Mesoionic Structures Research Articles

Development of Imidazo[1,2-a]pyridines Containing Sulfonyl Piperazines as Potential Antivirals against Tomato Spotted Wilt Virus.

Mesoionic structures have become important advancements in recent agrochemical design. However, their potential beyond serving as excellent insecticides remains unexplored with limited reports available. Herein, a series of imidazo[1,2-a]pyridine mesoionics were developed by structurally incorporating sulfonyl piperazine moieties into imidazo[1,2-a]pyridines. Many of the obtained derivatives demonstrated bioactivity against tomato spotted wilt virus (TSWV) in bioassays. In particular, compound Z40, identified via three-dimensional quantitative structure activity relation models, displayed encouraging protective performance (half-maximal effect concentration = 252 μg/mL) compared to the positive controls ningnanmycin (332 μg/mL) and vanisulfane (523 μg/mL). Through defense enzyme assays, real-time quantitative polymerase chain reaction, and proteomics analysis, Z40 was identified as a plant immunomodulator that promotes defense enzyme activity and the mediates oxidative phosphorylation pathway, enabling plants to resist TSWV. We expect this study to help expand the possibilities of mesoionic compounds.

Design, Synthesis, and Insecticidal Activity of Pyridino[1,2-a]pyrimidines Containing Indole Moeites at the 1-Position.

Research on mesoionic structures in pesticide design has gained significant attention in recent years. However, the 1-position of pyridino[1,2-a]pyrimidine is usually designed with 2-chlorothiazole, 2-chloropyridine, or cyano moieties commonly found in neonicotinoid insecticides. In order to enrich the available pharmacophore library, here, we disclose a series of new pyridino[1,2-a]pyrimidine mesoionics bearing indole-containing substituents at the 1-position. Most of these target compounds are confirmed to have good insecticidal activity against aphids through bioevaluation. In addition, a three-dimensional structure-activity relationship model is established to allow access to optimal compound F45 with an LC50 value of 2.97 mg/L. This value is comparable to the property achieved by the positive control triflumezopyrim (LC50 = 2.94 mg/L). Proteomics and molecular docking analysis suggest that compound F45 has the potential to modulate the functioning of the aphid nervous system through its interaction with neuronal nicotinic acetylcholine receptors. This study expands the existing pharmacophore library for the future development of new mesoionic insecticides based on 1-position modifications of the pyridino[1,2-a]pyrimidine scaffold.

Criteria for a Structure to be Mesoionic

In the article, at the mathematical level of rigor, it is shown that the pair of concepts "covalence – mesoionicity" correlates in the same way as the pair "kekuleness – non-kekuleness". A criterion for a structure to be mesoionic (mesoionicity criterion) is formulated and proved, which makes it possible to enumerate all mono-charged mesoionic structures (mesomeric betaines) on a given graph. The mesoionicity criterion and the Kasteleyn theorem (on counting the number of perfect matchings in a graph) were used as the basis for a computer program that classifies dipolar resonance structures. The work of the program is demonstrated on the lists of obtained mesoionic structures. A general approach to mesoionicity is discussed.

Abstract 5877: Antitumor activity of the mesoionic compound MI H 2.4 on breast cancer cell lines

Abstract Breast cancer is the most commonly diagnosed cancer in women under 60. Localized breast cancer is easily treated, resulting in high survival rates. However, treatment for advanced disease is inadequate, with a five-year survival rate of less than 24%. Thus, there is a great need for new therapies capable of increasing therapeutic efficacy. Synthetic mesoionic compounds, belonging to the 1,3-thiazolium-5-thiolate group, are recognized for their broad spectrum of biological activities including antibiotic, antiparasitic, antiviral, anticonvulsant, antidepressant, antioxidant, analgesic, anti-inflammatory, and more recently for their potential antitumor activity. These compounds have the ability to cross cell membranes; the characteristic of mesoionic structures having distinct regions of positive and negative charge associated with a poly-heterocyclic aromatic ring system, indicates the capability of strong interactions with biomolecules such as DNA and proteins. In this study, the cytotoxic effects of mesoionic compound MI H 2.4 alone and in combination with zinc was examined in breast cancer cell lines (4TI, BT-20, BT-549, MCF7, MDA-MB-231, MDA-MB-436, MM2MT, T-47D, and ZR-75-1) and normal breast cell lineages (HuMEC, MCF-10A, and MCF-12A) were evaluated. The effect of this agent on cell cycle was also investigated. Different concentrations of mesoionic compound MI H 2.4 (MI H 2.4 free) and in combination with zinc (MI H 2.4 Zinc) were added to the cultured cells and incubated for 24, 48, 72 and 96 h. Cell survival and cytotoxicity were evaluated using crystal violet and MTT assays. Cell cycle analysis was performed using MCF7 cells that were stained with propidium iodide and analyzed by flow cytometry. The cytotoxic effects of mesoionic compounds (MI H 2.4 free and MI H 2.4 Zinc) were highest at72 and 96 h. The MI H 2.4 free and MI H 2.4 Zinc showed a similar inhibitory effect on breast cancer cell growth in the μM range. In contrast, the normal breast cell lineages showed low cytotoxicity to treatment with the mesoionic compounds. Treatment of MCF7 cells cultured with MI H 2.4 free blocked cell cycle progression at the G2 phase of the cell cycle after 24 h of treatment. Mitochondrial function of MCF7 cells was determined using a Seahorse XF-24 Extracellular Flux Analyzer. Treatment with MI H 2.4 free and MI H 2.4 Zinc for 24 h resulted in a decreased basal and maximal mitochondrial respiration. In summary, mesoionic compound MI H 2.4 may offer a novel therapeutic strategy in the treatment of breast cancer, considering that it has significant antitumoral activity in breast cancer cell lines and low cytotoxicity in normal cells. Citation Format: Luciana Amaral de Mascena Costa, Filipe Cássio Silva de Lima, Rodrigo da Silva Viana, Silvany de Sousa Araujo, Aurea Wischral, Helivaldo Diógenes da Silva Souza, Petrônio Filgueiras de Athayde-Filhoa, Leandro Araújo de Azevedo, Severino Alves Júnior, Manoel Adrião, J. Michael Mathis. Antitumor activity of the mesoionic compound MI H 2.4 on breast cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5877.

PYRROLES FROM OXAZOLES

The review is devoted to the transformation of oxazoles (including those with cationoid and mesoionic structures) into compounds of the pyrrole series. Author: E. V. Babaev. English translation in Chemistry of Heterocyclic Compounds , 2012, 48 (1), pp 59-72 http://link.springer.com/article/10.1007/s10593-012-0970-x

Reaction of carbon disulfide with 2-bromoimidazolium salts. Novel bicyclic mesoionic thiazolo[3,2-a]imidazoles

Abstract A new class of thiazolo[3,2-a]imidazole derivatives is obtained in good yields, by reacting 1-methyl-2-bromoimidazolium salts bearing N+-CH2COAr, N+-CH2COMe, N+-CH2COOMe, or N+-CH2CN fragments, with carbon disulfide in the presence of Et3N at room temperature. The mesoionic structures of these compounds are established by NMR spectroscopy and by single-crystal X-ray analysis.

ChemInform Abstract: Pyrroles from Oxazoles

AbstractReview: 51 refs.

Pyrroles from oxazoles

The review is devoted to the transformation of oxazoles (including those with cationoid and mesoionic structures) into compounds of the pyrrole series.

Push-pull 1,3-thiazolium-5-thiolates. Formation via concerted and stepwise pathways, and theoretical evaluation of NLO properties,

The transformation of münchnones (mesoionic rings featuring the 1,3-oxazolium-5-olate core) into their sulfur counterparts (1,3-thiazolium-5-thiolates) by reaction with CS(2), pioneered by Huisgen and his group in the early 1970s, has been re-investigated in detail by means of both experimental and theoretical methods. The synthetic strategy can be tuned to incorporate donor and acceptor groups in appropriate positions. Calculations of molecular hyperpolarizabilities together with orbital topologies evidence that these sulfur-containing heterocycles exhibit nonlinear optical responses, thereby pointing to potential applications of mesoionic structures in the NLO field. From a mechanistic viewpoint, modeling of the whole systems at the B3LYP/6-31G(d) level reveals that concerted and stepwise pathways are operative depending on the substitution pattern of the parent münchnone, which also account for the experimental results.

Multicomponent Access to Functionalized Mesoionic Structures Based on TFAA Activation of Isocyanides: Novel Domino Reactions

AbstractThe reactions of azines (isoquinolines, pyridine) with TFAA and isocyanides in a new domino process yield mesoionic acid fluorides with an imidazo[1,2‐a]azine core. This multicomponent reaction has a general character, tolerating a wide range of substitution patterns on each component, and displays an unprecedented arrangement of reaction pathways. The protocol allows the incorporation of a fourth synthetic input by the reaction of a suitable nucleophile (alcohols, thiols, amines) with the acid fluoride moiety.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Push−Pull vs Captodative Aromaticity

Vinylogs of fulvalenes with cyclopropenyl and cyclopentadienyl moieties attached either to different carbon atoms ( c-C 3H 2CHCHC 5H 4- c, 7) or to the same carbon atom [XC( c-C 3H 2)( c-C 5H 4), 10] [X = CH 2; C(CN) 2; C(NH 2) 2; C(OCH 2) 2; O; c-C 3H 2; c-C 5H 4; SiH 2; CCl 2] of the double bond inserted between the two rings are examined theoretically at the B3LYP/6-311G(d,p) level. Both types of compounds are shown to possess aromaticity, which was called "push-pull" and "captodative" aromaticity, respectively. For the captodative mesoionic structures XC( c-C 3H 2)( c-C 5H 4), the presence of both the two aromatic moieties and the CC double bond is the necessary and sufficient condition for their existence as energetic minima on the potential energy surface. Aromatic stabilization energy (ASE) was assessed by the use of homodesmotic reactions and heats of hydrogenation. Spatial magnetic criteria (through space NMR shieldings, TSNMRS) of the two types of vinylogous fulvalenes 7 and 10 have been calculated by the GIAO perturbation method employing the nucleus independent chemical shift (NICS) concept of Paul von Rague Schleyer, and visualized as iso-chemical-shielding surfaces (ICSS) of various sizes and directions. TSNMRS values can be successfully employed to visualize and quantify the partial push-pull and captodative aromaticity of both the three- and five-membered ring moieties. In addition, the push -pull effect in compounds 7 and 10 could be quantified by the occupation quotient pi* CC/pi CC of the double bond inserted between the two rings.

Multinuclear magnetic resonance study of some mesoionic oxatriazoles containing nitrogenous exocyclic groups

1H,13C,14N and15N NMR measurements are reported for four mesoionic 1-oxa-2, 3, 4-triazoles containing exocyclic nitrogenous groups. The NMR signal assignments are discussed and compared with those previously published for some corresponding oxatriazoles. The results obtained support the proposed cyclic mesoionic structures for the compounds studied. The questions of possible charge delocalization and valence tautomerism are addressed. Compound with N− H as a exocyclic group (Fig. 1) is found to be relatively unstable, this is attributed to proton migration in the corresponding non-cyclic form of this molecule.

13C and 15N NMR study of 2,3‐diphenyl‐1,2,3,4‐tetrazolium‐5‐aminides

Abstract13C, 14N and 15N NMR data are reported for some mesoionic 2,3‐diphenyltetrazoles with nitrogen‐containing exocyclic groups, and the data confirm their cyclic structures. The protonated forms of these mesoionic structures contain hydrogen atoms at the exocyclic groups.

On the Tautomeric Structure of 5‐hydroxy‐ and 5‐mercapto‐1H‐1,2,3‐triazoles: −13C NMR analysis

AbstractThe title compounds have been analyzed by 13C NMR spectroscopy and compound with the N‐3 methyl and O/S alkyl derivatives. The mesoionic structures 2a,b are rejected in favour of 1a,b on the basis of the C5=CH coupling constants and the chemical shifts. Incremental substituent effects for triazoles are discussed.

CHEMISTRY OF NITROSOIMINES. IX. ESCA STUDY OF 3-SUBSTITUTED 2-NITROSOIMINO-2,3-DIHYDROBENZOTHIAZOLES: MESOIONIC STRUCTURE

Abstract Core electron binding energies of 3-substituted 2-nitrosoimino-2,3-dihydrobenzothiazoles (1) and related compounds were measured by ESCA to show large contribution of mesoionic structures for 1 and this was also supported by observed chemical shifts (NMR) of 3-methyl groups of benzothiazolines.

Mesoionic purinone analogs. II. A PPP π‐SCF variable integral study of mesoionie analogs based upon six‐membered ring mesoionie systems

AbstractA large virtually unknown class of mesoionic structures which are isoconjugate to the purinones may be formulated as bicyclie derivatives of known six‐membered ring mesoionie compounds. These mesoionic purinone analogs have been investigated via variable‐electronegativity PPP‐SCF treatments of their π‐electron systems. The electronic structures of these analogs are compared with those of their covalent isomers and with other mesoionie purinone analogs.

Heterocyclic mesoionic structures, a novel class of monoamine oxidase inhibitors. I. Arylsynones.

Heterocyclic mesoionic structures, a novel class of monoamine oxidase inhibitors. I. Arylsynones.

ULTRAVIOLET ABSORPTION SPECTRA AND ACIDITIES OF ISOMERIC THIATRIAZOLE AND TETRAZOLE DERIVATIVES

The ultraviolet absorption spectra of 5-(substituted)amino-1,2,3,4-thiatriazoles and the corresponding isomeric 1-substituted-tetrazoline-5-thiones have been studied. The spectra and the dipole moments of the 5-(substituted)amino-1,2,3,4-thiatriazoles eliminate the possibility of meso-ionic structures for these compounds. The dipole moments of 5-amino-, 5-methylamino-, and 5-dimethylamino-1,2,3,4-thiatriazole were all high but approximately of the same value (5.77 to 5.84 D). This suggests that the amino thiatriazoles are best represented by conventional covalent structures with significant ionic resonance contributions. The thiatriazole ring system exhibits a characteristic absorption maximum at 250–255 mμ and an electron-withdrawing effect approximately equal to the tetrazolyl ring system. The tetrazolinethionolyl ring system is similarly electron-withdrawing. The relative acidities of the 1-substituted-tetrazoline-5-thiones and the 5-alkylmercaptotetrazoles have also been studied and the results support the observations made on the basis of their ultraviolet absorption spectra.