ABSTRACT
Aldehyde dehydrogenases (ALDHs) are a family of enzymes that aid in detoxification and are overexpressed in several different malignancies. There is a correlation between increased expression of ALDH and a poor prognosis, stemness, and resistance to several drugs. Several ALDH inhibitors have been generated due to the crucial role that ALDH plays in cancer stem cells. All of these inhibitors, however, are either ineffective, very toxic, or have yet to be subjected to rigorous testing on their effectiveness. Although various drug-like compounds targeting ALDH have been reported in the literature, none have made it to routine use in the oncology clinic. As a result, new potent, non-toxic, bioavailable, and therapeutically effective ALDH inhibitors are still needed. In this study, we designed and synthesized potent multi-ALDH isoform inhibitors based on the isatin and indazole pharmacophore. Molecular docking studies and enzymatic tests revealed that among all of the synthesized analogs, compound 3 is the most potent inhibitor of ALDH1A1, ALDH3A1, and ALDH1A3, exhibiting 51.32%, 51.87%, and 36.65% inhibition, respectively. The ALDEFLUOR assay further revealed that compound 3 acts as an ALDH broad spectrum inhibitor at 500 nM. Compound 3 was also the most cytotoxic to cancer cells, with an IC50 in the range of 2.1 to 3.8 µM for ovarian, colon, and pancreatic cancer cells, compared to normal and embryonic kidney cells (IC50 7.1 to 8.7 µM). Mechanistically, compound 3 increased ROS activity due to potent multi-ALDH isoform inhibition, which increased apoptosis. Taken together, this study identified a potent multi-isoform ALDH inhibitor that could be further developed as a cancer therapeutic.
Subject(s)
Aldehyde Dehydrogenase , Enzyme Inhibitors , Isatin , Molecular Docking Simulation , Humans , Isatin/chemistry , Isatin/pharmacology , Aldehyde Dehydrogenase/antagonists & inhibitors , Aldehyde Dehydrogenase/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemical synthesis , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Structure-Activity Relationship , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Molecular StructureABSTRACT
The reaction mechanism of tthe formation of azomethine ylides from isatins and sarcosine is addressed in the literature in a general manner. This computational study aims to explore the mechanistic steps for this reaction in detail and to assess the reactivity of formed ylide in a 1,3-dipolar cycloaddition reaction with 7-oxabenzonorbornadiene. For this purpose, density functional theory (DFT) calculations at the M06-2X(SMD,EtOH)/6-31G(d,p) level were employed. The results indicate that CO2 elimination is the rate-determining step, the activation barrier for 1,3-dipolar cycloaddition is lower, and the formed ylide will readily react with dipolarophiles. The substitution of isatine with electron-withdrawal groups slightly decreases the activation barrier for ylide formation.
Subject(s)
Azo Compounds , Cycloaddition Reaction , Sarcosine , Thiosemicarbazones , Thiosemicarbazones/chemistry , Azo Compounds/chemistry , Sarcosine/chemistry , Sarcosine/analogs & derivatives , Isatin/chemistry , Models, Molecular , Density Functional Theory , Norbornanes/chemistry , Molecular StructureABSTRACT
A comprehensive review presents an illuminating exploration of the vast potential of isatin, an easily accessible organic compound. This review is a valuable resource, offering a concise yet comprehensive account of the recent breakthroughs in isatin applications in medicinal chemistry, fluorescence sensing, and organic synthesis. Moreover, it dives into the exciting advancements in isatin-based chemosensors, demonstrating their remarkable ability to detect and recognize diverse cations and anions with exceptional precision. Researchers and scientists in the fields of sensing and organic chemistry will find this review indispensable for sparking innovation and developing cutting-edge technologies with significant real-world impact.
Subject(s)
Isatin , Isatin/chemistry , Fluorescent Dyes/chemistry , Fluorescent Dyes/chemical synthesis , Molecular StructureABSTRACT
The isatin group is widespread in nature and is considered to be a privileged building block for drug discovery. In order to develop novel SHP1 inhibitors with fluorescent properties as tools for SHP1 biology research, this work designed and synthesized a series of isatin derivatives. The presentive compound 5a showed good inhibitory activity against SHP1PTP with IC50 of 11 ± 3 µM, displayed about 92% inhibitory rate against MV-4-11 cell proliferation at the concentration of 20 µM, exhibited suitable fluorescent properties with a long emission wavelength and a large Stokes shift, and presented blue fluorescent imaging in HeLa cells with low cytotoxicity. This study could offer chemical tool to further understand SHP1 biology and develop novel SHP1 inhibitors in therapy.
Subject(s)
Cell Proliferation , Isatin , Isatin/chemistry , Isatin/pharmacology , Isatin/chemical synthesis , Humans , HeLa Cells , Cell Proliferation/drug effects , Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 6/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Structure-Activity Relationship , Molecular Structure , Fluorescent Dyes/chemistry , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/pharmacology , Cell Line, Tumor , FluorescenceABSTRACT
A new series of isatin-Schiff base linked 1,2,3-triazole hybrids has been synthesized using CuAAC approach from (E)-3-(phenylimino)-1-(prop-2-yn-1-yl)indolin-2-one derivatives in high yield (73-91â %). These synthesized derivatives were characterized using FT-IR, 1H NMR, 13C NMR, 2D-NMR and HRMS spectral techniques. The in vitro antimicrobial activity assay demonstrated that most of the tested hybrids exhibited promising activity. Compoundâ 5 j displayed significant antibacterial efficacy against P. aeruginosa and B. subtilis with MIC value of 0.0062â µmol/mL. While, 5 j also showed better antifungal potency against A. niger with MIC value of 0.0123 µmol/mL. The docking studies of most promising compounds were performed with the well-known antibacterial and antifungal targets i. e. 1KZ1, 5TZ1. Molecular modelling investigations demonstrated that hybrids 5 h and 5 l exhibited good interactions with 1KZN and 5TZ1, with binding energies of -9.6 and -11.0â kcal/mol, respectively. Further, molecular dynamics studies of the compounds showing promising binding interactions were also carried out to study the stability of complexes of these hybrids with both the targets.
Subject(s)
Anti-Bacterial Agents , Antifungal Agents , Isatin , Microbial Sensitivity Tests , Schiff Bases , Triazoles , Schiff Bases/chemistry , Schiff Bases/pharmacology , Schiff Bases/chemical synthesis , Isatin/chemistry , Isatin/pharmacology , Triazoles/chemistry , Triazoles/pharmacology , Triazoles/chemical synthesis , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Antifungal Agents/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/chemical synthesis , Aspergillus niger/drug effects , Bacillus subtilis/drug effects , Molecular Docking Simulation , Molecular Structure , Pseudomonas aeruginosa/drug effects , Structure-Activity Relationship , Dose-Response Relationship, DrugABSTRACT
In this study, a series of isatin-chalcone linked triazoles were synthesized using Cu-promoted Azide-Alkyne Cycloaddition (CuAAC) reaction and evaluated for their cytotoxicity against various cancer cell lines. The most potent compound displayed approximately 2.5â times greater activity compared to both reference compounds against ovarian cancer cell lines. These findings were supported by caspase-mediated apoptosis and molecular docking analyses. Docking revealed comparable VEGFR-2 affinities for 5 b and 5-FU but highlighted stronger interaction of 5 b with EGFR, evident from its lower docking score. Overall, these results signify the notable anti-proliferative potential of most synthesized hybrids, notably emphasizing the efficacy of compound 5 b in suppressing cancer cell growth.
Subject(s)
Antineoplastic Agents , Cell Proliferation , Drug Design , Drug Screening Assays, Antitumor , Isatin , Molecular Docking Simulation , Triazoles , Humans , Triazoles/chemistry , Triazoles/pharmacology , Triazoles/chemical synthesis , Isatin/chemistry , Isatin/pharmacology , Cell Proliferation/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Structure-Activity Relationship , Cell Line, Tumor , Chalcone/chemistry , Chalcone/pharmacology , Chalcone/chemical synthesis , Molecular Structure , Apoptosis/drug effects , Dose-Response Relationship, Drug , Chalcones/chemistry , Chalcones/pharmacology , Chalcones/chemical synthesis , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
Multi target directed ligands (MTDLs) are one of the promising tools for treatment of complex disease like Alzheimer's disease (AD). In this study, using rational design, we synthesized new 15 hybrids of the s-triazine, isatin and aniline derivatives as anti- AD compounds. The design was as way as that new compounds could had anti cholinesterase (ChE), antioxidant and biometal chelation ability. In vitro biological evaluation against ChE enzymes showed that these molecules were excellent inhibitors with IC50 values ranging from 0.2 nM to 734.5 nM for acetylcholinesterase (AChE), and 0.02 µM to 1.92 µM for butyrylcholinesterase (BChE). Among these compounds, 8 l with IC50 AChE = 0.7 nM, IC50 BChE = 0.09 µM and 8n with IC50 AChE = 0.2 nM, IC50 BChE = 0.03 µM were the most potent compounds. In silico studies showed that these molecules had key and effective interactions with the corresponding enzymes residues. The molecules with hydroxyl group on aniline moiety had also good antioxidant activity with EC50 values ranging from 64.2 µM to 103.6 µM. The UV-Vis spectroscopy study revealed that molecule 8n was also able to chelate biometals such as Zn2+, Cu2+and Fe2+ properly. It was concluded that these molecules could be excellent lead compounds for future studies.
Subject(s)
Acetylcholinesterase , Alzheimer Disease , Aniline Compounds , Butyrylcholinesterase , Cholinesterase Inhibitors , Drug Design , Isatin , Triazines , Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Aniline Compounds/chemical synthesis , Antioxidants/pharmacology , Antioxidants/chemistry , Antioxidants/chemical synthesis , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/chemical synthesis , Dose-Response Relationship, Drug , Isatin/chemistry , Isatin/pharmacology , Isatin/chemical synthesis , Molecular Docking Simulation , Molecular Structure , Structure-Activity Relationship , Triazines/chemistry , Triazines/pharmacology , Triazines/chemical synthesisABSTRACT
The synthesis of hybrid molecules is one of the current strategies of drug discovery for the development of new lead compounds. The 1,2,3-triazole moiety represents an important building block in Medicinal Chemistry, extensively present in recent years. In this paper, we presented the design and the synthesis of new 1,2,3-triazole hybrids, containing both an isatine and a phenolic core. Firstly, the non-commercial azide and the alkyne synthons were prepared by different isatines and phenolic acids, respectively. Then, the highly regioselective synthesis of 1,4-disubstituted triazoles was obtained in excellent yields by a click chemistry approach, catalyzed by Cu(I). Finally, a molecular docking study was performed on the hybrid library, finding four different therapeutic targets. Among them, the most promising results were obtained on 5-lipoxygenase, an enzyme involved in the inflammatory processes.
Subject(s)
Isatin , Molecular Docking Simulation , Phenols , Alkynes , TriazolesABSTRACT
OBJECTIVE: Aim: To evaluate the cytotoxic activity of newly synthesized a series of novel HDAC inhibitors comprising sulfonamide as zinc binding group and Isatin derivatives as cap group joined by mono amide linker as required to act as HDAC inhibitors. PATIENTS AND METHODS: Materials and Methods: The utilization of sulfonamide as zinc binding group joined by N-alkylation reaction with ethyl-bromo hexanoate as linker group that joined by amide reaction with Isatin derivatives as cap groups which known to possess antitumor activity in the designed of new histone deacetylase inhibitors and using the docking and MTT assay to evaluate the compounds. RESULTS: Results: Four compounds have been synthesized and characterized successfully by ART-FTIR, NMR and ESI-Ms. the compounds were synthesized and characterized by successfully by ART-FTIR, NMR and ESI- Ms. Assessed for their cytotoxic activity against human colon adenocarcinoma MCF-7 (IC50, I=105.15, II=60.00, III=54.11, IV=56.57, vorinostat=28.41) and hepatoblastoma HepG2 (IC50, I=63.91, II=135.18, III=118.85, IV=51.46, vorinostat=37.50). Most of them exhibited potent HDAC inhibitory activity and significant cytotoxicity. CONCLUSION: Conclusions: The synthesized compounds (I, II, III and IV) showed cytotoxicity toward MCF-7 and HepG2 cancer cell lines and their docking analysis provided a preliminary indication that they are viable [HDAC6] candidates.
Subject(s)
Adenocarcinoma , Antineoplastic Agents , Colonic Neoplasms , Isatin , Humans , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/chemistry , Vorinostat/pharmacology , Isatin/pharmacology , Cell Line, Tumor , Amides/pharmacology , Drug Design , Antineoplastic Agents/pharmacology , Sulfonamides/pharmacology , Zinc/metabolism , Zinc/pharmacology , Cell Proliferation , Molecular StructureABSTRACT
The literature reports that thiazole and isatin nuclei present a range of biological activities, with an emphasis on anticancer activity. Therefore, our proposal was to make a series of compounds using the molecular hybridization strategy, which has been used by our research group, producing hybrid molecules containing the thiazole and isatin nuclei. After structural planning and synthesis, the compounds were characterized and evaluated in vitro against breast cancer cell lines (T-47D, MCF-7 and MDA-MB-231) and against normal cells (PBMC). The activity profile on membrane proteins involved in chemoresistance and tumorigenic signaling proteins was also evaluated. Among the compounds tested, the compounds 4c and 4a stood out with IC50 values of 1.23 and 1.39 µM, respectively, against the MDA-MB-231 cell line. Both compounds exhibited IC50 values of 0.45 µM for the MCF-7 cell line. Compounds 4a and 4c significantly decreased P-gp mRNA expression levels in MCF-7, 4 and 2 folds respectively. Regarding the impact on tumorigenic signaling proteins, compound 4a inhibited Akt2 in MDA-MB-231 and compound 4c inhibited the mRNA expression of VIM in MCF-7.
Subject(s)
Antineoplastic Agents , Breast Neoplasms , Isatin , Proto-Oncogene Proteins c-akt , RNA, Messenger , Thiazoles , Humans , Proto-Oncogene Proteins c-akt/metabolism , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Breast Neoplasms/drug therapy , Isatin/pharmacology , Isatin/chemistry , Isatin/chemical synthesis , Cell Line, Tumor , RNA, Messenger/metabolism , RNA, Messenger/genetics , Thiazoles/pharmacology , Thiazoles/chemistry , Female , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Molecular Docking Simulation , MCF-7 Cells , Drug Screening Assays, Antitumor , Structure-Activity RelationshipABSTRACT
Isatin (indoldione-2,3) is an endogenous biological regulator found in the brain, peripheral tissues, and biological fluids of humans and animals. Its biological activity is realized via isatin-binding proteins, many of which were identified during proteomic profiling of the brain of mice and rats. A number of these proteins are related to the development of neurodegenerative diseases. Previously, using a model of experimental Parkinsonism induced by a seven-day course of rotenone injections, we have observed behavioral disturbances, as well as changes in the profile and relative content of brain isatin-binding proteins. In this study, we have investigated behavioral responses and the relative content of brain isatin-binding proteins in rats with rotenone-induced Parkinsonism 5 days after the last administration of this neurotoxin. Despite the elimination of rotenone, animals exhibited motor and coordination impairments. Proteomic profiling of isatin-binding proteins revealed changes in the relative content of 120 proteins (the relative content of 83 proteins increased and that of 37 proteins decreased). Comparison of isatin-binding proteins characterized by the changes in the relative content observed in the brain right after the last injection of rotenone (n=16) and 5 days later (n=11) revealed only two common proteins (glyceraldehyde-3-phosphate dehydrogenase and subunit B of V-type proton ATPase). However, most of these proteins are associated with neurodegeneration, including Parkinson's and Alzheimer's diseases.
Subject(s)
Isatin , Parkinsonian Disorders , Humans , Animals , Rats , Carrier Proteins , Isatin/pharmacology , Rotenone/pharmacology , Proteomics , Brain , Parkinsonian Disorders/chemically inducedABSTRACT
During this coronavirus pandemic, when a lot of people are already severely afflicted with SARS-CoV-19, the dispersion of black fungus is making it worse, especially in the Indian subcontinent. Considering this situation, the idea for an in silico study to identify the potential inhibitor against black fungal infection is envisioned and computational analysis has been conducted with isatin derivatives that exhibit considerable antifungal activity. Through this in silico study, several pharmacokinetics properties like absorption, distribution, metabolism, excretion, and toxicity (ADMET) are estimated for various derivatives. Lipinski rules have been used to observe the drug likeliness property, and to study the electronic properties of the molecules, quantum mechanism was analyzed using the density functional theory (DFT). After applying molecular docking of the isatin derivatives with sterol 14-alpha demethylase enzyme of black fungus, a far higher docking affinity score has been observed for the isatin sulfonamide-34 (derivative 1) than the standard fluconazole. Lastly, molecular dynamic (MD) simulation has been performed for 100 ns to examine the stability of the proposed drug complex by estimating Root Mean Square Deviation (RMSD), Radius of gyration (Rg), Solvent accessible surface area (SASA), Root Mean Square Fluctuation (RMSF), as well as hydrogen bond. Listed ligands have precisely satisfied every pharmacokinetics requirement for a qualified drug candidate and they are non-toxic, non-carcinogenic, and have high stability. This natural molecule known as isatin derivative 1 has shown the potential of being a drug for fungal treatment. However, the impact of the chemicals on living cells requires more investigation and research.
Subject(s)
Coronavirus Infections , Isatin , Humans , Molecular Docking Simulation , Antifungal Agents , FungiABSTRACT
A new series of isatin-linked benzenesulfonamide derivatives (9a-w) were synthesized using the tail approach and assayed for their inhibitory potency against four different human carbonic anhydrase (hCA) isoforms, hCA I, II, IX, and XII. Most of these synthesized compounds exhibited interesting inhibition potency against isoforms hCA I, IX, and XII in the nanomolar range and by taking the standard drug acetazolamide. The most potent compounds in the case of hCA I were 9c (435.8 nM) and 9s (956.4 nM), for hCA IX, 9a (60.5 nM), 9d (95.6 nM), 9g (92.1 nM), and 9k (75.4 nM), and for hCA XII, 9p (84.5 nM). However, these compounds showed more selectivity toward hCA IX over hCA I, II, and XII. Thus, these compounds can be further developed as potential lead molecules for the development of isoform-selective hCA IX inhibitors with further structural modifications.
Subject(s)
Benzenesulfonamides , Carbonic Anhydrase Inhibitors , Carbonic Anhydrases , Drug Design , Sulfonamides , Carbonic Anhydrase Inhibitors/pharmacology , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrase Inhibitors/chemistry , Humans , Structure-Activity Relationship , Sulfonamides/pharmacology , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Carbonic Anhydrases/metabolism , Molecular Structure , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Isatin/pharmacology , Isatin/chemistry , Isatin/chemical synthesis , Dose-Response Relationship, DrugABSTRACT
The gut microbiota produces a variety of bioactive molecules that facilitate host-microbiota interaction. Indole and its metabolites are focused as possible biomarkers for various diseases. However, data on indole metabolism and individual metabolites remain limited. Hence, we investigated the metabolism and distribution of indole, indolin-2-one, isatin, and 3-hydroxyindolin-2-one. First, we orally administered a high dose of indole into C57BL/6J mice and measured the concentrations of indole metabolites in the brain, liver, plasma, large and small intestines, and cecum at multiple time points using HPLC/MS. Absorption in 30 min and full metabolization in 6 h were established. Furthermore, indole, indolin-2-one, and 3-hydroxiindolin-2-one, but not isatin, were found in the brain. Second, we confirmed these findings by using stable isotope-carrying indole. Third, we identified 3-hydroxyindolin-2-one as an indole metabolite in vivo by utilizing a 3-hydroxyindolin-2-one-converting enzyme, IifA. Further, we confirmed the ability of orally administered 3-hydroxyindolin-2-one to cross the blood-brain barrier in a dose-dependent manner. Finally, we detected upregulation of the CYP1A2 and CYP2A5 genes, confirming the importance of these cytochrome isoforms in indole metabolism in vivo. Overall, our results provide a basic characterization of indole metabolism in the host and highlight 3-hydroxyindolin-2-one as a potentially brain-affecting indole metabolite.
Subject(s)
Isatin , Microbiota , Mice , Animals , Mice, Inbred C57BL , Indoles/metabolismABSTRACT
Trisindoles are of tremendous interest due to their wide range of biological activities. In this context, a number of methods have been reported in the past to synthesize 3,3',3''-trisindoles. However, most of the methods are only able to produce symmetrical 3,3',3''-trisindoles. Herein, we develop a sustainable and efficient approach to synthesize symmetrical as well as unsymmetrical 3,3',3''-trisindoles in a very selective manner using the α-amylase enzyme as a catalyst. Furthermore, various differently substituted isatin and indoles were used to prove the generality of the protocol and symmetrical or unsymmetrical 3,3',3''-trisindoles were obtained in 43-97% isolated yields. Next, a probable mechanism is proposed and investigated using molecular dynamics (MD) investigation to gain more insight into the role of residues available in the active site of the α-amylase enzyme. These studies revealed that Glu230, Lys209, and Asp206 in the active site of α-amylase play an important role in this catalysis. Moreover, the DFT studies suggested the formation of bisindole and alkylideneindolenine intermediates during the transformation. We synthesized four different biologically important 3,3',3''-trisindoles on a gram scale, which proved the robustness and scalability of this protocol.
Subject(s)
Isatin , Molecular Structure , alpha-Amylases , Indoles/chemistry , CatalysisABSTRACT
Heterocyclic compounds containing 1,2,3-triazole and isatin as core structures have emerged as promising drug candidates due to their diverse biological activities such as anti-cancer, antifungal, antimicrobial, antitumor, anti-epileptic, antiviral, and more. The presence of 1,2,3-triazoles and isatin heterocycles in these hybrids, both individually known for their medicinal significance, has increasingly piqued the interest of drug discovery researchers, as they seek to delve deeper into their extensive pharmacological potential for enhancing therapeutic efficacy. Moreover, these hybrid compounds are synthetically accessible using readily available materials. Therefore, there is a pressing need to provide a comprehensive overview of the existing knowledge in this field, offering valuable insights to readers and paving the way for the discovery of novel 1,2,3-triazole-linked isatin hybrids with therapeutic potential.
Subject(s)
Anti-Infective Agents , Isatin , Neoplasms , Humans , Triazoles/pharmacology , Triazoles/chemistry , Structure-Activity Relationship , Isatin/pharmacology , Isatin/chemistry , Anti-Infective Agents/pharmacologyABSTRACT
This article reports one-pot synthesis of ten novel spirooxindoles using 5-methyl-2-thiohydantoin, isatin derivatives, and malononitrile in good to high yields (65-90 %). The structures of the synthesized compounds were deduced by 1H-NMR, 13C NMR, FT-IR, and Mass spectral data. The antibacterial activity of the compounds was evaluated against two Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis) and two Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) based on the Kirby-Bauer method. According to the obtained data, the synthesized compounds show more activity against Gram-positive bacteria than Gram-negative bacteria. Also, the antioxidant activity of these compounds was measured using the DPPH radical scavenging test method, which showed good to excellent activity (59.65-94.03 %). Among them, the chlorinated derivatives (4 f-j) exhibited more antioxidant activity (84.85-94.03 %) than the other compounds (4 a-e) (56.65-74.4 %) and even ascorbic acid as a standard antioxidant compound (82.3 %).
Subject(s)
Anti-Bacterial Agents , Antioxidants , Indoles , Microbial Sensitivity Tests , Spiro Compounds , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Antioxidants/pharmacology , Antioxidants/chemical synthesis , Antioxidants/chemistry , Biphenyl Compounds/antagonists & inhibitors , Biphenyl Compounds/chemistry , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Indoles/chemistry , Indoles/pharmacology , Indoles/chemical synthesis , Molecular Structure , Oxindoles/pharmacology , Oxindoles/chemistry , Oxindoles/chemical synthesis , Picrates/antagonists & inhibitors , Pseudomonas aeruginosa/drug effects , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Spiro Compounds/chemical synthesis , Spirooxindoles , Staphylococcus aureus/drug effects , Structure-Activity Relationship , Isatin/chemical synthesis , Isatin/chemistry , Isatin/pharmacologyABSTRACT
Isatin derivatives have attracted a lot of interest for their potential in the development of new anticancer drugs. A library of 38 isatin derivatives, created through an Ugi four-component reaction, underwent an initial screening in a panel of six human solid tumor cell lines. The four most active derivatives were then selected for further testing. These compounds showed selectivity towards the non-small cell lung cancer (NSCLC) cell line SW1573, whilst NSCLC A549 cells were barely affected. The combination of phenotypic assays, including wound healing, clonogenic and continuous live cell imaging provided a deeper understanding of the compounds' mode of action. In particular, the latter demonstrated that isatin derivatives were able to induce necroptosis in SW1573 cells. The kinetics of cell death showed that necroptosis appeared after 2.5 h of exposure, which could be delayed to 7 h when co-treated with necrostatin-1. Interaction between the isatin derivatives and the KRAS G12C protein variant was discarded after in silico studies. Further studies are warranted to identify the cellular target responsible for the observed selectivity among cell lines.
Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Isatin , Lung Neoplasms , Humans , Cytotoxins , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Isatin/pharmacology , Drug Screening Assays, Antitumor , Structure-Activity Relationship , Cell Proliferation , Molecular StructureABSTRACT
In this work, a novel isatin-Schiff base L2 had been synthesized through a simple reaction between isatin and 2-amino-5-methylthio-1,3,4-thiadiazole. The produced Schiff base L2 was then subjected to a hydrothermal reaction with cerium chloride to produce the cerium (III)-Schiff base complex C2. Several spectroscopic methods, including mass spectra, FT-IR, elemental analysis, UV-vis, 13C-NMR, 1H-NMR, Thermogravimetric Analysis, HR-TEM, and FE-SEM/EDX, were used to completely characterize the produced L2 and C2. A computer simulation was performed using the MOE software program to find out the probable biological resistance of studied compounds against the proteins in some types of bacteria or fungi. To investigate the interaction between the ligand and its complex, we conducted molecular docking simulations using the molecular operating environment (MOE). The docking simulation findings revealed that the complex displayed greater efficacy and demonstrated a stronger affinity for Avr2 effector protein from the fungal plant pathogen Fusarium oxysporum (code 5OD4) than the original ligand. The antibacterial activity of the ligand and its Ce3+ complex were applied in vitro tests against different microorganism. The study showed that the complex was found to be more effective than the ligand.
Subject(s)
Cerium , Isatin , Molecular Docking Simulation , Spectroscopy, Fourier Transform Infrared , Isatin/pharmacology , Isatin/chemistry , Cerium/pharmacology , Schiff Bases/pharmacology , Schiff Bases/chemistry , Computer Simulation , Ligands , Anti-Bacterial Agents/pharmacology , Microbial Sensitivity TestsABSTRACT
Breast cancer causes a high rate of mortality all over the world. Therefore, the present study focuses on the anticancer activity of new lower rim-functionalized calix[4]arenes integrated with isatin and the p-position of calixarenes with 1,4-dimethylpyridinium iodine against various human cancer cells such as MCF-7 and MDA-MB-231 breast cancer cell lines, as well as the PNT1A healthy epithelial cell line. It was observed that compound 6c had the lowest values in MCF-7 (8.83 µM) and MDA-MB-231 (3.32 µM). Cell imaging and apoptotic activity studies were performed using confocal microscopy and flow cytometry, respectively. The confocal imaging studies with 6c showed that the compound easily entered the cell, and it was observed that 6c accumulated in the mitochondria. The Comet assay test was used to detect DNA damage of compounds in cells. It was found that treated cells had abnormal tail nuclei and damaged DNA structures compared with untreated cells. In vitro human aromatase enzyme inhibition profiles showed that compound 6c had a remarkable inhibitory effect on aromatase. Compound 6c displayed a significant inhibition capacity on aromatase enzyme with the IC50 value of 0.104 ± 0.004 µM. Thus, not only the anticancer activity of the new fluorescent derivatives, which are the subject of this study, but the aromatase inhibitory profiles have also been proven.