Five-membered Heterocycles Research Articles

Time and Atom Economical Regio- and Chemoselective Radical Cyclization of Unactivated 1,6-Enynes Under Metal- and Oxidant-Free Conditions.

We developed time-atom economic regio- and chemoselective sulfonyl radical triggered 5-exo-dig cyclization of unactivated 1,6-enynes with sulfonyl halides under metal, additive-free reaction conditions to achieve highly substituted five-membered heterocyclic compounds. This transformation creates three new bonds, such as C-SO2 , C-C, and active C-I/Br bonds. Importantly, one-pot protocols produce desired products directly from sodium sulfinates and have an additional advantage such as minimising chemical waste, saving time, and simplifying practical aspects compared to existing protocols.

Regio- and stereoselectivity of the 1,3-dipolar cycloaddition of azomethine ylides to (E)-3-(2-oxo-2-(pyren-1-yl)ethylidene)indolin-2-ones: A combined experimental and theoretical study

Functionalized oxindoles and pyrrolizidines form the central structural framework for numerous natural products with extensive biological and pharmacological applications. The requirement for high regio- and stereoselectivity is the main obstacle in the synthesis of such five-membered heterocycles. Multicomponent cycloaddition reactions often provide an efficient and straightforward approach for the preparation of specific regio- and stereoisomers. In this article, the regio- and stereochemistry of the polar [3 + 2]-cycloaddition (32CA) reaction of azomethine ylides prepared by the reaction of isatin derivatives and L-proline with a series of ( E )-3-(2-oxo-2-(pyren-1-yl)ethylidene)indolin-2-ones was investigated by experimental and theoretical methods. Among the isatin and ( E )-3-(2-oxo-2-(pyren-1-yl)ethylidene)indolin-2-one derivatives, a remarkable inversion of regioselectivity was observed in the 32CA reaction of azomethine ylide generated by the reaction of L-proline and 5-chloroisatin or N -methyl-5-chloroisatin with ( E )-5-chloro-3-(2-oxo-2-(pyren-1-yl)ethylidene)indolin-2-one. The regio- and stereochemical assignment of the structures of the cycloaddition products was determined by one- and two-dimensional (1D&2D) homonuclear and heteronuclear correlation nuclear magnetic resonance spectroscopy. The molecular mechanism as well as the regio- and stereoselectivity of the cycloaddition were investigated by means of global and local reactivity indices and a density functional theory (DFT) and explained in detail on the basis of the transition state stabilities of the reactants.

A quantum chemistry study on C–H homolytic bond dissociation enthalpies of five-membered and six-membered heterocyclic compounds

The C–H homolytic bond dissociation enthalpies (BDEs) of 27 heterocyclic compounds of small systems (less than 8 non-hydrogen atoms) were evaluated by the composite ab initio methods of G4 and CBS-Q. In addition, the C–H BDEs of an extended database including 60 heterocyclic compounds were assessed by 16 DFT functionals. The correlation between the theoretical and experimental values reveals that the BMK functional provided the lowest root mean square error (RMSE) of 10.2 kJ/mol, and the correlation coefficient (R2) was 0.955. The mean deviation (MD), mean absolute deviation (MAD) of BMK are 0.1 kJ/mol and 7.9 kJ/mol separately. Therefore, we utilized BMK to research C–H BDEs together with the substituent effects of five-membered and six-membered heterocyclic compounds including large systems. The nature of C–H BDE change pattern was analyzed by the natural bond orbital (NBO).

A Review of the Recent Development in the Synthesis and Biological Evaluations of Pyrazole Derivatives.

Pyrazoles are five-membered heterocyclic compounds that contain nitrogen. They are an important class of compounds for drug development; thus, they have attracted much attention. In the meantime, pyrazole derivatives have been synthesized as target structures and have demonstrated numerous biological activities such as antituberculosis, antimicrobial, antifungal, and anti-inflammatory. This review summarizes the results of published research on pyrazole derivatives synthesis and biological activities. The published research works on pyrazole derivatives synthesis and biological activities between January 2018 and December 2021 were retrieved from the Scopus database and reviewed accordingly.

Recent Developments in Oxazole Derivatives as Anticancer Agents: Review on Synthetic Strategies, Mechanism of Action and SAR Studies.

Cancer is the world's third deadliest disease. Despite the availability of numerous treatments, researchers are focusing on the development of new drugs with no resistance and toxicity issues. Many newly synthesized drugs fail to reach clinical trials due to poor pharmacokinetic properties. Therefore, there is an imperative requisite to expand novel anticancer agents with in vivo efficacy. This review emphasizes synthetic methods, contemporary strategies used for the inclusion of oxazole moiety, mechanistic targets, along with comprehensive structure-activity relationship studies to provide perspective into the rational design of highly efficient oxazole-based anticancer drugs. Literature related to oxazole derivatives engaged in cancer research is reviewed. This article gives a detailed account of synthetic strategies, targets of oxazole in cancer, including STAT3, Microtubules, G-quadruplex, DNA topoisomerases, DNA damage, protein kinases, miscellaneous targets, in vitro studies, and some SAR studies. Oxazole derivatives possess potent anticancer activity by inhibiting novel targets such as STAT3 and Gquadruplex. Oxazoles also inhibit tubulin protein to induce apoptosis in cancer cells. Some other targets such as DNA topoisomerase enzyme, protein kinases, and miscellaneous targets including Cdc25, mitochondrial enzymes, HDAC, LSD1, HPV E2 TAD, NQO1, Aromatase, BCl-6, Estrogen receptor, GRP-78, and Keap-Nrf2 pathway are inhibited by oxazole derivatives. Many derivatives showed excellent potencies on various cancer cell lines with IC50 values in nanomolar concentrations. Oxazole is a five-membered heterocycle, with oxygen and nitrogen at 1 and 3 positions, respectively. It is often combined with other pharmacophores in the expansion of novel anticancer drugs. In summary, oxazole is a promising entity to develop new anticancer drugs.

Biological activity of oxadiazole and thiadiazole derivatives.

The 5-membered oxadiazole and thiadiazole scaffolds are the most privileged and well-known heterocycles, being a common and essential feature of a variety of natural products and medicinal agents. These scaffolds take up the center position and are the core structural components of numerous drugs that belong to different categories. These include antimicrobial, anti-tubercular, anti-inflammatory, analgesic, antiepileptic, antiviral, and anticancer agents. In this review, we mostly talk about the isomers 1,2,4-oxadiazole and 1,3,4-thiadiazole because they have important pharmacological properties. This is partly because they are chemical and heat resistant, unlike other isomers, and they can be used as bio-isosteric replacements in drug design. We are reviewing the structural modifications of different oxadiazole and thiadiazole derivatives, more specifically, the anti-tubercular and anticancer pharmacological activities reported over the last 5 years, as we have undertaken this as a core area of research. This review article desires to do a thorough study and analysis of the recent progress made in the important biological isomers 1,2,4-oxadiazole and 1,3,4-thiadiazol. This will be a great place to start for future research.Key points • Five-membered heterocyclic compound chemistry and biological activity recent survey. • Synthesis and pharmacological evolution of 1,2,4-oxadiazole and 1,3,4-thiadiazole are discussed in detail. • The value and significance of heterocyclic compounds in the field of drug designing are highlighted. Supplementary InformationThe online version contains supplementary material available at 10.1007/s00253-022-11969-0.

Novel 1, 2, 4-Triazoles as Antifungal Agents.

The development of innovative antifungal agents is essential. Some fungicidal agents are no longer effective due to resistance development, various side effects, and high toxicity. Therefore, the synthesis and development of some new antifungal agents are necessary. 1,2,4-Triazole is one of the most essential pharmacophore systems between five-membered heterocycles. The structure-activity relationship (SAR) of this nitrogen-containing heterocyclic compound showed potential antifungal activity. The 1,2,4-triazole core is present as the nucleus in a variety of antifungal drug categories. The most potent and broad activity of triazoles have confirmed them as pharmacologically significant moieties. The goal of this review is to highlight recent developments in the synthesis and SAR study of 1,2,4-triazole as a potential fungicidal compound. In this study, we provide the results of a biological activity evaluation using various structures and figures. Literature investigation showed that 1, 2, 4-triazole derivatives reveal the extensive span of antifungal activity. This review will assist researchers in the development of new potential antifungal drug candidates with high effectiveness and selectivity.

Aspects of green chemistry toward synthesis of benzazoles and quinoxalines: Bovine serum albumin-water system for C–N/C–S bond formation

In this report, a biocatalytic divergent approach of therapeutically important five-membered benzazole heterocyclic compounds such as benzothiazoles and benzimidazoles has been described wherein Bovine serum albumin (BSA) and water play cooperative role for oxidative cyclo-condensation reaction between 2-mercapto/amino anilines and aromatic aldehydes under air at room temperature. Further, this green strategy also extended for the synthesis of privileged and biologically important six membered quinoxalines, 2-phenylimidazo [1,2-a]pyridine and benzo[d]imidazo[2,1-b]thiazoles. Moreover, the present biocatalytic protocol for the synthesis of such five- and six-membered heterocyclic compounds also have the added benefits of high atom economy, operational simplicity, excellent yields, recyclability (up to four cycles), and gram scalability.

Disparate effects of four anions on the non-radical oxidation process of sulfamethoxazole by peroxymonosulfate: kinetics, mechanism and toxicity variation

In the present work, the impact of four anions (Cl-, HCO3- CO32- and PO43-) on sulfamethoxazole (SMX) degradation during in suit chemical oxidation by peroxymonosulfate (PMS) was investigated. Results shows that the degradation of SMX follows a two-phase kinetic model (fast stage and slow stage), and the degradation efficiency is enhanced by the four anions. Based on transient species determination, theoretical calculation and intermediate identification, the fast stage for SMX degradation may be caused by direct oxidation of PMS, and the slow stage is involved with reaction with singlet oxygen and peroxoanion radical. The site reaction with peroxoanion radical is nitrogen-oxygen bond in five-membered heterocycles. Ecological risk of degradation products in the absence of four anions is higher than the parent compound, accompanying with Escherichia coli death cell increasing from 51.7% to 91.6%. In the presence of Cl-, the dead cell percentage further increases to 93.3% due to the generation of chlorinated derivatives. On the contrast, HCO3- CO32- and PO43- can alleviate the dead cell percentage to 26.4%, 24.4%, and 17.9%, respectively. These results suggest that the anion plays an important role in the degradation of organic pollutants by PMS technology.

Thiophene-containing compounds with antimicrobial activity.

Thiophene, as a member of the group of five-membered heterocycles containing one heteroatom, is one of the simplest heterocyclic systems. Many synthetic strategies allow the accurate positioning of various functionalities onto the thiophene ring. This review provides a comprehensive, systematic and detailed account of the developments in the field of antimicrobial compounds featuring at least one thiophene ring in their structure, over the last decade.

Thiophene Ring-opening Reactions III: One-Pot Synthesis and Antitumor Activity of 1,3,4-Thiadiazoline-Benzothiazolo[3,2-b]pyridazine Hybrids†.

The preparation of model 6-chloro-5-nitrothieno[2,3-c]pyridazines incorporating (2'-halo-5'-nitrophenyl) entity is described. Interaction of these substrates with N'-(aryl)benzothiohydrazides, in the presence of triethylamine, followed a formal [4+1] annulation, furnishing the respective 1,3,4-thiadiazoline-benzothiazolo [3,2-b]pyridazine hybrids directly. This one-pot synthesis implies thiophene ring-opening and two consecutive intramolecular cyclizations. The structures of the synthesized new hybrids are supported by MS, NMR, and IR spectral data and further confirmed by single-crystal X-ray diffraction. These hybrids exhibit antiproliferative activity with notable selectivity against solid tumor cell lines (IC50: 4-18 μM). This study aimed at exploring the scope and applicability of thiophene ring-opening reaction towards the synthesis of new thiadiazoline-[fused]tricyclic conjugates. α-Chloro-β-nitrothienopyridazine underwent ring-opening upon reacting with N'-(aryl)benzothiohydrazides generating 1,3,4-thiadiazoline-benzothiazolo[3,2-b]pyridazines. This new thiophene ring-opening reaction is applied to the one-pot synthesis of thiadiazoline-benzothiazolo[3,2-b]pyridazine couples. A direct interaction of α-chloro-β-nitrothienopyridazine with N'-(aryl)benzothio-hydrazide at room temperature for 1-2 h occurred. a-Chloro-β-nitrothieno[2,3-c]pyridazines are suitable substrates for the facile synthesis of thiadiazoline-benzothiazolo[3,2-b]pyridazine hybrids. This novel ring-opening reaction proceeds via formal [4+1] annulation and provides a versatile approach to various conjugated and/or fused five-membered heterocycles.

DFT insights into the adsorption mechanism of five-membered aromatic heterocycles containing N, O, or S on Fe(1 1 0) surface

Understanding the interaction of five-membered aromatic heterocycles with Fe(110) surface is crucial to the design of novel inhibitors against the corrosion of iron and steel. Herein, we report a detailed study of the adsorption properties and the bonding mechanism of pyrrole, furan, and thiophene on Fe(110) surface employing density functional theory (DFT) calculations. In the most stable adsorption geometries, the adsorbates lie flat at the hollow site and form covalent bonds with surface Fe atoms. The chemisorptions are demonstrated by large adsorption energies and charge transfers from Fe(110) to the adsorbates. Taking vdW corrections into account in the DFT calculations has a minimal effect on the adsorption geometries whereas it significantly increases the adsorption energies. The energetic and structural analysis demonstrates large molecular distortion induced by the adsorbate–surface interaction, and thiophene experiences the least molecular distortions, thereby having the largest adsorption energy among the adsorbates. The electronic structure analysis reveals that the electronic interactions of pyrrole, furan, and thiophene and Fe(110) are due to the overlaps of the frontier molecular orbitals with Fe-3dz2 and Fe-(3dxz + 3dyz) states. The charge transfer between the adsorbates and Fe(110) are elucidated by the charge density difference plot and Bader charge analysis.

Design, Synthesis, and Herbicidal Activity of Diphenyl Ether Derivatives Containing a Five-Membered Heterocycle.

Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) is an important target for discovering novel herbicides, and it causes bleaching symptoms by inhibiting the synthesis of chlorophyll and heme. In this study, the active fragments of several commercial herbicides were joined by substructure splicing and bioisosterism, and a series of novel diphenyl ether derivatives containing five-membered heterocycles were synthesized. The greenhouse herbicidal activity and the PPO inhibitory activity in vitro were discussed in detail. The results showed that most compounds had good PPO inhibitory activity, and target compounds containing trifluoromethyl groups tended to have higher activity. Among them, compound G4 showed the best inhibitory activity, with a half-maximal inhibitory concentration (IC50) of 0.0468 μmol/L, which was approximately 3 times better than that of oxyfluorfen (IC50 = 0.150 μmol/L). In addition, molecular docking indicated that compound G4 formed obvious π-π stacking interactions and hydrogen bond interactions with PHE-392 and ARG-98, respectively. Remarkably, compound G4 had good safety for corn, wheat, rice, and soybean, and the cumulative concentration in crops was lower than that of oxyfluorfen. Therefore, compound G4 can be used to develop potential lead compounds for novel PPO inhibitors.

Recent developments in green approaches for sustainable synthesis of indole-derived scaffolds.

An important issue to discover biological structures is the design of sustainable, safe, clean, cost-effective, excellent efficient synthetic reactions, and minimal energy consumption to provide structural diversity compounds with interesting biological properties. Among five-membered nitrogen-containing heterocyclic compounds, indole-containing scaffolds are heterocyclic structures found in abundance in natural products and various synthetic compounds, which have received remarkable attention in recent years due to their therapeutic and pharmaceutical properties and valuable role in the process of drug discovery. Indoles can be synthesized by various procedures although most of these procedures have their own restrictions and drawbacks such as performing the reaction in a toxic solvent, need of transition-metal catalysts, and amount of waste solvents. Due to the medicinal importance of indole and the need for green methods of drug synthesis, this review highlights the latest green synthetic methods leading to the formation of indole-containing compounds focusing on the past 4years with typical examples. This review is divided into two sections: green solvents and green techniques that lead to the synthesis of indole-derived scaffolds.

A Recent Overview of 1,2,3-Triazole-Containing Hybrids as Novel Antifungal Agents: Focusing on Synthesis, Mechanism of Action, and Structure-Activity Relationship (SAR)

A pharmacophore system has been found as 1,2,3-triazole, a five-membered heterocycle ring with nitrogen heteroatoms. These heterocyclic compounds can be produced using azide-alkyne cycloaddition processes catalyzed by ruthenium or copper. The bioactive compounds demonstrated antitubercular, antibacterial, anti-inflammatory, anticancer, antioxidant, antiviral, and antidiabetic properties. This heterocycle molecule, in particular, with one or more 1,2,3-triazole cores has been found to have the most powerful antifungal effects. The goal of this review is to highlight recent developments in the synthesis and structure-activity relationship (SAR) investigation of this prospective fungicidal chemical. Also there have been explained drugs and mechanism of action of a triazole compound with antifungal activity. This review will be useful in a variety of fields, including medicinal chemistry, organic chemistry, mycology, and pharmacology.

TDOS/PDOS/OPDOS, reduced density gradient (RDG) and molecular docking studies of [3-(3-bromophenyl)-cis-4,5-dihydroisoxazole-4,5-diyl]bis(methylene) diacetate

Due to the wide range of biological activity, 4,5-dihydroisoxazole compounds form an important family of five-membered heterocycles containing an oxygen atom and a nitrogen atom in the adjacent position. Therefore, [3- (3-bromophenyl) -cis-4,5-dihydroisoxazol-4,5-yl] bis (methylene) diacetate [BDBD] compound, which is a derivative of 4,5-dihydroisoxazole, was investigated in this study. The partial density of state (PDOS), the overlap population density of state (OPDOS) and total density of state (TDOS) of functional groups of the [BDBD] compound were theoretically evaluated using the DFT / B3LYP / 6-311G (d, p) method. Reduced density gradient (RDG) was also given to study the weak interaction, strong attraction, and strong repulsion interactions of the studied molecule. The PASS (Prediction of Activity Spectra) analysis predicts the carcinogenic activities with probability to be active value of 0.273 for the studied molecule. The antibacterial and anti-inflammatory activities of the [BDBD] compound against various the HIV-1 protease (1HSG), GyrB ATPase (3U2D), and VEGFR-2 kinase enzyme (4AG8) proteins were studied using molecular docking. The binding energies of 1HSG, 3U2D, and 4AG8 target proteins with [BDBD] ligand were calculated to be -6.11, -4.54, and -4.80 kcal/mol, respectively. Results were interpreted by comparing with the literature.

Non-heme manganese(ii) complex-catalysed oxidative cleavage of 1,2-diols via alcohol-assisted O2 activation

A well-defined, biologically relevant Mn(ii) complex is found to catalyse the aerobic oxidative cleavage of a wide range of diverse 1,2-diols to afford valuable carbonyl compounds and five-membered heterocycles under irradiation of visible light.

Nanocatalysts: applications for the synthesis of N-containing five-membered heterocycles.

Using transition metals as nanocatalysts has opened up a vast new area in heterocyclic chemistry in the modern day. Heterocyclic moieties are significant scaffolds that have both pharmacological and industrial applications. Various scientific groups have focused their attention on the expansion of simple reaction protocols by introducing better functional group compatibilities under mild reaction conditions through the use of easily available starting materials. This review provides an outline of the applications of metallic nanoparticles as proficient, recyclable, low-cost and green heterogeneous catalysts for the preparation of a wide range of key therapeutic five-membered nitrogen-containing heterocyclic compounds as well as some other significant functionalizations over the rings. This review mainly covers the literature published through the period from 2004 to 2021.

Five-Membered Nitrogen Heterocycles as New Lead Compounds in Drug Discovery

Five-Membered Nitrogen Heterocycles as New Lead Compounds in Drug Discovery

Planar inorganic five-membered heterocycles with σ + π dual aromaticity in both S0 and T1 states.

Cyclic species being aromatic in both the lowest singlet and triplet electronic states (so-called adaptive aromaticity) are scarce. To date, the reported systems have been mostly organometallic heterocycles with the aromaticities in the two states having the same origin of either σ- or π-electron delocalization (i.e., adaptive σ or π aromaticity). Herein, an exhaustive density functional theory study was conducted for 90 planar inorganic five-membered heterocycles in the forms of XY4 and XY2Z2 (X = O or S; Y and Z = N, P, As, Sb or Bi). They all contain 6π electrons and thus should be aromatic and antiaromatic in the lowest singlet and triplet states, respectively, according to classical Hückel's 4n + 2 and Baird's 4n π-electron rules. To our surprise, however, several of them (e.g., ON2As2, ON2Bi2 and SAs2Sb2) exhibit considerable aromatic characters in both S0 and T1 states, as confirmed by multiple aromaticity indices. More interestingly, further analyses reveal that their aromaticities in the two states may unprecedentedly stem from both σ- and π-electron delocalization. Thus, they likely bear unusual adaptive σ + π dual aromaticity. By finding adaptive aromatics in rather simple inorganic unsaturated systems, our work extends this emerging aromaticity concept to the big inorganic world.