Spiro Heterocycles Research Articles

Microwave‐Assisted Synthesis of Spiro Heterocyclic Scaffolds Using Graphite Oxide as a Heterogeneous Carbocatalyst and Study of their Anti‐Microbial Activities

AbstractEven though an astonishing variety of spirooxindole derivatives has been synthesized until now, the look for rapid, highly efficacious, environmental‐friendly and more skilful methods is yet an ongoing challenge. Here, we present a microwave‐assisted synthetic approach for the one‐pot synthesis of spirooxindole‐pyrimidine and spiro‐chromeno indoline‐trione derivatives in water using graphite oxide (GO) as a charismatic heterogeneous metal‐free carbocatalyst.Microwave‐assisted synthesis reduces the reaction times from hours (conventional heating) to minutes. The use of a heterogeneous catalyst allows for efficient recovery and reusability up to eight cycles without losing much of its effectiveness, thereby enhancing sustainability. This method offers high product yields of diverse substrates with low catalyst loading and simple work‐up and catalyst handling. In addition, the antimicrobial activities for some randomly taken compounds have also been studied against gram positive bacteria Staphylococcos aureus (MTCC96) and gram negative bacteria Escherichia coli(MTCC730).

Syntheses and medicinal chemistry of spiro heterocyclic steroids.

There is compelling evidence that incorporating a heterocyclic moiety into a steroid can alter its pharmacological and pharmacokinetic properties, driving intense interest in the synthesis of such hybrids among research groups. In this review, we present an overview of recent synthetic methodologies, spanning the period from 2000 to 2023, for the preparation of spiro heterocyclic steroids. The compounds surveyed encompass four-, five-, six-, and seven-membered heterocycles appended to various positions of steroidal backbones, with spirocycles containing oxygen, nitrogen, and sulfur atoms being predominant. The outlined synthetic procedures emphasize the pivotal steps for constructing the heterocycles, often accompanied by a detailed account of the overall synthesis pathway. The review encompasses innovative compounds, including bis-steroids linked by a spiro heterocycle and steroids conjugated to heterocyclic moieties containing three or more (hetero)cycles. Moreover, many compounds are accompanied by data on their biological activities, such as antiproliferative, antimalarial, antimicrobial, antifungal, steroid antagonist, and enzyme inhibition, among others, aimed at furnishing pertinent insights for the future design of more potent and selective drugs.

Synthesis of Spiro Heterocycles through a Three-Component Reaction

Synthesis of Spiro Heterocycles through a Three-Component Reaction

Synthesis, Characterization, and Antimicrobial Activity of Spiro Heterocyclic Compounds from Statin

Synthesis, Characterization, and Antimicrobial Activity of Spiro Heterocyclic Compounds from Statin

Dual Brønsted acidic-basic function immobilized on the 3D mesoporous polycalix [4]resorcinarene: As a highly recyclable catalyst for the synthesis of spiro acenaphthylene/indene heterocycles

In this study, a novel dual Brønsted acidic-basic nano-scale porous organic polymer catalyst, PC4RA@SiPr-Pip-BuSO3H, was synthesized through various steps: preparation of a 3D network of polycalix, modification with (3-chloropropyl)-trimethoxysilane, then functionalization of polymer with piperazine and n-butyl sulfonic acid under the provided conditions. The catalyst characterization was performed by FT-IR, TGA, EDS, elemental mapping, PXRD, TEM, and FE-SEM analyses, confirming high chemical stability, activity, recoverability, and excellent covalent anchoring of functional groups. So, the designed catalyst was utilized for preparing spiro-acenaphthylene and amino-spiroindene heterocycles, providing good performance with a high yield of the corresponding products. Accordingly, this catalyst can be used in different organic transformations. Necessary experiments were conducted for the recyclability test of the polymeric catalyst, and the results showed the PC4RA@SiPr-Pip-BuSO3H catalyst can be reused 10 times without any decrease in its activity or quality with excellent stability. The structure of resultant spiro heterocycles was confirmed using 1H NMR, 13C NMR, and FT-IR.

Three-Component Reaction for the Synthesis of Spiro-Heterocycles from Isatins, Substituted Ureas, and Cyclic Ketones.

We reported an efficient three-component reaction to access new spiro heterocycles through the annulation reactions of isatins, substituted ureas, and cyclic ketones under normal laboratory conditions, which is another example of isatins being used to build spiro compounds by the ring-opening and recyclization processes. The wide range of substrates, simple operation, normal experimental conditions, and high yields make the approach of high practical value.

Recent advances in microwave-assisted multicomponent synthesis of spiro heterocycles.

Spiro heterocycle frameworks are a class of organic compounds that possesses unique structural features making them highly sought-after targets in drug discovery due to their diverse biological and pharmacological activities. Microwave-assisted organic synthesis has emerged as a powerful tool for assembling complex molecular architectures. The use of microwave irradiation in synthetic chemistry is a promising method for accelerating reaction rates and improving yields. This review provides insights into the current state of the art and highlights the potential of microwave-assisted multicomponent reactions in the synthesis of novel spiro heterocyclic compounds that were reported between 2017 and 2023.

Recent advances in post Ugi-4CR dearomatizations for constructing spiro heterocycles

This review summarizes recent advances in the combination of Ugi-4CR and dearomatization for the synthesis of spirocycles.

Single Step Upgradation of Isatin to Bioactive Fused Heterocycles via Ring Expansion Reactions

AbstractIsatin, also known as indoline‐2,3‐dione, is a fused, N‐heterocyclic aromatic compound first isolated and purified in 1841. Since then, isatin and its derivatives emerged as a hot research topic for the scientific community. The number of research publications on isatin justifies their popularity. Researchers explored isatins and their derivatives as potential candidates in multidisciplinary research areas, including medicinal chemistry, synthetic organic chemistry, and polymer science. Synthetic chemists’ perspective of tailoring isatin and its family members led to more efficient synthesis strategies in which ring‐opening reactions of isatins were particularly significant due to the product's importance. Our investigation aims to group the different types of cascade ring expansion reactions of isatin to synthesise fused heterocyclic compounds such as derivatives of quinolines, quinazolinones, acridines, acridones, and few spiro heterocyclic compounds, all of which highlight an inevitable role in the field of medicinal chemistry.

Antimicrobial evaluation of spirooxindolopyrrolidine engrafted indoles against multidrug resistant ESKAPE clinical pathogens

The synthesis of a new class of effective antibiotics and antimicrobial agents with less toxicity is highly desirable due to bacterial resistance to antibiotics has increased dramatically. In this context, molecules that embedding a spiro moiety are attractive from a medicinal chemistry point of view as these spiro heterocycles show a vital part in the development of delivery systems for antimicrobial therapies. In the present study, the synthesis and antimicrobial evaluation of structurally attractive complex hybrid heterocycles comprising spriooxindolopyrrolidine and indole heterocycles was attained in quantitative yields by cycloaddition strategy. The new class of spirocompouds were unequivocally assigned through spectroscopic analysis and the antimicrobial efficacy were assessed against six microbial pathogens. Among them, compound 4a, bearing chlorine substituted derivative showed significant activity against tested ESKAPE pathogens. The maximum zone of inhibition observed against ESKAPE microbial pathogens causing infectious disease ranged from 6.75 ± 0.40 to 19.75 ± 1.15 mm, with MIC values ranging between 16.00 to > 256.00 µg/ml .

Diastereoselective construction of carbazole‐based spiropyrrolidines and spiropyrrolizidines via cycloaddition reaction

AbstractA series of new spiro heterocyclic compounds having carbazole and pyrrolidine units were successfully synthesized through a one‐pot, three component, 1,3‐dipolar cycloaddition reaction in good yields with high diastereoselectivity. Simple reaction, easily accessible chemicals, high yield and diastereoselective formation of monospiropyrrolidine and monospiropyrrolizidine carbazole derivatives in one step are some advantages of this method. The structure of the obtained products was characterized by using spectroscopic techniques.

Enantioselective MW-US-assisted Synthesis, DFT Simulation and Molecular Docking of Spiro Pyrrolidine-2,3'-Thieno [2,3-d]Pyridazin-Hydrazide as Green Agricultural Product

Effecient green tools of β-(3,4-dichlorophenyl-acrylic acid, thioglycolic acid and β-(2-oxopyrrolidin-1-yl) ethanol under ultrasonic and microwave-assisted irradiation (MW-US) as found to be a simple approach for preparing interesting Spiro derivatives. A novel class Spiro-pyrrolidine-2,3'-thieno[2,3-d]pyridazine derivatives (2–6) were efficiently synthesized via one-pot multicomponent reactions. Ethoxy acetyl Spiro pyrrolidine-2,3'-thieno[2,3-d]pyridazin-hydrazide (5) assessed as ecofriendly microbicidal and insecticidal activities to establish a structure-activity relationship. Elemental analysis and spectroscopic data were used to describe the structures of all synthesized products. The Spiro-heterocyclic compounds are exclusive non-planar structures and branded for binding to biomolecules. The microbicidal and insecticidal activities of the compounds were investigated on ATCC coded test microorganisms upon the applied dose and time was studied through two kinetic study. The interaction with these antibacterial and insect’s third instar larvae was medicinal and economically valuable. The preliminary testing demonstrated flourishing microbicidal capability to prevent the growth of threatening pathogenic bacteria as well as blossoming insecticidal efficacy. Moreover, Molecular docking and density functional theory simulations can be used to validate the experimental results. Also, we utilized the docking approach with secondary bacterial infection indicated that Ethoxy acetyl Spiro hydrazide (5) and Spiro arylidene hybrid (6) have exerted the strongest docking binding value against the active sites of 6LU7.

3 + 2] Cycloaddition reaction of disubstituted-3-benzylidene succinimide with C, N-disubstituted nitrile imines for synthesizing spiro-heterocycles: A computational study

The relevance of spiro heterocycles in the biomedical sector is enormous. This computational work extensively investigates the stereo-, regio-, chemo-, and site- selectivities of the [3 + 2] cycloaddition reaction of disubstituted-3-benzylidene succinimide (3-BS) with C, N-disubstituted nitrile imines derivatives for the formation of spiro heterocycles. This study employs the B3LYP, B3LYP-D3, M06, M06-2X, and MPWB1K hybrid density functional calculations with the 6-311G(d, p) basis sets. Various computations show that the attachment of the nitrile imine across the olefinic functionality of the disubstituted-3-BS has relatively lower barriers compared to the carbonyl functionalities present. Generally, electron-releasing groups on disubstituted-3-BS increase the activation barriers, whereas electron-withdrawing groups significantly reduce the activation barrier. The GEDT values predicts a low polar character for the [3 + 2] Cycloaddition reaction. Results from local and global parr functions calculations are in accordance with the selectivities and energetic trends observed.

Green Stereoselective Synthesis and In Silico Anticancer Evaluation of Tetrahydro-β-carboline-Derived Spiro Heterocycles

AbstractA green stereoselective synthesis of spiroheterocycles incorporating a spirooxindole and a 1,2,3,4-tetrahydro-β-carboline (THβC) are demonstrated here by the one-pot, three-component reaction of THβC, isatins, and chalcones. Operational simplicity and chromatography-free isolation are the highlights of the reaction which resulted in densely substituted spiroheterocycles with four-contiguous stereocenters in excellent yields. The activity of the compounds as anticancer agents was studied in silico against MDM2 and PLK1 target proteins and they show excellent binding interactions compared to reference drugs.

Spiroleiferthione A and Oleiferthione A: Two Unusual Isothiocyanate-Derived Thioketone Alkaloids from Moringa oleifera Lam. Seeds.

Spiroleiferthione A (1), with a 2-thiohydantoin a heterocyclic spiro skeleton, and oleiferthione A (2), an imidazole-2-thione derivative, were isolated from the aqueous extract of Moringa oleifera Lam. seeds. The unprecedented structures of 1 and 2 were elucidated by extensive spectroscopic data, X-ray diffraction, and gauge-independent atomic orbital (GIAO) NMR calculation, as well as electronic circular dichroism (ECD) calculation. The structures of 1 and 2 were determined to be (5R,7R,8S)-8-hydroxy-3-(4'-hydroxybenzyl)-7-methyl-2-thioxo-6-oxa-1, 3-diazaspiro [4.4] nonan-4-one, and 1-(4'-hydroxybenzyl)-4,5-dimethyl-1,3-dihydro-2H-imidazole-2-thione, respectively. Biosynthetic pathways for 1 and 2 have been proposed. Compounds 1 and 2 are considered to have originated from isothiocyanate and then undergone a series of oxidation and cyclization reactions to form 1 and 2. Compounds 1 and 2 demonstrated weak inhibition rates of NO production, 42.81 ± 1.56% and 33.53 ± 2.34%, respectively, at a concentration of 50 μM. Additionally, Spiroleiferthione A demonstrated moderate inhibitory activity against high glucose-induced human renal mesangial cell proliferation in a dosage-dependent manner. A wider range of biological activities, and the diabetic nephropathy protective activity of Compound 1 in vivo and its mechanism of action, need further investigation after the sufficient enrichment of Compound 1 or total synthesis.

Enantioselective Synthesis of Spiro Heterocyclic Compounds Using a Combination of Organocatalysis and Transition-Metal Catalysis.

Over the last ten years, the combination of organocatalysis with transition metal (TM) catalysis has become one of the most important toolboxes used for synthesizing optically pure compounds containing chiral quaternary centers, including spiro heterocyclic molecules. The dominant method in the enantioselective synthesis of spiro heterocyclic compounds based on synergistic catalysis includes chiral aminocatalysis and NHC catalysis, as already established covalent organocatalytic strategies. Another area of organocatalysis widely combined with TM catalysis producing enantiomerically enriched spiro heterocyclic compounds is non-covalent catalysis, dominated by chiral phosphoric acids, thiourea, and squaramide derivatives. This review article aims to summarize enantioselective methods used for constructing spirocyclic heterocycles based on a combination of organocatalysis and transition metal catalysis.

Green and Efficient Synthesis of Spiroheterocyclic Compounds from Reactions of Isatins, 3-Amino-1-phenyl-1H-pyrazol-5(4H)-one, and Monocyclic Ketones

The reactions of isatins, 3-amino-1-pheyl-1H-pyrazol-5(4H)-one, and monocyclic ketones, have been developed for preparation of spiro[indoline-3,4'-pyrazolo[3,4-b]quinoline]-2,3'(6'H)-dione, spiro[cyclohepta[b]pyrazolo[4,3-e]pyridine-4,3'-indoline]-2′,3-dione, spiro[cycloocta[b]pyrazolo[4,3-e]pyridine-4,3'-indoline]-2′,3(6H)-dione, and spiro[cyclo dodeca[b]pyrazolo[4,3-e]pyridine-4,3'-indoline]-2′,3(6H)-dione derivatives in aqueous and acetic acid mixed medium. Studies have shown that water was an excellent medium for this reaction. The significant features of this method are wide substrate scope, high yields, operational simplicity, and minimal environment impact.

DFT Studies on the Molecular Structure, Regioisomerism, Ground and Excited state Charge Transfer Properties of Spiro‐heterocycles

AbstractThe electronic structure, stereochemical aspects and charge transfer properties of the spiro compound (5S,8S) spiro‐{6‐phenyl‐1‐aza‐3‐oxa‐7‐thia‐bicyclo[3,3,0]‐octene‐8,3’(2’H)‐indol}‐2’‐one (spiro bicyclo adduct) synthesized using the multi‐component reaction via 1,3‐dipolar cycloaddition of isatin and thioproline with the dipolarophile phenylacetylene have been studied. The two lowest energy regio‐isomers of the spiro heterocycle formed from the stereospecific dipolar reaction have been analysed along with the electron‐withdrawing and releasing substituents using DFT method at the CAM‐B3LYP/6‐311++G(d,p) level of theory. The atomic charges and the stabilization energy due to the intramolecular charge delocalization process calculated using the natural orbitals at the different molecular sites reveal the different donor‐acceptor interactions occurring in the system. The intramolecular electronic transitions (specifically n to π* and π to π*) is found to occur from the localized donor end component to the acceptor end components in the multi‐component system. The hole produced by the ionization of the entities is found to migrate from the thioproline component to the phenyl acetylene part in a time scale of around 4 fs. The electron‐withdrawing and donating substituents on the spirobicyclo adduct have been proven to tune the excited and ground state charge transfer properties uniquely. The results can shed light on how multi‐component reactions can be directed to produce spiro adducts with versatile applications.

Spiro heterocycles bearing piperidine moiety as potential scaffold for antileishmanial activity: synthesis, biological evaluation, and in silico studies

New spiro-piperidine derivatives were synthesised via the eco-friendly ionic liquids in a one-pot fashion. The in vitro antileishmanial activity against Leishmania major promastigote and amastigote forms highlighted promising antileishmanial activity for most of the derivatives, with superior activity compared to miltefosine. The most active compounds 8a and 9a exhibited sub-micromolar range of activity, with IC50 values of 0.89 µM and 0.50 µM, respectively, compared to 8.08 µM of miltefosine. Furthermore, the antileishmanial activity reversal of these compounds via folic and folinic acids displayed comparable results to the positive control trimethoprim. This emphasises that their antileishmanial activity is through the antifolate mechanism via targeting DHFR and PTR1. The most active compounds showed superior selectivity and safety profile compared to miltefosine against VERO cells. Moreover, the docking experiments of 8a and 9a against Lm-PTR1 rationalised the observed in vitro activities. Molecular dynamics simulations confirmed a stable and high potential binding to Lm-PTR1.

New Synthetic Approaches to Benzo-Fused Spiro Heterocycles

New Synthetic Approaches to Benzo-Fused Spiro Heterocycles