Related Heterocyclic Systems Research Articles

Resolution of Expanded Porphyrinoids: A Path to Persistent Chirality and Appealing Chiroptical Properties.

Chirality is a fundamental characteristic of nature. Expanded porphyrinoids and their analogues offer an attractive platform for delving into the intricacies of chirality. Expanded porphyrinoids comprise pyrrolic macrocycles and related heterocyclic systems. As a class, expanded porphyrinoids are widely recognized for their flexible structural features, nontrivial coordination capabilities, and intriguing optical and electronic properties. With limited exceptions, their inherent conformational flexibility coupled with a low racemization barrier allows for the facile interchange between enantiomers. As a result, achieving the effective chiral resolution of individual enantiomers and the subsequent exploration of their chiroptical properties represents a significant challenge. This review summarizes strategies used to realize the chiral resolution of expanded porphyrinoids and the understanding of intrinsic chiroptical properties that has emerged from these separation efforts. It is our hope that this review will serve not only to codify our current understanding of chiral expanded porphyrinoids, but also inspire advances in the generalized area of chiral functional materials.

Thiazole and Related Heterocyclic Systems as Anticancer Agents: A Review on Synthetic Strategies, Mechanisms of Action and SAR Studies.

Cancer is the second leading cause of death worldwide. Many anticancer drugs are commercially available, but lack of selectivity, target specificity, cytotoxicity, and development of resistance lead to serious side effects. Several experiments have been going on to develop compounds with minor or no side effects. This review mainly emphasizes synthetic strategies, SAR studies, and mechanism of action if thiazole, benzothiazole, and imidazothiazole-containing compounds as anticancer agents. Recent literature related to thiazole and thiazole-related derivatives endowed with encouraging anticancer potential is reviewed. This review emphasizes contemporary strategies used for the synthesis of thiazole and related derivatives, mechanistic targets, and comprehensive structural activity relationship studies to provide perspective into the rational design of high-efficiency thiazole-based anticancer drug candidates. Exhaustive literature survey indicated that thiazole derivatives are associated with properties of inducing apoptosis and disturbing tubulin assembly. Thiazoles are also associated with the inhibition of NFkB/mTOR/PI3K/AkT and regulation of estrogenmediated activity. Furthermore, thiazole derivatives have been found to modulate critical targets, such as topoisomerase and HDAC. Thiazole derivatives seem to be quite competent and act through various mechanisms. Some of the thiazole derivatives, such as compounds 29, 40, 62, and 74a with IC50 values of 0.05 μM, 0.00042 μM, 0.18 μM, and 0.67 μM, respectively, not only exhibit anticancer activity, but they also have lower toxicity and better absorption. Therefore, some other similar compounds could be investigated to aid in the development of anticancer pharmacophores.

In silico screening of drug-like molecules for the treatment of cardiovascular diseases on the basis of five-membered privileged heterocycles

Among various heterocyclic systems, the derivatives of five-membered heterocycles are of special interest. Most of the above mentioned heterocycles are treatred as so-called privileged structures in modern medicinal chemistry. In silico screening among five-membered heterocycles of molecules for the treatment of cardiovascular diseases is actual.
 The aim of the work was the search for synthetic drug-like molecules based on functionalized five-membered heterocycles and related heterocyclic systems as an element of the theoretical platform for rational design of compounds acting on the cardiovascular system, and prediction of their possible mechanism of action.
 The objects of the study were derivatives of uncondensed and condensed five-membered heterocycles. In the work, in silico approaches were applied using the programs: Hyper-Chem, PASS, AutoDock, PROTOX.
 Based on the previous studies, focused sub-libraries of small synthetic drug-like molecules based on functionalized five-membered heterocycles and related heterocyclic systems have been selected. The compounds were divided on 12 groups. The optimization of the compound structures, the drug-like parameters calculation were carried out. The activity prediction, the acute toxicity level and docking studies to probable bio-targets which are related with cardiovascular drug mechanism of action have been carried out. It was shown that thiazole and thiadiazole based compounds possessed the highest calculated affinity levels to selected bio-targets. This is consistent with PASS-based prediction data.
 Diverse functionalized derivatives of five-membered heterocycles (thiazole, thiazolidine, thiadiazole, pyrazole, thiophene, triazole) and related fused heterocycles have been grouped in focused sub-libraries of compounds. it has been established that thiazole and thiadiazole based compounds are promising objects for directed synthesis and further modification as potential cardiovascular agents based on the prediction of biological activity, the calculation of affinity to potent bio-targets, and the prediction of the drug-like features and acute toxicity level. The prognostic values of the parameters of the above mentioned groups of compounds may be used as the element of theoretical platform for the search and de novo design of potential drugs for the treatment of cardiovascular diseases.

Thioether-Directed Selective C4 C-H Alkenylation of Indoles under Rhodium Catalysis.

A thioether-directed Rh(III)-catalyzed C4 selective C-H alkenylation of indoles via the formation of 5-membered metallacycle intermediates is reported. This protocol allows a wide functional group compatibility and broad substrate scope. The directing group can be readily removed or transformed into other functional groups after the C-H functionalization event. The catalytic method is also applicable to related heterocyclic systems involving benzo[ b]thiophene and benzo[ b]furan scaffolds.

Minimizing CYP2C9 Inhibition of Exposed-Pyridine NAMPT (Nicotinamide Phosphoribosyltransferase) Inhibitors.

NAMPT inhibitors may show potential as therapeutics for oncology. Throughout our NAMPT inhibitor program, we found that exposed pyridines or related heterocyclic systems in the left-hand portion of the inhibitors are necessary pharmacophores for potent cellular NAMPT inhibition. However, when combined with a benzyl group in the center of the inhibitors, such pyridine-like moieties also led to consistent and potent inhibition of CYP2C9. In an attempt to reduce CYP2C9 inhibition, a parallel synthesis approach was used to identify central benzyl group replacements with increased Fsp3. A spirocyclic central motif was thus discovered that was combined with left-hand pyridines (or pyridine-like systems) to provide cellularly potent NAMPT inhibitors with minimal CYP2C9 inhibition. Further optimization of potency and ADME properties led to the discovery of compound 68, a highly potent NAMPT inhibitor with outstanding efficacy in a mouse tumor xenograft model and lacking measurable CYP2C9 inhibition at the concentrations tested.

SYNTHESIS OF PHENANTHRIDINONE DERIVATIVES BY DIRECT ARYLATION. CHARACTERIZATION OF THE ABSORPTION AND EMISSION SPECTRA FOR REPRESENTATIVE EXAMPLES

The phenanthridinone heterocyclic system has attracted considerable attention in recent years due to the diverse array of physical, chemical and pharmacological properties demonstrated by natural and synthetic derivatives. As a consequence there has been considerable development of synthetic methodology for the synthesis of this and related heterocyclic ring systems. The synthetic literature is discussed and is compared with a direct arylation methodology for the intramolecular cyclization of tertiary (2-iodo)benzoylamides to generate the biaryl bond of these compounds. The efficient methodology allowed the synthesis of a number of previously unknown phenanthridinone products. The photoluminescent properties of representative examples were characterized and it is proposed that the previously unknown compound 1s reveals dual fluorescence in a manner similar to the known compound 1r.

A Further Decrease in the Catalyst Loading for the Palladium‐Catalyzed Direct Intramolecular Arylation of Amides and Sulfonamides

AbstractThe direct arylation of N‐substituted o‐bromobenzanilides and benzenesulfonamides via CH bond functionalization has been developed using very low catalyst loadings. This novel cost‐effective and more sustainable method relies on a PCN‐type palladium pincer complex as a highly active palladium source, providing a general and efficient access to phenanthridinones, biaryl sultams and related heterocyclic systems. The beneficial effect of water as cosolvent has been observed in this process, which is not seriously influenced by electronic effects at the arene moieties or sterically demanding substituents at the amide or sulfonamide nitrogen. In addition, a number of experiments (kinetic plot, poisoning assays, TEM, ESI) have been performed in order to understand the role of the employed palladium complex in this reaction.magnified image

ChemInform Abstract: Synthesis of Pyrido[2′,3′: 3,4]pyrazolo[1,5‐a]pyrimidine, Pyrido[2′,3′:3,4]pyrazolo[5,1‐c][1,2,4]triazine, and Pyrazolyl Oxadiazolylthieno[2,3‐b]pyridine Derivatives.

AbstractConvenient methods for the synthesis of the title heterocycles and related heterocyclic systems starting from aminopyrazolopyridine and ‐thienopyridine derivatives, resp., are given.

Synthesis and Heteroannulation of Pyridine and Related Heterocyclic Systems Having Surface and Biological Activities.

Possible approaches to the synthesis of functionalized, pyrazole, isoxazole, pyrimidine, pyridine and fused pyridine derivatives The sequence involves the heterocyclization of ethyl 3-oxo-2-(4-stearamidobenzoyl)butanoate (3) with appropriate reagents. Propoxylated of these heterocycles using propylene oxide to produce nonionic surface active agents having a long alkyl chain with molecular weight suitable for becoming an amphiphilic molecule with correct hydrophilic-lypophilic balance which enhances solubility, biodegradability and hence lowers the toxicity to human beings and becomes environmentally friendly. The antimicrobial activity of the newly synthesized was examined and it was found that some of these compounds have similar or higher activity compared with commercial antibiotic drugs (sulphadiazine), which make them suitable for diverse applications like the manufacturing of drugs, pesticides, emulsifiers, cosmetics, etc.

Imidazothiazole and related heterocyclic systems. Synthesis, chemical and biological properties.

Fused heterobicyclic systems have gained much importance in the field of medicinal chemistry because of their broad spectrum of physiological activities. Among the heterocyclic rings containing bridgehead nitrogen atom, imidazothiazoles derivatives are especially attractive because of their different biological activities. Since many imidazothiazoles derivatives are effective for treating several diseases, is interesting to analyze the behavior of some isosteric related heterocycles, such as pirrolothiazoles, imidazothiadiazoles and imidazotriazoles. In this context, this review summarizes the current knowledge about the syntheses and biological behavior of these families of heterocycles. Traditional synthetic methodologies as well as alternative synthetic procedures are described. Among these last methodologies, the use of multicomponent reaction, novel and efficient coupling reagents, and environmental friendly strategies, like microwave assistance and solvent-free condition in ionic liquids are also summarized. This review includes the biological assessments, docking research and studies of mechanism of action performed in order to obtain the compounds leading to the development of new drugs.

ChemInform Abstract: Ruthenium‐Catalyzed Carbonylation of ortho C—H Bonds in Arylacetamides: C—H Bond Activation Utilizing a Bidentate‐Chelation System.

AbstractThe presence of a 2‐pyridylmethylamine moiety (Pym) as a bidentate directing group is essential for successful carbonylation of the substrates to produce isoquinoline diones and related heterocyclic systems.

PdII-Catalyzed Di-o-olefination of Carbazoles Directed by the Protecting N-(2-Pyridyl)sulfonyl Group

Despite the significance of carbazole in pharmacy and material science, examples of the direct C-H functionalization of this privileged unit are quite rare. The N-(2-pyridyl)sulfonyl group enables the Pd(II)-catalyzed ortho-olefination of carbazoles and related systems, acting as both a directing and readily removable protecting group. This method features ample structural versatility, affording typically the double ortho-olefination products (at C1 and C8) in satisfactory yields and complete regiocontrol. The application of this procedure to related heterocyclic systems, such as indoline, is also described.

ChemInform Abstract: Microwave‐Assisted One‐Pot Synthesis of Isoquinolines, Furopyridines, and Thienopyridines by Palladium‐Catalyzed Sequential Coupling—Imination—Annulation of 2‐Bromoarylaldehydes with Terminal Acetylenes and Ammonium Acetate.

AbstractA wide range of isoquinolines and related heterocyclic systems can be prepared starting from aldehyde substrates.

A Modular Synthesis of Polysubstituted Indolizines

AbstractThe N‐alkylation of pyridines with cyanohydrin triflates or α‐halonitriles furnishes 1‐(1‐cyanoalkyl)pyridinium salts that can react with nitroolefins under basic conditions to furnish polysubstituted indolizines. Overall, the indolizine core can be constructed from a pyridine, two aldehydes, and a nitroalkane, and no undesired functional groups remain in the products. When bromoacetonitrile was used for the N‐alkylation, indolizine‐3‐carbonitriles were obtained instead. The pyridine component may be replaced by other azines, giving rise to related heterocyclic systems.

Benzobistriazinones and related heterocyclic ring systems as potent, orally bioavailable positive allosteric AMPA receptor modulators

AMPA receptors (AMPARs) are an important therapeutic target in the CNS. A series of substituted benzobistriazinone, benzobispyrimidinone and related derivatives have been prepared with high potency and selectivity for the allosteric binding site of AMPARs. Further improvements have been made to previously reported series of positive AMPAR modulators and these compounds exhibit excellent in vivo activity and improved in vivo metabolic stability with up to 100% oral bioavailability in rat.

Preparation and Reactions of 2‐Methyl‐7‐(3‐methyl‐5‐oxo‐1‐phenyl‐2‐pyrazolin‐4‐yl)‐5‐arylthiazolo[3,2‐a]‐pyrimido[4,5‐d]oxazin‐4(5H)‐one

AbstractEthyl 7‐amino‐3‐(3‐methyl‐5‐oxo‐1‐phenyl‐2‐pyrazolin‐4‐yl)‐5‐aryl‐5H‐thiazolo[3,2‐a]pyrimidine‐6‐carboxylate was hydrolyzed with an ethanolic sodium hydroxide and the sodium salt thus formed underwent cyclization with acetic anhydride to afford 2‐methyl‐7‐(3‐methyl‐5‐oxo‐1‐phenyl‐2‐pyrazolin‐4‐yl)‐5‐arylthiazolo[3,2‐a]pyrimido[4,5‐d]oxazin‐4(5H)‐one. This compound was transformed to related heterocyclic systems via its reaction with various reagents. The biological activity of the prepared compounds was tested against Gram positive and Gram negative bacteria as well as yeast‐like and filamentous fungi. They revealed in some cases excellent biocidal properties.

Thiazolidinone motif in anticancer drug discovery. Experience of DH LNMU medicinal chemistry scientific group

Keywords: synthesis, 4-thia(imida)zolidinones, thiopyrano[2,3-d]thiazoles, anticancer activity, (Q)SAR

Manganese(III)-promoted reactions for formation of carbon–heteroatom bonds

Manganese(III) reagent is an important one- electron oxidant for initiation of free-radical reactions and formation of carbon-carbon bonds. The reactions are usually carried out under mild conditions, have high regio- and stereo-selectivities, and good functional group tolerance. Summarized in this article are the developments of manganese (III)-based reactions for the formation of carbon-heteroatom bonds including carbon-oxygen, carbon-phosphorus, carbon-sulfur, and carbon-nitrogen bonds, and their applications for the synthesis of related heterocyclic systems.

ChemInform Abstract: A Facile Synthesis and Heteroannulation of Thiazolopyrimidine and Related Heterocyclic Systems.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A facile synthesis and heteroannulation of thiazolopyrimidine and related heterocyclic systems

Abstractmagnified imageReaction of pyrimidinylacetic acid 2 with different electrophilic and nucleophilic reagents gave annulated pyrimidine derivatives 3‐11, respectively. Compound 3 was transformed to pyrimidinylacetyl azide 12, which upon heterocyclization with active methylene compounds, acidic and basic reagents furnished functionally substituted heteroaromatic compounds 13‐21, respectively. The antimicrobial activity of some synthesized compounds was investigated. The structures of the synthesized derivatives were elucidated by elemental and spectral analyses.