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Small Molecules with Spiro-Conjugated Cycles: Advances in Synthesis and Applications

by Elena K. Beloglazkina

Int. J. Mol. Sci. 2023, 24(24), 17584; https://doi.org/10.3390/ijms242417584 - 18 Dec 2023

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Dear Colleagues, [...] Full article

(This article belongs to the Special Issue Small Molecules with Spiro-Conjugated Cycles: Advances in Synthesis and Applications)

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24 pages, 6208 KiB

Open AccessArticle

Synthesis and Properties of (1R(S),5R(S),7R(S),8R(S))-1,8-Bis(hydroxymethyl)-6-azadispiro[4.1.4.2]tridecane-6-oxyl: Reduction-Resistant Spin Labels with High Spin Relaxation Times

by Yulia V. Khoroshunova, Denis A. Morozov, Danil A. Kuznetsov, Tatyana V. Rybalova, Yurii I. Glazachev, Elena G. Bagryanskaya and Igor A. Kirilyuk

Int. J. Mol. Sci. 2023, 24(14), 11498; https://doi.org/10.3390/ijms241411498 - 15 Jul 2023

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Abstract

Site-directed spin labeling followed by investigation using Electron Paramagnetic Resonance spectroscopy is a rapidly expanding powerful biophysical technique to study structure, local dynamics and functions of biomolecules using pulsed EPR techniques and nitroxides are the most widely used spin labels. Modern trends of [...] Read more.

Site-directed spin labeling followed by investigation using Electron Paramagnetic Resonance spectroscopy is a rapidly expanding powerful biophysical technique to study structure, local dynamics and functions of biomolecules using pulsed EPR techniques and nitroxides are the most widely used spin labels. Modern trends of this method include measurements directly inside a living cell, as well as measurements without deep freezing (below 70 K), which provide information that is more consistent with the behavior of the molecules under study in natural conditions. Such studies require nitroxides, which are resistant to the action of biogenic reductants and have high spin relaxation (dephasing) times, T_m. (1R(S),5R(S),7R(S),8R(S))-1,8-bis(hydroxymethyl)-6-azadispiro[4.1.4.2]tridecane-6-oxyl is a unique nitroxide that combines these features. We have developed a convenient method for the synthesis of this radical and studied the ways of its functionalization. Promising spin labels have been obtained, the parameters of their spin relaxation T₁ and T_m have been measured, and the kinetics of reduction with ascorbate have been studied. Full article

(This article belongs to the Special Issue Small Molecules with Spiro-Conjugated Cycles: Advances in Synthesis and Applications)

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16 pages, 2770 KiB

Open AccessArticle

N-N(+) Bond-Forming Intramolecular Cyclization of O-Tosyloxy β-Aminopropioamidoximes and Ion Exchange Reaction for the Synthesis of 2-Aminospiropyrazolilammonium Chlorides and Hexafluorophosphates

by Lyudmila Kayukova, Anna Vologzhanina, Pavel Dorovatovskii, Elmira Yergaliyeva, Asem Uzakova and Aidana Duisenali

Int. J. Mol. Sci. 2023, 24(14), 11315; https://doi.org/10.3390/ijms241411315 - 11 Jul 2023

Cited by 1 | Viewed by 2131

Abstract

Our research area is related to the spiropyrazolinium-containingcompounds, which are insufficiently studied compared with pyrazoline-containing compounds. Nitrogen-containing azoniaspiromolecules have also been well studied. In drug design and other areas, they are a priori important structures, since rigid spirocyclic scaffolds with the reduced conformational [...] Read more.

Our research area is related to the spiropyrazolinium-containingcompounds, which are insufficiently studied compared with pyrazoline-containing compounds. Nitrogen-containing azoniaspiromolecules have also been well studied. In drug design and other areas, they are a priori important structures, since rigid spirocyclic scaffolds with the reduced conformational entropy are able to organize a closely spaced area. Azoniaspirostructures are currently of wide practical interest as ionic liquids, current sources (membranes), structure-directing agents in organocatalysis, and in the synthesis of ordered ceramics. Our goal was the synthesis of 2-aminospiropyrazolilammonium chlorides and hexafluorophosphates. Our methodology is based on the tosylation of β-aminopropioamidoximes with six-membered N-heterocycles (piperidine, morpholine, thiomorpholine, and phenylpiperazine) at the β-position. 2-Aminospiropyrazolilammonium chlorides and hexafluorophosphates were obtained by the reaction of double ion substitution in the reaction of toluenesulfonates of 2-aminospiropyrazolinium compounds with an ethereal solution of HCl in ethanol and with ammonium hexafluorophosphate in ethanol in quantitative yields of 55–97%. The physicochemical characteristics of the synthesized compounds and their IR and NMR spectra are presented. The obtained salts were additionally characterized by the single-crystal XRD analysis. The presence of both axial and equatorial conformations of spirocations in solids was confirmed. 2-Aminospiropyrazolilammonium chlorides and hexafluorophosphates have weak in vitro antimicrobial activity on Gram-positive and Gram-negative bacterial lines. Full article

(This article belongs to the Special Issue Small Molecules with Spiro-Conjugated Cycles: Advances in Synthesis and Applications)

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16 pages, 7923 KiB

Open AccessArticle

3-[N,N-Bis(sulfonyl)amino]isoxazolines with Spiro-Annulated or 1,2-Annulated Cyclooctane Rings Inhibit Reproduction of Tick-Borne Encephalitis, Yellow Fever, and West Nile Viruses

by Kseniya N. Sedenkova, Artem S. Sazonov, Dmitry A. Vasilenko, Kristian S. Andriasov, Marina G. Eremenko, Yuri K. Grishin, Evgeny V. Khvatov, Alexander S. Goryashchenko, Victoria I. Uvarova, Dmitry I. Osolodkin, Aydar A. Ishmukhametov and Elena B. Averina

Int. J. Mol. Sci. 2023, 24(13), 10758; https://doi.org/10.3390/ijms241310758 - 28 Jun 2023

Cited by 1 | Viewed by 1131

Abstract

Spirocyclic compounds containing heterocyclic moieties represent promising 3D scaffolds for modern drug design. In the search for novel anti-flaviviral agents, we have obtained a series of 3-[N,N-bis(sulfonyl)amino]isoxazolines containing spiro-annulated cyclooctane rings and assessed their antiviral activity against tick-borne encephalitis (TBEV), yellow [...] Read more.

Spirocyclic compounds containing heterocyclic moieties represent promising 3D scaffolds for modern drug design. In the search for novel anti-flaviviral agents, we have obtained a series of 3-[N,N-bis(sulfonyl)amino]isoxazolines containing spiro-annulated cyclooctane rings and assessed their antiviral activity against tick-borne encephalitis (TBEV), yellow fever (YFV), and West Nile (WNV) viruses. The structural analogs of spirocyclic compounds with a single sulfonyl group or 1,2-annulated cyclooctane ring were also investigated. Almost all the studied 3-[N,N-bis(sulfonyl)amino]isoxazolines revealed antiviral activity against TBEV and WNV. The most active against TBEV was spiro-isoxazoline derivative containing p-nitrophenyl groups in the sulfonyl part (EC₅₀ 2.0 ± 0.5 μM), while the highest potency against WNV was found for the compounds with lipophilic substituents in sulfonyl moiety, naphtyl being the most favorable one (EC₅₀ 1.3 ± 0.5 μM). In summary, two novel scaffolds of anti-flaviviral agents based on N,N-bis(sulfonyl)amino]isoxazoline were proposed, and the compounds of this type demonstrated activity against TBEV and WNV. Full article

(This article belongs to the Special Issue Small Molecules with Spiro-Conjugated Cycles: Advances in Synthesis and Applications)

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14 pages, 2649 KiB

Open AccessArticle

Synthesis and Antibacterial Evaluation of Ciprofloxacin Congeners with Spirocyclic Amine Periphery

by Alexei Lukin, Kristina Komarova, Lyubov Vinogradova, Elizaveta Rogacheva, Lyudmila Kraeva and Mikhail Krasavin

Int. J. Mol. Sci. 2023, 24(2), 954; https://doi.org/10.3390/ijms24020954 - 04 Jan 2023

Cited by 3 | Viewed by 1622

Abstract

The synthesis of novel fluoroquinolones, congeners of ciprofloxacin, which was inspired by earlier work on spirocyclic ciprofloxacin, is described. An antibacterial evaluation of the 11 fluoroquinolone compounds synthesized against the ESKAPE panel of pathogens in comparison with ciprofloxacin revealed that the more compact [...] Read more.

The synthesis of novel fluoroquinolones, congeners of ciprofloxacin, which was inspired by earlier work on spirocyclic ciprofloxacin, is described. An antibacterial evaluation of the 11 fluoroquinolone compounds synthesized against the ESKAPE panel of pathogens in comparison with ciprofloxacin revealed that the more compact spirocycles in the fluoroquinolone periphery resulted in active compounds, while larger congeners gave compounds that displayed no activity at all. In the active cohort, the level of potency was comparable to that of ciprofloxacin. However, the spectrum of antibacterial activity was quite different, as the new compounds showed no activity against Pseudomonas aeruginosa. Among the prepared and tested compounds, the broadest range of activity (five pathogens of the six in the ESKAPE panel) and the highest level of activity were demonstrated by 1-yclopropyl-7-[8-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)-6-azaspiro[3.4]oct-6-yl]-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, which is the lead compound nominated for further characterization and development. Full article

(This article belongs to the Special Issue Small Molecules with Spiro-Conjugated Cycles: Advances in Synthesis and Applications)

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17 pages, 4605 KiB

Open AccessArticle

Synthesis, Structure and Stereochemistry of Dispirocompounds Based on Imidazothiazolotriazine and Pyrrolidineoxindole

by Alexei N. Izmest’ev, Valentina A. Karnoukhova, Alexander A. Larin, Angelina N. Kravchenko, Leonid L. Fershtat and Galina A. Gazieva

Int. J. Mol. Sci. 2022, 23(22), 13820; https://doi.org/10.3390/ijms232213820 - 10 Nov 2022

Cited by 3 | Viewed by 1136

Abstract

Methods for the synthesis of two types of isomeric dispirocompounds based on imidazothiazolotriazine and pyrrolidineoxindole, differing in the structure of imidazothiazolotriazine fragment, namely, linear dispiro[imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazine-6,3′-pyrrolidine- 4′,3″-indolines] and angular dispiro[imidazo[4,5-e]thiazolo[2,3-c][1,2,4]triazine-7,3′-pyrrolidine-4′,3″-indolines] were proposed. The first method relies [...] Read more.

Methods for the synthesis of two types of isomeric dispirocompounds based on imidazothiazolotriazine and pyrrolidineoxindole, differing in the structure of imidazothiazolotriazine fragment, namely, linear dispiro[imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazine-6,3′-pyrrolidine- 4′,3″-indolines] and angular dispiro[imidazo[4,5-e]thiazolo[2,3-c][1,2,4]triazine-7,3′-pyrrolidine-4′,3″-indolines] were proposed. The first method relies on a 1,3-dipolar cycloaddition of azomethine ylides generated in situ from paraformaldehyde and N-alkylglycine derivatives to the corresponding oxindolylidene derivatives of imidazothiazolotriazine. The cycloaddition leads to a mixture of two diastereomers resulted from anti- and syn-approaches of azomethine ylide in approximately a 1:1 ratio, which were separated by column chromatography. Another method consists in rearrangement of linear dispiro[imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazine-6,3′-pyrrolidine-4′,3″-indolines] into hitherto unavailable angular dispiro[imidazo[4,5-e]thiazolo[2,3-c]-[1,2,4]triazine-7,3′-pyrrolidine-4′,3″-indolines] upon treatment with KOH. It was found that the anti-diastereomer of linear type underwent rearrangement into the isomeric angular syn-diastereomer, while the rearrangement of the linear syn-diastereomer gave the angular anti-diastereomer. Full article

(This article belongs to the Special Issue Small Molecules with Spiro-Conjugated Cycles: Advances in Synthesis and Applications)

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24 pages, 5039 KiB

Open AccessArticle

11H-Benzo[4,5]imidazo[1,2-a]indol-11-one as a New Precursor of Azomethine Ylides: 1,3-Dipolar Cycloaddition Reactions with Cyclopropenes and Maleimides

by Alexander S. Filatov, Yulia A. Pronina, Stanislav I. Selivanov, Stanislav V. Shmakov, Anton A. Uspenski, Vitali M. Boitsov and Alexander V. Stepakov

Int. J. Mol. Sci. 2022, 23(21), 13202; https://doi.org/10.3390/ijms232113202 - 30 Oct 2022

Cited by 3 | Viewed by 1495

Abstract

The possibility of generating azomethine ylides from 11H-benzo[4,5]imidazo[1,2-a]indol-11-one and amino acids is shown for the first time. Based on the cycloaddition reactions of these azomethine ylides with cyclopropenes and maleimides, cyclopropa[a]pyrrolizines, 3-azabicyclo[3.1.0]hexanes, and pyrrolo[3,4-a]pyrrolizines spiro-fused with a benzo[4,5]imidazo[1,2-a]indole fragment were synthesized. [...] Read more.

The possibility of generating azomethine ylides from 11H-benzo[4,5]imidazo[1,2-a]indol-11-one and amino acids is shown for the first time. Based on the cycloaddition reactions of these azomethine ylides with cyclopropenes and maleimides, cyclopropa[a]pyrrolizines, 3-azabicyclo[3.1.0]hexanes, and pyrrolo[3,4-a]pyrrolizines spiro-fused with a benzo[4,5]imidazo[1,2-a]indole fragment were synthesized. Spirocyclic compounds were obtained in moderate to good yields, albeit with poor diastereoselectivity. Density functional theory calculations were performed to obtain an insight into the mechanism of the 1,3-dipolar cycloaddition of 11H-benzo[4,5]imidazo[1,2-a]indol-11-one-derived azomethine ylides to cyclopropenes. The cytotoxic activity of some of the obtained cycloadducts against the human erythroleukemia (K562) cell line was evaluated in vitro by MTS-assay. Full article

(This article belongs to the Special Issue Small Molecules with Spiro-Conjugated Cycles: Advances in Synthesis and Applications)

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19 pages, 4048 KiB

Open AccessArticle

Selective and Reversible 1,3-Dipolar Cycloaddition of 2-(2-Oxoindoline-3-ylidene)acetates with Nitrones in the Synthesis of Functionalized Spiroisoxazolidines

by Dmitriy D. Karcev, Mariia M. Efremova, Alexander P. Molchanov, Nikolai V. Rostovskii, Mariya A. Kryukova, Alexander S. Bunev and Dmitry A. Khochenkov

Int. J. Mol. Sci. 2022, 23(20), 12639; https://doi.org/10.3390/ijms232012639 - 20 Oct 2022

Cited by 3 | Viewed by 1474

Abstract

The 1,3-dipolar cycloaddition of 2-(2-oxoindoline-3-ylidene)acetates with functionalized aldo- and ketonitrones proceeds with good selectivity to provide new highly functionalized 5-spiroisoxazolidines. A characteristic feature of these reactions is reversibility that allows for the control of the diastereoselectivity of cycloaddition. The reduction of obtained adducts [...] Read more.

The 1,3-dipolar cycloaddition of 2-(2-oxoindoline-3-ylidene)acetates with functionalized aldo- and ketonitrones proceeds with good selectivity to provide new highly functionalized 5-spiroisoxazolidines. A characteristic feature of these reactions is reversibility that allows for the control of the diastereoselectivity of cycloaddition. The reduction of obtained adducts using zinc powder in acetic acid leads to 1,3-aminoalcohols or spirolactones. For a number of the spiro compounds obtained, anticancer activity was found. Full article

(This article belongs to the Special Issue Small Molecules with Spiro-Conjugated Cycles: Advances in Synthesis and Applications)

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24 pages, 10483 KiB

Open AccessArticle

Spiropyran/Merocyanine Amphiphile in Various Solvents: A Joint Experimental–Theoretical Approach to Photophysical Properties and Self-Assembly

by Vladyslav Savchenko, Nino Lomadze, Svetlana Santer and Olga Guskova

Int. J. Mol. Sci. 2022, 23(19), 11535; https://doi.org/10.3390/ijms231911535 - 29 Sep 2022

Cited by 3 | Viewed by 2344

Abstract

This joint experimental-theoretical work focuses on molecular and photophysical properties of the spiropyran-containing amphiphilic molecule in organic and aqueous solutions. Being dissolved in tested organic solvents, the system demonstrates positive photochromism, i.e., upon UV stimulus the colorless spiropyran form is transformed into colorful [...] Read more.

This joint experimental-theoretical work focuses on molecular and photophysical properties of the spiropyran-containing amphiphilic molecule in organic and aqueous solutions. Being dissolved in tested organic solvents, the system demonstrates positive photochromism, i.e., upon UV stimulus the colorless spiropyran form is transformed into colorful merocyanine isomer. However, the aqueous solution of the amphiphile possesses a negative photochromism: the orange-red merocyanine form becomes thermodynamically more stable in water, and both UV and vis stimuli lead to the partial or complete photobleaching of the solution. The explanation of this phenomenon is given on the basis of density functional theory calculations and classical modeling including thermodynamic integration. The simulations reveal that stabilization of merocyanine in water proceeds with the energy of ca. 70 kJ mol

^{- 1}

, and that the Helmholtz free energy of hydration of merocyanine form is 100 kJ mol

^{- 1}

lower as compared to the behavior of SP isomer in water. The explanation of such a difference lies in the molecular properties of the merocyanine: after ring-opening reaction this molecule transforms into a zwitterionic form, as evidenced by the electrostatic potential plotted around the opened form. The presence of three charged groups on the periphery of a flat conjugated backbone stimulates the self-assembly of merocyanine molecules in water, ending up with the formation of elongated associates with stack-like building blocks, as shown in molecular dynamics simulations of the aqueous solution with the concentration above critical micelle concentration. Our quantitative evaluation of the hydrophilicity switching in spiropyran/merocyanine containing surfactants may prompt the search for new systems, including colloidal and polymeric ones, aiming at remote tuning of their morphology, which could give new promising shapes and patterns for the needs of modern nanotechnology. Full article

(This article belongs to the Special Issue Small Molecules with Spiro-Conjugated Cycles: Advances in Synthesis and Applications)

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23 pages, 7834 KiB

Open AccessArticle

Biological Evaluation of 3-Azaspiro[Bicyclo[3.1.0]Hexane-2,5′-Pyrimidines] as Potential Antitumor Agents

by Stanislav V. Shmakov, Diana K. Latypova, Tatiana V. Shmakova, Artem A. Rubinshtein, Mark V. Chukin, Sergei G. Zhuravskii, Nickolay A. Knyazev, Alexander V. Stepakov, Michael M. Galagudza and Vitali M. Boitsov

Int. J. Mol. Sci. 2022, 23(18), 10759; https://doi.org/10.3390/ijms231810759 - 15 Sep 2022

Cited by 3 | Viewed by 1739

Abstract

A series of heterocyclic compounds containing spirofused barbiturate and 3-azabicyclo[3.1.0]hexane frameworks have been studied as potential antitumor agents. Antiproliferative activity of products was screened in human erythroleukemia (K562), T lymphocyte (Jurkat), and cervical carcinoma (HeLa) as well as mouse colon carcinoma (CT26) and [...] Read more.

A series of heterocyclic compounds containing spirofused barbiturate and 3-azabicyclo[3.1.0]hexane frameworks have been studied as potential antitumor agents. Antiproliferative activity of products was screened in human erythroleukemia (K562), T lymphocyte (Jurkat), and cervical carcinoma (HeLa) as well as mouse colon carcinoma (CT26) and African green monkey kidney epithelial (Vero) cell lines. The most effective among the screened compounds show IC₅₀ in the range from 4.2 to 24.1 μM for all tested cell lines. The screened compounds have demonstrated a significant effect of the distribution of HeLa and CT26 cells across the cell cycle stage, with accumulation of cells in SubG1 phase and induced apoptosis. It was found, using a confocal microscopy, that actin filaments disappeared and granular actin was distributed diffusely in the cytoplasm of up to 90% of HeLa cells and up to 64% of CT26 cells after treatment with tested 3-azaspiro[bicyclo [3.1.0]hexane-2,5′-pyrimidines]. We discovered that the number of HeLa cells with filopodium-like membrane protrusions was reduced significantly (from 91% in control cells to 35%) after treatment with the most active compounds. A decrease in cell motility was also noticed. Preliminary in vivo experiments on the impact of the studied compounds on the dynamics of CT26 tumor growth in Balb/C mice were also performed. Full article

(This article belongs to the Special Issue Small Molecules with Spiro-Conjugated Cycles: Advances in Synthesis and Applications)

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16 pages, 12169 KiB

Open AccessCommunication

Dispirooxindole-β-Lactams: Synthesis via Staudinger Ketene-Imine Cycloaddition and Biological Evaluation

by Vadim E. Filatov, Dmitrii A. Iuzabchuk, Viktor A. Tafeenko, Yuri K. Grishin, Vitaly A. Roznyatovsky, Dmitrii A. Lukianov, Yulia A. Fedotova, Maxim A. Sukonnikov, Dmitry A. Skvortsov, Nikolai V. Zyk and Elena K. Beloglazkina

Int. J. Mol. Sci. 2022, 23(12), 6666; https://doi.org/10.3390/ijms23126666 - 15 Jun 2022

Cited by 2 | Viewed by 2188

Abstract

In this work, we present the first synthesis of dispirooxindole-β-lactams employing optimized methodology of one-pot Staudinger ketene-imine cycloaddition with N-aryl-2-oxo-pyrrolidine-3-carboxylic acids as the ketene source. Spiroconjugation of indoline-2-one with β-lactams ring is considered to be able to provide stabilization and wide scope of [...] Read more.

In this work, we present the first synthesis of dispirooxindole-β-lactams employing optimized methodology of one-pot Staudinger ketene-imine cycloaddition with N-aryl-2-oxo-pyrrolidine-3-carboxylic acids as the ketene source. Spiroconjugation of indoline-2-one with β-lactams ring is considered to be able to provide stabilization and wide scope of functionalization to resulting scaffolds. The dispipooxindoles obtained demonstrated medium cytotoxicity in the MTT test on A549, MCF7, HEK293, and VA13 cell lines, and one of the compounds demonstrated antibacterial activity against E. coli strain LPTD. Full article

(This article belongs to the Special Issue Small Molecules with Spiro-Conjugated Cycles: Advances in Synthesis and Applications)

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