RESUMO
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.
Assuntos
Aldeído Desidrogenase , Inibidores Enzimáticos , Isatina , Simulação de Acoplamento Molecular , Humanos , Isatina/química , Isatina/farmacologia , Aldeído Desidrogenase/antagonistas & inibidores , Aldeído Desidrogenase/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Relação Estrutura-Atividade , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura MolecularRESUMO
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.
Assuntos
Proliferação de Células , Isatina , Isatina/química , Isatina/farmacologia , Isatina/síntese química , Humanos , Células HeLa , Proliferação de Células/efeitos dos fármacos , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 6/antagonistas & inibidores , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Relação Estrutura-Atividade , Estrutura Molecular , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Linhagem Celular Tumoral , FluorescênciaRESUMO
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.
Assuntos
Antineoplásicos , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Isatina , Simulação de Acoplamento Molecular , Triazóis , Humanos , Triazóis/química , Triazóis/farmacologia , Triazóis/síntese química , Isatina/química , Isatina/farmacologia , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Relação Estrutura-Atividade , Linhagem Celular Tumoral , Chalcona/química , Chalcona/farmacologia , Chalcona/síntese química , Estrutura Molecular , Apoptose/efeitos dos fármacos , Relação Dose-Resposta a Droga , Chalconas/química , Chalconas/farmacologia , Chalconas/síntese química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
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.
Assuntos
Adenocarcinoma , Antineoplásicos , Neoplasias do Colo , Isatina , Humanos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Vorinostat/farmacologia , Isatina/farmacologia , Linhagem Celular Tumoral , Amidas/farmacologia , Desenho de Fármacos , Antineoplásicos/farmacologia , Sulfonamidas/farmacologia , Zinco/metabolismo , Zinco/farmacologia , Proliferação de Células , Estrutura MolecularRESUMO
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.
Assuntos
Benzenossulfonamidas , Inibidores da Anidrase Carbônica , Anidrases Carbônicas , Desenho de Fármacos , Sulfonamidas , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Humanos , Relação Estrutura-Atividade , Sulfonamidas/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/química , Anidrases Carbônicas/metabolismo , Estrutura Molecular , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Isatina/farmacologia , Isatina/química , Isatina/síntese química , Relação Dose-Resposta a DrogaRESUMO
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.
Assuntos
Antineoplásicos , Neoplasias da Mama , Isatina , Proteínas Proto-Oncogênicas c-akt , RNA Mensageiro , Tiazóis , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Isatina/farmacologia , Isatina/química , Isatina/síntese química , Linhagem Celular Tumoral , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Tiazóis/farmacologia , Tiazóis/química , Feminino , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Simulação de Acoplamento Molecular , Células MCF-7 , Ensaios de Seleção de Medicamentos Antitumorais , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Infecções por Coronavirus , Isatina , Humanos , Simulação de Acoplamento Molecular , Antifúngicos , FungosRESUMO
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.
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Isatina , Neoplasias Pulmonares , Humanos , Citotoxinas , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Isatina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Relação Estrutura-Atividade , Proliferação de Células , Estrutura MolecularRESUMO
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.
Assuntos
Anti-Infecciosos , Isatina , Neoplasias , Humanos , Triazóis/farmacologia , Triazóis/química , Relação Estrutura-Atividade , Isatina/farmacologia , Isatina/química , Anti-Infecciosos/farmacologiaRESUMO
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.
Assuntos
Antineoplásicos , Neoplasias da Mama , Isatina , Humanos , Feminino , Inibidores da Aromatase/farmacologia , Antineoplásicos/química , Isatina/farmacologia , Isatina/química , Aromatase/metabolismo , Relação Estrutura-Atividade , Linhagem Celular Tumoral , Mitocôndrias , DNA , Proliferação de Células , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
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.
Assuntos
Isatina , Estrutura Molecular , Isatina/química , Compostos de Sulfidrila , CisteínaRESUMO
Due to the versatile bioreactivity of aroyldihydrazone complexes as cost-effective alternatives with different transition metals, two novel bimetallic homo-complexes (VOLph and CuLph) were prepared via the coordination of a terephthalic dihydrazone diisatin ligand (H2Lph) with VO2+ and Cu2+ ions, respectively. The structure elucidation was confirmed by alternative spectral methods. Biologically, the H2Lph ligand and its MLph complexes (M2+ = VO2+ or Cu2+) were investigated as antimicrobial and anticancer agents. Their biochemical activities towards ctDNA (calf thymus DNA) were estimated using measurable titration viscometrically and spectrophotometrically, as well as the gel electrophoresis technique. The growth inhibition of both VOLph and CuLph complexes against microbial and cancer cells was measured, and the inhibition action, MIC, and IC50 were compared to the inhibition action of the free H2Lph ligand. Both VOLph and CuLph showed remarkable interactive binding with ctDNA compared to the free ligand H2Lph, based on Kb = 16.31, 16.04 and 12.41 × 107 mol-1 dm3 and ΔGb≠ = 47.11, -46.89, and -44.05 kJ mol-1 for VOLph, CuLph, and H2Lph, respectively, due to the central metal ion (VIVO and CuII ions). VOLph (with a higher oxidation state of the V4+ ion and oxo-ligand) exhibited enhanced interaction with the ctDNA molecule compared to CuLph, demonstrating the role and type of the central metal ion within the performed electronegative and electrophilic characters.
Assuntos
Anti-Infecciosos , Isatina , Ligantes , Anti-Infecciosos/farmacologia , Bioensaio , ÍonsRESUMO
Sixteen isatin-based hydrazone derivatives (IS1-IS16) were synthesized and assessed for their ability to inhibit monoamine oxidases (MAOs). All the molecules showed improved inhibitory MAO-B activity compared to MAO-A. Compound IS7 most potently inhibited MAO-B with an IC50 value of 0.082 µM, followed by IS13 and IS6 (IC50 = 0.104 and 0.124 µM, respectively). Compound IS15 most potently inhibited MAO-A with an IC50 value of 1.852 µM, followed by IS3 (IC50 = 2.385 µM). Compound IS6 had the highest selectivity index (SI) value of 263.80, followed by IS7 and IS13 (233.85 and 212.57, respectively). In the kinetic study, the Ki values of IS6, IS7, and IS13 for MAO-B were 0.068 ± 0.022, 0.044 ± 0.002, and 0.061 ± 0.001 µM, respectively, and that of IS15 for MAO-A was 1.004 ± 0.171 µM, and the compounds were reversible-type inhibitors. The lead compounds were central nervous system (CNS) permeable, as per parallel artificial membrane permeability assay (PAMPA) test results. The lead compounds were examined for their cytotoxicity and potential neuroprotective benefits in hazardous lipopolysaccharide (LPS)-exposed SH-SY5Y neuroblastoma cells. Pre-treatment with lead compounds enhanced anti-oxidant levels (SOD, CAT, GSH, and GPx) and decreased ROS and pro-inflammatory cytokine (IL-6, TNF-alpha, and NF-kB) production in LPS-intoxicated SH-SY5Y cells. To confirm the promising effects of the compound, molecular docking, dynamics, and MM-GBSA binding energy were used to examine the molecular basis of the IS7-MAO-B interaction. Our findings indicate that lead compounds are potential therapeutic agents to treat neurological illnesses, such as Parkinson's disease.
Assuntos
Isatina , Neuroblastoma , Fármacos Neuroprotetores , Humanos , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/química , Isatina/farmacologia , Fármacos Neuroprotetores/farmacologia , Simulação de Acoplamento Molecular , Lipopolissacarídeos , Relação Estrutura-Atividade , Monoaminoxidase/metabolismo , Corantes/farmacologiaRESUMO
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.
Assuntos
Antineoplásicos , Isatina , Neoplasias Hepáticas , Humanos , Animais , Camundongos , Linhagem Celular Tumoral , Isatina/química , Ensaios de Seleção de Medicamentos Antitumorais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Proliferação de Células , Relação Estrutura-Atividade , Estrutura MolecularRESUMO
Humanity is currently facing various diseases with significant mortality rates, particularly those associated with malignancies. Numerous enzymes and proteins have been identified as highly promising targets for the treatment of cancer. The poly(ADP-ribose) polymerases (PARPs) family comprises 17 members which are essential in DNA damage repair, allowing the survival of cancer cells. Unlike other PARP family members, PARP-1 and, to a lesser extent, PARP-2 show more than 90% activity in response to DNA damage. PARP-1 levels were shown to be elevated in various tumor cells, including breast, lung, ovarian, and prostate cancer and melanomas. Accordingly, novel series of phthalimide-tethered isatins (6a-n, 10a-e, and 11a-e) were synthesized as potential PARP-1 inhibitors endowed with anticancer activity. All the synthesized molecules were assessed against PARP-1, where compounds 6f and 10d showed nanomolar activities with IC50 = 15.56 ± 2.85 and 13.65 ± 1.42 nM, respectively. Also, the assessment of the antiproliferative effects of the synthesized isatins was conducted on four cancer cell lines: leukemia (K-562), liver (HepG2), and breast (MCF-7 and HCC1937) cancers. Superiorly, compounds 6f and 10d demonstrated submicromolar IC50 values against breast cancer MCF-7 (IC50 = 0.92 ± 0.18 and 0.67 ± 0.12 µM, respectively) and HCC1937 (IC50 = 0.88 ± 0.52 and 0.53 ± 0.11 µM, respectively) cell lines. In addition, compounds 6f and 10d induced arrest in the G2/M phase of the cell cycle as compared to untreated cells. Finally, in silico studies, including docking and molecular dynamic simulations, were performed to justify the biological results.
Assuntos
Isatina , Inibidores de Poli(ADP-Ribose) Polimerases , Masculino , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Relação Estrutura-Atividade , Ftalimidas/farmacologia , Linhagem Celular TumoralRESUMO
Isatin, known as 1H-indole-2,3-dione, was originally recognised as a synthetic molecule until its discovery in the fruits of the cannonball tree, Couroupita guianensis. It is naturally occurring in plants of the genus Isatis and serves as a metabolic derivative of adrenaline in humans. Isatin possesses significant pharmacological importance, and its synthetic versatility has prompted extensive interest in its derivative compounds due to their diverse biological and pharmacological properties. These derivatives represent a valuable class of heterocyclic compounds with potential applications as precursors for synthesizing numerous valuable drugs. In the pursuit of advancing our research on isatin hybrids, we investigate the utilisation of readily available hydrazonoindolin-2-one and isatin as starting materials for the synthesis of a wide range of analogues. Characterisation of the synthesized compounds was carried out through various analytical techniques. Furthermore, the obtained compounds were subjected to extensive testing to evaluate their anticancer and antimicrobial activities. Specifically, their efficacy against key proteins, namely Staphylococcus aureus protein (PDB ID: 1JIJ), Escherichia coli protein (PDB ID: 1T9U), Pseudomonas aeruginosa protein (PDB ID: 2UV0), and Acinetobacter baumannii protein (PDB ID: 4HKG), was examined through molecular docking calculations. Several molecules, such as 3, 4, 6, 16, and 19, displayed remarkable activity against the renal cancer cell line UO-31. Additionally, the results of antimicrobial activity testing revealed that compound 16 exhibited significant cytotoxicity against Candida albicans and Cryptococcus neoformans. Subsequently, ADME/T calculations were performed to gain insights into the potential effects and reactions of these molecules within human metabolism. This comprehensive study provides valuable insights into the potential pharmacological applications of isatin derivatives and underscores their significance in drug development.
Assuntos
Anti-Infecciosos , Antineoplásicos , Isatina , Humanos , Simulação de Acoplamento Molecular , Isatina/farmacologia , Antineoplásicos/farmacologia , Anti-Infecciosos/farmacologia , Linhagem Celular , Estrutura Molecular , Relação Estrutura-Atividade , Antibacterianos/farmacologiaRESUMO
Herein, a series of isatin tethered indolo[2,3-b]quinoxaline hybrids was synthesized by considering the pharmacophoric features of known DNA intercalators and topoisomerase II inhibitors. The anti-proliferative properties of the synthesized compounds were evaluated against ovarian cancer cell lines (SKOV-3 and Hey A8). Four of the compounds exhibited promising anti-proliferative activities, with one of them being 10-fold more potent than cisplatin against drug-resistant Hey A8 cells. Further investigations were carried out to determine the DNA intercalating affinities of the most active compounds as potential mechanisms for their anti-proliferative activities. ADMET in silico studies were performed to assess the physicochemical, pharmacokinetics, and toxicity parameters of active compounds. This study, to the best of our knowledge, is the first report on the potential of isatin-indoloquinoxaline hybrids as structural blueprints for the development of new DNA intercalators. Additionally, it explores their potential to circumvent platinum-based resistance in ovarian cancer.
Assuntos
Antineoplásicos , Isatina , Neoplasias Ovarianas , Humanos , Feminino , Isatina/farmacologia , Substâncias Intercalantes/farmacologia , Substâncias Intercalantes/química , Linhagem Celular Tumoral , Antineoplásicos/química , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , DNA/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of new fluorinated 1-benzylisatins was synthesized in high yields via a simple one-pot procedure in order to explore the possible effect of ortho-fluoro (3a), chloro (3b), or bis-fluoro (3d) substitution on the biological activity of this pharmacophore. Furthermore, the new isatins could be converted into water-soluble isatin-3-hydrazones using their acid-catalyzed reaction with Girard's reagent P and its dimethyl analog. The cytotoxic action of these substances is associated with the induction of apoptosis caused by mitochondrial membrane dissipation and stimulated reactive oxygen species production in tumor cells. In addition, compounds 3a and 3b exhibit platelet antiaggregation activity at the level of acetylsalicylic acid, and the whole series of fluorine-containing isatins does not adversely affect the hemostasis system as a whole. Among the new water-soluble pyridinium isatin-3-acylhydrazones, compounds 7c and 5c,e exhibit the highest antagonistic effect against phytopathogens of bacterial and fungal origin and can be considered useful leads for combating plant diseases.
Assuntos
Antineoplásicos , Isatina , Isatina/farmacologia , Hidrazonas/farmacologia , Água/farmacologia , Antineoplásicos/farmacologia , Apoptose , Relação Estrutura-AtividadeRESUMO
SARS-CoV-2 chymotrypsin-like cysteine protease (3CLpro ) is one of the most widely developed drug targets for COVID-19. This study aimed to design and synthesize isatin derivatives to target SARS-CoV-2 3CLpro in a covalent binding manner. Through the process, a potent 3CLpro inhibitor (5g) was discovered with an IC50 value of 0.43 ± 0.17 µM. To understand the binding affinity and specificity of 5g as a candidate inhibitor of SARS-CoV-2 3CLpro , several assays were conducted, including FRET enzyme activity assays, thermodynamic-based and kinetic-based validation of inhibitor-target interactions, and cell-based FlipGFP assays. The interaction mechanism between 3CLpro -5g was characterized by docking. Overall, these findings suggest that 5g is a new potent SARS-CoV-2 3CLpro inhibitor for the treatment of COVID-19.
Assuntos
COVID-19 , Isatina , Humanos , SARS-CoV-2 , Isatina/farmacologia , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , Termodinâmica , Antivirais/química , Simulação de Acoplamento MolecularRESUMO
Monoamine oxidase (MAO, EC 1.4.3.4) is responsible for the oxidative breakdown of both endogenous and exogenous amines and exists in MAO-A and MAO-B isomers. Eighteen indole-based phenylallylidene derivatives were synthesized via nucleophilic addition reactions comprising three sub-series, IHC, IHMC, and IHNC, and were developed and examined for their ability to inhibit MAO. Among them, compound IHC3 showed a strong MAO-B inhibitory effect with an IC50 (half-maximal inhibitory concentration) value of 1.672 µM, followed by IHC2 (IC50 = 16.934 µM). Additionally, IHC3 showed the highest selectivity index (SI) value of >23.92. The effectiveness of IHC3 was lower than the reference pargyline (0.14 µM); however, the SI value was higher than pargyline (17.16). Structurally, the IHC (-H in the B-ring) sub-series exhibited relatively stronger MAO-B inhibition than the others. In the IHC series, IHC3 (-F in the A-ring) exhibited stronger MAO-B suppression than the other substituted derivatives in the order -F > -Br > -Cl > -OCH3, -CH3, and -H at the 2-position in the A-ring. In the reversibility and enzyme kinetics experiments, IHC3 was a reversible inhibitor with a Ki value of 0.51 ± 0.15 µM for MAO-B. Further, it was observed that IHC3 greatly decreased the cell death caused by rotenone in SH-SY5Y neuroblastoma cells. A molecular docking study of the lead molecule was also performed to determine hypothetical interactions in the enzyme-binding cavity. These findings suggest that IHC3 is a strong, specific, and reversible MAO-B inhibitor that can be used to treat neurological diseases.