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One‐pot synthesis of spirooxindoles bearing α‐metylene‐γ‐butyrolactone moiety has been carried out by the reaction of Morita–Baylis–Hillman (MBH) carbonates of isatins and paraformaldehyde in the presence of 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) in refluxing 1,2‐dichloroethane in moderate yields. The reaction proceeded via (i) the formation of resonance‐stabilized N‐ylide from DBU and the MBH carbonate of isatin, (ii) a selective γ‐attack of N‐ylide to formaldehyde, (iii) lactonization to liberate methoxide ion, (iv) addition of methoxide ion to the iminium part of DBU, (v) intramolecular hydride transfer via a six‐membered transition state, and finally (vi) elimination of DBU. [ABSTRACT FROM AUTHOR]

Hybridization of spirooxindole with different pharmacophores such as triazole and heterocycle such as thiophene and furan moiety was achieved by the [3 + 2] cycloaddition (32CA) reaction approach. Structural investigations of the compounds 4a and 4b were performed using X-ray single crystal structure determinations and Hirshfeld analysis. Both compounds crystallized in monoclinic crystal system. The space group is P21/c for 4a and P21/n for 4b. The crystal parameters are a = 10.2619(3) Å, b = 13.6776(3) Å, c = 10.9318(3), β = 116.640(4)° for the former while a = 13.0012(1) Å, b = 14.9692(1) Å, c = 14.1178(1) Å, β = 97.101(1)° for the latter. In both compounds, the aryl group and the triazole moieties are twisted from one another. The twist angle is 84.75˚for 4a while 86.64˚ for 4b. Based on Hirshfeld calculations, the Cl...H, O...H, N...H and C...H non-covalent interactions in 4a while the O...H interactions in 4b are the most important. The molecular mechanism of the key 32CA reaction between the in situ generated azomethine ylides and the corresponding chalcones has been studied within the Molecular Electron Density Theory (MEDT). The MEDT study reveals that the low activation energies and high experimental selectivity are the result of the supernucleophilic character of the ylides and the strong electrophilicity of the chalcones, which favour the process through a high polar character. This high polar character accounts for the total endo selectivity experimentally found. [ABSTRACT FROM AUTHOR]

Spirooxindoles represent a special scaffold for pharmaceuticals and natural products, and significant advancements have been achieved in their synthesis in recent years. Among these, transition metal catalysis, particularly copper catalysis, has emerged as an efficient and reliable method for the synthesis of spirooxindoles. Based on different reaction types, two distinct substrate types have been summarized and classified by us for constructing spirooxindole scaffolds via intramolecular and intermolecular annulations. This review outlines the latest advancements in copper‐catalyzed cyclization reactions for synthesizing spirooxindoles and provides detailed insights into the types of annulation reactions and their possible reaction mechanisms. [ABSTRACT FROM AUTHOR]

Abstract Hybridization of spirooxindole with different pharmacophores such as triazole and heterocycle such as thiophene and furan moiety was achieved by the [3 + 2] cycloaddition (32CA) reaction approach. Structural investigations of the compounds 4a and 4b were performed using X-ray single crystal structure determinations and Hirshfeld analysis. Both compounds crystallized in monoclinic crystal system. The space group is P2 1 /c for 4a and P2 1 /n for 4b. The crystal parameters are a = 10.2619(3) Å, b = 13.6776(3) Å, c = 10.9318(3), β = 116.640(4)° for the former while a = 13.0012(1) Å, b = 14.9692(1) Å, c = 14.1178(1) Å, β = 97.101(1)° for the latter. In both compounds, the aryl group and the triazole moieties are twisted from one another. The twist angle is 84.75˚for 4a while 86.64˚ for 4b. Based on Hirshfeld calculations, the Cl…H, O…H, N…H and C…H non-covalent interactions in 4a while the O…H interactions in 4b are the most important. The molecular mechanism of the key 32CA reaction between the in situ generated azomethine ylides and the corresponding chalcones has been studied within the Molecular Electron Density Theory (MEDT). The MEDT study reveals that the low activation energies and high experimental selectivity are the result of the supernucleophilic character of the ylides and the strong electrophilicity of the chalcones, which favour the process through a high polar character. This high polar character accounts for the total endo selectivity experimentally found.

Abstract The synthesis of Octakis [3- (3-amino propyl triethoxysilane) propyl] octa-silsesquioxane (APTPOSS), a derivative of polyhedral oligomeric silsesquioxane, was utilized to produce an efficient nanocomposite. MNPs@Silica/APTPOSS was characterized through scanning electron microscopy, Fourier transform infrared spectroscopy, vibrating sample magnetometry, X-ray diffraction, and Thermogravimetric analysis. These magnetic nanoparticles, a combination of organic-inorganic hybrid polyhedral oligomeric silsesquioxane, were utilized as a proficient heterogeneous catalyst in the one-pot synthesis of spirooxindoles derivatives. Furthermore, they could be swiftly isolated and reused six times while maintaining their catalytic efficiency.

The synthesis of Octakis [3- (3-amino propyl triethoxysilane) propyl] octa-silsesquioxane (APTPOSS), a derivative of polyhedral oligomeric silsesquioxane, was utilized to produce an efficient nanocomposite. MNPs@Silica/APTPOSS was characterized through scanning electron microscopy, Fourier transform infrared spectroscopy, vibrating sample magnetometry, X-ray diffraction, and Thermogravimetric analysis. These magnetic nanoparticles, a combination of organic-inorganic hybrid polyhedral oligomeric silsesquioxane, were utilized as a proficient heterogeneous catalyst in the one-pot synthesis of spirooxindoles derivatives. Furthermore, they could be swiftly isolated and reused six times while maintaining their catalytic efficiency. [ABSTRACT FROM AUTHOR]

The present report demonstrates an efficient use of bentonite clay to bring about multicomponent synthesis of substituted spirooxindoles 4a-h in Water/ ethanol solvent system under the mild reaction conditions. [ABSTRACT FROM AUTHOR]

A straightforward [3+2] annulation method for synthesizing bisspiro(oxindole) derivatives has been developed by using isatin‐derived Morita‐Baylis‐Hillman carbonates and p‐quinone methides (p‐QMs) with 4‐dimethylaminopyridine (DMAP) as the catalyst. The optimized protocol in dichloromethane (DCM) solvent achieves good yields (up to 87 %) and diastereoselectivity (>20 : 1). The versatility of the method is shown through the synthesis of various derivatives, including chiral variants with up to 82 % ee. The intermediates were captured by HRMS, and a plausible reaction pathway was proposed. [ABSTRACT FROM AUTHOR]

The exploration of the complex chemical diversity of bicyclo[n.1.1]alkanes and their use as benzene bioisosteres has garnered significant attention over the past two decades. Regiodivergent syntheses of thiabicyclo[4.1.1]octanes (S‐BCOs) and highly substituted bicyclo[2.1.1]hexanes (BCHs) using a Lewis acid‐catalyzed formal cycloaddition of bicyclobutanes (BCBs) and 3‐benzylideneindoline‐2‐thione derivatives have been established. The first hetero‐(4+3) cycloaddition of BCBs, catalyzed by Zn(OTf)2, was achieved with a broad substrate scope under mild conditions. In contrast, the less electrophilic BCB ester undergoes a Sc(OTf)3‐catalyzed [2π+2σ] reaction with 1,1,2‐trisubstituted alkenes, yielding BCHs with a spirocyclic quaternary carbon center. Control experiments and preliminary theoretical calculations suggest that the diastereoselective [2π+2σ] product formation may involve a concerted cycloaddition between a zwitterionic intermediate and E‐1,1,2‐trisubstituted alkenes. Additionally, the hetero‐(4+3) cycloaddition may involve a concerted nucleophilic ring‐opening mechanism. [ABSTRACT FROM AUTHOR]

This research showcases a methodology for crafting highly intricate hydrocarbazole spirooxindole frameworks endowed with three consecutive stereocenters. Achieved through a trienamine‐catalyzed remote [4+2]‐annulation reaction, the method's significance is underscored by synthesizing an extensive array of library molecules (up to 27 examples). These compounds mimic natural products, exhibit good yields (up to 85 %), exceptional diastereo‐, enantiomeric ratios (up to 17 : 1 dr, 99.9 : 0.1 er). The practicality of our strategy is further exemplified by successfully synthesizing a hexahydroepoxyethanocarbazole spirooxindole scaffold via a sequential [4+2]‐annulation/‐reduction/epoxidation‐cyclization reaction, achieving a 75 % overall yield, maintaining an excellent stereoselectivity (99.5 : 0.5 er). [ABSTRACT FROM AUTHOR]

Forty-one derivatives of spirooxindoles, active against HCT-116 colon cancer cells, underwent pharmacophore-based 3D-QSAR analysis to understand their correlation with anti-cancer activity. The study identified a seven-point pharmacophore model (ADHHRRR1) and QSAR models, offering insights for lead optimization and novel analogue design, thus advancing anti-cancer drug discovery. This research underscores the value of molecular modeling in elucidating structure-activity relationships and enhancing drug development efforts.

We report here a practical protocol for the asymmetric synthesis of amino acids (AAs) with a CF3‐containing 3,2'‐pyrrolidinyl spirooxindole skeleton with three defined carbon stereocenters via a sequential Michael/Mannich [3+2]‐cycloaddition reaction. The coupling of a robust and stereochemically stable chiral dehydroalanine Ni(II) complex with various N‐2,2,2‐trifluoroethylisatin ketimines in the presence of triethylamine afforded a library of single diastereomeric complexes with a 3,2'‐pyrrolidinyl spirooxindole moiety in 36–71% yields. In particular, the change of base to LiOH allowed to obtain predominantly the Michael addition product in 76% yield. Finally, the decomposition of the obtained Ni(II) complexes with 3 N HCl provided the target complex AA with a 3,2'‐pyrrolidinyl spirooxindole core and (2S,4R)‐2,4‐diamino‐5,5,5‐trifluoropentanoic acid – an (S)‐norvaline derivative, together with easy recovery of the chiral auxiliary ligand for the synthesis of the starting dehydroalanine complex. [ABSTRACT FROM AUTHOR]

Spirocyclic compounds have always attracted attention due to their presence as a structural core in a wide variety of natural and bioactive molecules and to exhibit pharmaceutical properties. An asymmetric synthesis of spiro[indoline‐3,4′‐pyrano[2,3‐c]pyrazoles] via Michael addition of trifluoromethyl substituted pyrazolone to isatylidene ethyl cyanoacetate derivatives was conducted with excellent enantioselectivities up to 99 % and up to 97 % isolated yield at room temperature with using 2 mol % of bifunctional quinine derived squaramide organocatalysts. [ABSTRACT FROM AUTHOR]

Spirooxindole is a compound with a unique framework and broad bioactivities in medicine. In this study, we have reviewed various approaches or methods in synthesizing spirooxindole derivatives focused on green synthesis. Synthesis of spirooxindoles is mainly carried out through multicomponent reactions combined with various green approaches such as the use of heterogeneous catalysts (nano-sized, magnetic, metal-complex, and metal-organic framework catalysts), deep eutectic solvent, solvent-free reactions, catalyst-free reactions, as well as the use of ultrasonic and microwaves irradiation. The green method is carried out in addition to obtaining high yields, it also offers reductions in the use of hazardous chemicals, energy use, purification processes, and waste generation. As a result, green synthesis methods in the synthesis of spirooxindole derivatives are more environmentally friendly. [ABSTRACT FROM AUTHOR]

In the present research, a novel, efficient, and green nanocatalyst has been afforded by coating Fe3O4 nanoparticles with chitosan through simple and readily available chemicals. Fourier-transform infrared spectroscopy, X-ray diffraction, scanning electron microscopy, dynamic light scattering, vibrating sample magnetometer, and thermogravimetric analyses were used to describe this nanocatalyst. The catalytic performance of the Fe3O4@chitosan heterogeneous nanocatalyst was investigated in an environmentally benign and efficacious fabrication of a variety of spirooxindole and spirochromene derivatives in high yields via employing three-component reactions of malononitrile, dimedone, and isatin in a solvent-free medium (Method A) and under ultrasonic conditions in EtOH/H2O (Method B) at ambient temperature. The achieved nanocatalyst could be easily removed from the mixture of the reaction and was recyclable seven times via a simple external magnet without appreciable loss in catalytic proficiency. Several other advantages of this methodology were environmental friendliness, simple operation, excellent yields, economical handling, and easy workup. [ABSTRACT FROM AUTHOR]

Spirooxindoles are privileged scaffolds in diverse bioactive natural products and pharmaceuticals, significant achievements for the construction of these molecules have thus been made in the past years. Among them, organocatalysis, in particular, nucleophilic Lewis base catalysis, has recently emerged as an efficient and reliable method for the preparation of diverse and valuable functionalized spirooxindoles. According to different kinds of nucleophilic catalysts, we summarize and classify three catalytic strategies; these are tertiary amine‐catalyzed cycloadditions, NHC‐catalyzed cycloadditions, and tertiary phosphine‐catalyzed cycloadditions, respectively. Through these methods, potential bioactive spirooxindole skeletons owning various functional groups can be produced to enrich the small organic molecule library. In this review, we describe a comprehensive and updated advances of nucleophilic Lewis base catalytic cycloaddition reactions for the construction of spirooxindoles. Meanwhile, the related mechanism and the application of these annulation strategies in natural product total synthesis will be highlighted in detail. [ABSTRACT FROM AUTHOR]

In a sustained search for novel potential drug candidates with multispectrum therapeutic application, a series of novel spirooxindoles was designed and synthesized via regioselective three-component reaction between isatin derivatives, 2-phenylglycine and diverse arylidene-imidazolidine-2,4-diones (Hydantoins). The suggested stereochemistry was ascertained by an X-ray diffraction study and NMR spectroscopy. The resulting tetracyclic heterocycles were screened for their in vitro and in vivo anti-inflammatory and analgesic activity and for their in vitro antimicrobial potency. In vitro antibacterial screening revealed that several derivatives exhibited remarkable growth inhibition against different targeted microorganisms. All tested compounds showed excellent activity against the Micrococccus luteus strain (93.75 µg/mL ≤ MIC ≤ 375 µg/mL) as compared to the reference drug tetracycline (MIC = 500 µg/mL). Compound 4e bearing a p-chlorophenyl group on the pyrrolidine ring exhibited the greatest antifungal potential toward Candida albicans and Candida krusei (MIC values of 23.43 µg/mL and 46.87 µg/mL, respectively) as compared to Amphotericin B (MIC = 31.25 and 62.50 µg/mL, respectively). The target compounds were also tested in vitro against the lipoxygenase-5 (LOX-5) enzyme. Compounds 4i and 4l showed significant inhibitory activity with IC50 = 1.09 mg/mL and IC50 = 1.01 mg/mL, respectively, more potent than the parent drug, diclofenac sodium (IC50 = 1.19 mg/mL). In addition, in vivo evaluation of anti-inflammatory and analgesic activity of these spirooxindoles were assessed through carrageenan-induced paw edema and acetic acid-induced writhing assays, respectively, revealing promising results. In silico molecular docking and predictive ADMET studies for the more active spirocompounds were also carried out. [ABSTRACT FROM AUTHOR]

A new series of spirooxindoles based on benzimidazole, triazole, and isatin moieties were synthesized via a [3+2] cycloaddition reaction protocol in one step. The single X-ray crystal structure of the intermediate triazole-benzimidazole 4 was solved. The new chemical structures of these spirooxindole molecules have been achieved for the first time. The final synthesized chemical architecture has differently characterized electronic effects. An MEDT study of the key 32CA reaction between in situ generated azomethine ylide (AY) and chalcones explained the low reaction rates and the total selectivities observed. The supernucleophilic character of AY and the strong electrophilicity of chalcones favor these reactions through a highly polar two-stage one-step mechanism in which bond formation at the β-conjugated carbon of the chalcones is more advanced. The present combined experimental and theoretical study reports the synthesis of new spirooxindoles with potential biological activities and fully characterizes the molecular mechanisms for their formation through the key 32CA reaction step. [ABSTRACT FROM AUTHOR]

[40] Recently, pyrazolone-based MBH carbonates have emerged as versatile precursors to access spiropyrazolone scaffolds. Keywords: annulation; spiropyrazolones; diastereoselectivity; Morita-Baylis-Hillman carbonates; spirooxindoles EN annulation spiropyrazolones diastereoselectivity Morita-Baylis-Hillman carbonates spirooxindoles 1732 1738 7 08/18/23 20230901 NES 230901 Graph The construction of spiro carbocyclic/heterocyclic structures has received enormous attention from synthetic and medicinal-chemistry researchers in recent decades. Under the optimized reaction conditions, the pyrazolone MBH carbonates B 1a b - B c b reacted efficiently with the 3-methyleneoxindoles B 2a b - B v b to afford the corresponding spiropyrazolone oxindole derivatives B 3a b - B x b in good to excellent yields (up to 98%) and with very high diastereoselectivities (dr 99:1) (Scheme 1). [36] Despite these recent advances in synthesizing spiropyrazolone-fused oxindole derivatives, few methods have been described for the synthesis of a spirocyclic molecule bearing three different scaffolds, such as pyrazolone, oxindole, and cyclopentene, in a diastereoselective manner. [Extracted from the article]

Heteropoly acids as nontoxic, dual Lewis–Brønsted acids with high thermal stability can develop acid‐catalyzed reactions. Combining these catalysts with other materials is of great interest to enhance their efficiency and capability. Despite all the outstanding properties of heteropoly acids, their solubility in water and most organic solvents limits their application. So, in presented research, immobilization of phosphomolybdic acid (PMA) on prepared N‐doped graphene oxide (NGO/PMA) was done to synthesize a solid acid, green and effective catalyst for the multicomponent synthesis of three kinds of spirooxindole structures. The preparation of new NGO‐based solid acid catalyst was performed through a three‐step method and identified by FTIR, TEM, mapping elemental analysis, SEM, EDX, and XRD techniques. Reusability of the catalyst, short reaction times (1:20–2 h), green condition, and easy workup as well as high yield of products (90–95%) are some merits of this research. [ABSTRACT FROM AUTHOR]

The stereochemistry of the 1,3-dipolar cycloaddition reaction of azomethine ylides to oxindolylidene derivatives of imidazo[4,5-e]-thiazolo[2,3-c][1,2,4]triazine leading to a mixture of diastereomeric derivatives of dispiro[imidazothiazolotriazine-7,3'-pyrrolidine-4',3''-oxindole] was studied. It was shown that the corresponding syn- and anti-stereoisomers can be isolated individually by fractional crystallization from reaction mixtures without the use of chromatographic methods. [ABSTRACT FROM AUTHOR]

Synthesis of spirooxindole derivatives was achieved by combining Knoevenagel condensation and Michael addition between isatin, malononitrile, and dimedone or cyclohexan-1,3-dione in presence of ammonium acetate by simple stirring in ethanol at room temperature. Spirooxindole derivatives possess promising biological activities like antitumor, antifungal, antimalarial, and anti-HIV. The analytically pure spirooxindoles formed in a concise reaction time without recrystallization or column chromatography. This method is safe and avoids the use of toxic chemicals and excess consumption of energy. [ABSTRACT FROM AUTHOR]

A divergent reaction of indoline‐derived azadienes with α‐bromohydroxamates for the selective synthesis of spiro‐indolinepyrrolidinones and indoline‐fused diazepinones was disclosed. This reaction sequence involved an initial formation of five‐membered spirocyclic products followed by an intramolecular ring‐opening and ring expansion to produce seven‐membered diazepinones. We demonstrated that controlling the reaction time could modulate the reaction pathway for formation of different molecular frameworks for the same set of substrates. Based on the experimental results, the reaction mechanism was also discussed and proposed to explain the phenomena observed in the process. [ABSTRACT FROM AUTHOR]

In this study, the 2‐oxospiro[indoline‐3,4′‐pyran]‐5′‐carbonitrile derivatives were synthesized, crystallized, and their molecular geometries were established by the SCXRD method. The significance of weak intermolecular interactions in the self‐assembly of 2‐oxospiro[indoline‐3,4′‐pyran]‐5′‐carbonitriles was then investigated. The supramolecular framework analysis indicated that 2‐oxospiro[indoline‐3,4′‐pyran]‐5′‐carbonitriles establish their network in self‐assembly mainly by N−H⋅⋅⋅O, N−H⋅⋅⋅N, C−H⋅⋅⋅O, C−H⋅⋅⋅C, C−H⋅⋅⋅N, and C−H⋅⋅⋅π interactions. The energy framework analysis revealed the dominant contribution of electrostatic energy in the crystal packing of the titled compounds. The PASS prediction of the titled compounds has shown a reasonably good affinity towards Insulin‐regulated aminopeptidase. Further, the molecular docking study with Insulin‐regulated aminopeptidase receptor has shown the higher affinity of the titled compounds to the zinc binding pocket over the other pockets. [ABSTRACT FROM AUTHOR]

A novel nano-wheat bran-OSO3H catalyst prepared from mesoporous wheat bran as a support treated with chlorosulfonic acid (ClSO3H) has been proposed for the synthesis of spirooxindole derivatives as an eco-friendly procedure. This catalyst is characterized by FT-IR, FE-SEM, EDX and DLS. The FE-SEM results confirmed the size of the nano-wheat bran-OSO3H catalyst below 50 nm. The efficiency of this solid acid catalyst was investigated in one-pot, three-component condensation reactions with malononitrile, isatin and cyclohexanedione derivatives under solvent-free conditions. As a result, spirooxindole derivatives were produced under facile conditions in high yield (89–96%) and high rate (10 min) using nano-wheat bran-OSO3H as a recyclable agri-food waste catalyst. [ABSTRACT FROM AUTHOR]

Herein, we present a one‐pot, three‐component synthesis of spirooxindole‐oxofuran carboxylate derivatives (4 a–d) through the Huisgen reaction. The newly synthesized spirocyclic compounds were tested for in vitroantiproliferative efficacy against 60 human cancer cell lines at the National Cancer Institute (NCI) in the United States. The screening results indicated that two spirooxindole compounds, 4 b and4 c, possessed the strongest anti‐cancer efficacy in terms of percentage growth inhibition (% GI), with values of 34.17 and 38.19 at 10−5 M concentration against the CNS cancer panel's SNB‐75 cell line, respectively. Furthermore, molecular docking investigations demonstrated the binding affinity for the P2Y12 receptor. The compound 4 c which exhibited strong antiproliferative activity with high binding energies might therefore, serve as a potential lead molecule for the development of more effective anti‐cancer agents. [ABSTRACT FROM AUTHOR]

3-Isothiocyanato oxindoles are a class of important building blocks which have been widely used in the synthesis of structurally diverse enantioenriched spirooxindoles. In this short review, it is attempted to cover the recent synthetic aspects of 3-isothiocyanato oxindoles participated cascade cyclizations in the last few years (i.e., from 2017 to 2022), with an emphasis on formal [3+2] cycloaddition reactions. 1 Introduction 2 Organocatalyzed Formal [3+2] Cycloaddition of 3-Isothiocyanato Oxindoles 3 Lewis Acid Catalyzed Formal [3+2] Cycloaddition of 3-Isothiocyanato Oxindoles 4 Conclusions [ABSTRACT FROM AUTHOR]

Spirocyclic compounds, particularly spirooxindoles that comprise a tetrahedral sp3‐hybridized carbon atom at the C‐3 position of an orthogonally shaped bicyclic structure have recently received increasing attention in drug discovery and development, besides their major potential in natural products and synthetic organic chemistry. They are found to be the major structural constituents of many alkaloids, and key active building blocks for the construction of various pharmaceutically significant molecules. On the other hand, with the increasing awareness of people about protecting their health and the living environment from the pollution caused by chemical laboratories and industry, the development of a synthetic method that provides alternatives to the traditional one by introducing atom economical sustainable processes is of scientifically and technically demanding but challenging. To address these concerns and inspired by the natural photosynthesis process, recently visible light‐induced chemistry appears to be a highly economic, sustainable, and alternative approach to organic synthesis. The present mini‐review aims to highlight the recent progress accomplished in the straightforward construction of spirooxindoles accelerated by visible light irradiation from the period of 2015 to date. Besides reviewing the advantages achieved in this field, we also attempt to find out the drawback, mechanistic rationalization, and scopes of future applications. [ABSTRACT FROM AUTHOR]

In this work, we first improved the aqueous solubility of biologically active spiro[cyclopropane-1,3′-oxindoles] (SCOs) via their complexation with different β-cyclodextrins (β-CDs) and proposed a possible mechanism of the complex formation. β-CDs significantly increased the water solubility of SCOs (up to fourfold). Moreover, the nature of the substituents in the β-CDs influenced the solubility of the guest molecule (MβCD > SBEβCD > HPβCD). Complexation preferably occurred via the inclusion of aromatic moieties of SCOs into the hydrophobic cavity of β-CDs by the numerous van der Waals contacts and formed stable supramolecular systems. The phase solubility technique and optical microscopy were used to determine the dissociation constants of the complexes (Kc~102 M−1) and reveal a significant decrease in the size of the formed crystals. FTIR-ATR microscopy, PXRD, and 1H-1H ROESY NMR measurements, as well as molecular modeling studies, were carried out to elucidate the host–guest interaction mechanism of the complexation. Additionally, in vitro experiments were carried out and revealed enhancements in the antibacterial activity of SCOs due to their complexation with β-CDs. [ABSTRACT FROM AUTHOR]

The development of non-natural enzymatic catalysis is important for multicomponent tandem organic transformations. However, the delicate acting environments of biological enzymes still present some challenges in the synthesis of spirooxindole skeleton via enzymatic catalysis. To address these issues, a lipase-catalyzed method was developed for the synthesis of spirooxindole frameworks. Using easily available isatins, cycloketones, and malononitriles as substrates, mild reaction conditions, and a reasonable reaction time, moderate to good yields (67–92%) and excellent functional group tolerance were accomplished via this protocol. The related mechanism explanation is also speculated in this paper. [ABSTRACT FROM AUTHOR]

In a sustained search for novel potential drug candidates with multispectrum therapeutic application, a series of novel spirooxindoles was designed and synthesized via regioselective three-component reaction between isatin derivatives, 2-phenylglycine and diverse arylidene-imidazolidine-2,4-diones (Hydantoins). The suggested stereochemistry was ascertained by an X-ray diffraction study and NMR spectroscopy. The resulting tetracyclic heterocycles were screened for their in vitro and in vivo anti-inflammatory and analgesic activity and for their in vitro antimicrobial potency. In vitro antibacterial screening revealed that several derivatives exhibited remarkable growth inhibition against different targeted microorganisms. All tested compounds showed excellent activity against the Micrococccus luteus strain (93.75 µg/mL ≤ MIC ≤ 375 µg/mL) as compared to the reference drug tetracycline (MIC = 500 µg/mL). Compound 4e bearing a p-chlorophenyl group on the pyrrolidine ring exhibited the greatest antifungal potential toward Candida albicans and Candida krusei (MIC values of 23.43 µg/mL and 46.87 µg/mL, respectively) as compared to Amphotericin B (MIC = 31.25 and 62.50 µg/mL, respectively). The target compounds were also tested in vitro against the lipoxygenase-5 (LOX-5) enzyme. Compounds 4i and 4l showed significant inhibitory activity with IC50 = 1.09 mg/mL and IC50 = 1.01 mg/mL, respectively, more potent than the parent drug, diclofenac sodium (IC50 = 1.19 mg/mL). In addition, in vivo evaluation of anti-inflammatory and analgesic activity of these spirooxindoles were assessed through carrageenan-induced paw edema and acetic acid-induced writhing assays, respectively, revealing promising results. In silico molecular docking and predictive ADMET studies for the more active spirocompounds were also carried out.

A new series of spirooxindoles based on benzimidazole, triazole, and isatin moieties were synthesized via a [3+2] cycloaddition reaction protocol in one step. The single X-ray crystal structure of the intermediate triazole-benzimidazole 4 was solved. The new chemical structures of these spirooxindole molecules have been achieved for the first time. The final synthesized chemical architecture has differently characterized electronic effects. An MEDT study of the key 32CA reaction between in situ generated azomethine ylide (AY) and chalcones explained the low reaction rates and the total selectivities observed. The supernucleophilic character of AY and the strong electrophilicity of chalcones favor these reactions through a highly polar two-stage one-step mechanism in which bond formation at the β-conjugated carbon of the chalcones is more advanced. The present combined experimental and theoretical study reports the synthesis of new spirooxindoles with potential biological activities and fully characterizes the molecular mechanisms for their formation through the key 32CA reaction step.

The [3+2] cycloaddition (32CA) reaction of an azomethine ylide (AY) with an electrophilic ethylene linked to triazole and ferrocene units has been studied within the Molecular Electron Density Theory (MEDT) at the ωB97X-D/6-311G(d,p) level. The topology of the electron localization function (ELF) of this AY allows classifying it as a pseudo(mono)radical species characterized by the presence of two monosynaptic basins, integrating a total of 0.76 e, at the C1 carbon. While the ferrocene ethylene has a strong electrophilic character, the AY is a supernucleophile, suggesting that the corresponding 32CA reaction has a high polar character and a low activation energy. The most favorable ortho/endo reaction path presents an activation enthalpy of 8.7 kcal·mol−1, with the 32CA reaction being exergonic by −42.1 kcal·mol−1. This reaction presents a total endo stereoselectivity and a total ortho regioselectivity. Analysis of the global electron density transfer (GEDT) at the most favorable TS-on (0.23 e) accounts for the high polar character of this 32CA reaction, classified as forward electron density flux (FEDF). The formation of two intermolecular hydrogen bonds between the two interacting frameworks at the most favorable TS-on accounts for the unexpected ortho regioselectivity experimentally observed. [ABSTRACT FROM AUTHOR]

Tumor progression depends on angiogenesis, which is stimulated by growth factors like VEGF, targeting VEGFR kinase with small molecules is an effective anti-angiogenic therapeutic approach. The rational modification of sunitinib (VEGFR-2 inhibitor) to spirocyclopropyloxindoline carboxamides have been performed and their in vitro cytotoxic profiling was evaluated. The molecular modelling studies enabled the screening of designed analogues and identifying the possible interactions within the type III allosteric inhibitor binding site of VEGFR-2. The biological screening of synthesized compounds 15 a-y, revealed the ability of compound 15 w to inhibit the cell growth in MCF-7 cell line with IC 50 value of 3.87±0.19 μM and alongside inhibition of VEGFR-2 kinase at a IC 50 concentration of 4.34±0.13 μM was observed. Also, VEGFR-2 inhibition was validated through HUVEC tube formation inhibition assay. The qualitative assessment of apoptosis induction by 15 w in MCF-7 cells was evaluated through staining studies such as AO/EB and DAPI staining, whereas quantification of apoptosis and cell cycle analysis were performed through FACS analysis. The metastatic ability of the cancer cells was evaluated through inhibition of cell migration by a scratch wound healing assay. The current study strives to sequentially optimize the structural attributes of the 3-alkenyl oxindole core to surpass the existing challenges of well-known VEGFR-2 inhibitors. The findings observed from this study highlights that compound 15 w to be a prominent lead towards the development of clinical drug candidates., (© 2024 Wiley-VCH GmbH.)

About 19 spirooxindole analogs 8 a–s engrafted with pyrazole scaffolds were designed and constructed via [3+2] cycloaddition reaction (32CA) approach. The synthesized spirooxindole analogs was screened for anti‐cholinesterase against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and antioxidant potentials against DPPH. The compounds 8 h and 8 i showed the strongest acetylcholine esterase (AChE) and butyrylcholinesterase (BChE) inhibition with IC50 values of 30 μg/mL respectively. The highest anti‐oxidant potential was demonstrated by compounds 8 p with IC50 values of 240 μg/mL, respectively. Molecular docking was used to study their interaction with the active site of enzymes. [ABSTRACT FROM AUTHOR]

The aim of the present study is to explore the spermicidal potential of the synthetic spirooxindole derivatives and to examine the pathway behind the spermicidal action of the compounds. The in vitro spermicidal activities of the compounds were examined against human sperm by the modified Sander‐Cramer test. The pathway behind the spermicidal action of lead compounds was assessed by (a) hypo‐osmotic swelling test, (b) double fluoroprobe staining, (c) flowcytometric detection of apoptosis by FITC‐AnnexinV labelling, and (d) JC1 labelling. The haemolytic assay for topical toxicity of the compounds was carried out using rabbit erythrocytes. Two spirooxindole derivatives 4 a and 4 c were found to be most effective against human spermatozoa with MEC values of 500 μg/mL and 600 μg/mL lying in the range of standard spermicide Nonoxynol‐9 or N‐9 (MEC 550 μg/mL). The studies on the mechanism of action of the compounds unveiled that the compounds mediated sperm death were due to cellular apoptosis rather than general cell necrosis. The haemolysis assay assured the safeness of the lead molecules for topical usage. Thus, these spirooxindole derivatives may further be explored as new leads for the development of a non‐detergent type of topically applicable contraceptive formulation. [ABSTRACT FROM AUTHOR]

• An efficient and green method for constructing imidazo[2,1- b ]thiazole fused 3,3′-spiroindoles in the absence of external photocatalysts, transition metals, and oxidants was reported for the first time. • A series of novel imidazo[2,1- b ]thiazole fused 3,3′-spirooxindoles were synthesized with a yield of up to 99 %. • This reaction is initiated by visible-light excitation of the substrate 3-alkenylindole-2-ones. • The reaction mechanism was studied through photo-irradiation ON/OFF experiment, UV/Vis absorption spectra, radical-trapping experiment, and EPR experiment. • This method exhibits simple operation, mild reaction conditions, high atom economy, good functional group tolerance. A visible-light-promoted [3 + 2] cycloaddition of 3-alkenylindole-2-ones with 2-mercaptoimidazoles for the construction of diverse imidazo[2,1- b ]thiazole fused 3,3′-spirooxindoles has been developed. Mechanism studies have shown that this transformation is initiated through visible-light excitation of 3-alkenylindole-2-ones, rather than an electron donor-acceptor (EDA) complexes-promoted process. In summary, we have successfully developed a method for simultaneously constructing C−N and C−S bonds under visible-light conditions, and synthesized over 40 examples of new nitrogen- and sulfur-containing fused heterocyclic compounds with potential biological activity with a yield of up to 99 %. This method exhibits simple operation, mild reaction conditions, high atom economy, good functional group tolerance and does not require the use of any transition metals and external photocatalysts. Gram-scale reaction further demonstrates the practicality of this protocol. A visible-light-promoted [3 + 2] cycloaddition of 3-alkenylindole-2-ones with 2-mercaptoimidazoles for the construction of diverse imidazo[2,1- b ]thiazole fused 3,3′-spirooxindoles has been developed. Mechanism studies have shown that this transformation is initiated through visible-light excitation of 3-alkenylindole-2-ones, rather than an electron donor-acceptor (EDA) complexes-promoted process. In summary, we have successfully developed a method for simultaneously constructing C−N and C−S bonds under visible-light conditions, and synthesized over 40 examples of new nitrogen- and sulfur-containing fused heterocyclic compounds with potential biological activity with a yield of up to 99 %. This method exhibits simple operation, mild reaction conditions, high atom economy, good functional group tolerance and does not require the use of any transition metals and external photocatalysts. Gram-scale reaction further demonstrates the practicality of this protocol. [Display omitted] [ABSTRACT FROM AUTHOR]

• Ultrasound-assisted synthesis of novel functionalized spirooxindole-pyrrolidines / spirooxindole-pyrrolizines 12a-j, 13a-e, 14a-d, and 15 is reported via one-pot three-component [3 + 2] cycloaddition reaction. • Single crystal X-ray diffraction studies confirmed the stereochemistry of the four chiral centres of cycloadduct. • The antibacterial and antitubercular activities and SAR studies of 12a-j, 13a-e, 14a-d , and 15 has been summarized. • In silico docking supported the wet results. • The structurally modified novel spirooxindole-pyrrolidines / spirooxindole-pyrrolizine proved to be highly potential antimicrobial and antitubercular agents. In an exploration of novel spirooxindole-pyrrolidine/spirooxindole-pyrrolizine-based compounds as antimicrobial and antitubercular agents, we have prepared a new series of pharmacologically privileged substructures, i.e., chalcone-isatin based spirooxindole compounds 12a-j, 13a-e, 14a-d , and 15–16 which were derived by the reaction of various substituted amino acids 11a-d , respectively, substituted chalcone (Me, OMe, Cl) 10a-m and isatins 9a-b via one-pot three-component [3 + 2] cycloaddition reaction. We also report the SAR, and in silico molecular docking studies of 12a-j, 13a-e, 14a-d , and 15. While compared to the standard drug ampicillin (MIC = 25 µg/mL), compounds 13c, 13e, 14a , and 15 (MIC = 12.5 µg/mL) have shown to be twice as potent against the Bacillus subtilis [BS] bacterial strain. Compounds 12a and 13c (MIC = 25 µg/mL) exhibited equipotent behavior towards ampicillin (MIC = 25 µg/mL), a bacterial strain of B. subtilis [BS]. Compounds 13b (MIC = 3.125 µg/Ml) and 15 (MIC = 1.56 µg/mL) demonstrated strong antitubercular activity in the antitubercular activity assay when compared to the conventional medications Rifampicin (MIC = 0.2 µg/mL) and INH (MIC = 0.1 µg/mL). We also report, for the first time, in vitro antimicrobial activity of some previously reported spiro compounds 12c, 12f and 12 g. [Display omitted] [ABSTRACT FROM AUTHOR]

A new [3+4] annulation between isatin N,N′cyclic azomethine 1,3-dipole and nitrosoalkenes in situ generated from α-haloketone oximes has been disclosed. This new protocol is tolerable for a series of substrates and a novel series of seven-membered spiro oxindoles containing oxygen and nitrogen atoms were obtained in moderate to good yields (up to 83%) under mild conditions. [Display omitted] • A new [3 + 4] annulation between isatin N,N′ –cyclic azomethine 1,3-dipole and nitrosoalkenes in situ generated from α-haloketone oximes. • A novel series of seven-membered spiro oxindoles containing oxygen and nitrogen atoms were obtained under mild conditions. • This new one-pot protocol is tolerable for a series of substrates. • Scaled-up performance was realized. A new [4 + 3] annulation between isatin N,N′ –cyclic azomethine 1,3-dipole and nitrosoalkenes in situ generated from α-haloketone oximes has been disclosed. This new protocol is tolerable for a series of substrates and a novel series of seven-membered spiro oxindoles containing oxygen and nitrogen atoms were obtained in moderate to good yields (up to 83 %) under mild conditions. [ABSTRACT FROM AUTHOR]

The additive‐free 1,3‐dipolar cycloaddition reaction of isatin‐derived azomethine ylides with α‐cyano‐α,β‐unsaturated compounds was developed, which enabled diversity‐oriented synthesis of a series of novel and structurally complex 3,3′‐pyrrolidinyl‐spirooxindoles derivatives containing four contiguous and two quaternary stereogenic centers in high yields (up to 92%) and excellent diastereoselectivities (up to >25:1 dr). The reaction displays switchable regioselectivity depending on the steric effect of the substrates. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

An efficient N -iodosuccinimide-promoted cyclization of readily available alkylidene oxindoles with annular β-dicarbonyl compounds has been demonstrated. With five-membered cyclic β-dicarbonyl compounds as the starting materials, a series of cyclopropyl oxindoles can be obtained in good to excellent yields, whereas the method affords dihydrofuranyl spirooxindoles almost quantitatively when six- or seven-membered cyclic β-dicarbonyl compounds are employed. This protocol provides a new alternative to the practical synthesis of structurally diverse spirooxindoles. [ABSTRACT FROM AUTHOR]

Various spirooxindole‐benzo[d]oxazoles and dihydrobenzofurans were prepared in good to excellent yields by [3+2] cycloaddition and selective rearrangement of N‐vinyl oxindole nitrones and arynes under transition metal‐free conditions. Experimental results showed that the substituent on the nitrone N‐vinyl group controlled the [1,3]‐ or [3,3]‐rearrangement of their cycloadduct owing to its steric effect. The present method features broad substrate scope, good functional group tolerance, controllable [1,3]‐ or [3,3]‐rearrangement, and diverse oxindole scaffolds. [ABSTRACT FROM AUTHOR]

Today, plant extracts based on synthetic procedures have drawn consideration over conventional methods like physical and chemical procedures to synthesize nanomaterials. Green synthesis of nanomaterials has become an area of interest because of numerous advantages such as non-hazardous, economical, and feasible methods with a variety of applications in biomedicine, nanotechnology and nano-optoelectronics and as catalysts for various organic transformations. In this research, silver nanoparticles were deposited on the surface of nano-silica spheres by an in-situ reduction of Ag+ ions using an aqueous extract of Thymus kotschyanus aerial parts as a natural reducing and a capping agent. The result recorded from ultraviolet–visible (UV–Vis) spectrometer, Fourier transform infrared spectroscopy (FT-IR), thermal gravimetric analysis, scanning electron microscopy with energy-dispersive X-ray spectroscopy (SEM–EDS) and X-ray powder diffraction supports the biosynthesis and characterization of Ag/SiO2 nanoparticles. The results indicated that the average size of Ag/SiO2 nanoparticles is 25–60 nm. The Ag/SiO2 nanoparticles act as an environmentally friendly heterogeneous catalyst in the synthesis of spirooxindoles via the three-component condensation reaction of isatins, activated methylene reagents, and 1,3-dicarbonyl compounds in aqueous media, and the desired products were obtained with yields ranging from 90 to 98%. The catalyst can be recovered easily and used repetitively without significant loss of catalytic activity. [ABSTRACT FROM AUTHOR]

An efficient method for the practical formation of functionalized spirooxindoles, which was accompanied by generating a sterically congested spiroketal system and bearing two quaternary stereocenters via a sequential palladium, catalyzed decarboxylative [3 + 2] cycloaddition of vinylethylene carbonates (VECs) and isatins. Importantly, the redox‐neutral catalytic system possesses the characteristics of operational convenience, good functional group tolerance, and good regioselectivity and diastereoselectivity, which enables a diastereoselective synthesis of spiroketal oxindole skeletons in an excellent yield. [ABSTRACT FROM AUTHOR]

Chlorosulfonic acid supported on coconut shell (nano-coc-OSO3H) as an efficient and novel nano catalyst for one-pot synthesis of spirooxindoles via three-component condensation of isatin derivatives, enolizable systems (dimedone, cyclohexadione, cyclopantadione) and malononitrile. Nano-coc-OSO3H was synthesized and characterized via FT-IR, TGA/DTG, XRD, EDX, FESEM and TEM techniques. It is rapid and efficient catalyst for one-pot synthesis of the biologically important spirooxindole derivatives. The significant features of this methodology are nontoxic catalyst, short reaction time (15 min.), recyclability, low catalyst loading, green organic solvent (ethanol), and avoiding tedious purification step. [ABSTRACT FROM AUTHOR]