Heterocyclic Hybrids Research Articles

Synthesis, characterizations and conformational analysis of some new 2-arylidene N-(1,3-dioxoisoindolin-2-yl)aminothiocarbohydrazides and their conversion to functionalized hybrids of isoindole core with thiadiazoline

A novel series of thiosemicarbazone derivatives having 1,3-dioxoisoindole core were synthesized from the reaction of N-(1,3-dioxoisoindolin-2-yl)aminothiocarbohydrazide (3) with a variety of aldehydes and ketones. Their geometrical and conformational isomers were investigated based on the analysis of their 1HNMR and 13CNMR spectra. The thiosemicarbazones were found to exist in the more stable structure III with an E configuration and a syn, syn disposition of both NH protons around the C=S bond. However, compounds 5b and 9c were existed as a mixture of E (major) and Z (minor) stereoisomers with a syn, syn conformation of both NH protons around the C=S bond as in structure III and VI, respectively. On the other hand, the thiosemicarbazones 9e,f and 15 derived from p-chloro-, p-bromoacetophenone and cyclopropylmethyl ketone 14 showed different behavior. They existed in solution of DMSO-d6 as a mixture of E (major) and Z (minor) geometrical isomers with syn, syn and, anti, anti disposition of both NH protons as in structure III and IV, respectively. Dehydrative cyclization of compounds 5b–g, i, 9a–d and 15 with acetic anhydride afforded only one stereoisomer of the hybrid heterocycles of the dioxoisoindole and thiadiazoline rings 16a–l as confirmed by 1H and 13C NMR spectra. DFT calculations revealed the extrastability of the E isomer relative to the Z one 5b, d and 15 as representative examples. The relative energies are small (5.1–5.8 kcal/mol) which further confirm their coexistence in solution.

Coumarin linked heterocyclic hybrids: A promising approach to develop multi target drugs for Alzheimer's disease

Alzheimer's disease (AD) is a major progressive and perplexing cortical degenerative disease of the brain in the elderly. It contributes to a significant socioeconomic burden on patients, families, and care providers in comparison to cancer, cardiovascular diseases, and stroke in general.Recently, a hybridized approach based on multi-target directed ligands (MTDLs) has received considerable attention to develop therapeutic agents for AD which act at multiple targets. Approximately 20% of the drugs approved in the past couple of years were developed using the same strategy and thus it seems to be the right approach to develop AD therapy. The comprehensive and updated review on coumarin hybrids as MTDLs in AD therapy is compiled using several electronic databases such as Scopus, Google Scholar, SciFinder, Mendeley, and PubMed. The research studies published on coumarin hybrids in the last decade (2010- 2020) have been covered in this review article.This updated review highlights the importance of coupling (hybridization) coumarin scaffold with other bioactive pharmacophores to develop MTDLs for AD therapy. It also covers the patents granted to coumarin derivatives for AD treatment, natural products containing coumarin scaffold with anti-Alzheimer spectrum, the rationale for coupling pharmacophore fragments, detailed structure activity relationship (SAR), and molecular docking studies. The most potent and promising hybrid compounds have also been identified for further development of AD drugs. Authors are of the opinion that hybridization strategy would soon yield drug candidates for the treatment of AD.

Stereoselective synthesis, structure and DFT studies on fluoro- and nitro- substituted spirooxindole-pyrrolidine heterocyclic hybrids

Structurally diverse highly functionalized flouro- and nitro - substituted spirooxindole-pyrrolidine heterocyclic hybrids have been achieved in good yields. The molecular structure of these diverse spiroheterocyclic hybrids was elucidated by spectroscopic analysis and further confirmed by single crystal X-ray crystallographic studies and density functional theory (DFT) calculations. Analysis of molecular packing for these hybrids was performed using Hirshfeld analysis. Geometric parameters calculated by DFT are in good agreement with the experimental data obtained from X-ray crystallography.

Stereoselective synthesis and discovery of novel spirooxindolopyrrolidine engrafted indandione heterocyclic hybrids as antimycobacterial agents

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).

Stereo- and regioselective synthesis of novel β-lactam tethered spiropyrrolizidine/pyrrolothiazole heterocyclic hybrids

Abstract 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.

Syntheses of Spiro(2-oxopyrrolidinyl)-5,4′-pyrazolones via Organocatalyzed Michael/Ammonolysis Cascade Reaction of 4-Aminopyrazolones and α,β-Unsaturated Acyl Phosphates

AbstractThe efficient organocatalyzed Michael/ammonolysis cascade reaction of N-protected 4-aminopyrazolones and α,β-unsaturated acyl phosphates has been developed. This tactic gives rise to architecturally multifarious spiro(2-oxopyrrolidinyl)-5,4′-pyrazolones in good productiveness (up to 88% yield) and with moderate to good diastereoselectivities (up to 20:1 dr). These novel hybrid heterocycles would be promising candidates for drug-discovery programs and chemical biology.

A stereo, regioselective synthesis and discovery of antimycobaterium tuberculosis activity of novel β-lactam grafted spirooxindolopyrrolidine hybrid heterocycles

A stereo- and regioselective synthesis of hitherto unexplored novel class of β-lactam embedded spirooxindolopyrrolidine hybrid heterocycles have been accomplished via ionic liquid accelerated [3 + 2]-cycloaddition reaction process. The expected unusual lactonization/lactamization product could not be observed even in traces. The in vitro antimycobacterium tubercular activity of the synthesized spiroheterocyclic hybrids were assessed against Mycobacterium tuberculosis H37Rv. Among them, the compounds with no substitution and chlorosubstitution on the oxindole ring showed the most potent activity with a MIC 0.78 μg/mL and 1.56 μg/mL, respectively which were two-fold and equal activity than the standard drug, ethambutol (MIC = 1.56 μg/mL).

Ionic liquid mediated synthesis and in vitro mechanistic exploration of polycyclic cage‐like heterocyclic hybrid

AbstractA three‐component, [3 + 2]‐cycloaddition/annulation domino protocol is described for the synthesis in excellent yield of a polycyclic cage‐like heterocyclic hybrid (PCHH) that comprises various advantaged structural units viz., α,β‐unsaturated ketone moiety, 4‐pyridinone and pyrroloisoquinoline in a cage‐like framework. The antitumor activity of PCHH on human breast (MCF7), colon (HCT116), cervical (JURKAT) and lung (NCI‐H460) malignant cell lines inhibited the propagation of all cell lines. This hybrid molecule displayed increased broad‐spectrum anticancer activity with higher doses of PCHH. Furthermore, the compound induced 45.21% of early apoptosis and 46.32% of late apoptosis in the Jurkat cancer cell line. Cell cycle analysis showed that this cage‐like compound caused cell cycle arrest of Jurkat cells at the S phase and sub G0/G1 phase. Additionally, it led to increased DNA fragmentation and mitochondrial membrane permeabilization through activation of caspase‐3 enzyme. Present investigation demonstrates the specific cytotoxic activity of the cage‐like compound and the induction of apoptosis through the intrinsic pathway of Jurkat cells.

A One-Pot Three-Component Synthesis and Investigation of the In Vitro Mechanistic Anticancer Activity of Highly Functionalized Spirooxindole-Pyrrolidine Heterocyclic Hybrids.

With an aim to develop more effective and affordable anticancer agents possessing a unique mechanism of action, we designed and synthesized derivatives of spirooxindole-pyrrolidine heterocyclic hybrids in good yields through a one-pot three-component (3+2) cycloaddition strategy. The synthesized compounds were characterized thoroughly for the physicochemical properties by making use of FT-IR, NMR spectroscopy, and mass spectrometry. Further, these compounds have been evaluated for the influence of anticancer activity against HepG2 cells up to 200 µg/mL concentration. The highly active molecular scaffold was tested for the in-depth mechanistic studies, and it was found that the major pathway of cell death is apoptosis which occurs through the induction of reactive oxygen species followed by the involvement of caspases.

Diastereoselective synthesis and anticancer potential of a small library of cage-like heterocyclic hybrids

With an aim to construct novel anticancer drugs, a series of polycyclic heterocycles comprising diverse structural sub-units based on molecular hybridization strategy have been designed and synthesized through a three-component [3 + 2]-cycloaddition/annulation strategy. Anticancer evaluation of these compounds against MCF-7 and NCI-H460 cell lines revealed dose dependent reduction with noteworthy anticancer activity. Compound 4b inhibited MCF-7 and NCI-H460 cell lines with IC50 values 10.86 ± 0.94 and 9.17 ± 0.63 µM respectively. Further, apoptosis and cell cycle analysis revealed that this compound was able to prompt apoptosis at an early stage in MCF-7 cell line besides increasing the threshold of MMP and % of cells expressing FITC-dUTP. These results suggest that compound 4b is a potential molecule for the further exploration.

In Vitro Molecular Biology Studies of Spirooxindole Heterocyclic Hybrids

In the present report, we provide the results of the molecular biology studies of spiroheterocyclic hybrids, where the derivatives are found to possess potential anticancer activity towards cancer cells. A series of spiroxindole–pyrrolidine heterocyclic hybrids were evaluated for cell viability and proliferation against HepG2 cancer cells at concentrations in the range of 12.5–200 µg/mL over two different time periods of 24 and 48 h. In addition, the highly active compounds were also verified for their behavior towards noncancer cells (L929 cells), and it was found that the tested derivatives were not aggressive due to the observation of only limited cell loss, as compared to the cancer cells. Further analysis of the observed toxicity mechanism showed the apoptotic pathway was mediated by oxidative stress, with the involvement of caspases.

Cholinesterase inhibitory activity of highly functionalized fluorinated spiropyrrolidine heterocyclic hybrids.

Two series of dimethoxyindanone imbedded novel fluorinated spiropyrrolidine heterocyclic hybrids were synthesized employing two different less explored azomethine ylides and were measured for their efficiency as inhibitors for Alzheimer’s disease. Among the spiropyrrolidine heterocyclic hybrids, the indole based fluorinated compound with a methoxy substituent at the meta- position of the aryl ring exhibited the utmost potent AChE and BChE inhibitory activities with an IC50 of 1.97 ± 0.19 µM and 7.08 ± 0.20 µM respectively. The plausible mechanism of inhibition on ChE receptors was unveiled via molecular docking studies.

Broad spectrum antimicrobial activity of dispirooxindolopyrrolidine fused acenaphthenone heterocyclic hybrid against healthcare associated microbial pathogens (HAMPs)

BackgroundHealthcare-associated infections (HAI) are prime health task worldwide and issue of patient safety besides intensifying antimicrobial drug resistance. It is essential to formulate structurally fascinating novel, active and cost-effective anti-microbial drugs possessing a peculiar way of action and capable of overcoming the resistance to effectively combat this disease. Materials and methodsThe synthesized spiro-heterocyclic hybrids (SHHs) were elucidated through spectroscopic analysis and were assessed for their in vitro antimicrobial activity by agar diffusion method and minimal inhibitory concentration (MIC) value was also determined. In addition, antioxidant potential was also evaluated through DPPH radical scavenging assays. ResultsThe novel class of SHHs 4a and 4b displayed significant antibacterial activity against selected healthcare associated microbial pathogens (HAMPs). In addition, SHH 4b showed potent antioxidant properties. ConclusionAntibacterial and antifungal activity of dispirooxindolopyrrolidine fused acenaphthenone heterocyclic hybrids were examined. Interestingly, SHH 4b exhibited potent antimicrobial activity against selected HAMPs. Further, these compounds were also showed potent antioxidant properties. These results revealed that SHH 4b is a promising lead for the development of new antimicrobial drugs.

Bmim]Br Accelerated One-Pot Three-Component Cascade Protocol for the Construction of Spirooxindole-Pyrrolidine Heterocyclic Hybrids.

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.

Caspase dependent apoptotic activity of polycyclic cage-like heterocyclic hybrids.

A small library of cage-like heterocyclic hybrids encompassing pyrroloisoquinolines, pyridinone and acenaphthene structural moieties have been synthesized and tested for their potential as anticancer agents against HCT116 and JURKAT cell lines. The results revealed that these cell lines are more sensitive towards compound 1g and it showed dose dependent cytotoxic effect at 48 hrs of incubation. The IC50 values of compound 1g against HCT116 and JURKAT cell lines are 12.14 ± 1.53 and 10.68 ± 0.68 µM, respectively. Further studies on the determination of mechanism of action of compound 1g discovered that it brought the cell death by inducing Caspase 3 dependent apoptosis and also by arresting the cell cycle at S phase. These studies revealed that compound 1g can be recommended as a potential anti-cancer agent.

An efficient, sustainable approach to the chemo and regioselective synthesis of novel spiroindenoquinoxaline grafted piperidone hybrid heterocycles

An efficient, eco-friendly and sustainable approach for the synthesis of novel spiroindeno[1,2-b]quinoxaline-3-phenylspiro[4,3″]benzylidenepiperidone ring system has been developed by a one-pot four component [3 + 2] cycloaddition strategy. The 1,3-dipole generated in situ from quinoxalinone and l-phenylalanine reacts with the highly functionalized dipolarophiles, bisarylidene piperidones affording spirohybrid heterocycles in good yields. The unexplored novel class of dispirohybrid heterocycles obtained possess three CN and two CC bonds with four adjacent stereogenic carbons, out of which two is spirocarbons. The structure of compounds was elucidated using 1H, 13C and mass spectroscopic studies.

β-Cyclodextrin as carrier of novel antioxidants: A structural and efficacy study

Antioxidants are radical scavengers that have been proposed to be involved in many pathological conditions, from aging to degenerative disorders. The aim of the present study is the preparation, structural characterization and antioxidant efficacy evaluation of inclusion complexes (ICs) of two synthetic antioxidants with β-CD. The compounds under study are heterocyclic hybrid molecules, which combine the quinolinone framework and the pyrazoline moiety in one molecular scaffold. The ICs were thoroughly investigated in terms of structure using various techniques such as DLS, NMR, FT-IR, TGA and DSC. The findings revealed a different structural profile between the two ICs. Furthermore, the ICs were examined for their ability to scavenge radicals such as DPPH and 4-hydroxy-TEMPO in ethanol medium. Overall, β-CD could act as a promising host for the synthesized antioxidants as it increases their water solubility without inhibiting their radical scavenging ability.

In vitro Mechanistic Exploration of Novel Spiropyrrolidine Heterocyclic Hybrids as Anticancer Agents.

Novel spiro acenaphthylene pyrrolo[1,2-b]isoquinoline/pyrrolidine hybrids have been achieved through Pictet-Spengler/Eschweiler-Clarke reactions depending on the substitution in the benzyl ring. The in vitro biological efficacy of N-methyl spiropyrrolidine derivatives toward different cancer and non-cancer cell lines revealed that these novel spiro heterocyclic hybrids induced cancer cell death at moderate concentrations, while slight reduction in non-cancer cell viability at the higher concentrations. The analysis of cancer cells proved that the major pathway of cell death is apoptosis and in addition, the role of caspases is confirmed by the appearance of fluorescent cells in microscopic images. Therefore, this study indicates a sustainable way of treating cancer cells by inducing apoptotic pathways and associated caspases, while simultaneously protecting the non-cancer cells.

Multicomponent and 1,3-dipolar cycloaddition synthesis of triazole- and isoxazole-acridinedione/xanthenedione heterocyclic hybrids: Cytotoxic effects on human cancer cells

A new series of diverse 1,2,3-triazole-acridinedione/xanthenedione and 1,2-isoxazole-acridinedione/xanthenedione heterocyclic hybrids have been synthesized via 1,3-dipolar coupling reaction of N/O-substituted-acridinedione-alkyne or O-substituted-xanthenedione-alkyne substrates with various aromatic azides or oximes. In all cases, the cycloaddition is totally regioselective. The chemical structures of the synthesized compounds are determined using 2D NMR and are further confirmed by single-crystal X-ray diffraction analysis. Preliminary in vitro cytotoxic assays on two human breast cancer cell lines (MDA-MB-231, T47-D) and one prostate cancer cell line (PC3) are performed on some selected compounds. The most active O-1,2,3-triazole-xanthenedione hybrid displays the best cytotoxicity effects with IC50 ≤ 20 μM in breast cancer and IC50 = 10 μM in prostate cancer cell lines.

Dispiropyrrolidine tethered piperidone heterocyclic hybrids with broad-spectrum antifungal activity against Candida albicans and Cryptococcus neoformans.

Invasive fungal infections along with rising incidence of resistance to antifungal drugs pose increasing threat to immunocompromised individuals, including cancer patients. In this study, we examined the antifungal activity of dispiropyrrolidine tethered piperidone heterocyclic hybrids. Results indicate that compounds 5a and 6i have demonstrated a potent antifungal effect on multiple fungal strains, including Candida albicans, without exhibiting cytotoxicity to mammalian cells. Furthermore, these two compounds exhibited significant inhibition on Candida albicans hyphae and biofilm development that surpasses the FDA-approved antifungal drug currently used for treatment. Taken together, our results suggest that 5a and 6i are promising candidates for development into new antifungal drugs.