Discovery of non-nucleoside oxindole derivatives as potent inhibitors against dengue RNA-dependent RNA polymerase.

A series of thiazole linked Oxindole-5-Sulfonamide (OSA) derivatives were designed as inhibitors of RNA-dependent RNA polymerase (RdRp) activity of Dengue virus. These were synthesized and then evaluated for their efficacy in ex-vivo virus replication assay using human cell lines. Among 20 primary compounds in the series, OSA-15 was identified as a hit. A series of analogues were synthesized by replacing the difluoro benzyl group of OSA-15 with different substituted benzyl groups. The efficacy of OSA-15derivatives was less than that of the parent compound, except OSA-15-17, which has shown improved efficacy than OSA-15. The further optimization was carried out by adding dimethyl (DM) groups to both the sulfonamide and oxindole NH's to produce OSA-15-DM and OSA-15-17-DM. These two compounds were showing no detectable cytotoxicity and the latter was more efficacious. Further, both these compounds were tested for inhibition in all the serotypes of the Dengue virus using an ex-vivo assay. The EC50 of OSA-15-17-DM was observed in a low micromolar range between 2.5 and 5.0 µg/ml. Computation docking and molecular dynamics simulation studies confirmed the binding of identified hits to DENV RdRp. OSA15-17-DM blocks the RNA entrance and elongation site for their biological activity with high binding affinity. Overall, the identified oxindole derivatives are novel compounds that can inhibit Dengue replication, working as non-nucleoside inhibitors (NNI) to explore as anti-viral RdRp activity.

Approved Small-Molecule ATP-Competitive Kinases Drugs Containing Indole/Azaindole/Oxindole Scaffolds: R&D and Binding Patterns Profiling.

Kinases are among the most important families of biomolecules and play an essential role in the regulation of cell proliferation, apoptosis, metabolism, and other critical physiological processes. The dysregulation and gene mutation of kinases are linked to the occurrence and development of various human diseases, especially cancer. As a result, a growing number of small-molecule drugs based on kinase targets are being successfully developed and approved for the treatment of many diseases. The indole/azaindole/oxindole moieties are important key pharmacophores of many bioactive compounds and are generally used as excellent scaffolds for drug discovery in medicinal chemistry. To date, 30 ATP-competitive kinase inhibitors bearing the indole/azaindole/oxindole scaffold have been approved for the treatment of diseases. Herein, we summarize their research and development (R&D) process and describe their binding models to the ATP-binding sites of the target kinases. Moreover, we discuss the significant role of the indole/azaindole/oxindole skeletons in the interaction of their parent drug and target kinases, providing new medicinal chemistry inspiration and ideas for the subsequent development and optimization of kinase inhibitors.

Synthesis and biological evaluation of 3-substituted 2-oxindole derivatives as new glycogen synthase kinase 3ß inhibitors.

Glycogen synthase kinase 3ß (GSK-3ß) is a widely investigated molecular target for numerous diseases including Alzheimer's disease, cancer, and diabetes mellitus. Inhibition of GSK-3ß activity has become an attractive approach for treatment of diabetes and cancer. We report the discovery of novel GSK-3ß inhibitors of 3-arylidene-2-oxindole scaffold with promising activity. The most potent compound 3a inhibits GSK-3ß with IC50 4.19 nM. In a cell-based assay 3a shows no significant leucocyte toxicity at 10 µM and is moderately cytotoxic against A549 cells. Compound 3a demonstrated high antidiabetic efficacy in obese streptozotocin-treated rats improving glucose tolerance at a dose of 50 mg/kg body weight thus representing an interesting lead for further optimization.

Oxindole-based intraocular pressure reducing agents.

The study represents the new findings at the crossroads of chemistry and medicine, particularly between medicinal and organic chemistry and ophthalmology. In this work we describe how the chemical reactivity of indolinone scaffold may be used to create small molecule ligands with strong biological response comparable with and larger than that of endogenous hormone. The synthesis of oxindole-based melatonin and 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT) analogues was proposed and their ability to influence intraocular pressure (IOP) was studied in vivo. Time-dependent study revealed the prolonged effect (more than 6h) of the lead-compound. This effect in combination with high IOP reducing effect (41±6%) in low concentrations of the active compound (0.1wt%) and with high water solubility represents a great potential of low-cost oxindole derivatives as potent antiglaucoma agents.

Design, synthesis, and biological evaluation of oxindole derivatives as antidepressive agents.

The 3-substituted oxindole derivatives were designed, synthesized, and evaluated for antidepressant activity by employing forced swimming test, tail suspension test, and MAO-A inhibition assay. Results of biological studies revealed that the majority of compounds exhibited potent to moderately potent activity and among them, 12 displayed potency comparable to that of the imipramine with %DID of 37.95 and 44.84 in the FST and TST, respectively. At the same time, imipramine showed %DID of 43.62 and 50.64 in the FST and TST, correspondingly. In the MAO-A inhibition assay, 12 showed an IC50 of 18.27 µmol, whereas the reference drug moclobemide displayed an IC50 of 13.1 µmol. The SAR study disclosed that the presence of bromo atom at the phenyl/furanyl or thienyl moiety in the oxindole derivatives was critical for the antidepressant activity.

3D QSAR based design of novel oxindole derivative as 5HT7 inhibitors.

To understand the structural requirements of 5-hydroxytryptamine (5HT7) receptor inhibitors and to design new ligands against 5HT7 receptor with enhanced inhibitory potency, a three-dimensional quantitative structure-activity relationship study with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) for a data set of 56 molecules consisting of oxindole, tetrahydronaphthalene, aryl ketone substituted arylpiperazinealkylamide derivatives was performed. Derived model showed good statistical reliability in terms of predicting 5HT7 inhibitory activity of the molecules, based on molecular property fields like steric, electrostatic, hydrophobic, hydrogen bond donor and hydrogen bond acceptor fields. This is evident from statistical parameters like conventional r2 and a cross validated (q2) values of 0.985, 0.743 for CoMFA and 0.970, 0.608 for CoMSIA, respectively. Predictive ability of the models to determine 5HT7 antagonistic activity is validated using a test set of 16 molecules that were not included in the training set. Predictive r2 obtained for the test set was 0.560 and 0.619 for CoMFA and CoMSIA, respectively. Steric, electrostatic fields majorly contributed toward activity which forms the basis for design of new molecules. Absorption, distribution, metabolism and elimination (ADME) calculation using QikProp 2.5 (Schrodinger 2010, Portland, OR) reveals that the molecules confer to Lipinski's rule of five in majority of the cases.

The protective role of two oxindole derivatives is mediated by modulating NLRP3/caspase-1 and PI3K/AKT pathways in a preclinical animal model of hepatic ischemia reperfusion injury.

Aim Hepatic ischemia reperfusion injury (HIRI) is a leading cause of mortality post liver transplantation, hypovolemic shock and trauma. In this study, we tested, on molecular bases, the possible protective role of two different derivatives of 2-oxindole in a preclinical model of HIRI in rats. MAIN METHODS: HIRI was operated in male Wistar albino rats and prophylactic treatment with oxindole-curcumin (Coxi) or oxindole-vanillin (Voxi) was carried out before the operation. The biochemical and histopathological investigations, in addition to the mechanistic characterizations of the effect of the tested drugs were performed. KEY FINDINGS: HIRI was assured with elevated liver enzymes and marked changes in histopathological features, inflammatory response and oxidative stress. Pretreatment with Coxi and Voxi improved the hepatic histopathological alterations, reduced the elevated serum liver enzymes level and hepatic Malondialdehyde (MDA) content, increased the hepatic Superoxide Dismutase (SOD) activity and reduced Glutathione (GSH) content, downregulated the expression of TNF-α, IL-6, Nod-Like Receptor p3 (NLRP3), Cleaved caspase1, Cleaved caspase 3 proteins, alongside the expression level of IL-1ß, ICAM-1, VCAM-1 and BAX genes, attenuated NF-кB p-P65 Ser536 and Myeloperoxidase (MPO)-positive neutrophils, and activated the PI3K/AKT pathway. SIGNIFICANCE: Coxi and Voxi have promising hepatoprotective activity against HIRI in rats through ameliorating the biochemical and histopathological alterations, attenuating inflammatory and oxidative stress status by modulating the inflammatory TNF-α/ICAM-1, the pyroptosis NLRP3/Caspase-1, and the antioxidant PI3K/AKT pathways.

3-aryl-indolinones derivatives as antiplasmodial agents: synthesis, biological activity and computational analysis.

Malaria is an infectious illness, affecting vulnerable populations in Third World countries. Inspired by natural products, indole alkaloids have been used as a nucleus to design new antimalarial drugs. So, eighteen oxindole derivatives, aza analogues were obtained with moderate to excellent yields. Also, the saturated derivatives of oxindole and aza derivatives via H2/Pd/C reduction were obtained in good yields, leading to racemic mixtures of each compound. Next, the inhibitory activity against P. falciparum of 18 compounds were tested, founding six compounds with IC50 < 20 µM. The most active of these compounds was 8c; however, their unsaturated derivative 7c was inactive. Then, a structure-activity relationship analysis was done, founding that focused LUMO lobe on the specific molecular zone is related to inhibitory activity against P. falciparum. Finally, we found a potential inhibition of lactate dehydrogenase by oxindole derivatives, using molecular docking virtual screening.

Structural insights of oxindole based kinase inhibitors as anticancer agents: Recent advances.

Small-molecule kinase inhibitors are being continuously explored as new anticancer therapeutics. Kinases are the phosphorylating enzymes which regulate numerous cellular functions such as proliferation, differentiation, migration, metabolism, and angiogenesis by activating several signalling pathways. Kinases have also been frequently found to be deregulated and overexpressed in cancerous tissues. Therefore, modulating the kinase activity by employing small molecules has emerged as a strategic approach for cancer treatment. On the other hand, oxindole motifs have surfaced as privileged scaffolds with significant multi-kinase inhibitory activity. The present review summarises recent advances in the development of oxindole based kinase inhibitors. The role of distinguished structural frameworks of oxindoles, such as 3-alkenyl oxindoles, spirooxindoles, 3-iminooxindoles and similar hydrazone derivatives have been described based on their kinase inhibition potential. Furthermore, the design strategies, mechanism of actions, structure activity relationships (SARs) and their mode of interaction with target protein have been critically highlighted.

In silico approach: docking study of oxindole derivatives against the main protease of COVID-19 and its comparison with existing therapeutic agents.

OBJECTIVES: Presently, the pandemic of COVID-19 has worsened the situation worldwide and received global attention. The United States of America have the highest numbers of a patient infected by this disease followed by Brazil, Russia, India and many other countries. Moreover, lots of research is going on to find out effective vaccines or medicine, but still, no potent vaccine or drug is discovered to cure COVID-19. As a consequence, many types of research have designated that computer-based studies, such as protein-ligand interactions, structural dynamics, and chembio modeling are the finest choice due to its low cost and time-saving features. Here, oxindole derivatives have been chosen for docking because of their immense pharmacological applications like antiviral, antidiabetic, anti-inflammatory, and so on. Molecular docking of 30 oxindole derivatives done on the crystallized structure of the protein (COVID-19 Mpro). METHODS: The process of docking, interaction, and binding the structure of ligand with protein has executed using Molegro Virtual Docker v.7.0.0 (MVD) and visualized the usage by Molegro Molecular Viewer v.7.0.0 (MMV). RESULTS: Among the 30 derivatives, the outcomes depicted better steric interaction and hydrogen bonding amongst OD-22 ligand, OD-16 ligand, OD-4 ligand, and OD-9 ligand (oxindole derivatives) with COVID-19. In addition to this, the comparative study of these four compounds with existing drugs that are under clinical trials shows comparatively good results in terms of its MolDock scores, H-bonding and steric interactions. CONCLUSIONS: Hence, It is proposed that these four oxindole derivatives have good potential as a new drug against coronavirus as possible therapeutic agents.

Synthesis and antiproliferative and apoptosis-inducing activity of novel 3-substituted-3-hydroxy-2-oxindole compounds.

Anticancer role of oxindole compounds is well documented. Here, we synthesized new derivatives of 3-hydroxy-2-oxindole functionalized at position 3 (1a-f) which are expected to have antiproliferative activity in cancer cells. Human prostate cancer cell line (DU145) was treated with the synthesized derivatives at 40-µM concentration for 24, 48, and 72 h. Compounds 1-ethyl-3-hydroxy-1,1',3,3'-tetrahydro-2H,2'H-3,3'-biindole-2,2'-dione (1d), 5-bromo-1-ethyl-3-hydroxy-1,1',3,3'-2H,2'H-3,3'-biindole-2,2'-dione (1e), and 5-chloro-1-ethyl-3-hydroxy-1,1',3,3'-tetrahydro-2H,2'H-3,3'-biindole-2,2'-dione (1f) were found to significantly reduce DU145 cell viability at 48 and 72 h whereas no significant changes were observed up to 24 h. The compounds 1e and 1f showed the most cytotoxicity effect and had a similar antiproliferative activity on DU145 cell line. They have halogen and ethyl substitutions at positions 5 and 1, respectively. The IC50 of compound 1e for DU145 and A375 cells at 48 h was determined. The apoptotic effects and cell cycle progression of compound 1e at 1/2 × IC50 (55 µM) concentration in DU145 cells were investigated by nuclei staining, comet assay, flow cytometry, and scanning electron microscopy (SEM). The results obtained showed that this compound increased the percentage of tail DNA, increased the occurrence of the sub-G1 phase, and induced G2M arrest and apoptosis in DU145 cells after exposure for 48 h to a 55-µM concentration. The SEM images revealed cell contraction at 24 h, cell condensation, plasma membrane blebbing, and formation of apoptotic bodies at 48 and 72 h. These observations suggest that the antiproliferative activity of compound 1e may be to induce apoptosis in DU145 cells.

Design, synthesis and biological evaluation of 3-substituted-2-oxindole hybrid derivatives as novel anticancer agents.

The 2-oxindole nucleus is the central core to develop new anticancer agents and its substitution at the 3-position can effect antitumor activity. Utilizing a pharmacophore hybridization approach, a novel series of antiproliferative agents was obtained by the modification of the structure of 3-substituted-2-oxindole pharmacophore by the attachment of the α-bromoacryloyl moiety, acting as a Michael acceptor, at the 5-position of 2-oxindole framework. The impact of the substituent at the 3-position of 2-oxindole core on the potency and selectivity against a panel of seven different cancer cell lines was examined. We found that these hybrid molecules displayed potent antiproliferative activity against a panel of four cancer cell lines, with one-to double digit nanomolar 50% inhibitory concentrations (IC50). A distinctive selective antiproliferative activity was obtained towards CCRF-CEM and RS4; 11 leukemic cell lines. In order to study the possible mechanism of action, we observed that the two most active compounds namely 3(E) and 6(Z) strongly induce apoptosis that follow the mitochondrial pathway. Interestingly a decrease of intracellular reduced glutathione content (GSH) and reactive oxygen species (ROS) production was detected in treated cells compared with controls suggesting that these effects may be involved in their mechanism of action.

1,3-Dipolar Cycloaddition Reactions for the Synthesis of Novel Oxindole Derivatives and Their Cytotoxic Properties.

The multicomponent reaction between isatin, amino acid, but-2-ynedioates, and phenacyl bromide has been developed using microwave irradiation under catalyst and base-free conditions in aqueous medium. This synthetic protocol is useful for the synthesis of various functionalized spirooxindole derivatives. This MCR exhibits a broad substrate scope with excellent yields and shorter reaction time. Additionally the synthesized spirooxindole derivatives were evaluated for their anticancer activity against three human cancer cell lines: MCF-7 (breast), A549 (lung), and HeLa cervical. Most of the compounds showed moderate to potent cytotoxic activity against the tested cell lines.

Locking PDK1 in DFG-out conformation through 2-oxo-indole containing molecules: Another tools to fight glioblastoma.

The phosphoinositide-dependent kinase-1 (PDK1) is one of the main components of the PI3K/Akt pathway. Also named the "master kinase" of the AGC family, PDK1 plays a critical role in tumorigenesis, by enhancing cell proliferation and inhibiting apoptosis, as well as in cell invasion and metastasis formation. Although there have been done huge efforts in discovering specific compounds targeting PDK1, nowadays no PDK1 inhibitor has yet entered the clinic. With the aim to pick out novel and potent PDK1 inhibitors, herein we report the design and synthesis of a new class of molecules obtained by merging the 2-oxo-indole nucleus with the 2-oxo-pyridonyl fragment, two moieties with high affinity for the PDK1 hinge region and its DFG-out binding site, respectively. To this purpose, a small series of compounds were synthesised and a tandem application of docking and Molecular Dynamic (MD) was employed to get insight into their mode of binding. The OXID-pyridonyl hybrid 8, possessing the lower IC50 (IC50 = 112 nM), was also tested against recombinant kinases involved in the PI3K/PDK1/Akt pathway and was subjected to vitro studies to evaluate the cytotoxicity and the inhibition of tumour cell migration. All together the results let us to consider 8, as a lead compound of a new generation of PDK1 inhibitors and encourage us to further studies in this direction.

Design and synthesis of 2-oxindole based multi-targeted inhibitors of PDK1/Akt signaling pathway for the treatment of glioblastoma multiforme.

Aggressive behavior and diffuse infiltrative growth are the main features of Glioblastoma multiforme (GBM), together with the high degree of resistance and recurrence. Evidence indicate that GBM-derived stem cells (GSCs), endowed with unlimited proliferative potential, play a critical role in tumor development and maintenance. Among the many signaling pathways involved in maintaining GSC stemness, tumorigenic potential, and anti-apoptotic properties, the PDK1/Akt pathway is a challenging target to develop new potential agents able to affect GBM resistance to chemotherapy. In an effort to find new PDK1/Akt inhibitors, we rationally designed and synthesized a small family of 2-oxindole derivatives. Among them, compound 3 inhibited PDK1 kinase and downstream effectors such as CHK1, GS3Kα and GS3Kß, which contribute to GCS survival. Compound 3 appeared to be a good tool for studying the role of the PDK1/Akt pathway in GCS self-renewal and tumorigenicity, and might represent the starting point for the development of more potent and focused multi-target therapies for GBM.