Five-membered Heterocycles Research Articles

Diverse Pharmacological Potential of different Substituted Pyrazole Derivatives.

The chemistry of heterocyclic compounds has been a topic of research interest. Some five-membered heterocyclic compounds have been the subject of extensive research due to their different types of pharmacological effects. The five-membered nitrogen-containing heterocyclic compounds pyrazole, pyrazoline, and pyrazolone derivatives have a lot of interest in the fields of medical and agricultural chemistry due to their diverse spectrum of therapeutic activities. Various substituted pyrazole, pyrazoline, and pyrazolone compounds exhibited diverse pharmacological effects like Anti-microbial, anti-inflammatory, anti-tubercular, anti-fungal, anti-malarial, anti-diabetic, diuretic, anti-depressant, anticonvulsant, antioxidant, anti-leishmanial, antidiabetic, and antiviral, etc. In recent decades, the synthesis of numerous pyrazole, pyrazoline, and pyrazolone derivatives by different synthetic methods as well as research into their chemical and biological behavior have become more important. This review focuses on synthetic methods of the pyrazole, pyrazoline, and pyrazolone derivatives, which have significant biological properties and a variety of applications.

1,3,4-Oxadiazole Scaffold in Antidiabetic Drug Discovery: An Overview.

Diabetes mellitus is one of the biggest challenges for the scientific community in the 21st century. With the increasing number of cases of diabetes and drug-resistant diabetes, there is an urgent need to develop new potent molecules capable of combating this cruel disease. Medicinal chemistry concerns the discovery, development, identification, and interpretation of the mode of action of biologically active compounds at the molecular level. Oxadiazole-based derivatives have come up as a potential option for antidiabetic drug research. Oxadiazole is a five-membered heterocyclic organic compound containing two nitrogen atoms and one oxygen atom in its ring. Oxadiazole hybrids have shown the ability to improve glucose tolerance, enhance insulin sensitivity, and reduce fasting blood glucose levels. The mechanisms underlying the antidiabetic effects of oxadiazole involve the modulation of molecular targets such as peroxisome proliferator-activated receptor gamma (PPARγ), α-glucosidase, α-amylase and GSK-3β which regulate glucose metabolism and insulin secretion. The present review article describes the chemical structure and properties of oxadiazoles and highlights the antidiabetic activity through action on different targets. The SAR for the oxadiazole hybrids has been discussed in this article, which will pave the way for the design and development of new 1,3,4-oxadiazole derivatives as promising antidiabetic agents in the future. We expect that this article will provide comprehensive knowledge and current innovation on oxadiazole derivatives with antidiabetic potential and will fulfil the needs of the scientific community in designing and developing efficacious antidiabetic agents.

Quantum chemical calculations and molecular docking studies of 5-amino-3-(2,5-dimethoxyphenyl)-1-isonicotinoyl-2,3-dihydro-1H-pyrazole-4-carbonitrile

Abstract The five-membered heterocycle pyrazole has two nitrogen atoms next to each other. Natural items and pharmaceuticals using pyrazole as the nucleus have demonstrated a wide range of biological activity. Medications with pyrazole cores may have better pharmacokinetics and pharmacological effects than medicines with similar heterocyclic rings. This is because the pyrazole core has unique physicochemical properties. In this study, 5-amino-3-(2,5-dimethoxyphenyl)-1-isonicotinoyl-2,3-dihydro-1H-pyrazole-4-carbonitrile is synthesized and characterized by means of spectrum and quantum chemical techniques. Using UV–vis absorption technique, Fourier transform infrared (FT-IR), and Fourier transform Raman (FT-Raman) techniques, the spectroscopic properties were examined. There were two regions visible in the experimental Raman as well as infrared spectra: 4,000–400 cm−1 along with 4,000–100 cm−1. The ideal molecular shape, vibrational frequencies, infrared intensity levels, and scattering from Raman were all assessed using density functional theory. The 13C (carbon) and 1H (proton) chemical shifts of the molecule were determined using nuclear magnetic resonance (NMR). The TD-DFT scheme was utilized to figure out speculative ultraviolet values and compare them to oscillator strength, electron excitation energies, and spectrum data from experiments. It is evident from the predicted HOMO-LUMO band separation energies that the transmission of charge takes place within a molecule’s structure. The chemical reactivity of the molecule has been calculated along with other global descriptive properties. Scientists investigated how charges move and the density of electrons inside a molecule using NBO analysis of the chemical they were studying. After examining the molecular electrostatic potential (MEP), a 3D picture was created that shows the compound’s nucleophilic and electrophilic areas. In addition to meeting all pertinent pharmacokinetic requirements, 5-amino-3-(2,5-dimethoxyphenyl)-1-isonicotinoyl-2,3-dihydro-1H-pyrazole-4-carbonitrile is also readily absorbed by the gastrointestinal system. Additionally, the chemical that was synthesized had a positive interaction with the target proteins of treatments for viruses, asthma, and heart failure, as shown by molecular docking.

Syn-Propanethial S-Oxide as an Available Natural Building Block for the Preparation of Nitro-Functionalized, Sulfur-Containing Five-Membered Heterocycles: An MEDT Study.

The regio- and stereoselectivity and the molecular mechanisms of the [3 + 2] cycloaddition reactions between Syn-propanethial S-oxide and selected conjugated nitroalkenes were explored theoretically in the framework of the Molecular Electron Density Theory. It was found that cycloadditions with the participation of nitroethene as well as its methyl- and chloro-substituted analogs can be realized via a single-step mechanism. On the other hand, [3 + 2] cycloaddition reactions between Syn-propanethial S-oxide and 1,1-dinitroethene can proceed according to a stepwise mechanism with a zwitterionic intermediate. Finally, we evaluated the affinity of model reaction products for several target proteins: cytochrome P450 14α-sterol demethylase CYP51 (RSCB Database PDB ID: 1EA1), metalloproteinase gelatinase B (MMP-9; PDB ID: 4XCT), and the inhibitors of cyclooxygenase COX-1 (PDB:3KK6) and COX-2 (PDB:5KIR).

Synthesis of Isoxazol-5-One Derivatives Catalyzed by Amine-Functionalized Cellulose

In this contribution, propylamine-functionalized cellulose (Cell-Pr-NH2) was employed as the catalyst in the three-component reaction between hydroxylamine hydrochloride and various types of aryl/heteroaryl aldehydes, ethyl acetoacetate/ethyl 4-chloroacetoacetate, or ethyl 3-oxohexanoate. The result of these experiments was the formation of 3,4-disubstituted isoxazol-5(4H)-one heterocycles. The desired five-membered heterocyclic compounds were obtained in good to high yields at room temperature. The investigation of different solvents led us to the conclusion that water is the best solvent to perform the current one-pot, three-component reactions. Attempts to find the optimal catalyst loading clearly showed that 14 mg of cell-Pr-NH2 seems to be sufficient to carry out the reactions. This method has highlighted some principles of green chemistry including less waste generation, atom economy, use of water as an environmentally friendly solvent, and energy saving. Purification without chromatographic methods, mild reaction conditions, simple work-up, low-cost reaction medium, saving time, and obtainable precursors are other notable features of this one-pot fashion.

Novel Organosulfur Building Blocks for Heterocycle Synthesis

AbstractThe present article provides a personalized account of our recent work on the synthesis of substituted and fused five-membered heterocycles using various organosulfur building blocks, derived primarily through base-mediated condensation of active methylene compounds with (het)aryl/alkyl dithioesters, which have not been previously explored. We initially describe the ring-opening transformations of 4-[(methylthio)-(het)aryl-methylene]-2-phenyl-5-oxazolones, leading to the synthesis of functionalized oxazoles, thiazoles, and bisoxazoles. We then go on to focus on the synthesis of substituted benzothiophenes, indoles, and benzofurans, as well as their hetero-fused analogs. These compounds are synthesized via transition-metal-catalyzed intramolecular C–heteroatom (C–S, C–N, C–O) bond formation (via cross-coupling or C–H bond functionalization) of various reactive organosulfur intermediates, derived from base-mediated condensation of 2-bromo(het)arylacetonitriles, acetates, or desoxybenzoins or the corresponding 2-unsubstituted precursors. Finally, we highlight the synthetic applications of a new class of previously unexplored organosulfur building blocks, namely, unsymmetrically substituted 1,3-bis(het)aryl-1,3-monothioketones, derived via base-mediated condensation of ketones with (het)aryl/alkyl dithioesters, for the regioselective synthesis of substituted pyrazoles, isoxazoles, thiophenes, imidazoles, and benzothiophenes.1 Introduction2 4-[(Methylthio)-het(aryl)-methylene]-2-phenyl/2-(2-thienyl)-5-oxazolones: Versatile Templates for the Synthesis of Oxazoles, Thiazoles, and Bisoxazoles3 Synthesis of Benzothiophenes, Indoles, and Benzofurans via Transition-Metal-Catalyzed Intramolecular C–Heteroatom Bond Formation4 1,3-Bis(het)arylmonothio-1,3-diketones and 1,3-Bis(Het)aryl-3-(methylthio)-2-propenones: Versatile Intermediates for the Regioselective Synthesis of Five-Membered Heterocycles5 Conclusion

Mechanochemical Conditions for Intramolecular N-O Couplings via Rhodium Nitrenoids Generated from N-Acyl Sulfonimidamides.

Starting from N-acyl sulfonimidamides, mechanochemically generated rhodium nitrenoids undergo intramolecular N-O couplings to provide unprecedented 1,3,2,4-oxathiadiazole 3-oxides in good to excellent yields. The cyclization proceeds efficiently with a catalyst loading of only 0.5 mol% in the presence of phenyliodine(III) diacetate (PIDA) as oxidant. Neither an inert atmosphere nor additional heating is required in this solvent-free procedure. Under heat or blue light, the newly formed five-membered heterocycles function as nitrene precursors reacting with sulfoxides as exemplified by the imidation of dimethyl sulfoxide.

Synthesis, Absolute Configuration, Biological Profile and Antiproliferative Activity of New 3,5-Disubstituted Hydantoins.

Hydantoins, a class of five-membered heterocyclic compounds, exhibit diverse biological activities. The aim of this study was to synthesize and characterize a series of novel 3,5-disubstituted hydantoins and to investigate their antiproliferative activity against human cancer cell lines. The new hydantoin derivatives 5a-i were prepared as racemic mixtures of syn- and anti-isomers via a base-assisted intramolecular amidolysis of C-3 functionalized β-lactams. The enantiomers of syn-5a and anti-hydantoins 5b were separated by preparative high-performance liquid chromatography (HPLC) using n-hexane/2-propanol (90/10, v/v) as the mobile phase. The absolute configuration of the four allyl hydantoin enantiomers 5a was assigned based on a comparison of the experimental electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectra with those calculated using density functional theory (DFT). The antiproliferative activity evaluated in vitro against three different human cancer cell lines: HepG2 (liver hepatocellular carcinoma), A2780 (ovarian carcinoma), and MCF7 (breast adenocarcinoma), and on the non-tumor cell line HFF1 (normal human foreskin fibroblasts) using the MTT cell proliferation assay. In silico drug-like properties and ADMET profiles were estimated using the ADMET Predictor ver. 9.5 and the online server admetSAR. Eighteen new 3,5-disubstituted hydantoins were synthesized and characterized. The compound anti-5c showed potent cytotoxic activity against the human tumor cell line MCF7 (IC50 = 4.5 µmol/L) and the non-tumor cell line HFF1 (IC50 = 12.0 µmol/L). In silico analyzes revealed that the compounds exhibited moderate water solubility and membrane permeability and are likely substrates for CYP3A4 and P-glycoprotein and have a high probability of antiarthritic activity.

In-depth quantitative and theoretical study of ambident electrophilies of 2-bromo-3-X-5-nitrothiophenes

As part of our continuing studies into the electron deficient nature of five-membered ring heterocycles, specifically 2‑methoxy-3-X-5-nitrothiophenes and 3-X-5-nitrothiophene, we report here a kinetic study of σ-complexation reactions involving 2‑bromo-3,5-dinitrothiophene 1 and various nitroalkyl anions in aqueous solution at 20 °C. Theoretical calculations at the density functional theory (DFT) level were performed to confirm the proposed mechanism. From the previously reported nucleophilicity parameters N and sN for the nucleophiles 2 and the derived second-order rate constants, the electrophilicity parameter (E) at the C-4 position of thiophene 1 was quantified according to the linear free enthalpy relationship log k (20 °C) = sN (E + N). Mayr's approach accurately predicted the rate constants for the reactions of this thiophene 1 with a series of para-substituted phenoxide anions in water at 20 °C. A reasonable correlation between calculated global electrophilicity index ω values and experimental electrophilic reactivities was observed and discussed.

1,3,4-Oxadiazole and Its Analogs: Recently Adopted Synthetic Approaches and Interaction with Targets

: 1,3,4-Oxadiazole is a five-membered heterocyclic compound with one oxygen, two nitrogen, and two carbon atoms arranged in a ring. Several research reports, patents, and marketed drugs have already established 1,3,4-oxadiazole and its analog as potential molecules having a diverse range of pharmacological activities. In this review, we focused on recently acknowledged straightforward synthesis approaches for 1,3,4-oxadiazole and its analogs. Additionally, interactions of the 1,3,4-oxadiazole derivative with different biological targets (enzymes and receptors) have been described. The present findings discussed in this review analysis will aid researchers in conducting future research on 1,3,4-oxadiazole.

The synthesis of salts of five-membered heterocyclic compounds based on N-containing cations/anions (microreview)

The synthesis of salts of five-membered heterocyclic compounds based on N-containing cations/anions (microreview)

An Insight into Rational Drug Design: The Development of In-House Azole Compounds with Antimicrobial Activity.

Antimicrobial resistance poses a major threat to global health as the number of efficient antimicrobials decreases and the number of resistant pathogens rises. Our research group has been actively involved in the design of novel antimicrobial drugs. The blueprints of these compounds were azolic heterocycles, particularly thiazole. Starting with oxadiazolines, our research group explored, one by one, the other five-membered heterocycles, developing more or less potent compounds. An overview of this research activity conducted by our research group allowed us to observe an evolution in the methodology used (from inhibition zone diameters to minimal inhibitory concentrations and antibiofilm potential determination) correlated with the design of azole compounds based on results obtained from molecular modeling. The purpose of this review is to present the development of in-house azole compounds with antimicrobial activity, designed over the years by this research group from the departments of Pharmaceutical and Therapeutical Chemistry in Cluj-Napoca.

Azopyridinium Ionic Photoswitches: Tuning Half-Lives of Z Isomers from Seconds to Days in Water.

Herein, we describe water-soluble heteroaryl azopyridinium ionic photoswitches (HAPIPs). We aim to combine variations in five-membered heterocycles, their substitutions, N-alkyl groups at pyridinium nitrogen, the position of pyridinium center relative to azo group, counterions, and solvents, in achieving better photoswitching. Through these studies, we successfully tuned the half-life of Z isomers of the resultant HAPIPs between seconds to days in water. Extensive spectroscopic studies and density functional theory (DFT) computations unravelled the factors responsible for thermal relaxation behavior. Considering the versatility of these photoswitches, the tunability of half-lives and photoswitching in aqueous medium allows the scope of applications in several fields.

Wide-ranging Study on Synthesis and Biological Evaluation of 1, 2, 3-triazole

Abstract: 1, 2, 3-Traizole is five-membered heterocyclic compounds having three nitrogen at 1, 2 and 3 positions. 1, 2, 3-Triazoles are important five-membered heterocyclic scaffolds due to their widespread biological activities. 1, 2, 3-Triazole derivative can be readily obtained in good to excellent yields through click chemistry, 1, 3-dipolar cycloaddition, Metal Catalysed azide-alyne cycloaddition method. 1, 2, 3-Triazoles showed various biological activities, such as antiinflammatory, anticonvulsant, antineoplastic, antimicrobial, analgesic, antimalarial, antiviral, antiproliferative, and anticancer activities. The objective of this review is to synthesize pharmacological activity of 1,2,3-triazole derivatives documented in recent literature.

Rational Design of Fluorophores Using MO Theory: Our Journey from BODIPYs to BOIMPYs

This short review demonstrates how MO-theoretical considerations can support the tailor-made design of new dye scaffolds, specifically the recently introduced BOIMPY class of fluorophores. Starting with historical and structural foundations, the influence of canonical streptocyanines on the electronic features of diarylmethenes and rhodamines is examined and the BODIPY scaffold is introduced as the primary structural inspiration for our work. The attachment of five-membered ring heterocycles at the meso position of the BODIPY core enables a relaxation into a co-planar and twofold chelating triarylmethene system. After introduction of two electron-withdrawing BF2 units, efficient rigidity is achieved since hindered rotation prevents non-radiative dissipation of energy via excited state relaxation. Hence, a lowered LUMO level allows the combination of a large red shift with high quantum efficiencies. The synthetic approach to BOIMPYs is straightforward and analogous to BODIPY syntheses starting from benzimidazole or tetrazole carbaldehydes. Cyclic voltammetric measurements prove that BOIMPYs are able to easily accept two electrons and might act as efficient photoredox catalysts.

A Phosphanyl Phosphagermene and its Reactivity.

Reaction of a nucleophilic germylene Ge[CH(SiMe3)2]2 with the phosphanyl phosphaketene [{(H2C)(NDipp)}2P]PCO induces decarbonylation to form a phosphanyl phosphagermene [{(H2C)(NDipp)}2P]P=Ge[CH(SiMe3)2]2 (1; Dipp=2,6-diisopropyl-phenyl). Addition of CO2 or MeCN to 1 results in [3+2]-cycloaddition reactions to afford five-membered heterocycles. This mode of reactivity is reminiscent of that observed for frustrated Lewis pairs, with the pendant phosphanyl group acting as a base and the germanium center as a Lewis acid. Contrastingly, 1,2-addition across the P=Ge bond was observed when using ammonia, small primary amines (NH2 nP), or metal complexes (e. g. Au(PPh3)Cl and ZnEt2). These latter reactions allow for the one-step synthesis of metal phosphide complexes.

The retention features of nitrogen-containing heterocyclic compounds in reversed-phase and hydrophilic HPLC-MS modes

Aromatic five- and six-membered nitrogen-containing heterocyclic compounds are biologically active substances and are widely used in biochemistry and medicine. In addition, such compounds are known as ecotoxicants formed during oxidation processes in industrial wastewater. High-performance liquid chromatography-mass spectrometry is widely used to determine nitrogen-containing heterocycles in various complex mixtures. Octadecyl silica gel is the main sorbent for chromatographic separation. However, octadecyl silica gel does not always enable satisfactory separation in the presence of highly polar isomeric molecules, and more selective chromatographic approaches are required. One of these is hydrophilic chromatography, which facilitates the separation of polar compounds. The aim of the study was to comparatively characterize the retention of a number of five- and six-membered nitrogen-containing heterocyclic compounds during reversed-phase and hydrophilic liquid chromatography with mass spectrometric detection. In addition, spectrophotometric detection at a wavelength of 210 nm was carried out. In the study, we used sorbents based on octadecyl silica gel and unmodified silica gel. High-resolution mass spectrometry was used in the electrospray ionization mode. We studied 19 nitrogen-containing heterocyclic compounds. We used aqueous acetonitrile mobile phases with added aqueous solutions of formic acid and diethylamine as acid-base modifiers. An ammonium formate solution was used as a modifier during hydrophilic chromatography. Reversed-phase chromatography showed that the introduction of 0.1% aqueous formic acid solution increased the ionization and the mass spectrometer signal intensity, but did not always result in a satisfactory separation of isomers upon elution from the octadecyl silica gel surface. The introduction of 0.01% diethylamine solution provided no significant improvement in the separation compared to the mobile phase without modifiers. The use of unmodified silica gel in hydrophilic chromatography mode allowed us to separate isomeric five-membered heterocycles, which was demonstrated by narrow symmetric peaks, but did not result in selective separation of isomeric diazines. Thus, we studied the retention of 19 nitrogen-containing heterocyclic compounds using reversed-phase and hydrophilic liquid chromatography with electrospray ionisation. It was determined that hydrophilic chromatography on unmodified silica gel could be used for satisfactory separation of isomeric five-membered heterocyclic compounds of different classes. For six-membered heterocycles, satisfactory separation was achieved by elution from the surface of octadecyl silica gel using aqueous acetonitrile mobile phase without modifiers.

Synthesis and reactivity of an N-heterocyclic carbene-stabilized diazoborane.

Diazo compounds and organic azides are widely used as reagents for accessing valuable molecules in multiple areas of fundamental and applied chemistry. Their capacity to undergo versatile chemical transformations arises from the reactive nature of an incipient dinitrogen molecule at the terminal position. In this work, we report the synthesis and characterization of an N-heterocyclic carbene (NHC)-stabilized diazoborane-a boron-centered analog of organic azides and diazoalkanes. The diazoborane displays a strong tendency to release dinitrogen, thus serving as a borylene source, in analogy to organic azides and diazoalkanes serving as nitrene and carbene sources, respectively. Also reminiscent of diazoalkane and organic azide reactivity, the diazoborane serves as a 1,3-dipole that undergoes uncatalyzed [3+2] cycloaddition with an unactivated terminal alkyne, affording a five-membered heterocycle after a two-step rearrangement.

Green Synthesis of Thiazoles and Thiadiazoles Having Anticancer Activities under Microwave Irradiation

Abstract: Sulfur and nitrogen-containing heterocycles have received a great deal of attention due to their unique structures and therapeutic relevance. Thiazoles and thiadiazoles are important five-membered heterocycles containing sulfur and nitrogen atoms that draw the special attention of re-searchers due to their synthetic diversity and potent pharmacological properties. Thiazoles and thi-adiazoles are used in agrochemicals, liquid crystals, sensors, the cosmetic industry, cyanine dyes, etc. Sometimes, organic synthesis, including thiazoles and thiadiazoles syntheses with the help of conventional methods, is laborious work, while synthesis of promising organic molecules using microwave irradiation provides better yields, diminishes the reaction time, and reduces unwanted side products. The major causes of death worldwide are due to cancer. Current research demands the design and preparation of novel compounds, including thiazoles and thiadiazoles, that may help to combat cancer, as chemotherapy or chemo drugs suffer from some demerits, including toxicity, lack of selectivity, resistance, and side effects. Hence, the review focuses on the microwave-assisted synthesis of thiazoles and thiadiazoles as a sustainable technique for the first time, and it also aims to highlight the anticancer activities of thiazoles and thiadiazole derivatives elegantly.

Insight into the Synthesis, Biological Activity, and Structure-activity Relationship of 1,2,4-Oxadiazole and Analogs: A Comprehensive Review

Abstract: A five-membered heterocyclic compound known as 1,2,4-oxadiazole has one oxygen, two carbon, and two nitrogen atoms within a ring. Numerous studies have shown that 1,2,4-oxadiazole has the potential to be an essential moiety in many harmful pharmacological conditions. 1,2,4-oxadiazole and its derivatives have been used as an antiviral, cough suppressant, vasodilator, anxiolytic, etc. To synthesize a single molecule with potent pharmacological action, two or more pharmacophores are combined currently. This enhances pharmacological effects, facilitates interaction possible with many targets, and reduces the adverse effects related to them. It has been reported that synthesis of 1,2,4-oxadiazole and its analog is possible using a variety of methods. In this present review, we emphasized recently accepted synthetic methods for 1,2,4-oxadiazole and its analogs synthesis. Additionally, the structure-activity relationship concerning several pharmacological effects, interactions with various targets, and the utility of different techniques for the analysis and purification has been described. On the behalf of the above study, the researchers can use this review study to better understand their 1,2,4-oxadiazole research in the future.