Five-membered Heterocyclic Systems Research Articles

Synthesis, Characterization, 'ADMET-SAR' Prediction, DPPH Assay, and Anti-Mycobacterium Study of 4-[(substituted benzyl) amino]benzo hydrazides and its Hydrazones as the Acyl-CoA Carboxylase, AccD5 Inhibitors.

Hydrazide-hydrazone derivatives have shown diverse biological activities, such as antitubercular (anti-TB), antibacterial, antifungal, anticancer, anti-inflammatory, antiviral, and antiprotozoal actions. Hydrazide-hydrazones contain azomethine (-NH-N=CH-) group connected with carbonyl group and are believed to be responsible for various pharmaceutical applications. They aid in the synthesis of different five-membered heterocyclic systems, such as oxadiazole, triazoles, etc. Methods: In the present study, various hydrazines/hydrazones were synthesized starting from 4- amino benzoic acid derivatives. Structures of all 9 newly synthesized compounds (6a-6d and 8a- 8e) were further characterized by using various spectroscopic methods, such as 1H-NMR (Nuclear Magnetic Resonance), FT-IR (Fourier-transform infrared spectroscopy), Gas chromatographymass spectrometry (GC-MS), etc. Furthermore, molecular docking analysis against the acyl-CoA carboxylase, AccD5 (PDB ID: 2A7S), was also carried out using the Glide module, which depicted good binding scores than standard drugs. The anti-tuberculosis activity of all the hydrazides and hydrazones (6a-6d and 8a-8e) were evaluated against the Mycobacterium tuberculosis H37 RV strain using the Alamar-Blue susceptibility (MABA) test. The activity was expressed as the minimum inhibitory concentration (MIC) in μg/mL values. The antioxidant activity was also carried out using a DPPH assay. Our findings demonstrated highly encouraging in-vitro results (MABA assay, MIC: 1.2 μg/mL) of hydrazones as depicted by good antimycobacterial activity. The antioxidant results showed a moderate to a good percentage of DPPH inhibition. Our in-silico ADMET analysis further suggested good pharmacokinetic and toxicity-free profiles of synthesized analogues (6a-6d and 8a-8e). Our results signify hydrazones/hydrazines as potential hit candidates against the future developments of potent and safer anti-TB agents.

Thiadiazole - A promising structure in design and development of anti-Alzheimer agents.

The design and development of effective multitargeted agents in treating Alzheimer disease (AD) has always been a hot topic in the field of drug discovery. Since AD is a multifactorial disorder, various key hidden players such as deficit of acetylcholine (ACh), tau-protein aggregation, and oxidative stress have been associated with the incidence and progress of AD. In pursuit of improving efficacy and expanding the range of pharmacological activities of current AD drugs, the molecular hybridization method is also used intensively. Five-membered heterocyclic systems such as thiadiazole scaffolds have previously been shown to have therapeutic activity. Thiadiazole analogs as an anti-oxidant compound have been known to include a wide range of biological activity from anti-cancer to anti-Alzheimer properties. The suitable pharmacokinetic and physicochemical properties of the thiadiazole scaffold have introduced it as a therapeutic target in medicinal chemistry. The current review portrays the critical role of the thiadiazole scaffold in the design of various compounds with potential effects in the treatment of Alzheimer's disease. Furthermore, the rationale used behind hybrid-based design strategies and the outcomes achieved through the hybridization of Thiadiazole analogs with various core structures have been discussed. In addition, the data in the present review may help researchers in the design of new multidrug combinations that may provide new options for the treatment of AD.

Microwave Radiations: A Green Approach to the Synthesis of Five- Membered Heterocyclic Compounds

Abstract: Synthesis of heterocyclic scaffolds by microwave irradiation is a green and clean process. The organic transformation induced by microwave irradiation, as an alternative source of energy, has been of great interest due to the high efficiency, yield, and short reaction time with minimum by-product production. Heterocyclic compounds, an important skeleton for pharmaceuticals, are the most privileged and prevalent class of organic chemistry. They have enormous medicinal value and pharmaceutical potential. This review demonstrates the effectiveness of microwave heating for the synthesis of heterocyclic compounds. The eco-friendly microwave-induced synthesis of five-membered heterocyclic systems covering recent literature is highlighted in this article.

Anticancer Potential of Compounds Bearing Thiazolidin-4-one Scaffold: Comprehensive Review

Thiazolidin-4-ones is a versatile and privileged nucleus comprising of a five five-membered heterocyclic ring system possessing sulphur heteroatom and a cyclic amide bond. Extensive research and review studies mainly published in the last decade explored the diverse types of biological activities of this nucleus with potential therapeutic applications. Various silent features like drug likeness behaviour, suitability for diversity-oriented synthesis, and its sensitivity toward the redox tumour m

Application of LFER to the N(1)-H Acidities of Five-Membered Nitrogen Heterocyclic Ring Systems: A Review on Graduate Chemical Education Exercise

Abstract: An attempt is made for the first time in our laboratory to apply the Hammett and Taft equations to the five-membered heterocyclic ring systems pyrroles, pyrazoles, imidazole, and triazoles. It is shown that the pKa values of N(1)-H acidities of 3-X-pyrroles, 3-Xpyrazole, 4-X-pyrazole, 4-X-imidazole, 3-X-1,2,4-triazole and 4-X-1,2,3-triazole correlated well with Hammett σ values.

H2 storage capacity of Li-doped five member aromatic heterocyclic superalkali complexes; an in silico study

Hydrogen adsorption characteristics of different Li dopped aromatic five-membered heterocyclic (Ar) systems; have been studied [Ar = Imidazole, Pyrazole, Oxazole, Isoxazole, Thiazole, and Isothiazole]. The Lithiated heterocyclic systems are stabilized as cation (Ar-Li)+ and behave as superalkali (the vertical electron affinity (VEA) value ranges from 4 − 1.99 eV). The bonding nature between Ar and Li as well as that between Li and adsorbed H2 molecule has been analyzed through the electron localization function (ELF) study. The first principle calculation reveals that (Ar-Li)+ complexes can adsorb up to five molecular hydrogens in a quasi-sorption way with the binding energy of ∼ −2.17 eV. The spontaneity of the hydrogen adsorption in (Ar-Li)+ complexes is studied to find in which temperature Gibbs free energy change (ΔG) for all H2 adsorbed systems will be negative. At 80 K temperature, it will be satisfied.

Synthesis and Neurotropic Activity of New Heterocyclic Systems: Pyridofuro[3,2-d]pyrrolo[1,2-a]pyrimidines, Pyridofuro[3,2-d]pyrido[1,2-a]pyrimidines and Pyridofuro[3',2':4,5]pyrimido[1,2-a]azepines.

Background: Neurotic disturbances, anxiety, neurosis-like disorders, and stress situations are widespread. Benzodiazepine tranquillizers have been found to be among the most effective antianxiety drugs. The pharmacological action of benzodiazepines is due to their interaction with the supra-molecular membrane GABA-a-benzodiazepine receptor complex, linked to the Cl-ionophore. Benzodiazepines enhance GABA-ergic transmission and this has led to a study of the role of GABA in anxiety. The search for anxiolytics and anticonvulsive agents has involved glutamate-ergic, 5HT-ergic substances and neuropeptides. However, each of these well-known anxiolytics, anticonvulsants and cognition enhancers (nootropics) has repeatedly been reported to have many adverse side effects, therefore there is an urgent need to search for new drugs able to restore damaged cognitive functions without causing significant adverse reactions. Objective: Considering the relevance of epilepsy diffusion in the world, we have addressed our attention to the discovery of new drugs in this field Thus our aim is the synthesis and study of new compounds with antiepileptic (anticonvulsant) and not only, activity. Methods: For the synthesis of compounds classical organic methods were used and developed. For the evaluation of biological activity some anticonvulsant and psychotropic methods were used. Results: As a result of multistep reactions 26 new, five-membered heterocyclic systems were obtained. PASS prediction of anticonvulsant activity was performed for the whole set of the designed molecules and probability to be active Pa values were ranging from 0.275 to 0.43. The studied compounds exhibit protection against pentylenetetrazole (PTZ) seizures, anti-thiosemicarbazides effect as well as some psychotropic effect. The biological assays evidenced that some of the studied compounds showed a high anticonvulsant activity by antagonism with pentylenetetrazole. The toxicity of compounds is low and they do not induce muscle relaxation in the studied doses. According to the study of psychotropic activity it was found that the selected compounds have an activating behavior and anxiolytic effects on the models of “open field” and “elevated plus maze” (EPM). The data obtained indicate the anxiolytic (anti-anxiety) activity of the derivatives of pyrimidines, especially pronounced in compounds 6n, 6b, and 7c. The studied compounds increase the latent time of first immobilization on the model of “forced swimming” (FST) and exhibit some antidepressant effect similarly to diazepam. Docking studies revealed that compound 6k bound tightly in the active site of GABAA receptor with a value of the scoring function that estimates free energy of binding (ΔG) at −7.95 kcal/mol, while compound 6n showed the best docking score and seems to be dual inhibitor of SERT transporter as well as 5-HT1A receptor. Conclusions: Тhe selected compounds have an anticonvulsant, activating behavior and anxiolytic effects, at the same time exhibit some antidepressant effect.

Synthesis and Biological Evaluations of Monocarbonyl Curcumin Inspired Pyrazole Analogues as Potential Anti-Colon Cancer Agent.

PurposeThe monocarbonyl analogs of curcumin (MCACs) have been widely studied for their promising antitumor activity. Pyrazole is a five-membered aromatic heterocyclic system with various bioactivities incorporated frequently in drugs. However, few of MCACs inspired pyrazole analogues were investigated. To search for more potent cytotoxic agents based on MCACs, a series of new 1,5-diaryl/heteroaryl-1,4-pentadien-3-ones inspired pyrazole moiety was synthesized and evaluated on their anti-colon cancer activities.MethodsFifteen new compounds were synthesized and characterized by spectral datum, and then they were tested preliminarily by MTT assay for their cytotoxic activities against a panel of four human cancer cell lines, namely, gastric (SGC-7901), liver (HepG2), lung (A549), and colon (SW620) cancer cells. Compound 7h exhibited excellent selectivity and outstanding anti-proliferation activity against SW620 cells among these 15 compounds. Further, the mechanisms were investigated by transwell migration and invasion assay, clonogenic assay, cell apoptosis analysis, cell cycle analysis, Western blot analysis.ResultsThe IC50 value of 7h against SW620 cells was 12 nM, being more potent than curcumin (IC50 = 9.36 μM), adriamysin (IC50 = 3.28 μM) and oxaliplatin (IC50 = 13.33 μM). Further assays showed that 7h inhibited SW620 cell migration, invasion and colony formation obviously, which was due to its ability to induce cell cycle arrest in the G2/M and S phases and apoptosis. Western blot assay revealed that 7h decreased the protein expression of ATM gene, which may primarily contribute to its anticancer activity against SW620 cells.ConclusionA new MCACs 7h was synthesized and found to exhibit excellent anti-proliferation activity against SW620 cells. Further studies indicated that 7h exerted its anticancer activity against SW620 cells probably via decreasing the ATM protein expression. The present study suggested that 7h was a promising candidate as an anti-colon cancer drug for future development.

Time-Resolved Photoelectron Spectroscopy Studies of Isoxazole and Oxazole.

The excited state relaxation pathways of isoxazole and oxazole upon excitation with UV-light were investigated by nonadiabatic ab initio dynamics simulations and time-resolved photoelectron spectroscopy. Excitation of the bright ππ*-state of isoxazole predominantly leads to ring-opening dynamics. Both the initially excited ππ*-state and the dissociative πσ*-state offer a combined barrier-free reaction pathway, such that ring-opening, defined as a distance of more than 2 Å between two neighboring atoms, occurs within 45 fs. For oxazole, in contrast, the excited state dynamics is about twice as slow (85 fs) and the quantum yield for ring-opening is lower. This is caused by a small barrier between the ππ*-state and the πσ*-state along the reaction path, which suppresses direct ring-opening. Theoretical findings are consistent with the measured time-resolved photoelectron spectra, confirming the timescales and the quantum yields for the ring-opening channel. The results indicate that a combination of time-resolved photoelectron spectroscopy and excited state dynamics simulations can explain the dominant reaction pathways for this class of molecules. As a general rule, we suggest that the antibonding σ*-orbital located between the oxygen atom and a neighboring atom of a five-membered heterocyclic system provides a driving force for ring-opening reactions, which is modified by the presence and position of additional nitrogen atoms.

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.

(R,R/S,S)-9-Benzyl-3-methyl-7-phenyl-1,6-dioxa-3,9-diazaspiro[4.4]nonane-2,8-dione

The title compound, C19H18N2O4, a rare example of a spirocyclic orthoamide, was synthesized by a double cyclization of a N-Boc protected sarcosine derivative. The crystal structure of the racemic (R,R/S,S) modification reveals two near-orthogonal five-membered heterocyclic ring systems, each in an envelope configuration.

Synthesis of fungicidally active succinate dehydrogenase inhibitors with novel difluoromethylated heterocyclic acid moieties

Novel fungicidally active succinate dehydrogenase inhibitors have been prepared, which either carry a difluoromethyl and methyl-bearing pyrazoline, pyrrole, or thiophene ring in the acid component, mimicking similar-substituted pyrazole carboxamides. As five-membered heterocyclic systems with such a special substitution pattern are barely known, unique synthesis routes had to be developed, which rely, e.g., on the van Leusen pyrrole synthesis and the halogen dance reaction. Synthesis and biological activity against selected Ascomycete pathogens of these difluoromethylated pyrazoline, pyrrole, and thiophene derivatives are reported.

Hydrogen bonded complexes of oxazole family: electronic structure, stability, and reactivity aspects

In the present study, five-membered heterocyclic ring systems containing oxygen with one, two, three, and four nitrogen atoms in the ring along with their isomeric forms and their corresponding 1:1 water complexes have been fully optimized at the ab initio molecular orbital theory and Density Functional Theory (DFT) using aug-cc-pVDZ basis set. The optimized geometric parameters and stabilization energies of the complexes are reported. The study suggests that nitrogen of heterocyclic ring is a stronger hydrogen bond acceptor in comparison to oxygen and ability of nitrogen to act as hydrogen bond acceptor increases in the order oxazole (OZ) > oxadiazole (ODZ) > oxatriazole (OTZ) > oxatetrazole (OTTZ). The results are corroborated by Natural Bond Orbital (NBO) analysis, Quantum Theory of Atoms in Molecules (QTAIM), Symmetry Adapted Perturbation Theory (SAPT), and Molecular Electrostatic Potential (MEP) studies. The blue- and red-shifts in the hydrogen bond donors X-H (X = O, C) stretching frequencies have also been analyzed. Hydrogen bond ability has also been governed in the presence of reactivity descriptors including chemical potential (μ), global hardness (η), and electrophilicity index (ω).

Thiadiazoles: the appropriate pharmacological scaffolds with leishmanicidal and antimalarial activities: a review.

Leishmaniasis and malaria are serious public health problems in tropical and sub-tropical regions worldwide. Development of drug-resistant strains has disrupted efforts to control the spread of these diseases in the world. The conventional antiparasitic chemotherapy still suffers from side effects and drug resistance. Therefore, the development of novel antimalarial and leishmanicidal drugs remains a critical topic to combat against these diseases. Five-membered heterocyclic systems have possessed antiparasitic activity such as thiadiazole scaffold which is a prevalent and an important heterocyclic ring. For this purpose, the authors introduce a series of synthetic thiadiazole derivatives with antileishamanial activity. Also, the authors searched a number of sources and articles to find thiadiazole derivatives with antileishamnial and antimalarial activity. Then all of the findings were reviewed. 5-nitroheteroaryl-1,3,4-Thiadiazole derivatives with different substituents at position 2 of the thiadiazole ring (8, 10-11) presented the best antileishmanial activity with low toxicity compared with reference drug. Also, 1,3,4-thiadiazole-2-sulfonamide derivative (18) showed excellent inhibitory activity against pfCA as a special enzyme in Plasmodium falciparum. Thiadiazole scaffold has the suitable physicochemical and pharmacokinetic properties and still stays as a therapeutic target for the development of a novel lead in the medicinal chemistry. Therefore, the current review provides a brief summary of medicinal chemistry of thiadiazole ring and introduces novel leads possessing this nucleus with antimalarial and antileishmanial activities.

Sensitivity of 3He NMR Parameters to the Proximity of Heterocyclic Rings. The Helium–Furan Dimer

The potential of the NMR technique in probing the interaction between a noble gas atom (used as a spectroscopic probe) and five-membered heterocyclic systems was theoretically studied. Selected 3He NMR parameters of the free noble gas atom and its dimer were calculated using density functional theory with three functionals (M06-2X, CAM-B3LYP, and APFD), combined with dedicated polarization-consistent basis sets, and critically compared with theoretical high level calculations from the literature. The change of isotropic nuclear magnetic shielding of the free noble gas atom in the presence of furan (3He placed above the middle of the ring and used as NMR probe) increased with its proximity to the heterocyclic ring.

Effect of novel arecoline thiazolidinones as muscarinic receptor 1 agonist in Alzheimer's dementia models

The discovery of cholinergic deficit in Alzheimer's disease (AD) patient's brain has triggered research efforts, using cholinomimetic approaches for their efficacy in AD therapy. Various therapies may be of potential clinical use in AD. Among these are cholinergic agents, which include muscarinic agonists, acetylcholinesterase inhibitors, and acetylcholine releasing agents. One of the muscarinic agonists tested in AD is arecoline and its bioisosters, which are widely explored as muscarinic receptor 1 agonist (M1 receptor agonist) in AD research. In this regard, five-membered heterocyclic ring system attached arecoline basic nucleus ( N-methyl tetrahydropyridines) at third position has been extensively researched on. The present research involved synthesis of arecoline thiazolidinones 5( a– j) by using dipolar addition of 3-aminopyridine and alkyl/aryl carboxaldehydes in presence of gamma ferrite as catalyst. The resulting products were methylated and reduced to get desired products. Subsequently the synthesized arecoline thiazolidinones were subjected to in vitro muscarinic receptor binding studies using male Wistar rat brain (cerebral cortex) membrane homogenate and extended this in vitro study to in vivo pharmacological evaluation of memory and learning in male Wistar rats. Four derivatives ( 5a– 5c and 5e) showed considerable M1 receptor binding affinity ( in vitro) and elicited beneficial effects in vivo memory and learning models (Rodent memory evaluation, plus and Y maze studies).

An efficient 1,3-dipolar cycloaddition between aromatic selenoaldehydes and nitrile oxides or nitrile imines: an easy access to selenium-containing five-membered heterocyclic ring system

1,3-Dipolar cycloaddition between aromatic selenoaldehydes, generated by thermal retro Diels–Alder reaction of anthracene cycloadducts, and nitrile oxides or nitrile imines proceeded efficiently to give the corresponding [3+2] cycloadducts as a single isomer in good yields, being 1,4,2-oxaselenazoles or 1,3,4-selenadiazoles, respectively.

Direct estimate of conjugation and aromaticity in cyclic compounds with the EDA method

The nature of the interatomic interactions in cyclic conjugated molecules has been investigated with the Energy Decomposition Analysis (EDA). The focus of this work is on the strength of the pi bonding and pi conjugation in carbocyclic and heterocyclic molecules. The calculated deltaE(pi) values suggest that the EDA may be used directly for estimating the strength of pi conjugation in aromatic, homoaromatic, homoantiaromatic and antiaromatic compounds. The theoretical data show a pattern which agrees with the 4n + 2 rule. The extra aromatic stabilization energy has been obtained by comparing cyclic conjugation with the strength of pi conjugation in acyclic reference compounds. The deltaE(pi) values indicate that benzene is significantly stabilized by aromatic stabilization, but the total pi bonding contribution to the carbon-carbon bonding becomes even more stabilizing when the geometry is distorted toward a D(3h) form which has three long and three short C-C bonds. The D(6h) equilibrium structure is enforced by the sigma orbital interactions and by the quasiclassical electrostatic attraction. The VRE and ASE values suggest that pyridine is more strongly stabilized by aromatic conjugation than benzene. The EDA data of the six-membered cyclic 6pi species C5H5E (E = CH, N-Bi) and (HB = NH)3 predicts strength of aromatic stabilization in the order N > CH > P > As > Bi >> borazine. The ASE values of the five-membered heterocyclic systems C4H4E (E = NH, O, S) are smaller than for the benzene analogues showing the order NH approximately S > O. The ASE value for Cp is very small which probably comes from the choice of the reference system. The VRE results indicate that Cp is strongly stabilized by cyclic conjugation. The ASE values for the cyclic singlet carbenes indicate weak aromatic stabilization in the 2pi system cyclopropenylidene which is much stronger in the 6pi compound cycloheptatrienylidene while the 4pi molecule cylopentadienylidene is clearly antiaromatic. The triplet states of all three cyclic carbenes are antiaromatic. The strength of the pi conjugation in the homoconjugated cyclic compounds suggests weak aromatic stabilization in the 6pi compounds 1,3-cyclobutene and 1,3-cyclopentadiene but weak antiaromatic destabilization in the 2pi compound cyclopropene and in the 8pi molecules 1,3-cyclohexadiene and 1,3,5-cycloheptatriene. The 4n + 2 rule thus holds also for homoconjugated systems. A large negative value for the ASE is calculated for 1,3-cyclobutadiene.

Convergence of non-linear optical calculations for infinite polymers: Second hyperpolarizabilities of polymers with cyclic π-conjugated elementary cells

We have selected several polymers with small elementary cells, poly-HF, poly-H 2O, poly-C 2H 2 and poly-CNH in order to study the convergence of static and dynamic (hyper) polarizabilities at the Coupled Perturbed Hartree–Fock crystal orbital (CO) level. The parameters determining the convergence are the number of k-points over the half Brillouin zone, the number of neighbouring cells treated exactly with the complete Hamiltonian, and the effect of long-range Coulomb interactions. We also present for the first time calculations of the static and dynamic second hyperpolarizabilities γ on polymers with middle-sized cells, the five-membered heterocyclic π-conjugated systems, at this level of theory taking into account the results of the convergence study.

Current density maps, magnetizability, and nuclear magnetic shielding tensors of bis-heteropentalenes. III. Thieno-thiophene isomers

Near Hartree–Fock values of the magnetic susceptibility and nuclear magnetic shielding of bis-heteropentalenes consisting of two thiophene units ([2,3-b], [3,2-b], [3,4-b], and [3,4-c] isomers) have been estimated via computational schemes relying on continuous transformation of the origin of the current density within the coupled Hartree–Fock approximation and extended gaugeless Gaussian basis sets. The results are compared with those obtained via London gauge-including orbitals. Maps of streamlines and the modulus of the ring current density induced by a magnetic field normal to the molecular plane are reported for the three isomers of higher symmetry, showing that the intense diamagnetic flow of the π electrons causes strong magnetic anisotropy and a down-field chemical shift of the out-of-plane component of the proton shielding tensor in thieno-thiophenes. ‘Diatropicity matrices' for the series of bis-heteropentalenes formed by two fused five-membered heterocyclic systems with different heteroatoms can be constructed by choosing the out-of-plane component of either the magnetic susceptibility or the proton magnetic shielding as indicator. Alternative measures of relative aromaticity are obtained by the modulus of the induced π current densities.