Five-membered Heterocyclic Ring Research Articles

Stable, aromatic, and electrophilic azepinium ions: Design using quantum chemical methods.

Cyclic nitrenium ions containing five-membered and six-membered rings are available, however, the seven-membered cyclic nitrenium ions (azepinium ions) are rare. The chemistry of these species is related to their stability originating from the aromaticity due to 6π electrons. Very few theoretical and experimental studies have been conducted on the azepinium ions. Related clozapine and olanzapine cations (diazepinium ions) were observed during drug metabolism studies. In this work, quantum chemical analysis has been carried out to estimate the stability, aromaticity, and electrophilicity of several derivatives of azepinium ions. A few of the designed azepinium ions carry ΔES-T values in the range of 50 kcal/mol favoring singlet state; π donating groups at the 2nd position increase the singlet-triplet energy differences. Most of the substituents reduce the NICS(1) values compared to the parent system. Ring fusion with heterocyclic five-membered rings generally increases the aromaticity and the stability of the azepinium ion ring systems. The electrophilicity parameters estimated in terms of HIA, FIA, and ω values indicate that it is possible to fine-tune the chemical properties of azepinium ions with appropriate modulation.

Facilitating exciton dissociation in conjugated microporous polymers for photocatalytic degradation of tetracycline via a gradient N doping strategy

As a leading green wastewater treatment technology, organic semiconductor photocatalysis for tetracycline (TC) degradation is widely recognized but currently constrained by excessive exciton binding energies and rapid charge recombination. In this work, conjugated microporous polymers (CMPs) with five-membered heterocyclic ring have been fabricated by gradient doping of nitrogen at the monomer level. It demonstrates satisfactory photocatalytic performance, with thiadiazole introduced into the unit, achieving a TC removal rate of 95.6% within 30 min under visible light. The underlying origin of the preferable property lies in the lower exciton binding energy (Eb) with the assistance of the donor–acceptor (D-A) structure constructed by thiadiazole monomer and triazine skeleton. Density Functional Theory (DFT) calculations reveal that this five-membered heterocyclic structure can appropriately regulate the local charge distribution and increase the dipole moment, thus accelerating the migration dynamics of charge carriers in the degradation process. This study provides a novel insight into the modulation of polymer exciton Eb and enlightens the designation of metal-free photocatalysts based on antibiotic degradation.

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.

Hydrazides: An Important Tool for the Synthesis of 1,3,4-Oxadiazole

Abstract: Hydrazides, derivatives of hydrazine, are widely used in pharmaceuticals, polymers, dyes, herbicides, and as chemical preservatives. A notable application is in synthesizing 1,3,4-oxadiazole, an important aromatic compound with a five-membered heterocyclic ring containing two nitrogen atoms and one oxygen atom. Among the four oxadiazole isomers, 1,3,4-oxadiazole is the most significant, used in drug discovery, pharmaceuticals, and dyes. It is synthesized from various substituted hydrazides or hydrazones using reagents like copper, cobalt, cerium, phosphorus oxychloride, mercury oxide, potassium iodide, triflic anhydride, and carbon disulfide. This study reviews the synthesis methods of 1,3,4-oxadiazole, highlighting the advantages and disadvantages of different catalysts and conditions, providing useful insights for researchers.

Recent Advances and New Insights in Genome Analysis and Transcriptomic Approaches to Reveal Enzymes Associated with the Biosynthesis of Dendrobine-Type Sesquiterpenoid Alkaloids (DTSAs) from the Last Decade.

Dendrobium species, which are perennial herbs widely distributed in tropical and subtropical regions, are notable for their therapeutic properties attributed to various bioactive compounds, including dendrobine-type sesquiterpenoid alkaloids (DTSAs). The objective of this review article is to provide a comprehensive overview of recent advances in the biosynthesis of DTSAs, including their extraction from Dendrobium species and endophytes, elucidation of associated genes through genomic and transcriptomic sequencing in both Dendrobium spp. and endophytes, exploration of the biosynthetic pathways of DTSAs, and drawing conclusions and outlining future perspectives in this field. Alkaloids, predominantly nitrogen-containing compounds found in medicinal orchids, include over 140 types discovered across more than 50 species. DTSAs, identified in 37 picrotoxane alkaloids, have a distinctive five-membered nitrogen heterocyclic ring. This review highlights endophytic fungi as alternative sources of DTSAs, emphasizing their potential in pharmaceutical applications when plant-derived compounds are scarce or complex. Genomic and transcriptomic sequencing of Dendrobium spp. and their endophytes has identified key genes involved in DTSAs biosynthesis, elucidating pathways such as the mevalonate (MVA) and 2-C-methyl-D-erythritol 4-phosphate (MEP) pathways. Genes encoding enzymes, such as acetyl-CoA C-acetyltransferase and diphosphomevalonate decarboxylase, are positively associated with dendrobine production. Despite significant advancements, the complexity of terpenoid biosynthesis in different subcellular compartments remains a challenge. Future research should focus on leveraging high-quality genomic data and omics technologies to further understand and manipulate the biosynthetic pathways of DTSAs and enhance their medicinal use.

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.

1,3,4-Oxadiazole as an Anticancer Agent

The modern era's fastest-growing disease is cancer, it poses a serious threat to people's lives. For the treatment of various cancers, the FDA has approved a number of medications. However, because of the rise in drug toxicity incidents, there is a continual need for the discovery of novel anti-cancer drugs. Five-membered heterocyclic ring with multifaceted biological action is the 1,3,4-oxadiazole. Their anti-proliferative actions are linked to a number of processes, including the inhibition of kinases, enzymes, and growth factors. Numerous 1,3,4-oxadiazoles have been found to be effective anticancer agents for a variety of cancer cell types. Oxadiazoles may target the NF-kB signalling system to exert their anti-cancer effects, according to certain reports. This study examines the importance of the 1,3,4-oxadiazole ring structure and how it can function as a model for a new anticancer drug. This in-depth analysis focuses on the research on 1,3,4-oxadiazole as a cancer preventative.

Synthesis and anticancer properties of novel dolastatin 10 analogs featuring five-membered heterocyclic rings with a linkable group at the C-terminus

Dolastatin 10 (Dol-10), a natural marine-source pentapeptide, is a powerful antimitotic agent regarded as one of the most potent anticancer compounds found to date. Dol-10 however, lacks chemical conjugation capabilities, which restricts the feasibility of its application in targeted drug therapy. This limitation has spurred the prospect that chemical structure of the parent molecule might allow conjugation of the derivatives to drug carriers such as antibodies. By first employing docking studies, we designed and prepared a series of novel Dol-10 analogs with a modified C-terminus, preserving high potency of the parent compound while enhancing conjugation capability. The modifications involved the introduction of a methyleneamine functionality at position 4 of the 1,3-thiazole ring, along with the substitution of the thiazole ring with a 1,2,3-triazole moiety, furnished with methylenehydroxy, carboxy, methyleneamine, and N(Me)-methyleneamine tethering functionalities at position 4. Among the synthesized pentapeptides, DA-1 exhibited the highest potency in prostate cancer (PC-3) cells, eliciting apoptosis (IC50 0.2 ± 0.1 nm) and cell cycle arrest at the mitotic stage after at least 6 days of culture. This delayed response suggests the accumulation of cellular stress or significant physiological alterations that profoundly impact the cell cycle. We believe that these novel Dol-10 derivates represent a new and straightforward route for the development of C-terminus modified Dol-10-based microtubule inhibitors, thereby advancing targeted anticancer therapy.

Crystal structure of a three-coordinate lithium complex with monodentate phenyloxazoline and hexamethyldisilylamide ligands

The reaction of lithium hexamethyldisilylamide, [Li{N(Si(CH3)3)2}] (LiHMDS), with 4,4-dimethyl-2-phenyl-2-oxazoline (Phox, C11H13NO) in hexane produced colourless crystals of bis(4,4-dimethyl-2-phenyl-2-oxazoline-κN)(hexamethyldisilylamido-κN)lithium, [Li(C6H18NSi2)(C11H13NO)2] or [Li{N(Si(CH3)3)2}(Phox)2] in high yield (89%). Despite the 1:1 proportion of the starting materials in the reaction mixture, the product formed with a 1:2 amide:oxazoline ratio. In the unit cell of the C2/c space group, the neutral molecules lie on twofold rotation axes coinciding with the Li—N(amide) bonds. The lithium(I) centre adopts a trigonal–planar coordination geometry with three nitrogen donor atoms, one from the HMDS anion and two from the oxazolines. All ligands are monodentate. In the phenyloxazoline units, the dihedral angle defined by the five-membered heterocyclic rings is 35.81 (5)°, while the phenyl substituents are approximately face-to-face, separated by 3.908 (5) Å. In the amide, the methyl groups assume a nearly eclipsed arrangement to minimize steric repulsion with the analogous substituents on the oxazoline rings. The non-covalent interactions in the solid-state structure of [Li{N(Si(CH3)3)2}(Phox)2] were assessed by Hirshfeld surface analysis and fingerprint plots. This new compound is attractive for catalysis due to its unique structural features.

[Fe(NCMe)6](BF4)2 is a bifunctional catalyst for styrene aziridination by nitrene transfer and heterocycle expansion by subsequent dipolar insertion

The solvated iron(II) salt [Fe(NCMe)6](BF4)2 (Me = methyl) is shown to be a bifunctional catalyst with respect to aziridination of styrene. The salt serves as an active catalyst for nitrene transfer from PhINTs to styrene to form 2-phenyl-N-tosylaziridine (Ph = phenyl; Ts = tosyl, –S{O}2–p-C6H4Me). The iron(II) salt also acts as a Lewis acid in non-coordinating CH2Cl2 solution, to catalyze heterolytic CN bond cleavage of the aziridine and insertion of dipolarophiles. The 1,3-zwitterionic intermediate is presumably supported by interaction of the metal dication with the anion, and by resonance stabilization of the carbocation. Nucleophilic dipolarophiles then insert to give a five-membered heterocyclic ring. The result is a two-step cycloaddition, formally [2 + 1 + 2], that is typically regiospecific, but not stereospecific. This reaction mechanism was confirmed by conducting a series of one-step, [3 + 2] additions of unsaturated molecules into pre-formed 2-phenyl-N-tosylaziridine, also catalyzed by [Fe(NCMe)6](BF4)2. Relevant substrates include styrenes, carbonyl compounds and alkynes. These yield five-membered heterocylic rings, including pyrrolidines, oxazolidines and dihydropyrroles, respectively. The reaction scope appears limited only by the barrier to formation of the dipolar intermediate, and by the nucleophilicity of the captured dipolarophile. The bifunctionality of an inexpensive, earth-abundant and non-toxic catalyst suggests a general strategy for one-pot construction of heterocyclic rings, as demonstrated specifically for pyrrolidine ring formation.

Continuous isomerisation of 2,5-dimethylfuran to 2,4-dimethylfuran over Ga-silicate.

2,4-dimethylfuran has a rare disubstitution pattern in the five-membered heterocyclic furan ring that is highly interesting chemically but challenging to access synthetically. We present a heterogeneously catalysed route to synthesise 2,4-dimethylfuran from commonly available 2,5-dimethylfuran using a zeolite packed-bed flow reactor. As supported by DFT calculations, the reaction occurs inside the zeolite channels, where the acid sites catalyse proton transfer followed by migration of a methyl group. The zeotype Ga-silicate (MFI type) appears superior to an aluminium-containing ZSM-5 by demonstrating higher selectivities and slower catalyst deactivation. This work provides new opportunities for the continuous valorisation of bio-feedstock molecules in the perspective of the emerging biorefinery era.

Glutathione Peroxidase-like Antioxidant Activity of 1,3-Benzoselenazoles: Synthesis and In Silico Molecular Docking Studies as Pancreatic Lipase Inhibitors.

The synthesis of 1,3-benzoselenazoles was achieved by the reaction of corresponding bis[3-amino-N-(p-tolyl)benzamide-2-yl] diselenide, bis[3-amino-N-(4-methoxyphenyl)benzamide-2-yl] diselenide, and bis[3-amino-N-(4-(dimethylamino)phenyl) benzamide-2-yl] diselenide with aryl aldehydes. The 1,3-benzoselenazoles continued to exist as planar molecules due to the presence of secondary Se···O interactions as revealed by the single-crystal X-ray analysis. The presence of secondary Se···O interactions in 1,3-benzoselenazoles was confirmed using natural bond orbital (NBO) and atoms in molecules (AIM) calculations. Nucleus-independent chemical shift (NICS) values suggested the presence of aromatic character in a five-membered benzoselenazole heterocyclic ring. The glutathione peroxidase (GPx)-like antioxidant activity of all 1,3-benzoselenazoles was assessed using a thiophenol assay, exhibiting greater antioxidant activity than Ph2Se2 used as a reference. The most active catalyst carrying a strong electron-donating group (-NMe2) at the ortho-position to the benzoselenazole ring was further investigated at different concentrations of thiophenol, H2O2, and 1,3-benzoselenazoles as catalyst for determining their catalytic parameters. Moreover, the potential applications of all 1,3-benzoselenazoles against pancreatic lipase (PL) have been identified using in silico interactions between the active sites of the 1LPB protein as evaluated using a molecular docking study.

Green synthesis, antibacterial and antifungal evaluation of new thiazolidine-2,4-dione derivatives: molecular dynamic simulation, POM study and identification of antitumor pharmacophore sites

In this study, a series of thiazolidine-2,4-dione derivatives 3a–i were synthesized and evaluated for antibacterial activity against Gram-positive and Gram-negative strains of Bacillus licheniformis, Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. Newly prepared thiazolidine (TZD) derivatives were further screened separately for in vitro antifungal activity against cultures of fungal species, namely, Aspergillus niger, Alternaria brassicicola, Chaetomium murorum, Fusarium oxysporum, Lycopodium sp. and Penicillium notatum. The electron-donating substituents (–OH and –OCH3) and electron-withdrawing substituents (–Cl and –NO2) on the attached arylidene moieties of five-membered heterocyclic ring enhanced the broad spectrum of antimicrobial and antifungal activities. The molecular docking study has revealed that compound 3h strongly interacts with the catalytic residues of the active site of the β-carbonic anhydrase (P. aeruginosa) and has the best docking score. In silico pharmacokinetics studies showed the drug-likeness and non-toxic nature of the synthesized compounds, which indicates the combined antibacterial, antiviral and antitumor pharmacophore sites of the targeted drug. This work demonstrates that potential TZD derivatives bind to different types of bacterial and fungal pathogens for circumventing their activities and opens avenues for the development of newer drug candidates that can target bacterial and fungal pathogens. Communicated by Ramaswamy H. Sarma

1,3-thiazole Derivatives: A Scaffold with Considerable Potential in the Treatment of Neurodegenerative Diseases.

1,3-thiazoles, which contain nitrogen and a sulfur atom is an unsaturated five-membered heterocyclic ring, have achieved a unique significant place in drug design and development because of their versatile structure and a variety of pharmacological activities, viz. anticancer, antiviral, antimicrobial, anticonvulsant, antioxidant, antidiabetic, etc. They have inspired researchers to design novel thiazole with different biological activities. The presence of the thiazole moiety has resulted in a large number of clinically useful drugs with a wide range of activities, such as Ritonavir (antiviral), Sulfathiazole (antimicrobial antibiotic), Abafungin, Ravuconazole (antifungal), Meloxicam (NSAID), etc., that further verify this statement. The prevalence of neurodegenerative diseases like Alzheimer's, Parkinson's, and Huntington's is increasing at a rapid pace but existing treatments mainly provide symptomatic relief and are associated with undesired effects. Consequently, designing novel compounds with more effectiveness and reduced toxicity are required. 1,3-thiazole derivatives have emerged as excellent candidate in this regard and have an important role for the treatment of neurodegenerative diseases. In the current review, we have gathered all the appropriate literature which demonstrate the remarkable role of 1,3-thiazole and its derivatives in these diseases that may help design new compounds with more desired characteristics. The literature was assessed through worldwide scientific databases like GOOGLE, SCOPUS, and PUBMED using different keywords, and only relevant information published in English was evaluated.

Evaluation of genotoxicity of (4-fluorophenyl) thiazolidin-4-one in CHO-K1 cells

4-thiazolidinones are five-membered heterocyclic ring compounds with diverse pharmacological impacts. In a previous study, we reported a series of newly synthesized derivatives of 4-thiazolidinones with different functional groups, which exhibited anticancer activity against ovarian (SKOV3) and cervical (HeLa) cancer cell lines. Among these derivatives, (4-fluorophenyl) thiazolidin-4-one (4-TH) demonstrated potent cytotoxic activity against SKOV3, with an IC50 value of 12.3 μM. However, it was also found to be extremely toxic to normal cells (CHO-K1) with an IC50 of 7.5 μM. Before considering its use in cancer research, it is crucial to gain a comprehensive understanding of its potential genotoxic effects on normal cells. In this study, we aimed to assess the in vitro cytogenetic toxicity of 4-TH using normal Chinese hamster ovary cells (CHO-K1). Referring to the IC50 of 4-TH, we selected three sub-lethal concentrations (2, 5, and 7.5 μM) and treated CHO-K1 cells for 24 h (one cell cycle duration) to estimate its dose-dependent induction of chromosome aberrations, and examine the effect of 4-TH on cell division, micronucleus induction potential and cell cycle arrest properties following standard protocols. The results showed that 4-TH was highly toxic to normal cells, as all three sublethal concentrations caused a statistically significant increase in the number of chromosomal aberrations (P < 0.001), formation of micronuclei (P < 0.01), and changes in the rate of cell division (mitotic index) (P < 0.05) compared to control. In addition, there was a significant increase in the number of cells in the G1 phase, indicating that all concentrations of 4-TH tested induced apoptosis. The evaluation of the cytotoxic, clastogenic, and aneugenic properties of 4-TH, a potent cytotoxic agent, will undoubtedly provide critical information for determining its safety and potential as an anticancer drug.

Attosecond charge migration in heterocyclic five-membered rings

Attosecond charge migration in heterocyclic five-membered rings

Theoretical Investigation of the E/Z Photoisomerization Pathway in 1-(2-Pyrrolyl)-2-(2-thienyl)ethylene.

Molecular-level understanding of photochemistry in simple vinylene-linked systems such as ethylene and stilbene has been a major area of research. However, the effect of replacing the two benzene rings by five-membered heterocyclic rings, thiophene and pyrrole, is yet to be reported. In the present theoretical study, our aim is to illustrate photoinduced processes in a vinylene-linked thiophene-pyrrole system. Computational studies are carried out at the RI-MP2/RI-ADC(2)/cc-pVTZ level to explore different isomerization pathways. Minimum-energy conical intersection (MECI) structures are categorized into two types: closed-ring and twisted-pyramidalized structures. Relaxation through the former MECIs is accessible only from the cis isomers. However, the latter MECIs are inaccessible due to high energy barriers along the linear interpolation in internal coordinate paths.

Pregnenolone sulfate analogues differentially modulate GABAA receptor closed/desensitised states.

GABAA receptors are regulated by numerous classes of allosteric modulators. However, regulation of receptor macroscopic desensitisation remains largely unexplored and may offer new therapeutic opportunities. Here, we report the emerging potential for modulating desensitisation with analogues of the endogenous inhibitory neurosteroid, pregnenolone sulfate. New pregnenolone sulfate analogues were synthesised incorporating various heterocyclic substitutions located at the C-21 position on ring D. The pharmacological profiles of these compounds were assessed using electrophysiology and recombinant GABAA receptors together with mutagenesis, molecular dynamics simulations, structural modelling and kinetic simulations. All seven analogues retained a negative allosteric modulatory capability whilst exhibiting diverse potencies. Interestingly, we observed differential effects on GABA current decay by compounds incorporating either a six- (compound 5) or five-membered heterocyclic ring (compound 6) on C-21, which was independent of their potencies as inhibitors. We propose that differences in molecular charges, and the targeted binding of analogues to specific states of the GABAA receptor, are the most likely cause of the distinctive functional profiles. Our findings reveal that heterocyclic addition to inhibitory neurosteroids not only affected their potency and macroscopic efficacy but also affected innate receptor mechanisms that underlie desensitisation. Acute modulation of macroscopic desensitisation will determine the degree and duration of GABA inhibition, which are vital for the integration of neural circuit activity. Discovery of this form of modulation could present an opportunity for next-generation GABAA receptor drug design and development.

A Review on Synthetic Strategies for Useful Oxadiazole Derivatives in Psychological Disorders

Abstract: Oxadiazole is a five-membered aromatic heterocyclic ring having two nitrogen and one oxygen atom. Various isomeric forms have been reported for oxadiazole, such as 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, etc. Currently, a considerable population worldwide is facing several mental problems due to a competitive lifestyle. The present status of available medicines do not promise complete cure without any adverse effects. Therefore, these disorders are continuously challenging the researchers to come up with new molecules with superior efficacy and minimum side effects. All the isomeric forms of oxadiazole have numerous potential in treating various mental problems such as Parkinsonism, Alzheimer’s, schizophrenia, and epileptic disorders. In this review article, we summarize several recently reported synthetic strategies for preparing different oxadiazole and its derivatives which were found effective in psychological disorders. The researchers will be able to obtain the necessary information (synthesis strategies) through this article for their future research on new molecules containing the oxadiazole moiety. Furthermore, this review article will help the researchers in the fight against mental disorders and highlights possible molecules for the treatment of mentally challenged people.

Theoretical Investigation of Electron Impact Scattering on Imidazole.

This study presents the results of electron scattering calculations on a biologically important molecule, imidazole, using the UK molecular R-matrix method. The R-matrix calculations are performed using SE, SEP, and CC models, and the resonance detected in the present SEP model is found to be in better agreement with available experimental data than previous theoretical data. The study also reports an inelastic scattering cross section, which comprises dissociative electron attachment (DEA), excitation, and ionization cross section, for the first time. The total scattering cross sections are also reported for the first time. We confirm the presence of the two well-known π* shape resonances predicted earlier experimentally. Due to the scarcity of total scattering cross section (TCS) data for imidazole, we have compared the TCS of imidazole with its isoelectronic target isoxazole and drawn important conclusions. A comparison among the resonances of imidazole with those of isoxazole helps us to conclude that electron attachment to π* molecular orbitals is a general feature displayed by these five-membered heterocyclic compounds. The comprehensive electron scattering studies presented in this work are expected to provide a deeper understanding of electron-induced biochemical processes and fill gaps in the available data. Furthermore, this study is anticipated to inspire further investigations on imidazole and other five-membered heterocyclic ring molecules, which have significant applications in medicine.