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An efficient and environmentally benign synthesis of a new class of acridinedione embedded spirooxindolo/acenaphthenothiopyrrolizidines and spirooxindolo/acenathenoindolizidines has been synthesized in good to excellent yields employing ionic liquid accelerated one-pot [3 + 2]-cycloaddition strategy. The pre-requisite starting substrates, O-acryloyl acridinediones were prepared from dimedone in three good yielding steps, while the 1,3-dipole was derived in situ from isatin/acenaphthenequinone and thiazolidine-4-carboxylc acid/l-pipecolinic acid via decarboxylative condensation. The cycloadduct possesses three stereogenic carbons, one of which is a spiro carbon through the formation of two C–C and one C–N bonds in one-pot synthetic transformation. Geometrical parameters of the synthesized compounds were calculated using the B3LYP/6-311g(d,p) level of theory. The activity of these molecules was evaluated against main protease of COVID-19 to screen them for their inhibitor efficiency. In order to get a broad understanding of the interactions of these synthesized ligands, a detailed molecular docking analysis was performed. Molecular docking analysis shows that compound 8b has the highest binding affinity toward the protein. The compound can be a potential candidate for the treatment of COVID-19.

Aggressive antimicrobial infections together with an increasing in resistance to antimicrobial medications cause a threat to immunocompromised individual. In this context, spiro compounds play an important role in drug discovery research due to their diverse biological activities including antimicrobial activity which is well documented in literature, because of their unique structural properties allow for easy interaction with the target enzyme of the biological system. This biological precedent encouraged us to design and synthesis of novel dispirooxindolopyrrolidine hybrid heterocycles via multicomponent cycloaddition protocol. Novel class of dispirooxindolopyrrolidine hybrid heterocycles has been synthesized by multicomponent 1,3-dipolar cycloaddition methodology and the structure of the products was determined through spectroscopic analysis. The synthesized organic compounds were evaluated for their antimicrobial activities using sensitivity test with standard agar well diffusion method. The synthesized new class of dispiropyrrolidine embedded indandione hybrids showed significant antimicrobial activity against carbapenemase producing Klebsiella pneumoniae (CKPs) isolated from hospital patients. Compound that possessing chlorine substituted on the aryl ring exhibited more potent antimicrobial activities and the zone of inhibitions was observed between 7.00 ± 0.09 and 18.40 ± 0.70 mm. The MIC value of compound 4b was 0.030 mg/mL against tested CKP. A new class of dispiropyrrolidine heterocyclic hybrids were synthesized in good to excellent yield employing multicomponent 1,3-dipolar cycloaddition strategy. Among them, compounds bearing 4-chloro substituted on the aryl ring exhibited notable activity just equal to the standard drug, ciprofloxacin. Future studies are needed to elucidate the pharmacological properties of new compounds that were synthesized in our laboratory for the novel therapeutic development. [ABSTRACT FROM AUTHOR]

• A new class of spirooxindolopyrrolidines was synthesized in excellent yields. • Compound was well characterized through spectroscopic studies. • Regio and stereochemistry of compounds clearly assigned by X-ray analysis. • Compound was determined through computational studies. • Compound displayed good antibacterial and antioxidant properties. An excellent yield of spiropyrrolidine grafted with two units of oxindole moieties was obtained employing a one-pot three component 1,3-dipolar cycloaddition cascade reaction strategy. In this cascade reaction, the key intermediate 1,3-dipole compound is formed in situ from isatin and l-phenylalanine, which was further reacted with highly functionalized 3-benzylideneindolin-2-one to form structurally complex heterocycles viz. 5-benzyl-2-spiro[2.3′]-3-spiro[3.3′′]-4-chlorophenylpyrrolidine with broad substrate diversity. The formation of a stereoselective spirocycloadduct with four contiguous stereogenic centers, two of which are spirocarbons. The structure of compound 4 was assigned through one-, two-dimensional NMR and mass spectroscopic analyses. The structure of the spiroadduct was undoubtable determined through single crystal analysis. The supramolecular structure aspects of 4 was found to depend on the O...H, N...H, C...O, and H...H interactions. Their percentages are 49.4, 24.4, 1.0 and 11.1%, respectively based on Hirshfeld analysis. The DFT/B3LYP optimized structure is found to agree well with the experimental one. Compound 4 has significant polarity where the calculated dipole moment is 4.2147 Debye. The antibacterial efficacy of the compound 4 showed more sensitive results against Shigella sp. (19.00±0.30 mm) followed by Acinetobacter sp. (17.00±0.15 mm), besides, the compound 4 showed notable antioxidant properties. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • A series of structurally intriguing pyrrolo[3,2- c ]quinolinones were synthesized in excellent yields. • These heterocyclic hybrids were achieved employing multicomponent domino protocol. • The reaction provided five new bonds, three new rings and four contiguous stereocenters. Abstract A series of structurally intriguing novel pyrrolo[3,2- c ]quinolinone heterocyclic hybrids have been synthesized for the first time via a one-pot multicomponent domino reaction sequence that involves a 1,3-dipolar cycloaddition and two subsequent annulation steps. Baylis-Hillman adducts derived from various substituted benzaldehyde and methyl acrylate in presence of DABCO were used as a dipolarophiles, while the 1,3-dipole components were azomethine ylides, formed in situ from isatin derivatives and l -phenylalanine. The reaction generated five new bonds, three new rings and four contiguous stereocenters, which were created with full diastereomeric control. [ABSTRACT FROM AUTHOR]

The stereoselective syntheses of novel dispiro acenaphthylene–indolizine–pyridinone hybrid heterocycles have been achieved through one-pot four-component domino 1,3-dipolar cycloaddition–Michael addition–air oxidation sequence of reactions. [ABSTRACT FROM AUTHOR]

A small library of novel spiropyrrolidine heterocyclic hybrids has been prepared regioselectively in 1-butyl-3-methylimidazoliumbromide ([bmim]Br) with good to excellent yields using a [3+2] cycloaddition reaction. These synthesized compounds were evaluated as potential agents for treating Alzheimer’s disease. Compound 4b showed the most potent activity, with an IC 50 of 7.9 ± 0.25 µM against acetylcholinesterase (AChE). The inhibition mechanisms for the most active compounds on AChE and butyrylcholinesterase (BChE) receptors were elucidated using molecular docking simulations. [ABSTRACT FROM AUTHOR]

The synthesis of highly functionalized dispiro oxindole–pyrrolo[1,2- c ]thiazole–piperidone hybrid has been achieved regioselectively employing microwave-assisted three-component 1,3-dipolar cycloaddition. Structural elucidation of the compound has been accomplished using NMR spectroscopy and further confirmed by single crystal X-ray crystallographic studies. The molecular structure of the compound crystallized in monoclinic, P 2 1 / c , a = 11.6182 (2) Å, b = 12.2466 (2) Å, c = 21.7061 (3) Å, β = 103.018 (1)°, V = 3009.04 (8) Å 3 , Z = 4. The cycloaddition was found to proceed by normal electronic demand (NED) character with a significant high charge transfer (0.1247 eV) from the 1,3-dipole to the dipolarophile. The regiochemistry has been explained using the local reactivity descriptors obtained from the DFT calculations. The DFT optimized molecular structure agreed well with the X-ray results. [ABSTRACT FROM AUTHOR]

A facile synthesis of dispirooxindolopyrrolidines has been accomplished via a one-pot three component 1,3-dipolar cycloaddition reaction. The reaction of azomethine ylides generated in situ from L-phenylalanine and substituted isatins with a series of unusual (E)-2-oxoindolino-3-ylidene acetophenone dipolarophiles in the ionic liquid 1-butyl-3-methylimidazolium bromide [bmim]BF4, furnished the cycloadducts in good yields, with the regioisomers 5a-f being obtained with high selectivity. Furthermore, the recyclability of [bmim]BF4, up to five times, was also investigated. [ABSTRACT FROM AUTHOR]

Abstract: A series of dispiropyrrolothiazoles compounds were synthesized using 1,3-dipolar cycloaddition and were screened for antimycobacterial activity against Mycobacterium tuberculosis H37Rv and INH resistant M. tuberculosis strains. Two of them were showing good activity with MIC of less than 1μM. Compound (5f) was found to be the most active with MIC of 0.210 and 8.312μM respectively. [Copyright &y& Elsevier]

Abstract: Four-component reactions of (R)-1-(1-phenylethyl)tetrahydro-4(1H)-pyridinone, aromatic aldehydes and malononitrile in a 1:2:1 molar ratio in the presence of solid sodium ethoxide under solvent free conditions afforded an inseparable mixture of two diastereomeric 4(H)-pyrans in near quantitative yields. These compounds upon 1,3-dipolar cycloaddition with nitrile oxides furnished two enantiomerically pure 1,2,4-oxadiazoles in moderate yields, which were screened for in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug resistant M. tuberculosis (MDR-TB). Among the compounds screened, compound 10h was found to be the most active in vitro with a MIC value of 0.07 and 0.14μM against MTB and MDR-TB respectively. [Copyright &y& Elsevier]

[Display omitted] • Novel spirooxindolopyrrolidine tethered indandiones have been synthesized in excellent yields. • A one-pot eco-friendly three component cycloaddition strategy have been employed. • Compounds were assessed for their antimycobacterium activity against Mtb H37Rv. • Compound with chloro substituent displayed two fold activity than that of standard drug, ethambutol. Novel spirooxindolopyrrolidine embedded indandione heterocyclic hybrids were obtained in excellent yields via a regio- and stereoselective one-pot three component reaction between Baylis-Hillman adduct and non-stabilized azomethine ylides. The structure of newly synthesized compounds was elucidated through 1D and 2D spectroscopic data and the stereochemistry was determined by single crystal X-ray diffraction analysis. In vitro tubercular activity against Mycobacterium tuberculosis H37Rv using MABA assay reveals that the compound bearing chlorine substituted on the oxindole ring displayed the most potent activity with MIC 0.78 μg/mL and is two-fold active than the standard drug, ethambutol (MIC 1.56 μg/mL). [ABSTRACT FROM AUTHOR]

• Structurally intriguing novel spiroheterocyclic hybrid has been synthesized in excellent yield. • Spiroheterocycle has been achieved via one-pot [bmim]Br accelerated multicomponent green protocol. • The structure and stereochemistry of the compound elucidated by spectroscopic and X-ray analysis. • Molecular packing and interaction has been investigated by Hirshfeld and DFT calculations. • Food borne bacterial inhibitory activity observed. Synthesis of a hybrid heterocycle comprising ferrocene, spiropyrrolidine and quinoxaline structural moieties have been achieved in good yield via ionic liquid expedited multicomponent 1,3-dipolar cycloaddition reaction. Structural properties of the synthesized compound were exploited using single crystal X-ray crystallographic studies. Hirshfeld analysis revealed the importance of H...H (59.6%), C H...π (22.4%) and N...H (3.5%) contacts within the molecular packing. The Fe-C interactions around ferrocenyl moiety were investigated using Natural Bond Orbital (NBO) and Atoms In Molecules (AIM) calculations. A predominant covalent character of interactions between Fe-C were been accessed from AIM calculation. A weaker extend of π-back donation appeared in cyclopentadienyl moiety carrying the substituent instead of unsubstituted one. Further, the in vitro antimicrobial potential of the synthesized compound against five food borne bacterial pathogens reveals its significant activity against E. coli and S. enterica with MIC values 6.00 µg/mL and 8.00 µg/mL, respectively. The antioxidant activity of compound 5 was found to be 84.37±0.55 at 250 µg/mL concentration with an IC 50 value = 33.80 µg/mL. [ABSTRACT FROM AUTHOR]

Our synthetic approach for the assembly of structurally complex spirooxindole heterocyclic hybrids was based on an ionic liquid, [bmim]Br mediated one-pot three-component cascade reaction strategy involving 1,3-dipolar cycloaddition reaction of N-1-(2-pyridinylmethyl)-3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones and azomethine ylide generated in situ from isatin and L-phenyl alanine, affording a series of spirooxindole–pyrrolidine heterocyclic hybrids in good-to-excellent yields. In addition to serving as the reaction medium, [bmim]Br also functioned as a catalyst in this cycloaddition reaction and hence accelerated the reaction rate affording the cycloadducts in short reaction time. [ABSTRACT FROM AUTHOR]

A series of spirooxindolopyrrolidine fused N-styrylpiperidone heterocyclic hybrids has been synthesized in excellent yield via a domino multicomponent protocol that involves one-pot three component 1,3-dipolar cycloaddition and concomitant enamine reactions performed in an inexpensive ionic liquid, namely 1-butyl-3-methylimidazolium bromide ([bmim]Br). Compounds thus synthesized were evaluated for their cytotoxicity against U-937 tumor cells. Interestingly; compounds 5i and 5m exhibited a better cytotoxicity than the anticancer drug bleomycin. In addition; the effect of the synthesized compounds on the nuclear morphology of U937 FaDu cells revealed that treatment with compounds 5a–m led to their apoptotic cell death. [ABSTRACT FROM AUTHOR]

Antifungal activity of spirooxindolo-pyrrolidine tethered indole and imidazole heterocyclic hybrid, 9c. Invasive fungal infections are one of the leading causes of nosocomial bloodstream infections with a limited treatment option. A series of derivatized spirooxindolo-pyrrolidine tethered indole and imidazole heterocyclic hybrids have been synthesized, and their antifungal activity against fungal strains were determined. Here we characterize the antifungal activity of a specific spirooxindolo-pyrrolidine hybrid, dubbed compound 9c , a spirooxindolo-pyrrolidine tethered imidazole synthesized with a 2-chloro and trifluoromethoxy substituent. The compound 9c exhibited no cytotoxicity against mammalian cell line at concentrations that inhibited fungal strains. Compound 9c also significantly inhibited the fungal hyphae and biofilm formation. Our results indicate that spirooxindolo-pyrrolidine heterocyclic hybrids potentially represent a broad class of chemical agents with promising antifungal potential. [ABSTRACT FROM AUTHOR]

The stereoselective syntheses of a library of novel spiro-tethered pyrazolo[3,4-b]quinoline-pyrrolidine/pyrrolothiazole/indolizine-oxindole/acenaphthene hybrid heterocycles have been achieved through the 1,3-dipolar cycloaddition of azomethine ylides generated in situ from α-amino acids and 1,2-diketones to dipolarophiles derived from pyrazolo[3,4-b]quinoline derivatives. [ABSTRACT FROM AUTHOR]

Abstract: A facile regio- and stereoselective synthesis of novel dispirooxindolyl-[acridine-2′,3-pyrrolidine]-1′-ones and dispirooxindolyl-[acridine-2′,3-thiapyrrolizidine]-1′-ones have been accomplished via 1,3-dipolar cycloaddition of azomethine ylides, generated in situ from the reaction of sarcosine/1,3-thiazolane-4-carboxylic acid and substituted isatins, to a series of (E)-2-[arylmethylidene]-3,4-dihydro-1(2H)-acridinones in good yields. [Copyright &y& Elsevier]

Novel cage-like indolizine-acenaphthene-pyridinone heterocyclic hybrids were synthesized in good yields through [bmim]Br mediated tandem 1,3-dipolar cycloaddition-annulation sequence. Four of these hybrids viz. 4b , 4d , 4e and 4j showed significant anti-inflammatory activities against acute and chronic inflammatory models. These compounds also showed significant inhibition of PGE 2 , TNF-α, and nitrite levels in carrageenan-induced hind paw oedema. • Novel cage-like indolizine-acenaphthene-pyridinone heterocyclic hybrids were achieved. • Anti-inflammatory activity of these hybrids was explored. • Noteworthy activities against acute and chronic inflammatory models observed. • Significant inhibition of PGE 2 , TNF-α, and nitrite levels. Novel cage-like indolizine-acenaphthene-pyridinone heterocyclic hybrids were synthesized in good yields through [bmim]Br mediated tandem 1,3-dipolar cycloaddition-annulation sequence. The anti-inflammatory activity of these hybrids was performed using carrageenan-induced hind paw oedema, croton oil-induced ear oedema and cotton pellet-induced granuloma models. Four of these cage-like heterocyclic hybrids viz. 4b , 4d , 4e and 4j showed substantial anti-inflammatory activities against acute and chronic inflammatory models and also showed significant inhibition of PGE 2 , TNF-α, and nitrite levels in carrageenan-induced hind paw oedema. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Eco-friendly synthesis of 2-aryl-7,8-dihydroquinolin-5(6 H)-ones. • Synthesis of 2-aryl-7,8-dihydroquinolin-5(6 H)-one based dipolarophiles. • Stereoselective synthesis of dispiro quinolinone hybrids via cycloaddition. • A facile multi-component [3 + 2] cycloaddition strategy. • Structural elucidation using NMR and single crystal X-ray studies. Abstract The syntheses of novel spiro-linked quinolinone-pyrrolidine/pyrrolo[1,2- c ]thiazole-oxindole/acenaphthalene hybrid heterocycles have been achieved through a one-pot three-component [3 + 2] cycloaddition strategy. The reaction proceeded stereoselectively affording these structurally intriguing multi-spiro compounds in excellent yields. [ABSTRACT FROM AUTHOR]

The combinatorial syntheses of a library of novel dihydrothiophenone-engrafted dispiro oxindole/indenoquinoxaline-pyrrolidine/pyrrolothiazole/indolizine hybrid heterocycles have been realized through a chemo-, regio-, and stereoselective multicomponent 1,3-dipolar cycloaddition strategy. [ABSTRACT FROM AUTHOR]

• Dispiropyrrolidines synthesized in excellent yield via cycloaddition strategy. • Compounds were elucidated by spectroscopic and single crystal X-ray analysis. • Molecular packing and structure reactivity descriptors were investigated. • Compounds assayed for their antimicrobial activity against K. pneumonia strains. • Antimicrobial efficacy was also performed through molecular docking study. A regio and stereoselective synthesis of a new class of spirooxindolopyrrolidine embedded indandione heterocycles was obtained in excellent yield employing a three-component cascade reaction protocol. The key step for this protocol is a 1,3-dipolar cycloaddition reaction involving azomethine ylide generated in situ from isatin and l -phenylalanine. The structure of newly synthesized compound was assigned based on the NMR spectroscopic analysis and the stereo/regiochemistry was undoubtable assigned by single crystal X-ray diffraction analysis. Further, the structural determination of the compound was assigned through density functional theory (DFT) and Hirshfeld surface analysis. It is found that the compound was highly stabilized by intermolecular interactions such as X-H-H-X (X = C and O) and also by hydrogen bonding interaction. The synthesized compounds were assayed for their antibacterial activity against five different clinical bacterial strains of K. pneumoniae and found that the compound possessing chloro‑substitution on aryl ring showed significant activity against tested K. pneumoniae strains. [Display omitted] [ABSTRACT FROM AUTHOR]

The syntheses of novel structurally intriguing hexacyclic cage-like compounds have been achieved from the three-component tandem [3+2] cycloaddition–intramolecular annulation reactions of ninhydrin, α-amino acids and ( E )-3-arylidene-1-methylpiperidin-4-ones. On the other hand the four-component reactions of ninhydrin, o -phenylenediamine, α-amino acids and ( E )-3-arylidene-1-methylpiperidin-4-ones afforded novel polycyclic dispiro compounds. [ABSTRACT FROM AUTHOR]

• Synthesis of structurally intriguing fused pyrroloquinoline hybrid heterocycle in excellent yield. • Compound was achieved via one-pot cascade protocol under eco-friendly solvent free condition. • Compound was assigned by spectroscopic and single crystal X-ray diffraction analysis. • Molecular packing and structure reactivity descriptors were investigated via computational studies. • Compound showed significant antimicrobial activity against tested bacterial and fungal pathogens. Synthesis of a structurally complex hitherto unexplored novel class of pyrene fused pyrroloquinolinone was achieved in excellent yield via an environmental friendly solid-state melt reaction condition employing multicomponent cascade protocol which involves 1,3-dipolar cycloaddition and subsequent double annulation process. The 1,3-dipole component was derived in situ from diketone and α-amino acid, whereas the Baylis-Hillman adduct synthesized from pyrene-1-carbaldehyde was utilized as a dipolarophile. Structure of the compound was elucidated by 1H and 13C NMR spectroscopic analysis and further confirmed through single crystal X-ray diffraction and the molecular packing was described by using Hirshfeld surface analysis. The structure-reactivity descriptors of the synthesized compound were examined through DFT calculations. The pyrroloquinoline was evaluated for its antibacterial activity against three multi drug resistant bacterial and two fungal pathogens. The MIC value of the tested microbial pathogens were exhibited with minimum (0.156 mg/mL) and maximum (1.250 mg/mL). The antimicrobial results disclosed that compound 6 is considered as a potent candidate for effective therapeutic applications. [ABSTRACT FROM AUTHOR]

Abstract: Pyrrolothiazolyloxindole analogues share vital pharmacological properties, considered useful in Alzheimer’s disease (AD). The aim of this study was synthesis and evaluate pyralothiazolyloxindole analogues if possess acetyl cholinesterase (AChE) inhibitory activity. The easily accessible one-pot synthesis of these compounds resulted to be significantly less difficult and expensive than that of donepezil. Several compounds possess anti-cholinesterase activity in the order of micro and sub-micromolar. Particularly, compound 6a was the most potent inhibitors of the series against acetyl cholinesterase enzyme with IC50 0.11μmol/L. [Copyright &y& Elsevier]

A regio- and diastereoselective synthesis of library of structurally intriguing novel hybrid heterocycles comprising spiropyrrolizidines/pyrrolothiazoles, oxindole/acenaphthenone and β -lactam moieties have been synthesized in good yields. The hitherto unexplored 2-((1-(4-methoxyphenyl)-4-oxo-3-phenylazetidin-2-yl)methylene) malononitriles were used as the dipolarophiles, while the dipoles were derived in situ from indoline-2,3-dione/acenaphthenequinone and l -proline/substituted 2-aryl-thiazolidine-4-carboxylic acids. The key step of this transformation is the 1,3-dipolar cycloaddition reaction involving the above-mentioned components offering a facile entry to biologically relevant classes of spiro heterocyclic hybrids. [Display omitted] [ABSTRACT FROM AUTHOR]