RESUMEN
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.
Asunto(s)
Aldehído Deshidrogenasa , Inhibidores Enzimáticos , Isatina , Simulación del Acoplamiento Molecular , Humanos , Isatina/química , Isatina/farmacología , Aldehído Deshidrogenasa/antagonistas & inhibidores , Aldehído Deshidrogenasa/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Relación Estructura-Actividad , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Estructura MolecularRESUMEN
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.
Asunto(s)
Proliferación Celular , Isatina , Isatina/química , Isatina/farmacología , Isatina/síntesis química , Humanos , Células HeLa , Proliferación Celular/efectos de los fármacos , Proteína Tirosina Fosfatasa no Receptora Tipo 6/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 6/antagonistas & inhibidores , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Relación Estructura-Actividad , Estructura Molecular , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/farmacología , Línea Celular Tumoral , FluorescenciaRESUMEN
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.
Asunto(s)
Isatina , Isatina/química , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Estructura MolecularRESUMEN
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.
Asunto(s)
Compuestos Azo , Reacción de Cicloadición , Sarcosina , Tiosemicarbazonas , Tiosemicarbazonas/química , Compuestos Azo/química , Sarcosina/química , Sarcosina/análogos & derivados , Isatina/química , Modelos Moleculares , Teoría Funcional de la Densidad , Norbornanos/química , Estructura MolecularRESUMEN
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.
Asunto(s)
Antibacterianos , Antifúngicos , Isatina , Pruebas de Sensibilidad Microbiana , Bases de Schiff , Triazoles , Bases de Schiff/química , Bases de Schiff/farmacología , Bases de Schiff/síntesis química , Isatina/química , Isatina/farmacología , Triazoles/química , Triazoles/farmacología , Triazoles/síntesis química , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Antifúngicos/farmacología , Antifúngicos/química , Antifúngicos/síntesis química , Aspergillus niger/efectos de los fármacos , Bacillus subtilis/efectos de los fármacos , Simulación del Acoplamiento Molecular , Estructura Molecular , Pseudomonas aeruginosa/efectos de los fármacos , Relación Estructura-Actividad , Relación Dosis-Respuesta a DrogaRESUMEN
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.
Asunto(s)
Acetilcolinesterasa , Enfermedad de Alzheimer , Compuestos de Anilina , Butirilcolinesterasa , Inhibidores de la Colinesterasa , Diseño de Fármacos , Isatina , Triazinas , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Compuestos de Anilina/síntesis química , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/síntesis química , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/síntesis química , Relación Dosis-Respuesta a Droga , Isatina/química , Isatina/farmacología , Isatina/síntesis química , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad , Triazinas/química , Triazinas/farmacología , Triazinas/síntesis químicaRESUMEN
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.
Asunto(s)
Antineoplásicos , Proliferación Celular , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Isatina , Simulación del Acoplamiento Molecular , Triazoles , Humanos , Triazoles/química , Triazoles/farmacología , Triazoles/síntesis química , Isatina/química , Isatina/farmacología , Proliferación Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Relación Estructura-Actividad , Línea Celular Tumoral , Chalcona/química , Chalcona/farmacología , Chalcona/síntesis química , Estructura Molecular , Apoptosis/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Chalconas/química , Chalconas/farmacología , Chalconas/síntesis química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
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.
Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Isatina , Proteínas Proto-Oncogénicas c-akt , ARN Mensajero , Tiazoles , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Isatina/farmacología , Isatina/química , Isatina/síntesis química , Línea Celular Tumoral , ARN Mensajero/metabolismo , ARN Mensajero/genética , Tiazoles/farmacología , Tiazoles/química , Femenino , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Simulación del Acoplamiento Molecular , Células MCF-7 , Ensayos de Selección de Medicamentos Antitumorales , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Bencenosulfonamidas , Inhibidores de Anhidrasa Carbónica , Anhidrasas Carbónicas , Diseño de Fármacos , Sulfonamidas , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Humanos , Relación Estructura-Actividad , Sulfonamidas/farmacología , Sulfonamidas/síntesis química , Sulfonamidas/química , Anhidrasas Carbónicas/metabolismo , Estructura Molecular , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Isatina/farmacología , Isatina/química , Isatina/síntesis química , Relación Dosis-Respuesta a DrogaRESUMEN
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.
Asunto(s)
Cerio , Isatina , Simulación del Acoplamiento Molecular , Espectroscopía Infrarroja por Transformada de Fourier , Isatina/farmacología , Isatina/química , Cerio/farmacología , Bases de Schiff/farmacología , Bases de Schiff/química , Simulación por Computador , Ligandos , Antibacterianos/farmacología , Pruebas de Sensibilidad MicrobianaRESUMEN
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.
Asunto(s)
Antiinfecciosos , Isatina , Neoplasias , Humanos , Triazoles/farmacología , Triazoles/química , Relación Estructura-Actividad , Isatina/farmacología , Isatina/química , Antiinfecciosos/farmacologíaRESUMEN
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 %).
Asunto(s)
Antibacterianos , Antioxidantes , Indoles , Pruebas de Sensibilidad Microbiana , Compuestos de Espiro , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antioxidantes/farmacología , Antioxidantes/síntesis química , Antioxidantes/química , Compuestos de Bifenilo/antagonistas & inhibidores , Compuestos de Bifenilo/química , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Indoles/química , Indoles/farmacología , Indoles/síntesis química , Estructura Molecular , Oxindoles/farmacología , Oxindoles/química , Oxindoles/síntesis química , Picratos/antagonistas & inhibidores , Pseudomonas aeruginosa/efectos de los fármacos , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Compuestos de Espiro/síntesis química , Espirooxindoles , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-Actividad , Isatina/síntesis química , Isatina/química , Isatina/farmacologíaRESUMEN
Proteins labelled site-specifically with small molecules are valuable assets for chemical biology and drug development. The unique reactivity profile of the 1,2-aminothiol moiety of N-terminal cysteines (N-Cys) of proteins renders it highly attractive for regioselective protein labelling. Herein, we report an ultrafast Z-selective reaction between isatin-derived Baylis Hillman adducts and 1,2-aminothiols to form a bis-heterocyclic scaffold, and employ it for stable protein bioconjugation under both in vitro and live-cell conditions. We refer to our protein bioconjugation technology as Baylis Hillman orchestrated protein aminothiol labelling (BHoPAL). Furthermore, we report a lipoic acid ligase-based technology for introducing the 1,2-aminothiol moiety at any desired site within proteins, rendering BHoPAL location-agnostic (not limited to N-Cys). By using this approach in tandem with BHoPAL, we generate dually labelled protein bioconjugates appended with different labels at two distinct specific sites on a single protein molecule. Taken together, the protein bioconjugation toolkit that we disclose herein will contribute towards the generation of both mono and multi-labelled protein-small molecule bioconjugates for applications as diverse as biophysical assays, cellular imaging, and the production of therapeutic protein-drug conjugates. In addition to protein bioconjugation, the bis-heterocyclic scaffold we report herein will find applications in synthetic and medicinal chemistry.
Asunto(s)
Isatina , Estructura Molecular , Isatina/química , Compuestos de Sulfhidrilo , CisteínaRESUMEN
A series of bis-isatin conjugates with lysine linker were synthesized with the aim of probing their antiproliferative potential. All the newly synthesized derivatives (0-100 µM) were first screened against liver cancer cell lines(Huh1, H22, Huh7, Hepa1-6, HepG2, Huh6 and 97H) using CCK-8 assay. Results indicated that the derivative 4d exhibited the most potent activity against Huh1 (IC50 = 17.13 µM) and Huh7(IC50 = 8.265 µM). In vivo anti-tumor study showed that compound 4d effectively inhibited tumor growth in Huh1-induced xenograft mouse model; the anti-tumor effect of compound 4d (15 mg/kg) was comparable with sorafenib (20 mg/kg). H&E staining analysis and routine blood test and blood serum biochemistry examination was performed to confirm the safety of compound 4d in xenograft models. The mechanism of action of 4d on tumor growth inhibition was further investigated by RNA-Seq analysis, which indicates a positive regulation of autophagy signaling pathway, which was further confirmed with key biomarker expression of autophagy after 4d treatment. Our results suggest that the bis-isatin conjugate compound 4d is a promising tumor inhibitory agent for some liver cancer.
Asunto(s)
Antineoplásicos , Isatina , Neoplasias Hepáticas , Humanos , Animales , Ratones , Línea Celular Tumoral , Isatina/química , Ensayos de Selección de Medicamentos Antitumorales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Proliferación Celular , Relación Estructura-Actividad , Estructura MolecularRESUMEN
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.
Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Isatina , Humanos , Femenino , Inhibidores de la Aromatasa/farmacología , Antineoplásicos/química , Isatina/farmacología , Isatina/química , Aromatasa/metabolismo , Relación Estructura-Actividad , Línea Celular Tumoral , Mitocondrias , ADN , Proliferación Celular , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
In this work, new isatin-based sulphonamides (6a-i, 11a-c, 12a-c) were designed and synthesised as potential dual VEGFR-2 and carbonic anhydrase inhibitors with anticancer activities. Firstly, all target isatins were examined for in vitro antitumor action on NCI-USA panel (58 tumour cell lines). Then, the most potent derivatives were examined for the potential CA inhibitory action towards the physiologically relevant hCA isoforms I, II, and tumour-linked hCA IX isoform, in addition, the VEGFR-2 inhibitory activity was evaluated. The target sulphonamides failed to inhibit the CA isoforms that could be attributable to the steric effect of the neighbouring methoxy group, whereas they displayed potent VEGFR-2 inhibitory effect. Following that, isatins 11b and 12b were tested for their influence on the cell cycle disturbance, and towards the apoptotic potential. Finally, detailed molecular modelling analyses, including docking and molecular dynamics, were carried out to assess the binding mode and stability of target isatins.
Asunto(s)
Antineoplásicos , Anhidrasas Carbónicas , Isatina , Estructura Molecular , Relación Estructura-Actividad , Anhidrasas Carbónicas/metabolismo , Isatina/farmacología , Isatina/química , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Antineoplásicos/farmacología , Antineoplásicos/química , Sulfonamidas/farmacología , Sulfonamidas/química , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/química , Anhidrasa Carbónica IX , Antígenos de Neoplasias/metabolismoRESUMEN
The traditional single-treatment strategy for cancer is frequently unsuccessful due to the complexity of cellular signaling. However, suppression of multiple targets is vital to defeat tumor cells. In this research, new compounds for the treatment of cancer were developed successfully as novel hybrid anticancer agents. Based on a molecular hybridization strategy, we designed hybrid agents that target multiple protein kinases to fight cancer cells. The proposed hybrid agents combined purine and isatin moieties in their structures with 4-aminobenzohydrazide and hydrazine as different linkers. Having those two moieties in one molecule enabled the capability to inhibit multiple kinases, such as human epidermal receptor (EGFR), human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor receptor 2 (VEGFR2) and cyclin-dependent kinase 2 (CDK2). Anticancer activity was evaluated by performing cytotoxicity assays, kinase inhibition assays, cell cycle analysis, and BAX, Bcl-2, Caspase 3 and Caspase 9 protein level determination assays. The results showed that the designed hybrids tackled the cancer by inhibiting both cell proliferation and metastasis. A molecular docking study was performed to predict possible binding interactions in the active site of the investigated protein kinase enzymes.
Asunto(s)
Antineoplásicos , Isatina , Neoplasias , Humanos , Isatina/farmacología , Isatina/química , Isatina/uso terapéutico , Simulación del Acoplamiento Molecular , Factor A de Crecimiento Endotelial Vascular , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Neoplasias/tratamiento farmacológico , Proliferación Celular , Apoptosis , Purinas/farmacología , Purinas/uso terapéutico , Línea Celular TumoralRESUMEN
Molecular hybridization is one of the recent stratagems in medicinal chemistry to synthesize a novel hybrid molecule having better affinity and efficacy by combining two or more pharmacophoric moieties. Molecular hybridization, i.e., a linker or framework integration technique, can be used to connect the two pharmacophoric components. It has often been found that hybrid compounds perform more effectively and possess lower toxicity than their parent molecules. In order to create a new generation of effective and safe therapeutic candidates, such as anti-cancer, anti-viral, anti-HIV, antioxidant, and antibacterial, for a variety of frontline diseases, several articles have been published that discuss the molecular hybridization of preclinically or clinically proven compounds. Isatin and its derivatives have been studied extensively due to diversified biological activities, including antitumor, antimicrobial, anti-inflammatory, analgesic, antiviral, antioxidant, anticonvulsant, etc. Similarly, 1,2,3-triazoles have received significant interest as a bio-isostere in medicinal chemistry for generating a large number of pharmaceutically significant molecules. As it possesses diversified physiochemical properties, such as hydrogen bond formation capacity, ease of synthesis, moderate dipole moment, stability towards acidic/basic hydrolysis, inertness towards oxidizing/ reducing agents, and good binding potential with several biological targets, triazole is an important choice of the medicinal chemists for the novel medication development. The aim of the current review is to summarize the research articles showing the pharmacological significance of hybrid molecules containing isatin and 1,2,3-triazole moieties. The present review may assist chemists in designing and synthesizing isatin-1,2,3-triazole hybrids with better efficacy and low cytotoxicity.
Asunto(s)
Isatina , Triazoles , Triazoles/farmacología , Triazoles/química , Relación Estructura-Actividad , Isatina/farmacología , Isatina/química , Antioxidantes/farmacología , Antibacterianos/farmacología , Antivirales/farmacologíaRESUMEN
In present era, heterocyclic compounds containing two or three nitrogen atoms play a vital role in drug discovery. In this context, a new class of isatin-semicarbazone tethered 1,2,3-triazole hybrids was synthesized via Cu(I)-mediated azide alkyne cycloaddition reaction. Structural characteristics of the newly derived compounds were identified by various spectral techniques like FTIR, 1H NMR, 13C NMR, HRMS and single crystal X-ray crystallography. Synthesized derivatives were also screened for in vitro antimicrobial and antibiofilm activity against different microbial species. Triazole hybrid 7e showed significant efficacy towards E. coli having MIC of 0.0063 µmol/mL, whereas 6a, 6b, 7a, 7c, 7e, and 7f showed highest percentage of biofilm inhibition against P. aeruginosa. Bioassay results suggested that these triazole hybrids could act as biomaterial for antimicrobial and antibiofilm applications and may constitute a new promising class of antimicrobial and antibiofilm agents. These results were further supported by in silico docking, DFT calculations and ADME studies.
Asunto(s)
Antiinfecciosos , Isatina , Semicarbazonas , Relación Estructura-Actividad , Isatina/farmacología , Isatina/química , Semicarbazonas/farmacología , Triazoles/farmacología , Triazoles/química , Escherichia coli , Antiinfecciosos/farmacología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Antibacterianos/farmacología , Antibacterianos/químicaRESUMEN
N-fused pyrrolidinyl spirooxindole belongs to a class of privileged heterocyclic scaffolds and is prevalent in natural alkaloids and synthetic pharmaceutical molecules. To realize the switchable synthesis of divergent N-fused pyrrolidinyl spirooxindoles for further biological activity evaluation via a substrate-controlled strategy, a chemically sustainable, catalysis-free, and dipolarophile-controlled three-component 1,3-dipolar cycloaddition of isatin-derived azomethine ylides with diverse dipolarophiles is described in this work. A total of 40 functionalized N-fused pyrrolidinyl spirooxindoles were synthesized in 76-95% yields with excellent diastereoselectivities (up to >99:1 dr). The scaffolds of these products can be well-controlled by employing different 1,4-enedione derivatives as dipolarophiles in EtOH at room temperature. This study provides an efficient strategy to afford a spectrum of natural-like and potentially bioactive N-fused pyrrolidinyl spirooxindoles.