Isatin Thiosemicarbazone Research Articles

Synthesis, bacterial and fungal inhibition assay, molecular docking study of substituted isatin (N-substituted 1,2,3,4-tetra-O-acetyl-β-glucopyranosyl)thiosemicarbazones

Synthesis, bacterial and fungal inhibition assay, molecular docking study of substituted isatin (N-substituted 1,2,3,4-tetra-O-acetyl-β-glucopyranosyl)thiosemicarbazones

The Prophylactic and Multimodal Activity of Two Isatin Thiosemicarbazones against Alzheimer's Disease In Vitro.

Alzheimer’s disease (AD) is a multifactorial disorder strongly involving the formation of amyloid-β (Aβ) oligomers, which subsequently aggregate into the disease characteristic insoluble amyloid plaques, in addition to oxidative stress, inflammation and increased acetylcholinesterase activity. Moreover, Aβ oligomers interfere with the expression and activity of Glycogen synthase kinase-3 (GSK3) and Protein kinase B (PKB), also known as AKT. In the present study, the potential multimodal effect of two synthetic isatin thiosemicarbazones (ITSCs), which have been previously shown to prevent Aβ aggregation was evaluated. Both compounds resulted in fully reversing the Aβ-mediated toxicity in SK-NS-H cells treated with exogenous Aβ peptides at various pre-incubation time points and at 1 μM. Cell survival was not recovered when compounds were applied after Aβ cell treatment. The ITSCs were non-toxic against wild type and 5xFAD primary hippocampal cells. They reversed the inhibition of Akt and GSK-3β phosphorylation in 5xFAD cells. Finally, they exhibited good antioxidant potential and moderate lipoxygenase and acetylcholinesterase inhibition activity. Overall, these results suggest that isatin thiosemicarbazone is a suitable scaffold for the development of multimodal anti-AD agents.

5-Substituted isatin thiosemicarbazones as inhibitors of tyrosinase: Insights of substituent effects

Seven isatin-thiosemicarbazone analogues bearing different substituents (R) attached at C-5 of the indoline ring, TSC-ISA-R (R = -H, -CH3, -OCH3, -OCF3, -F, -Cl and -NO2), were synthesized and evaluated as inhibitors of mushroom tyrosinase (TYR). The inhibitory behaviour and performance of TSC-ISA-R were investigated spectroscopically in relation to the substituent modifications through examining their inhibition against the diphenolase activity of TYR using L-DOPA as a substrate. The IC50 values of TSC-ISA-R were determined to be in the range of 81–209 μM. The kinetic analysis showed that TSC-ISA-R were reversible and mixed type inhibitors. Three potential non-covalent interactions rather than complexation including the binding of TSC-ISA-R with free TYR, TYR-L-DOPA complex, and with substrate L-DOPA were found to be involved in the inhibition. The substituent modifications affected these interactions by varying the characters of the resulting TSC-ISA-R in different degrees. The thiosemicarbazido moiety of each TSC-ISA-R contributed predominantly to the inhibition, and the isatin moiety seemed to play a regulatory role in the binding of TSC-ISA-R to the target molecules. The results of theoretical calculations using density functional theory method indicated a different effect of –R on the electron distribution in HOMO of TSC-ISA-R. The LUMO-HOMO energy gap of TSC-ISA-R almost accords with the trend of their experimental inhibition potency.

N-substitution in isatin thiosemicarbazones decides nuclearity of Cu(II) complexes - Spectroscopic, molecular docking and cytotoxic studies.

The mono- (1) and bi-nuclear (2) copper(II) complexes containing N-substituted isatin thiosemicarbazone(s) were synthesized, and characterized by analytical and spectroscopic (UV-Visible, FT-IR and EPR) techniques. Bimetallic nature of complex 2 was confirmed by single crystal X-ray crystallography. The structures predicted by spectroscopic and crystallographic methods were validated by computational studies. From the spectroscopic, crystallographic and computational data, the structures were found to be distorted square planar for 1 and distorted square pyramidal for 2. Molecular docking studies showed hydrogen bonding and hydrophobic interactions of the complexes with tyrosinase kinase receptors. Complex 1 exhibited promising cytotoxic activity against Jurkat (leukemia) cell line, and complex 2 displayed more activity against HeLa S3 (cervical) and Jurkat cell lines with the IC50 values of 3.53 and 3.70μM, respectively. Cytotoxicity of 1 (Jurkat) and 2 (Jurkat and HeLa S3) was better than that of cisplatin. Morphological changes in A549 (lung), HeLa S3 and Jurkat cell lines were examined in presence of the active complexes with the co-staining of Hoechst, AO (acridine orange) and EB (ethidium bromide) by fluorescence microscope.

Isatin thiosemicarbazone derivatives as inhibitors against corrosion of AA6060 aluminium alloy in acidic chloride medium: substituent effects

Five isatin thiosemicarbazone derivatives bearing different substituents (R) at 5-position of the isatin moiety, ISA-R, being R = -H, -CH3, -F, -Cl and -NO2, were synthesized and fully characterized. The corrosion inhibition action of ISA-R on AA6060 aluminium alloy in acidic chloride medium was studied in relation to the substituent effects using field emission scanning electron microscopy (FE-SEM), energy dispersive X-ray spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS), electrochemical potentiodynamic polarization (PDP) and weight loss measurements. The results showed that the inhibition behaviors of ISA-R were strongly correlated with the substituent modifications. ISA-NO2 was found to possess the highest capability to increase the corrosion resistance of the alloy and ISA-Cl exhibited some inhibition efficacy, whereas the others have little action. ISA-H, ISA-F, ISA-Cl and ISA-NO2 acted as cathodic-type inhibitors, and ISA-CH3 as a mixed-type inhibitor primarily retarding the cathodic processes of the alloy in the corrosion solution. ISA-R can be adsorbed on the alloy surface as evidenced by the results of EDS and XPS. The π-electron density on the isatin ring of ISA-NO2 is more deficient over the other ISA-R, which facilitates the adsorption of ISA-NO2 and formation of a barrier film on the alloy surface, and accordingly enhances its anti-corrosive performance for the alloy.

Novel Isatin Thiosemicarbazone Derivatives as Potent Inhibitors of β-Amyloid Peptide Aggregation and Toxicity

Inhibition of β-amyloid peptide (Αβ) aggregation in Alzheimer's disease (AD) is among the therapeutic approaches against AD which still attracts scientific research interest. In the search for compounds that interact with Aβ and disrupt its typical aggregation course toward oligomeric or polymeric toxic assemblies, small organic molecules of natural origin, combining low molecular weight (necessary blood-brain barrier penetration) and low toxicity (necessary for pharmacological application), are greatly sought after. Isatin (1H-indoline-2,3-dione), a natural endogenous indole, and many of its derivatives exhibit a wide spectrum of neuropharmacological and chemotherapeutic properties. The synthesis and biological evaluation of four new isatins as inhibitors of Aβ aggregation is presented herein. In these derivatives, the N-phenyl thiosemicarbazide moiety is joined at the 3-oxo position of isatin through Schiff base formation, and substitutions are present at the indole nitrogen and position 5 of the isatin core. Biophysical studies employing circular dichroism, thioflavin T fluorescence assay, and transmission electron microscopy reveal the potential of the isatin thiosemicarbazones (ITSCs) to alter the course of Αβ aggregation, with two of the derivatives exhibiting outstanding inhibition of the aggregation process, preventing completely the formation of amyloid fibrils. Furthermore, in in vitro studies in primary neuronal cell cultures, the ITSCs were found to inhibit the Aβ-induced neurotoxicity and reactive oxygen species production at concentrations as low as 1 μM. Taken all together, the novel ITSCs can be considered as privileged structures for further development as potential AD therapeutics.

Biological Activities of Isatin Thiosemicarbazone Derivatives and their Metal Complexes: A Review of Past Three Decades (1991-2020)

Biological Activities of Isatin Thiosemicarbazone Derivatives and their Metal Complexes: A Review of Past Three Decades (1991-2020)

Molecular structures, Hirshfeld analysis and biological investigations of isatin based thiosemicarbazones

The synthesized isatin thiosemicarbazone compounds (1–10) were well characterized by elemental analysis, and UV–Visible, FT-IR and NMR spectroscopic methods. The crystal structure of two of the compounds (6 and 9) was confirmed by single crystal X-ray crystallography. Hirshfeld surface analysis was performed to analyze the intermolecular interactions. The compounds were evaluated for their in vitro antioxidant and cytotoxicity against MCF-7 (breast) cancer cell line through DPPH and MTT assays, respectively. The results clearly indicated that compounds 5, 6, 7 and 8 showed significant antioxidant property and compound 7 exhibited greater cytotoxicity than the other compounds. Anti-inflammatory activity of the compounds was determined by in vitro PLA2 inhibition assay and in silico molecular docking study, which showed promising results for all the compounds.

Palladium(II) complexes of 5-substituted isatin thiosemicarbazones: Synthesis, spectroscopic characterization, biological evaluation and in silico docking studies

Substituted heterocyclic (isatin) appended thiosemicarbazone ligands (L1-L3) are synthesized by condensation of substituted isatin molecule with N(4)-phenyl-3-thiosemicarbazide in good yields. The palladium(II) complexes are synthesized from ligands (L1-L3) and PdCl2, with a general formula [PdCl(X-C15H10N4OS)] where X = 5-chloro (1), 5-bromo (2), and 5-nitro (3). Both analytical and spectroscopic methods have been used for the analysis and characterization of the synthesized compounds. The antimicrobial activity results observed that complexes, 1 and 2 have registered potent antibacterial activity against B. subtilis and K. pneumoniae and also complex 2 has shown good antifungal activity against the micro organisms. The antioxidant activity analysis revealed that the complex 3 showed significant activity with IC50 values 7.24 ± 0.09 µM. Moreover, the in vitro antiproliferative activity results suggested that complex 3 exhibited high activity against HeLa cell line compared with the standard with the IC50 value 16.52 ± 1.08 µM. The docking results correlate well.

Analysis of DNA protection, interaction and antimicrobial activity of isatin derivatives

Isatin, thiosemicarbazone and their derivatives have been widely used in biological applications such as antimicrobial, antiviral and anticancer therapies. Herein, eight isatin and thiosemicarbazone derivative compounds were re-synthesized and evaluated for DNA binding analysis including DNA protection studies using plasmid DNA (pUC19) and DNA interaction experiments using calf thymus DNA (CT-DNA). All compounds were also utilized in vitro assay to assess the antimicrobial activity of compounds against different pathogenic bacterial strains. All isatin and thiosemicarbazone derivative compounds exhibited DNA protection activity which ranged from 23.5 to 59.5%. Among them, I3-(N-2-MP)-TSC had the greatest DNA protective activity. For DNA binding analysis, all compounds had the same constant concentration (40 μM), which interacts with CT-DNA. It was also observed that DNA interactions gave a high intrinsic binding constant (Kb = 1.72 × 104 M−1–9.73 × 105 M−1). Besides, several derivatives of isatin thiosemicarbazone exhibited significant and selective antibacterial activity with low concentration. These compounds primarily affected Gram-positive bacteria, but were not effective against P. vulgaris and E. coli. The Gram-positive methicillin-resistant S. aureus ATCC 43300 (MRSA) was the most influenced strain by these compounds. It was found that methyphenyl group at isatin was essential for its antibacterial activity for MRSA.

Nickel(II) bis(isatin thiosemicarbazone) complexes induced apoptosis through mitochondrial signaling pathway and G0/G1 cell cycle arrest in IM-9 cells

Three novel complexes (1, 3 and 4) ligating N-substituted isatin thiosemicarbazone derivatives have been synthesized and their structural and biological characteristics have been compared with those of the known analogs (2, 5–7 and 8). In addition, the structure of the representative ligands (L1, L3 and L4) and complex (4) was confirmed by single crystal X-ray diffraction method. All the complexes (1–8) were assessed for their cytotoxic property against a panel of four human cancer cells such as HepG-2 (liver), MOLM-14 (acute monocytic leukemia), U937 (histiocytic lymphoma). and IM-9 (myeloma). Complex 4 exhibited prominent cytotoxic property against MOLM-14, U937 and IM-9 cell lines. Moreover, the results were compared with the well-known anticancer drugs like doxorubicin, cisplatin and daunorubicin. Besides, complex 4 enhanced the apoptotic cell death in IM-9 cell line and induced cell cycle arrest at G1 phase. Western blot analysis revealed the down-regulation of Bcl-2 (b-cell lymphoma-2), up-regulation of Bax (bcl-2 associated X protein), release of cytochrome c and activation of caspases-3 in IM-9 cells by complex 4. Importantly, complex 4 was not toxic to the normal Vero cell line (IC50 > 300 μM). In addition, complex 4 showed the concentration dependent cleavage of supercoiled (SC) DNA to its nicked circular (NC) form.

An investigation on the DNA/protein binding, DNA cleavage and in vitro anticancer properties of SNO pincer type palladium(II) complexes with N-substituted isatin thiosemicarbazone ligands

Three pincer type palladium(II) complexes (1–3) were synthesised from the reactions of PdCl2 with thiosemicarbazone ligands (L1–L3), and characterized by elemental analyses and UV Visible, FT-IR, 1H &13C NMR spectroscopic techniques. The molecular structure of 2 was confirmed by single crystal X-ray crystallography. The X-ray diffraction study of complex 2 revealed the pincer type tridentate SNO coordination of N-substituted isatin thiosemicarnbazone with the palladium ion. The binding affinity and mode of the palladium(II) complexes (1–3) toward calf thymus DNA (CT-DNA) and bovine serum albumin (BSA) were determined by UV–Visible and fluorescence spectrophotometric methods. Spectral evidences showed intercalative mode of DNA binding with the palladium(II) complexes. The magnitude of hypochromism is in the order of 3>2>1, which reflects the DNA binding efficacy of the complexes. The binding mode was further confirmed by CD spectra which indicate the non-groove mode of binding; hence the intercalative mode of binding is proposed. The alterations in the secondary structure of the protein by the complexes were confirmed by synchronous fluorescence spectroscopic studies. Spectral evidences also showed good binding property of the complexes with the protein. Complexes (1–3) cleaved the pUC19 plasmid DNA in the absence of an external agent. The complexes were found to possess significant in vitro cytotoxicity against human breast (MCF7) and lung (A549) cancer cell lines.

Synthesis, structure and in vitro anticancer, DNA binding and cleavage activity of palladium (II) complexes based on isatin thiosemicarbazone derivatives

Six novel palladium(II) complexes of a thiosemicarbazone Schiff base with isatin moiety (PdL1 to PdL6) were synthesized by the reaction of palladium(II) with the following: (Z)‐2‐(2‐oxoindolin‐3‐ylidene)‐N‐phenylhydrazinecarbothioamide (L1H), (Z)‐2‐(5‐methyl‐2‐oxoindolin‐3‐ylidene)‐N‐phenylhydrazinecarbothioamide (L2H), (Z)‐2‐(5‐fluoro‐2‐oxoindolin‐3‐ylidene)‐N‐phenylhydrazinecarbothioamide (L3H), (Z)‐N‐methyl‐2‐(5‐nitro‐2‐oxoindolin‐3‐ylidene)hydrazinecarbothioamide (L4H), (Z)‐N‐methyl‐2‐(5‐methyl‐2‐oxoindolin‐3‐ylidene)hydrazinecarbothioamide (L5H) and (Z)‐N‐ethyl‐2‐(5‐methyl‐2‐oxoindolin‐3‐ylidene)hydrazinecarbothioamide (L6H). The structures of these complexes were characterized using elemental analysis and infrared, UV–visible, 1H NMR and mass spectroscopies. The structure of PdL5 was further characterized using single‐crystal X‐ray diffraction. The interaction of these complexes with calf thymus DNA was characterized with a high intrinsic binding constant (Kb = 5.78 × 104 to 1.79 × 106 M−1), which reflected the intercalative activity of these complexes towards calf thymus DNA. This result was also confirmed from viscosity data. Electrophoresis studies revealed that complexes PdL1 to PdL6 could cleave DNA via an oxidative pathway in the presence of an external agent. Data obtained from an in vitro anti‐proliferative study clearly established the anticancer potency of these compounds against the human colorectal carcinoma cell line HCT 116.

Isatin thiosemicarbazones promote honeycomb structure formation in spin-coated polymer films: concentration effect and release studies

Isatin thiosemicarbazone mixed biopolymer films as potential biomaterial for antibacterial and anti-inflammatory protection.

Synthesis and crystal structure of new monometallic and bimetallic copper(II) complexes with N-substituted isatin thiosemicarbazone ligands: Effects of the complexes on DNA/protein-binding property, DNA cleavage study and in vitro anticancer activity

A novel series of N-substituted isatin thiosemicarbazone ligands (L1–L3) and their copper(II) complexes [Cu(II)(ITSC)] were synthesized and characterized by elemental analyses and UV–Vis, FT-IR, 1H &13C NMR/EPR and mass spectroscopic techniques. The molecular structures of L1, L2, L3, 2 and 3 were confirmed by single crystal X-ray crystallography. The X-ray diffraction studies of the complexes 2 and 3 reveal the square planar and square pyramidal geometry. The binding affinity and binding mode of the monometallic and bimetallic complex toward calf thymus DNA (CT-DNA) and bovine serum albumin (BSA) were determined by UV–Vis and fluorescence spectrophotometric methods. Spectral evidences show intercalative mode of DNA binding with the copper(II) complexes. Complexes (1, 2 and 3) cleaved the pUC19 plasmid DNA in the absence of an external agent. An in vitro cytotoxicity study of the complex 3 found good activity against human breast (MCF7) and lung (A549) cancer cell lines.

Synthesis, X-ray crystal structure, DNA/protein binding and DNA cleavage studies of novel copper(ii) complexes of N-substituted isatin thiosemicarbazone ligands

Copper(ii) complexes containing isatin thiosemicarbozone ligands have been synthesized and evaluated for its biological applications like DNA/protein binding and DNA cleavage studies.

Some Molecular Properties and Reaction Mechanism of Synthesized Isatin Thiosemicarbazone and Its Zinc(II) and Nickel(II) Complexes

Some Molecular Properties and Reaction Mechanism of Synthesized Isatin Thiosemicarbazone and Its Zinc(II) and Nickel(II) Complexes

Synthesis, DNA/protein binding, molecular docking, DNA cleavage and in vitro anticancer activity of nickel(ii) bis(thiosemicarbazone) complexes

Cytotoxic nickel(ii) complexes with an N-substituted isatin thiosemicarbazone were synthesized and their interaction with CT DNA and BSA protein was investigated, which was supported by molecular docking studies.

Study of the Inhibitory Action of Marboran on the Replication Cycle of Cowpox Virus

Research Project The project undertaken involved a study of the effects of the inhibitor N-methyl isatin thiosemicarbazone (Marboran) on the replication cycle of cowpox virus in monolayers of baby hamster kidney cells (BHK). The cytotoxic effects of Marboran on the BHK cells were studied and were found to be directly related to the time of exposure to the inhibitor with a maximum tolerated dose of Marboran of 30/UM/ml. after 7 days. This drug concentration was subsequently used to avoid the occurrence of a cytotoxic effect of Marboran masking any cytopathic effect (CPE) of the virus when both inhibitor and virus were used in conjunction.

Synthesis of nickel(II) complexes of isatin thiosemicarbazone derivatives: in vitro anti-cancer, DNA binding, and cleavage activities

Six new nickel(II) complexes of thiosemicarbazone Schiff base with isatin moiety [Ni(L1)2–Ni(L6)2] were synthesized through reaction of Ni(II) with (Z)-2-(2-oxoindolin-3-ylidene)-N-phenylhydrazinecarbothioamide (L1H), (Z)-2-(5-methyl-2-oxoindolin-3-ylidene)-N-phenylhydrazinecarbothioamide (L2H), (Z)-2-(5-fluoro-2-oxoindolin-3-ylidene)-N-phenylhydrazinecarbothioamide (L3H), (Z)-N-methyl-2-(5-nitro-2-oxoindolin-3-ylidene)hydrazinecarbothioamide (L4H), (Z)-N-methyl-2-(5-methyl-2-oxoindolin-3-ylidene)hydrazinecarbothioamide (L5H), and (Z)-N-ethyl-2-(5-methyl-2-oxoindolin-3-ylidene)hydrazinecarbothioamide (L6H). The structures of the Ni complexes were characterized through elemental analysis, infrared, and mass spectral data. The structure of the NiL2 complex was further characterized through single-crystal X-ray diffraction. The interaction of these complexes with calf thymus (CT-DNA) exhibited high intrinsic binding constants (Kb = 1.4 × 105–2.4 × 106 M−1), which reflected their intercalative activity toward CT-DNA. This result was also confirmed by viscosity data. Electrophoresis studies revealed that these complexes could cleave the DNA through the oxidative pathway. The in vitro anti-proliferative study establishes the anticancer potency of these compounds against human colorectal carcinoma cell line.