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Induction of apoptosis is often necessary for successful cancer therapy, and the non-invasive monitoring of apoptosis post-therapy could assist in clinical decision making. Isatins are a class of compounds that target activated caspase-3 during apoptosis. Here we report the synthesis of the 5-iodo-1,2,3-triazole (FITI) analog of the PET tracer [ 18 F]ICMT11 as a candidate tracer for imaging of apoptosis with SPECT, as well as PET. Labelling with radioiodine ( 123,125 I) was achieved in 55 ± 12% radiochemical yield through a chelator-accelerated one-pot cycloaddition reaction mediated by copper(I) catalysis. The caspase-3 binding affinity and selectivity of FITI compares favourably to that of [ 18 F]ICMT11 (K i = 6.1 ± 0.9 nM and 12.4 ± 4.7 nM, respectively). In biodistribution studies, etoposide-induced cell death in a SW1222 xenograft model resulted in a 2-fold increase in tumour uptake of the tracer. However, the tumour uptake was too low to allow in vivo imaging of apoptosis with SPECT.

Spirooxindoles occupy an important place in heterocyclic chemistry. Many natural spirooxindole-containing compounds have been identified as bio-promising agents. Synthetic analogs have also been synthesized utilizing different pathways. The present article summarizes the recent development of both natural and synthetic spirooxindole-containing compounds prepared from isatin or its derivatives reported in the last five years. The spirooxindoles are categorized based on their mentioned biological properties.

Due to the notable biological activity of isatin hydrazone compounds, we synthesized and structurally characterized three arylidene isatin hydrazone derivatives ( 3a-3c ) utilizing the SBA-Pr-N-Is-Bu-SO 3 H nanocatalyst. A comparative investigation was performed through an integrated approach combining experimental assays and theoretical modeling. In vitro biological assays performed on normal umbilical vein endothelial cells (HUVECs) and breast cancer cell lines (MCF-7 and MDA-MB-231) revealed noteworthy anticancer activity, with all derivatives significantly reducing cancer cell viability in a concentration- and time-dependent manner. Furthermore, compound 3c exhibited the most potent antioxidant effect, achieving up to 80% inhibition at higher concentrations. Biomolecule (DNA and BSA) interaction studies were performed utilizing UV-Vis spectroscopic analysis and molecular docking simulations. The values of K app for the interaction of compounds 3a (1.01 × 10 4 M − 1 ), 3b (1.17 × 10 4 M − 1 ), and 3c (2.03 × 10 4 M − 1 ), along with docking simulations, indicate that the studied compounds are likely to bind to CT-DNA via a groove-binding mechanism. Lipophilicity assessments demonstrated that compounds 3b and 3c had significantly higher log P values than cisplatin, indicating enhanced lipid affinity and superior cellular membrane permeability potential. Comprehensive computational analyses, including DFT/TD-DFT, topology analysis, and ADME-Tox profiling, were employed to further validate the observed biological activity and pharmacokinetic potential. The convergence of computational insights and experimental findings provides robust validation for the potential of these compounds as promising anticancer agents.

Bromodomain-containing protein 9 (BRD9) belongs to the non-canonical BAF chromatin remodeling complex and represents a relevant therapeutic target in pathologies featuring dysregulated epigenetic control. The absence of clinically validated inhibitors and the need for diversified chemical entities highlight the interest in identifying new scaffolds targeting this protein. In this study, Saturation Transfer Difference Nuclear Magnetic Resonance (STD NMR) was employed to assess its suitability for characterizing BRD9–ligand interactions within a fragment-based discovery framework. STD NMR conditions were first optimized using the known BRD9 ligand 1, verifying the presence of interaction signals. A pharmacophore-based virtual screening campaign was then performed using libraries of commercially available fragments, leading to the selection of a novel isatin derivative, i.e., compound 2, whose binding was demonstrated in AlphaScreen assays. STD NMR experiments provided epitope mapping consistent with the predicted binding mode, thus supporting the stability of the interaction in solution. Moreover, a competitive STD experiment demonstrated displacement of 2 by a reference ligand, confirming the binding within the canonical BRD9 pocket. Overall, this study establishes STD NMR as a reliable approach for probing BRD9–ligand interactions and for the identification and validation of BRD9-targeting scaffolds suitable for future structure-guided optimization.

The emergence of diverse infections worldwide, which is a serious global threat to human existence, necessitates the urgent development of novel therapeutic candidates that can combat these diseases with efficacy. Molecular hybridization has been established as an efficient technique in designing bioactive molecules capable of fighting infections. Isatin, a core nucleus of an array of compounds with diverse biological properties can be modified at different positions leading to the creation of novel drug targets, is an active area of medicinal chemistry. This review containing published articles from 2005 to 2022 highlights isatin hybrids which have been synthesized and reported in the literature alongside a discussion on their biological properties. The enriched structure–activity relationship studies discussed provides insights for the rational design of novel isatin hybrids with tailored biological properties as effective therapeutic candidates inspired by nature.

Oximes have been reported to exhibit useful pharmaceutical properties, including compounds with anticancer, anti-arthritis, antibacterial, and neuroprotective activities. Many oximes are kinase inhibitors and have been shown to inhibit various kinases. Herein, a panel of oxime derivatives of tricyclic isatins was synthesized and evaluated for inhibition of cellular inflammatory responses and binding affinity to several kinases. Compounds 5a and 5d (a.k.a. NS-102), which have an unsubstituted oxime group, inhibited lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) transcriptional activity in human THP-1Blue monocytic cells and interleukin-6 (IL-6) production in human MonoMac-6 monocytic cells, with IC50 values in the micromolar range. These compounds also inhibited LPS-induced production of several other proinflammatory cytokines, including IL-1α, IL-1β, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor (TNF) in MonoMac-6 cells. Compounds 5a and 5d exhibited nanomolar/submicromolar binding affinity toward several kinase targets. The most potent inhibitor, 5d (3-(hydroxyimino)-5-nitro-1,3,6,7,8,9-hexahydro-2H-benzo[g]indol-2-one), demonstrated high binding affinity for 12 kinases, including DYRK1A, DYRK1B, PIM1, Haspin, HIPK1-3, IRAK1, NEK10, and DAPK1-3. Molecular modeling suggested modes of binding interaction of selected compounds in the DYRK1A and PIM1 catalytic sites that agreed with the experimental binding data. Our results demonstrate that tricyclic isatin oximes could be potential candidates for developing anti-inflammatory drugs with neuroprotective effects for treating neurodegenerative diseases.

A series of new isatin hydrazones bearing phosphorus-containing moiety was synthesized through a simple, high-yield and easy work-up reaction of phosphine oxide (Phosenazide) or phosphinate (2-chloroethyl (4-(dimethylamino)phenyl)(2-hydrazinyl-2-oxoethyl)phosphinate, CAPAH) hydrazides with aryl-substituted isatins. The 31P NMR technique showed that, in most cases, out of 12 examples in solution, the ratio of the two spatial isomers varied from 1:1 to 1:3. Quantum chemical calculations confirmed the predominance of Z,syn form both in the gas phase and in solution. According to X-ray analysis data in crystals, they exist only in Z,syn form too. Most of the phosphine oxide derivatives and 5-methoxy- and 5-bromoaryl phosphinate analogs exhibit anti-aggregant activity at the level of acetylsalicylic acid but inhibit platelet activation processes more effectively. The 5-chloro type phosphinate derivative exhibits anti-aggregant properties more effectively than acetylsalicylic acid under the conditions of the tissue factor (TF)-activated thromboelastography (TEG) model, the ex vivo thrombosis model. Thus, all the obtained results can become the basis for future pharmaceutical developments to create effective anti-aggregation drugs with broad antithrombotic potential.

Three series of 6-aryl-2-methylnicotinohydrazides 4a–i, N′-arylidene-6-(4-bromophenyl)-2-methylnicotino hydrazides 7a–f, and N′-(un/substituted 2-oxoindolin-3-ylidene)-6-(4-fluorophenyl)-2-methylnicotinohydrazides 8a–c were synthesized and evaluated for their potential in vitro antimycobacterial activity against M. tuberculosis. The results showed that isatin hydrazides 8a–c are remarkably more active than the parent hydrazide 4c. Hydrazides 8b and 8c exhibited the highest activity among all the tested compounds (MIC = 12.5 and 6.25 µg/mL, respectively). Compounds 8b and 8c were also devoid of apparent cytotoxicity to HT-29, PC-3, A549, HepG2 and MCF-7 cancer cell lines. Besides, 8b and 8c showed good drug-likeness scores of 0.62 and 0.41, respectively. Those two isatin hydrazides could offer an excellent framework for future development to obtain more potent antitubercular agents. The SAR study suggested that lipophilicity of the synthesized derivatives is a crucial element that accounts for their antimycobacterial activity. Finally, a theoretical kinetic study was established to predict the ADME of the active derivatives.

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.

Isatin (indole-2,3-dione) is an endogenous regulator, exhibiting a wide range of biological and pharmacological activities. At doses of 100 mg/kg and above, isatin is neuroprotective in different experimental models of neurodegeneration. Good evidence exists that its effects are realized via interaction with numerous isatin-binding proteins identified in the brain and peripheral tissues studied. In this study, we investigated the effect of a single dose administration of isatin to mice (100 mg/kg, 24 h) on differentially expressed proteins and a profile of the isatin-binding proteins in brain hemispheres. Isatin administration to mice caused downregulation of 31 proteins. However, these changes cannot be attributed to altered expression of corresponding genes. Although at this time point isatin influenced the expression of more than 850 genes in brain hemispheres (including 433 upregulated and 418 downregulated genes), none of them could account for the changes in the differentially expressed proteins. Comparative proteomic analysis of brain isatin-binding proteins of control and isatin-treated mice revealed representative groups of proteins sensitive to isatin administration. Control-specific proteins (n = 55) represent specific targets that interact directly with isatin. Appearance of brain isatin-binding proteins specific to isatin-treated mice (n = 94) may be attributed to the formation of new clusters of protein–protein interactions and/or novel binding sites induced by a high concentration of this regulator (ligand-induced binding sites). Thus, isatin administration produces multiple effects in the brain, which include changes in gene expression and also profiles of isatin-binding proteins and their interactomes. Further studies are needed for deeper insight into the mechanisms of the multilevel changes in the brain proteome induced by isatin. In the context of the neuroprotective action, these changes may be aimed at interruption of pathological links that begin to form after initiation of pathological processes.