Substituted Isatin Derivatives Research Articles

One Pot Synthesis, Crystal Structure, Hirshfeld Studies, Docking Simulation and Antimicrobial Efficacy Assay of New Fused/Substituted Pyrazolinyl–Thiazolidinyl–Indolone Triheterocyclic Hybrid Scaffolds

In this present investigation, a new series of functionalized hybrid compounds containing three bioactive triheterocyclic templates, pyrazolines, thiazolidinones, and indolones are designed and synthesized via multicomponent, one-pot reaction of 3-(4-chlorophenyl)-5-[4-(propan-2-yl)phenyl]-4,5-dihydro-1H-pyrazole-1-carbothioamide with various substituted isatin derivatives and chloroacetic acid in the presence of fused sodium acetate and glacial acetic acid viz ring closure mechanism followed by dehydration. The formation of new scaffolds 4–7(a–c) is evidenced by analytical and spectral studies. The single-crystal X-ray diffraction study supported the molecular structure of compound 4a as a triclinic crystal system with a P space group and Z = 2. Interestingly, the compound is crystallized with two molecules (A/B) and one water molecule in the asymmetric unit, and the crystal packing is stabilized by intra and intermolecular hydrogen bonds. To quantify the percentage of intermolecular contacts and electrostatic potential distribution in crystal packing, Hirshfeld surface analysis was performed. All the compounds were screened for their preliminary antimicrobial activity against a panel of bacterial and fungal strains. The newly synthesized compounds exhibited fairly encouraging in vitro antibacterial activity, so the validation of the potent compound was done by docking against the antibacterial target Escherichia coli FabH (PDB: 5BNS). The virtual screening is focused on ADME and drug-likeliness properties to identify their putative ligand-protein interactions using Schrödinger software.

Palladium-Catalyzed Chemoselective Oxygenation of C(sp2)–H and C(sp3)–H Bonds in Isatins

The palladium-catalyzed chemoselective C(sp2)-H and C(sp3)-H bond oxygenation of substituted isatin derivatives is reported. This mild protocol exhibits the C5 C(sp2)-H oxygenation of isatins through electrophilic intermolecular C-H palladation in concentrated solutions using PhI(OAc)2 or Selectfluor as an oxidant, whereas it exhibits-N-CH3 C(sp3)-H oxygenation in dilute solutions via carbonyl-assisted intramolecular palladation in the presence of K2S2O8. This oxygenation reaction provides a direct and unified approach for synthesizing diverse oxygenated isatins with sensitive functionalities, including biorelevant compounds.

Lead optimization study on indoline-2,3-dione derivatives as potential fatty acid amide hydrolase inhibitors

Based on the known isatin-based fatty acid amide hydrolase (FAAH) inhibitor BSS-7, we designed and synthesized two small sets (6–13 and 17–20) of N-1 and C-3 substituted isatin derivatives and evaluated them for their in vitro FAAH inhibition properties. The lead simplification by modification of bulky aryl moiety at N-1 with a flexible allyl group produced a nanomolar (IC50 = 6.7 nM, K i = 5 nM) inhibitor 11 (Z)-3-((1H-benzo[d]imidazol-2-yl)imino)-1-allylindolin-2-one which exhibited a reversible and competitive FAAH inhibition with 1500 times more potency to BSS-7 (1.49 ± 0.03 µM). The lead compound 11 also showed a high blood–brain permeability and a significant antioxidant profile with no neurotoxicity. Docking results suggested that the inhibitor molecules occupied the active site of FAAH and offered optimal binding interactions. A molecular dynamics simulation study ascertained the stability of the lead inhibitor 11-FAAH complex. In silico ADMET profiling studies unveiled that compound 11 possesses good drug-like properties and merits further evaluation. Communicated by Ramaswamy H. Sarma

Interaction Study of 1, 3 Substituted Isatin Derivatives with Anti Inflammatory Properties with Cyclooxygenase 1 and 2 Enzymes by Molecular Docking Method

Introduction: Inflammation as the body's defense response is accompanied with various diseases. Prostaglandins are major mediators of inflammation produced by the cyclooxygenase enzymes. So inhibitors of these enzymes can be effective in treating inflammation. There are reports of inhibition of these enzymes by isatin derivatives to control inflammation. Isatin is a heterocyclic compound whose derivatives have been shown outstanding biological profile in medicinal chemistry studies especially anti-inflammatory effects. In this study, derivatives of isatin were investigated for interaction with cyclooxygenase enzymes in order to confirm the experimental results whit theory to suggest a possible mechanism.
 Methods: In this study, some of the isatin –based synthesized derivatives which have been shown anti-inflammatory effects in in- vitro tests, evaluated by docking program for interaction with cyclooxygenase 1 and 2 enzymes. Also, the pharmacokinetic properties and compliance with the Lipinski law of synthesized compounds were investigated.
 Results: The results showed that compounds I2 and I3 have the lowest values of binding energy to both forms of the cyclooxygenase enzymes. All studied compounds followed Lipinski's law.
 Conclusion: Compounds I2 and I3 showed moderate anti-inflammatory activity in in vitro anti-inflammatory studies which is in accordance with docking studies. It can be a confirmation of the possible mechanism of these compounds through inhibition of this enzyme. ٍEnzyme inhibition studies by these derivatives through diagnostic kits are also required for more confirmation.

Regio- and Stereoselective Synthesis of a New Series of Spirooxindole Pyrrolidine Grafted Thiochromene Scaffolds as Potential Anticancer Agents

A series of new spiro-heterocycles engrafted spirooxindole/pyrrolidine/thiochromene scaffolds was synthesized by the three-component 1,3-dipolar cycloaddition reactions in a fully controlled regio- and stereo-selective fashion. Condensation of several substituted isatin derivatives with L-proline generated the azomethine ylides which subsequently reacted with chalcones based thiochromene scaffold, and finally afforded the target spiro-compounds. This simple protocol furnished a structurally complex, biologically relevant spiro-heterocycles in good yields through a one-pot process. All synthesized chalcone-based thiochromene, along with the spirooxindole/pyrrolidine/thiochromene scaffolds, were tested for their anticancer activity against four cancer cell lines (PC3, HeLa, MCF-7, and MDA-MB231). Toxicity of these compounds was also evaluated against human fibroblast BJ cell line, and they appeared to be not cytotoxic. For the prostate cancer (PC3) cell line, the most active hybrid, among synthesized series, was compound (7f, IC50 = 8.7 ± 0.7 µM). The most potent spirooxindole/pyrrolidine/thiochromene hybrid against cervical (HeLa) cancer cells was compound (7k, IC50 = 8.4 ± 0.5 µM) having chlorine and p-trifluoromethyl substituents attached to phenyl rings. Finally, against the MCF-7 and MDA-MB231 breast cancer cell lines, compound (7d) was the most active member of this series (IC50 = 7.36 ± 0.37, and 9.44 ± 0.32 µM, respectively).

Design, Synthesis, Antimicrobial and Anticancer Activity of some Novel Benzoxazole-Isatin Conjugates

A series of novel benzoxazole-isatin conjugates were synthesized by treating 2-amino benzoxazole with 5 and 7 substituted isatin derivatives and were screened for in vitro antimicrobial and cytotoxic activities. The results showed that all the synthesized compounds shown mild to potent antibacterial activity. The MIC values were found between 10 and 100 µg/ml against tested bacterial and fungal organisms. Among all the compounds, 3d & 3c showed good antimicrobial. In vitro cytotoxic activities were evaluated by MTT assay of all the test compounds against the different human cancer cell lines. The compounds having substitution with electron-withdrawing groups (halides) at the 5th position on the isatin ring showed the most significant biological activity than substituted at the 7th position. The molecular docking interactions have shown good binding interactions with the protein targets glucosamine-6-phosphate synthase (GlcN-6-P synthase) and telomerase.

Synthesis and anti-inflammatory effects evaluation of 1,3 substituted isatin derivatives

Synthesis and anti-inflammatory effects evaluation of 1,3 substituted isatin derivatives

Design, Synthesis, Characterisation & Anticonvulsant Activities of Novel Heterocyclic Substituted Isatin Derivatives

Twelve new isoxazole/pyrazole/pyrimidine substituted 5-nitrosation analogues were designed according to the requirements of the anticonvulsant drugs pharmacophore model and synthesised from indole-2,3-dione. Entire prepared compounds chemical structures were established from its IR, proton-NMR, Mass spectrum & microanalysis data. Anticonvulsant potency of final isatin analogues was assessed by MES technique & sc PTZ technique. Besides rotarod test was used to assess the neurotoxicity of all potent title analogues. Title compounds exhibited a varying degree of anticonvulsant potency ranging from mild to good. In the present study, it was concluded that pyrazole derivatives exhibited higher anti-epileptic activity than isoxazole derivatives. However, pyrimidine analogues displayed inferior activity than isoxazole analogues. 4-(2-(4-(1-((Dimethylamino)methyl)-5-nitro-2-oxindole-3-ylideneamino)phenyl) hydrazone)-1-(4-chlorophenyl)-3-amino-1H-pyrazole-5(4H)-one 7c was established as the most active analog of this series. Hence this derivative can act as a pilot molecule for further progress of new effective anticonvulsant drugs.

Development of indanones and isatins as non-cytotoxic inhibitors of cholinesterases

A small library of indanone-amides and substituted isatin derivatives has been prepared; these compounds have been investigated for their ability to act as inhibitors for the enzymes acetyl- and butyrylcholinesterase (AChE, BChE). Several of them were moderate inhibitors for AChE and not cytotoxic for a variety of human tumor cell lines as well as for non-malignant mouse fibroblasts. In this library consisting of 49 derivatives, 5,7-dibromo-4-iodoisatin was shown to be a good mixed-type inhibitor for AChE (K­i = 2.52 ± 0.61 µM and Ki´ = 11.74 ± 1.31 µM) but this compound also acted as a dual inhibitor for BChE (Ki = 4.49 ± 0.32 µM and Ki´ = 6.56 ± 0.57 µM). Interestingly, N-hexyl-1-oxo-2,3-dihydro-1H-indene-2-carboxamide was cytotoxic especially for MCF-7 breast adenocarcinoma cells (EC50 = 4.28 ± 0.5 µM).

Evaluation of a class of isatinoids identified from a high-throughput screen of human kinase inhibitors as anti-Sleeping Sickness agents.

New treatments are needed for neglected tropical diseases (NTDs) such as Human African trypanosomiasis (HAT), Chagas disease, and schistosomiasis. Through a whole organism high-throughput screening campaign, we previously identified 797 human kinase inhibitors that grouped into 59 structural clusters and showed activity against T. brucei, the causative agent of HAT. We herein report the results of further investigation of one of these clusters consisting of substituted isatin derivatives, focusing on establishing structure-activity and -property relationship scope. We also describe their in vitro absorption, distribution, metabolism, and excretion (ADME) properties. For one isatin, NEU-4391, which offered the best activity-property profile, pharmacokinetic parameters were measured in mice.

Molecular Design, Synthesis, Computational Screening, Antimicrobial Evaluation and Molecular Docking Study of Acetylinic Isatin Hybrids

AbstractAs a part of our program to compose multicomponent hybrid templates with potential pharmaceutical recognition, we have designed a library of acetylinic isatin hydrazones (1 b‐1 p) and acetylinic spiroisatins (1 q‐1 s). All the synthesized motifs were thoroughly characterized and then evaluated for their antimicrobial activities followed by cytotoxic appraisal of the more potent compounds in Hek293 and HeLa human cancer cell lines. Computer aided drug design filtered the compounds considered unsuitable for screening purposes. Acetylinic isatin 1 e was the most potent antibacterial scaffold with IC50 ≈ 1.95 μM against E. coli while 1 n with bis‐isatin assembly was the lead compound against C. albicans with IC50 ≈ 15.67 μM. SAR allowed to have a thorough anticipation of the substituent effect on the observed bioactivities of the compounds. Further, docking studies of the selected scaffolds on admissible bacterial and fungal proteins elicited isatin 1 a to exhibit highest ligand efficiency. Molecular interactions disclosed that 3’N substituted isatin derivatives may be considered ==as efficient candidates to curb bacterial and fungal diseases.

Exploration of Anticancer Potential of Spiropyranopyrazole Derivatives as CDK7 Inhibitors

Purpose : The Spiropyranopyrazole derivatives are used as cytotoxic agents and nitrogen containing heterocyclic analogs targeting CDK7 inhibition shows better cytotoxic activity. Methodology : A new series of compounds were synthesized using various substituted isatin derivatives and then characterized and analyzed for biological activity by in-silico and using MTT assay targeting CDK7. All the synthesized compounds were analyzed for their biological activity for this purpose breast cancer cell lines (MCF7) were used and analyzed by MTT assay. Docking studies into ATP binding site of CDK7 were performed to predict their binding affinity scores and possible interactions with receptor to evaluate bioactivity in-silico using VLife MDS 4.3. Findings : A novel series of Spiropyranopyrazole derivatives were successfully synthesized via Multicomponent reaction (MCR). From experimental data indicated that compounds 2c and 3c showed most promising results as their inhibitory activity with 23.20% and 26.50% respectively at 10μM and these were selected for further preclinical studies. Social Implications : If the present findings of spiropyranopyrazole derivatives passes preclinical studies and we develop drug like candidate then it is a massive achievement in anticancer therapy that could save many lives. Original : Successfully develop a novel series of spiropyranopyrazole having CDK7 inhibitor activity. This could be helpful for development of a drug like candidate having significant cytotoxic activity.

Synthesis and Fragmentation Behavior Study of n-alkyl/benzyl Isatin Derivatives Present in Small/Complex Molecules: Precursor for the Preparation of Biological Active Heterocycles

N-Alkyl/benzyl substituted isatin derivatives are intermediates and synthetic precursors for the preparation of biolog- ical active heterocycles. N-alkyl/benzyl isatins have showed various biological activities, such as cytotoxicity, antiviral, caspase inhibition, cannabinoid receptor 2 agonists for the treatment of neuropathic pain, etc. In this study, N-alkyl/benzyl isatin deriva- tives were synthesized from isatin and alkyl/benzyl halides in presence of K2CO3 in DMF and excellent to quantitative yields (~95%) were obtained. Isatins and benzyl-isatins were condensed with fluorescein hydrazide to form fluorescein hydrazone. All the compounds were subjected to their fragmentation behavior study using LC/MS n . N-Alkyl substituted isatin derivatives frag- mented at nitrogen-carbon (N-C) bond, hence gave daughter ion as (RN+H) + . Whereas, N-benzyl substituted isatin derivatives fragmented at carbon-carbon (C-C) bond of alkyl chain which linked with nitrogen molecules, therefore gave N-methyl frag- ments (RNCH2) + . This study demonstrated that, isatin moiety present in a small/large molecule or in a matrix of reaction mixture with/without N-alkyl/benzyl substituents can be identified by mass spectroscopic fragmentation behavior study.

Design of novel dispirooxindolopyrrolidine and dispirooxindolopyrrolothiazole derivatives as potential antitubercular agents.

With the aim to develop new potent antitubercular agents, a series of novel dispirooxindolopyrrolidines and dispirooxindolopyrrolothiazoles have been synthesized via a three-component 1,3-dipolar cycloaddition of (Z)-3-arylidenebenzofuran-2-ones, substituted isatin derivatives and α-aminoacids. The stereochemistry of the spiroadducts has been confirmed by an X-ray diffraction analysis. All the target heterocycles were evaluated for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain and the most active compounds were subjected to cytotoxicity studies against (RAW 264.7) cell lines. Among them, twelve compounds showed potent anti-tubercular activity with MIC ranging from 1.56 to 6.25 μg/mL. In particular dispirooxindolopyrrolothiazole derivatives 5c and 5f were found to be the most active (MIC of 1.56 μg/mL) with a good safety profile (27.53% and 20.74% at 50 μM, respectively). This is the first report demonstrating the benzofuranone oxindole hybrids as potential antimycobacterial agents.

Synthesis and evaluation of neuropharmacological profile of isatin-3-[ N 2-(2-benzalaminothiazol-4-yl)] hydrazones

Background and objective Isatin and its derivatives are versatile lead molecule for potential bioactive agents and are reported to possess a wide spectrum of activities such as central nervous system (CNS), antibacterial, antifungal, anticonvulsant, anti-HIV, antidepressant, anti-inflammatory, etc. In this study, we evaluated neuropharmacological profile of isatin-3-[N2 -(2-benzalaminothiazol-4-yl)] hydrazone derivatives using well-defined preclinical models. Materials and methods The isatin-3-[N2 -(2-benzalaminothiazol-4-yl)] hydrazone derivatives ( Va-Vj ) were synthesized and characterized using spectral data. Neuropharmacological profile of Va-Vj (10 and 100 mg/kg, orally) was investigated by gross behavioural profile, hole board, locomotor activity, hypnotic activity, forced swim test, tail suspension test and rota rod test in mice. Imipramine (10 mg/kg) and diazepam (2 mg/kg) were used as standard for antidepressant and sedative as well as a hypnotic drug, respectively. Results and conclusion Isatin derivatives showed dose-dependent neuropharmacological action on the CNS, such as anxiolytic, sedative, hypnotic and depressant action. Among all the derivatives, halogen-substituted compounds ( Vh and Vi ) at 100 mg/kg showed significant (P < 0.001) action when compared with the control group (0.1% sodium carboxy methylcellulose (CMC)), and other substituted isatin derivatives Va, Vb, Vc, Vd, Ve, Vf, Vg and Vj also proved to possess a significant (P < 0.05) action at 100 mg/kg compared with the control group. From these results, we concluded that Va-Vj compounds possessed a wide range of CNS activities.

3D QSAR Analysis on Isatin Derivatives as Carboxyl Esterase Inhibitors Using K-Nearest Neighbor Molecular Field Analysis

A three dimensional quantitative structure activity relationship (3D QSAR) using k nearest neighbor molecular field analysis (kNN MFA) method was performed on a series of isatin derivatives as carboxylesterase (CE) inhibitors. This study was performed with 49 compounds (data set) using sphere exclusion (SE) algorithm for the division of the data set into training and test set. SE algorithm allows constructing training sets covering all descriptor space areas occupied by representative points. Between 3.0 to 5.5 dissimilarity levels which comprises of test set size 4 to 10, kNN-MFA methodology with stepwise (SW), simulated annealing (SA) and genetic algorithm (GA) was used for building the QSAR models. Four predictive models were generated with SW-kNN MFA (pred_r2=0.7552 to 0.9376), three predictive models were generated with SA-kNN MFA (pred_r2=0.7019 to 0.9367) and two predictive models were generated with GA-kNN MFA (pred_r2=0.8226 to 0.8497). Most significant model generated by stepwise kNNMFA showed internal predictivity 82.11% (q2=0.8211) and external predictivity 93.76% (q2=0.9376). In this model hydrophobic and steric interactions dominate the CE inhibitory activity. Hydrophobic field descriptor (H_977) with positive range indicates that positive hydrophobic potential is favorable for increase in activity and hence more hydrophobic substituent group is preferred in that region. Steric field descriptor (S_619) with negative range indicates that negative steric potential is favorable for increase in activity and hence less bulky substituent group is preferred in that region. The kNN-MFA contour plots provided further understanding of the relationship between structural features of substituted isatin derivatives and their activities which should be applicable to design newer potential CE inhibitors.

X-ray crystallographic study of diversely substituted isatin derivatives

A series of isatin derivatives were synthesized and studied by XRD. For the first time the peculiarities of the molecule structure and crystal packing effects were analyzed. Indoline heterocycles are planar in all the investigated structures. The molecules bearing the sterically hindered substituents at nitrogen atom of indoline heterocycle have the maximum deviations of two oxygen atoms from the indoline plane. The substituent nature at nitrogen atom does not effect on the bond lengths of indoline moiety. The value of endocyclic bond angle at nitrogen not so strongly depends on the substituent and is almost equal to the one in unsubstituted isatin. In contrast to the unsubstituted isatin, where the system of classical hydrogen NH⋯O-bonds is realized, in crystals of investigated compounds there is no opportunity to reveal ones, and the crystal structure is stabilized by CH⋯O- and π–π-interactions.

Design, Synthesis and Biological Activity Evaluation of Novel N-Acylation Substituted Isatin Derivatives

Isatin, an endogenous compound existent in many organisms, shows a wide range of biological activities. In this paper, we like to report the design and synthesis of several isatin derivatives through the acetalization and N-Acylation. Six newly synthesized compounds were characterized on the basis of 1H NMR, and those compounds were determined using two different human cancer cell . Anti-cancer activity showed those compounds IC50＜50 μm.

Synthesis, biological activity and docking study of some new isatin Schiff base derivatives

A set of novel Schiff bases of isatin were synthesized and characterized by reaction of isatin with various aromatic or heterocyclic primary amines. Cytotoxic activities for some of the synthesized compounds were evaluated by MTT assay in three human cancer cell lines (HeLa, LS180 and Raji). Half of the tested compounds showed good cytotoxicity in HeLa cells. 3-(2-(4-nitrophenyl) hydrazono) indolin-2-one was found to be the most potent molecule among the studied isatin derivatives. Docking studies of 3-substituted indolin-2-one scaffolds on vascular endothelial growth factor receptor 2 (VEGFR-2) involved in cell proliferation and angiogenesis was performed. 3-(naphthalen-1-ylimino) indolin-2-one and 3-(2-(4-nitrophenyl) hydrazono) indolin-2-one exhibited higher docking binding energies with receptor. For 3-(2-(4-nitrophenyl) hydrazono) indolin-2-one, H-bond interaction with Cys917 residue of target active site was in common with reported crystallographic benzoimidazole derivative (PDB code: 2OH4). New key H-bonds involving Glu915, Asn921, and Arg1049 residues in VEGFR-2 active site could be detected for 3-(2-(4-nitrophenyl) hydrazono) indolin-2-one. Extended lipophilic rings containing H-bond acceptors on the 3 position of indoline scaffold seemed to be important factors in developing potent VEGFR-2 inhibitors virtually. Based on the ligand efficiency indices, some isoxazole or thiazole substituted isatin derivatives may be regarded as efficient candidates for further molecular developments of anticancer agents.

In vitro cytotoxicity evaluation of some substituted isatin derivatives

A range of substituted 1 H-indole-2,3-diones (isatins) were synthesized using standard procedures and their cytotoxicity evaluated against the human monocyte-like histiocytic lymphoma (U937) cell line in vitro. SAR studies identified C 5, C 6, and C 7 substitution greatly enhanced activity with some di- and tri-halogenated isatins giving IC 50 values <10 μM. Of the 23 compounds tested, four were selected for further screening against a panel of five human cancer cell lines. These compounds, in general, showed greater selectivity toward leukemia and lymphoma cells over breast, prostate, and colorectal carcinoma cell lines. The most active compound, 5,6,7-tribromoisatin ( 2p), was found to be antiproliferative at low micromolar concentrations and also activated the effector caspases 3 and 7 in a dose-dependent manner. These results indicate that di- and tri-substituted isatins may be useful leads for anticancer drug development in the future.