other azole heterocycles which would otherwise be difficult to access by existing methods.

Biosynthesis of Translation Inhibitor Klebsazolicin Proceeds through Heterocyclization and N-Terminal Amidine Formation Catalyzed by a Single YcaO Enzyme.

Klebsazolicin (KLB) is a recently discovered Klebsiella pneumonia peptide antibiotic targeting the exit tunnel of bacterial ribosome. KLB contains an N-terminal amidine ring and four azole heterocycles installed into a ribosomally synthesized precursor by dedicated maturation machinery. Using an in vitro system for KLB production, we show that the YcaO-domain KlpD maturation enzyme is a bifunctional cyclodehydratase required for the formation of both the core heterocycles and the N-terminal amidine ring. We further demonstrate that the amidine ring is formed concomitantly with proteolytic cleavage of azole-containing pro-KLB by a cellular protease TldD/E. Members of the YcaO family are diverse enzymes known to activate peptide carbonyls during natural product biosynthesis leading to the formation of azoline, macroamidine, and thioamide moieties. The ability of KlpD to simultaneously perform two distinct types of modifications is unprecedented for known YcaO proteins. The versatility of KlpD opens up possibilities for rational introduction of modifications into various peptide backbones.

3,5-[5-Arylisoxazol-3-yl(4,5-dichloroisothiazol-3-yl)]-substituted 1,2,4- and 1,3,4-oxadiazoles: synthesis, palladium complexes, and catalysis of Suzuki reactions in aqueous media

A reaction sequence involving transformations of 5-(4-methylphenyl)isoxazole and 4,5-dichloroisothiazole derivatives containing an amidoxime group at position 3 allowed to synthesize the respective 3,5-isoxazolyl(isothiazolyl)-substituted 1,2,4-oxadiazoles. Selective recyclization of 4,5-dichloro-3-(1Н-tetrazol-5-yl)isothiazole and 5-(4-methylphenyl)-3-(1Н-tetrazol-5-yl)isoxazole gave 2,5-isoxazolyl-(isothiazolyl)-substituted 1,3,4-oxadiazoles. The obtained compounds combining three azole heterocycles in one molecule formed palladium complexes that showed high catalytic activity in Suzuki reactions in aqueous and aqueous alcohol media. The bimetallic reusable Pd/Fe catalyst obtained from palladium polyazole complex retained high catalytic activity after five uses.

Pd-Catalyzed Hydroamination of Alkoxyallenes with Azole Heterocycles: Examples and Mechanistic Proposal.

Palladium-catalyzed regio- and enantioselective addition of azole heterocycles to alkoxyallenes was developed (up to 92% yields and up to 94% ee). DFT calculations suggest a new Pd(0)-driven mechanistic pathway proceeding through protonation of the Pd-coordinated allene (4-PdL2), which develops a strongly nucleophilic character at the central C atom.

Concise routes to fused azole heterocycles and their application in the synthesis of potential drug candidates

Concise routes to fused azole heterocycles and their application in the synthesis of potential drug candidates

Biological properties of novel ruthenium- and osmium-nitrosyl complexes with azole heterocycles.

Since the discovery that nitric oxide (NO) is a physiologically relevant molecule, there has been great interest in the use of metal nitrosyl compounds as antitumor pharmaceuticals. Particularly interesting are those complexes which can deliver NO to biological targets. Ruthenium- and osmium-based compounds offer lower toxicity compared to other metals and show different mechanisms of action as well as different spectra of activity compared to platinum-based drugs. Novel ruthenium- and osmium-nitrosyl complexes with azole heterocycles were studied to elucidate their cytotoxicity and possible interactions with DNA. Apoptosis induction, changes of mitochondrial transmembrane potential and possible formation of reactive oxygen species were investigated as indicators of NO-mediated damage by flow cytometry. Results suggest that ruthenium- and osmium-nitrosyl complexes with the general formula (indazolium)[cis/trans-MCl4(NO)(1H-indazole)] have pronounced cytotoxic potency in cancer cell lines. Especially the more potent ruthenium complexes strongly induce apoptosis associated with depolarization of mitochondrial membranes, and elevated reactive oxygen species levels. Furthermore, a slight yet not unequivocal trend to accumulation of intracellular cyclic guanosine monophosphate attributable to NO-mediated effects was observed.Electronic supplementary materialThe online version of this article (doi:10.1007/s00775-016-1345-z) contains supplementary material, which is available to authorized users.

Ruthenium Carbonyl Complexes with Azole Heterocycles – Synthesis, X‐ray Diffraction Structures, DFT Calculations, Solution Behavior, and Antiproliferative Activity

The reactions of (H2azole)[trans-RuCl4(Hazole)2] [Hazole = 1H-pyrazole (Hpz), 1H-indazole (Hind), 1-methylindazole (1-Me-ind), or 1H-benzimidazole (Hbzim)] with 1:1 mixtures of 12 M HCl and formic acid resulted in the formation of trans-[RuCl4(CO)(Hazole)]– complexes, which were isolated and identified by X-ray diffraction as nBu4N[trans-RuCl4(CO)(Hpz)] (1a), nBu4N[trans-RuCl4(CO)(Hind)] (2a), [(Hind)2H][trans-RuCl4(CO)(Hind)] (2b), nBu4N[trans-RuCl4(CO)(1-Me-ind)] (3a), and nBu4N[trans-RuCl4(CO)(Hbzim)] (6a), whereas a prolonged reaction with 1H-benzimidazole afforded (nBu4N)2[trans-RuCl5(CO)] (7a). The reactions of [(DMSO)2H][trans-RuCl4(CO)(DMSO)] with different azole heterocycles in dichloromethane afforded five similar complexes, which were isolated as azolium salts (H2azole)[trans-RuCl4(CO)(Hazole)] [Hazole = 1H-indazole (2), 1-methylindazole (3), 2-methylindazole (4), 1H-imidazole (5), and 1H-benzimidazole (6)]. Complexes 2–6 were characterized by elemental analysis, high-resolution electrospray ionization (ESI) mass spectrometry, UV/Vis spectroscopy, and IR spectroscopy, and 3 was also characterized by X-ray diffraction. The pH of the solution was crucial for the stability of the obtained compound series. The interactions of 2–4 with the model proteins myoglobin and ubiquitin and the influence of the indazole tautomer identity on those processes were investigated by high-resolution mass spectrometry. The ruthenium(III) complexes interact with the proteins to form protein–RuII(CO) adducts, that is, metal reduction appears to be responsible for the release of the azole heterocycle but not CO. Moreover, the binding of the RuII(CO) unit to myoglobin reduces the observed global charge state of the adduct with respect to that of free myoglobin, which suggests that the Ru(CO) fragment can cross-link the protein backbone. Complexes 2–6 show low antiproliferative activity against the human cancer cell lines HeLa and MDA-MB-231 and the noncancerous cell line MRC-5, and this activity correlates with the low stability of complexes in aqueous media, especially at neutral or basic pH. The results are compared to previously reported data on ruthenium nitrosyl analogues and KP1019.