Heterocyclic Libraries Research Articles

Comprehensive screening of heterocyclic compound libraries to identify novel inhibitors for PfRIO-2 kinase through docking and substrate competition studies

Malaria is most prevalent in tropical climate and causes 1–3 million deaths annually. RIO-2 kinase, an atypical kinase regulates ribosome biogenesis and is necessary for cell cycle progression. Structural characterization of PFD0975w (PfRIO-2 kinase) indicates N-terminal DNA binding winged helix domain (1–84), a linker region (85–147), and C-terminal kinase domain (148–275). Heterocyclic compounds present in different databases represent an enormous reservoir to screen and develop the suitable inhibitor. An extensive screening of heterocyclic compounds present in zinc database, PubChem and ChemBank database was done to identify potent PfRIO-2 kinase specific inhibitors. Initial screening gave 41 compounds with high affinity toward PfRIO-2 kinase than natural substrate ATP. A substrate competition experiment and analysis of binding mode conformation within the ATP binding pocket identifies five compounds; Zc-49775260, Pc-44415375, Pc-44215930, Cb-2082655, and Cb-832054 as potential PfRIO-2 kinase inhibitors. Further analysis of top hits in ADMET parameters, Caco-2 cell permeability profile, human oral absorption, and drug-like properties indicates Pc-44215930 as the best suitable compound among the top hits. Searching top hits candidate heterocyclic compounds in the drug database picked up clindamycin, nelfinavir, methacycline, and other drugs in circulation. Most of these drugs are targeting ribosome maturation and highlights the possibility of PfRIO-2 kinase as a drug target. Hence, screening and substrate competition studies along with ADME analysis of top hit compounds allowed us to identify potential PfRIO-2 kinase inhibitors. We are hopeful that the current study will help to develop effective chemotherapy against malaria utilizing PfRIO-2 kinase as a target.

Rapid Access to Compound Libraries through Flow Technology: Fully Automated Synthesis of a 3-Aminoindolizine Library via Orthogonal Diversification

A novel methodology for the synthesis of druglike heterocycle libraries has been developed through the use of flow reactor technology. The strategy employs orthogonal modification of a heterocyclic core, which is generated in situ, and was used to construct both a 25-membered library of druglike 3-aminoindolizines, and selected examples of a 100-member virtual library. This general protocol allows a broad range of acylation, alkylation and sulfonamidation reactions to be performed in conjunction with a tandem Sonogashira coupling/cycloisomerization sequence. All three synthetic steps were conducted under full automation in the flow reactor, with no handling or isolation of intermediates, to afford the desired products in good yields. This fully automated, multistep flow approach opens the way to highly efficient generation of druglike heterocyclic systems as part of a lead discovery strategy or within a lead optimization program.

ChemInform Abstract: Iodocyclization, Followed by Palladium‐Catalyzed Coupling. A Versatile Strategy for Heterocyclic Library Construction

AbstractReview: 83 refs.

Assembly of Four Diverse Heterocyclic Libraries Enabled by Prins Cyclization, Au-Catalyzed Enyne Cycloisomerization, and Automated Amide Synthesis

We describe a unified synthetic strategy for efficient assembly of four new heterocyclic libraries. The synthesis began by creating a range of structurally diverse pyrrolidinones or piperidinones. Such compounds were obtained in a simple one-flask operation starting with readily available amines, ketoesters, and unsaturated anhydrides. The use of tetrahydropyran-containing ketoesters, which were rapidly assembled by our Prins cyclization protocol, enabled efficient fusion of pyran and piperidinone cores. A newly developed Au(I)-catalyzed cycloisomerization of alkyne-containing enamides further expanded heterocyclic diversity by providing rapid entry into a wide range of bicyclic and tricyclic dienamides. The final stage of the process entailed diversification of each of the initially produced carboxylic acids using a fully automated platform for amide synthesis, which delivered 1872 compounds in high diastereomeric and chemical purity.

Functionalized Orthoesters as Powerful Building Blocks for the Efficient Preparation of Heteroaromatic Bicycles

By combining substituted anilines with functionalized orthoesters, an efficient and connective methodology for the preparation of benzoxazole, benzothiazole, and benzimidazole derivatives has been established. The versatility of this approach enables the development of new libraries of heterocycles containing multifunctional sites.

Phosphomolybdic Acid (H3Mo12O40P) as a Reusable Heterogeneous Catalyst for the Synthesis of 5-Substituted 1H-Tetrazoles via [2 + 3] Cycloaddition of Nitriles and Sodium Azide

An efficient and practical protocol for the preparation of 5-substituted 1H-tetrazole derivatives is reported using phosphomolybdic acid as an effective heterogeneous catalyst. Good yields, simple methodology, and easy workup make this protocol more attractive for the diversity-oriented synthesis of these heterocycle libraries. The catalyst can be recycled three times with good yields.

Iodocyclization, Followed by Palladium-Catalyzed Coupling: A Versatile Strategy for Heterocyclic Library Construction

The iodocyclization of functionally-substituted alkynes provides an excellent way to prepare a wide range of iodoheterocycles, which can then be readily elaborated through palladium-catalyzed Suzuki-Miyaura, Sonogashira, Heck, Hartwig-Buchwald, and carbonylation processes into libraries of medicinally relevant heterocycles. The synthesis of libraries of indoles, benzofurans, benzothiophenes, isocoumarins and pyrones, cyclic imidates, isoxazoles, furans using this approach is reviewed. This technology is very versatile, proceeds under mild reaction conditions in high yields, and tolerates considerable functionality.

Switching between ring closed and open N-incorporated heterocycles with tuneable charges and modular reactivity based upon 5-(2-bromoethyl)phenanthridinium bromide

5-(2-bromoethyl)phenanthridinium bromide (BEP) undergoes a 3-step-one-pot cyclisation reaction with primary amines allowing the facile synthesis of a vast library of heterocycles. A diverse range of primary aryl amines were explored as reactants to gain insight into the product isolated as a result of the steric and electronic effects of the aryl precursors. Analysis and reaction monitoring with UV-vis and NMR spectroscopy revealed that excessively electron withdrawing groups and sterically hindered amines do not allow for isolation of the common neutral tetrahydroimidazophenanthridine (TIP) structure but allow either the isolation of the charged dihydroimadazophenanthridinium (DIP) or aminoethylphenanthridinium (AEP) products.

Novel Chiral Skeletons for Drug Discovery: Antibacterial Tetramic Acids

Modification of the ring nucleus of tetramic acids derived from serine gives chiral heterocyclic libraries that exhibit antibacterial activity, and correlation with various physicochemical parameters indicates that chiral tetramic acids may provide a potentially valuable non-aromatic skeleton for fragment-based drug discovery.

Pyrrolo[3,2-e][1,4]diazepin-2-one Synthesis: A Head-to-Head Comparison of Soluble versus Insoluble Supports

Aryldiazepin-2-ones are known as "privileged structures", because they bind to multiple receptor types with high affinity. Toward the development of a novel class of aryldiazepin-2-one scaffolds, the synthesis of pyrrolo[3,2-e][1,4]diazepin-2-ones on a support was explored starting from N-(PhF)-4-hydroxyproline and featuring an acid-catalyzed Pictet-Spengler reaction to form the diazepine ring. Three supports [Wang resin, tetraarylphosphonium (TAP) soluble support, and Merrifield resin] were examined in the synthesis of the heterocycle and exhibited different advantages and disadvantages. Wang resin proved effective for exploratory optimization of the synthesis by identification of intermediates after resin cleavage under mild conditions; however, the acidic conditions of the Pictet-Spengler reaction caused premature loss of resin-bound material. Direct monitoring of reactions by TLC, RP-HPLC-MS, and in certain cases NMR spectroscopy was possible with the TAP support, which facilitated purification of intermediates by precipitation; however, incomplete precipitation of material led to overall yields lower than those from solid-phase approaches on resin. Merrifield resin proved stable to the conditions for the synthesis of the pyrrolo[3,2-e][1,4]diazepin-2-one targets and would be amenable to "split-and-mix" chemistry; however, relatively harsh conditions were necessary for final product cleavage. Perspective for the application of different solid-phase approaches in heterocycle library synthesis was thus obtained by demonstration of the respective utility of the three supports for preparation of pyrrolo[3,2-e][1,4]diazepin-2-one.

One-Pot Synthesis of Five and Six Membered N, O, S-Heterocycles Using a Ditribromide Reagent

In a one-pot procedure, bromine less brominating reagent 1,1'-(ethane-1,2-diyl)dipyridinium bistribromide (EDPBT) has been utilized as an efficient desulfurizing agent for the construction of a library of heterocycles containing N, O, and S starting from aryl/alkyl isothiocyanates. In this approach, aryl/alkyl isothiocyanate reacts with o-phenylenediamine (o-PD), o-aminophenol, and o-aminothiophenol to form their monothiourea which on desulfurization with EDPBT led to the formation of corresponding 2-aminobenzimidazoles, 2-aminobenzoxazoles, and 2-aminobenzothiazoles, respectively. An interesting regioselectivity was observed for unsymmetrical thiourea having a naphthyl moiety on the one side and an ortho amino or an ortho hydroxy phenyl group on the other side giving a completely different product which is mainly dependent on the nature of the nucleophiles (-OH or -NH(2)). Further, the bis-thioureas resulted from the aliphatic 1,2-diamine with 2 equiv of aryl isothiocyanates on treatment with EDPBT gave imidazolidenecarbothioamides, whereas bis-thioureas resulted from aromatic 1,2-diamine yielded benzimidazoles with concurrent expulsion of an isothiocyanate unit. This method is simple and applied to various substrates which are amenable to bromination that reveals the desulfurizing ability of EDPBT predominating over its brominating ability. Finally, the spent reagent EDPDB can be recovered, regenerated, and reused without any loss of activity.

Synthesis of a high-purity chemical library reveals a potent inducer of oxidative stress.

Synthesis of high-purity biogenic heterocyclic library enabled identification of a small molecule, which potently inhibited proliferation of several cancer cell lines and induces rapid oxidative stress. This agent elicited unusual mechanism of cell death induction, which entailed activation of both caspase-dependent and independent pathways.

Enriching chemical space with diversity-oriented synthesis: parallel synthesis of low molecular weight acyclic and heterocyclic compounds from resin-bound polyamides

Diversity-Oriented Synthesis (DOS), also known as combinatorial synthesis, is a process, by which multiple compounds are generated simultaneously, in a predictable fashion using techniques that involve parallel chemical transformations. Through diversity-oriented synthesis organic chemists are now able to achieve more structural complexity than in the early days of combinatorial chemistry. Combinatorial chemistry techniques offer unique enhancement in the potential identification of new and/or therapeutic candidates. Over the past fifteen years in the design and diversity oriented synthesis of low molecular weight acyclic and heterocyclic combinatorial libraries derived from amino acids, peptides and/or peptidomimetics are described. Employing a “toolbox” of various chemical transformations, the “libraries from libraries” concept has enabled the continued development of an ever-expanding, structurally varied, series of organic chemical libraries.

Synthesis of heterocycles via alkoxyallenes

Lithiated alkoxyallenes are very versatile components for the synthesis of heterocycles such as furans, pyrroles, and 1,2-oxazines, easily allowing the preparation of natural products via these heterocyclic intermediates. A surprising three-component synthesis of N-acylated enaminones allowed the synthesis of highly functionalized 4-hydroxypyridines, 5-acetyloxazoles, and pyrimidines. All these heterocyclic products are ready for further functionalizations, in particular for palladium-catalyzed reactions, leading to libraries of new interesting heterocycles.

Abstract 3219: Heterocyclic cations: Highlighting the importance of selectivity in biologically relevant quadruplex DNA recognition and binding

Abstract Small molecules that target G-quadruplex DNA structures represent a potential approach for anticancer drug development. Stabilization of G-quadruplex structures leads to the inhibition of the telomerase enzyme that is overexpressed in the tumor cells resulting in an exciting new anticancer receptor. The purpose of this study is to explore conformational space in a series of heterocyclic cations in order to discover novel structural motifs that can selectively bind and stabilize specific G-quadruplex structures such as those present in oncogene promoters. As target DNA sequences we selected the human telomere and the oncogene promoter c myc, which can fold into specific quadruplex arrangements. The compounds investigated, characterized by a curved shape motif, were selected from a preliminary study between linear, partially curved and highly curved heterocyclic compound libraries. Their DNA recognition properties have been investigated by biophysical experiments. Affinity was evaluated by thermal melting experiments, biosensor surface plasmon resonance, circular dichroism, fluorescence displacement assay and mass spectrometry methods. Biological studies as TRAP assay, inhibition of Taq polymerase enzyme and cytotoxicity on two series of cancer cells were also performed to complement the biophysical data. From our results, compounds with a large number of rings show an impressive selectivity for the G-quadruplex folded c myc oncogene promoter in comparison to the human telomere and to the double helix model systems. The results suggest also a novel binding mechanism which involves the grooves of the folded quadruplex structures. Most of the compounds that have been found to effectively target G-quadruplexes show aromatic arrays that resemble the planar guanine tetrads so “end-stacking” to the G-quartet is the traditionally considered binding mode for this type of ligand. The quadruplex grooves represent attractive targets as they are different from the duplex grooves, and because their dimensions can also vary according to the type of quadruplex sequence. We use these results to explain how the novel class of compounds here presented is able to drive the selectivity not only over duplex but also through different quadruplex conformations. The importance of selectivity and of the evaluation of ligands towards biological relevant sequences is a major issue to be considered in drug design to avoid the important problem of nonspecific cytotoxicity. These results can be useful for the development of new efficient and selective telomerase inhibitors, endowed with pharmacological activity. Acknowledgements: This work was supported by University of Padova (Italy) and NIH grant AI064200 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3219.

Multi‐Step Synthesis by Using Modular Flow Reactors: The Preparation of YneOnes and Their Use in Heterocycle Synthesis

Multi-step in flow: The palladium-catalysed acylation of terminal alkynes for the synthesis of yneones as well as their further transformation to various heterocycles in a continuous-flow mode is presented. Furthermore, an extension of the simple flow configuration that allows for easy batch splitting and the generation of a heterocyclic library is described (see scheme).

Diversity-oriented synthesis of benzimidazole, benzoxazole, benzothiazole and quinazolin-4(3H)-one libraries via potassium persulfate–CuSO4-mediated oxidative coupling reactions of aldehydes in aqueous micelles

Libraries of 2-substituted-benzimidazoles, benzoxazoles, benzothiazoles as well as quinazolin-4(3H)-ones were synthesized via potassium persulfate-CuSO(4)-mediated oxidative coupling of aldehydes with o-phenylenediamines, o-aminophenols, o-aminothiophenols, and anthranilamide, respectively, in aqueous micelles. The strategy opens a way for rapid generation of libraries of small heterocycles for biological screening. The reagent is commercially available, cheap, and highly chemoselective. The yields were superior in aqueous micelles to those in organic solvents. Short reaction times, large-scale synthesis, excellent chemoselectivity, excellent yields, as well as environmental friendliness are the main advantages of this diversity-oriented synthesis.

Heteroaromatic Rings of the Future

Small aromatic ring systems are of central importance in the development of novel synthetic protein ligands. Here we generate a complete list of 24,847 such ring systems. We call this list and associated annotations VEHICLe, which stands for virtual exploratory heterocyclic library. Searches of literature and compound databases, using this list as substructure queries, identified only 1701 as synthesized. Using a carefully validated machine learning approach, we were able to estimate that the number of unpublished, but synthetically tractable, VEHICLe rings could be over 3000. However, analysis also shows that the rate of publication of novel examples to be as low as 5-10 per year. With this work, we aim to provide fresh stimulus to creative organic chemists by highlighting a small set of apparently simple ring systems that are predicted to be tractable but are, to the best of our knowledge, unconquered.

Microwave-Assisted Parallel Synthesis of Fused Heterocycles in a Novel Parallel Multimode Reactor

New rotor types using disposable glass vials for small-scale parallel synthesis in multimode microwave reactors are introduced. One rotor comprises 16 groups of four vials, whereas the second uses four silicon carbide plates with a 6 x 4 matrix to process the vials. Both rotors achieve utmost temperature homogeneity upon microwave irradiation and can be used for microwave-mediated reactions at temperatures of up to 200 degrees C and pressures of 20 bar. The generation of three different heterocycle libraries furnishing thiophenes, oxindoles, and benzimidazoles using the new rotor types is described.

1,3-Dipolar Cycloadditions of Acetylenic Sulfones in Solution and on Solid Supports

Several representative acetylenic sulfones were immobilized on a polymer support derived from Merrifield resin by means of ester linkers that were used to couple free carboxylic acid groups on the solid support with benzylic hydroxyl functions on the arylsulfonyl moieties of the acetylenes. Several examples of reversed ester linkers, using Merrifield resin directly, were also successfully prepared. The 1,3-dipolar cycloadditions of the solid-supported acetylenic sulfones were investigated with a series of 1,3-dipoles, including benzyl azide, ethyl diazoacetate, diazomethane, as well as representative nitrile oxides, nitrile imines, nitrile ylides, nitrones, azomethine imines, azomethine ylides, munchnones, and sydnones. In general, analogous cycloadditions were also performed with acetylenic sulfones in solution phase for comparison. The cycloadditions typically afforded good to excellent yields of the desired products in both solution and solid phase, although the latter reactions sometimes required more vigorous conditions. Except in the case of benzyl azide and diazo compounds, where mixtures of regioisomers were obtained, the other 1,3-dipoles reacted with high regioselectivity and afforded essentially unique regioisomers. Cleavage of the products from the resin was smoothly effected by alkaline hydrolysis, while several attempts at reductive desulfonylation with sodium amalgam or samarium diiodide-HMPA resulted in N-O or C-O scission, in addition to cleavage from the polymer. The method provides access to a number of important classes of heterocycles, including variously substituted and functionalized triazoles, pyrazoles, 1,2-oxazoles, pyrroles, as well as their dihydro and bicyclic analogues. The success of the cycloadditions on polymer supports paves the way to future investigations of sequential transformations leading to libraries of useful heterocycles.