Synthesis, Characterization, and Antibacterial Activity of New Isatin Derivatives.

1H-indol-2,3-dione (isatin) class of biologically active compounds have analgesic, anti-microbial, anti-inflammatory, anti-tubercular, anti-proliferative properties, and is also useful for the treatment of SARS-CoV. Schiff bases containing isatin moiety are known to have broad spectrum of biological activities like anti-viral, anti-tubercular, anti-fungal, and anti-bacterial. In this work, several Schiff base derivatives have been synthesized using two methods (synthetic and microwave) by reacting isatin with o-phenylenediamine. The synthesized compounds were structurally characterized and their in-vivo antimicrobial activity was tested against Gram-negative and Gram-positive bacteria using the inhibition zone method. Several newly synthesized isatin derivatives were found effective as antimicrobial agents and showed good potency (compounds 3c, 3d, 6a, 6b, 6d). Compound 3c displayed higher antimicrobial activity than standard drug (Amoxicillin) against Staphylococcus aureus at higher concentration (16 µg/mL) and against Escherichia coli at lower concentration (1 µg/mL).

QSAR and molecular docking studies of isatin and indole derivatives as SARS 3CLpro inhibitors.

The 3C-like protease (3CLpro), known as the main protease of SARS-COV, plays a vital role in the viral replication cycle and is a critical target for the development of SARS inhibitor. Comparative sequence analysis has shown that the 3CLpro of two coronaviruses, SARS-CoV-2 and SARS-CoV, show high structural similarity, and several common features are shared among the substrates of 3CLpro in different coronaviruses. The goal of this study is the development of validated QSAR models by CORAL software and Monte Carlo optimization to predict the inhibitory activity of 81 isatin and indole-based compounds against SARS CoV 3CLpro. The models were built using a newer objective function optimization of this software, known as the index of ideality correlation (IIC), which provides favorable results. The entire set of molecules was randomly divided into four sets including: active training, passive training, calibration and validation sets. The optimal descriptors were selected from the hybrid model by combining SMILES and hydrogen suppressed graph (HSG) based on the objective function. According to the model interpretation results, eight synthesized compounds were extracted and introduced from the ChEMBL database as good SARS CoV 3CLpro inhibitor. Also, the activity of the introduced molecules further was supported by docking studies using 3CLpro of both SARS-COV-1 and SARS-COV-2. Based on the results of ADMET and OPE study, compounds CHEMBL4458417 and CHEMBL4565907 both containing an indole scaffold with the positive values of drug-likeness and the highest drug-score can be introduced as selected leads.

Isatin derivatives as broad-spectrum antiviral agents: the current landscape.

In recent decades, several viruses have resulted in large outbreaks with serious health, economic and social consequences. The current unprecedented outbreak of the new coronavirus, SARS-COV-2, necessitates intensive efforts for delivering effective therapies to eradicate such a deadly virus. Isatin is an opulent heterocycle that has been proven to provide tremendous opportunities in the area of drug discovery. Over the last fifty years, suitably functionalized isatin has shown remarkable and broad-spectrum antiviral properties. The review herein is an attempt to compile all of the reported information about the antiviral activity of isatin derivatives with an emphasis on their structure-activity relationships (SARs) along with mechanistic and molecular modeling studies. In this regard, we are confident that the review will afford the scientific community a valuable platform to generate more potent and cost-effective antiviral therapies based on isatin templates.

Synthesis, characterization, theoretical study and molecular docking studies of some new cobalt(II), chromium(II) and nickel (II) complexes

Three transition metal complexes with general formula [M(L)(2)] (Co = (1), Cr = (2) and Ni = (3)), were synthesized by treating CoCl2/CrCl3 center dot 6H(2)O/NiCl2 center dot 6H(2)O with an ONS-donor Schiff base ligand (HL) derived from the condensation of 3,5-Diiodosalicylaldehyde and 4,4-Dimethyl-3-thiosemicarbazide. The geometry around the centre metal ions was octahedral as revealed by the data collection from spectroscopic studies. The newly synthesized compounds were fully characterized by various physicochemical and spectroscopic methods. DFT calculations were performed on the compounds to get a structure-property relationship. Some global reactivity descriptors like chemical potential (mu), electronegativity (chi), hardness (eta) and electrophilicity index (omega) were also evaluated using DFT method. The ADMET prediction analyses have been explored. Molecular dynamics simulations were also studied. Besides this, to find a potential inhibitor for anti-SARS-CoV-2, metal complexes are also assessed through molecular docking and 3-D visualizations of intermolecular interactions against main protease (M-pro) of SARS-CoV-2 (PDB ID: 7JKV). The molecular docking calculations of the complex (1) into the main protease of SARS-CoV-2 virus (PDB ID: 7JKV) revealed the binding energy of -7.2 kcal/mol with an inhibition constant of 2.529 mu M at inhibition binding site of receptor protein. Complex (2) with SARS-CoV-2 resulted in the binding energy of -7.8 kcal/mol and the inhibition constant of 5.231 mu M. Similarly, complex (3) with SARS-CoV-2 (PDB ID: 7JKV) exhibited the binding energy and the inhibition constant of -7.5 kcal/mol and 3.585 mu M respectively at inhibition binding site of receptor protein. Overall, in silico studies explored the potential role of metal complexes, which would offer new drug candidates against SARS-CoV-2.

Insighting isatin derivatives as potential antiviral agents against NSP3 of COVID-19.

The world is now facing intolerable damage in all sectors of life because of the deadly COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2. The discovery and development of anti-SARS-CoV-2 drugs have become pragmatic in the time needed to fight against this pandemic. The non-structural protein 3 is essential for the replication of transcriptase complex (RTC) and may be regarded as a possible target against SARS-CoV-2. Here, we have used a comprehensive in silico technique to find potent drug molecules against the NSP3 receptor of SARS-CoV-2. Virtual screening of 150 Isatin derivatives taken from PubChem was performed based on their binding affinity estimated by docking simulations, resulting in the selection of 46 ligands having binding energy greater than -7.1 kcal/mol. Moreover, the molecular interactions of the nine best-docked ligands having a binding energy of ≥ -8.5 kcal/mol were analyzed. The molecular interactions showed that the three ligands (S5, S16, and S42) were stabilized by forming hydrogen bonds and other significant interactions. Molecular dynamic simulations were performed to mimic an in vitro protein-like aqueous environment and to check the stability of the best three ligands and NSP3 complexes in an aqueous environment. The binding energy of the S5, S16, and S42 systems obtained from the molecular mechanics Poisson-Boltzmann surface area also favor the system's stability. The MD and MM/PBSA results explore that S5, S16, and S42 are more stable and can be considered more potent drug candidates against COVID-19 disease. Supplementary Information: The online version contains supplementary material available at 10.1007/s11696-022-02298-7.

Sequential Nucleophilic Addition and Regioselective Ring-Expansion Reactions of α-Diazophosphonates with Isatins: Access to 4-Phosphonylated-3-hydroxyquinolin-2(1H)-ones

A sequential protocol of α-diazophosphonates with isatins to access a series of α-diazo-β-hydroxyphosphonate derivatives via the inorganic base catalysis was reported. The resulting α-diazo-β-hydroxyphosphonates could then be readily transformed to 4-phosphonylated-3-hydroxyquinolin-2(1H)-ones with moderate to excellent yields through a catalyst-free regioselective ring-expansion rearrangement. Control experiment demonstrates that intramolecular cyclization pathway is more reasonable for the ring-expansion process. In addition, a benzo[b]thiophene-derived isatin featured with the inhibition of SARS-CoV Mpro was also suitable for this transformation and generated the corresponding scaffolds with potential anti-virus activities for further development. © 2022 Wiley-VCH GmbH.

One-Pot Synthesis and Molecular Modeling Studies of New Bioactive Spiro-Oxindoles Based on Uracil Derivatives as SARS-CoV-2 Inhibitors Targeting RNA Polymerase and Spike Glycoprotein.

The first outbreak in Wuhan, China, in December 2019 was reported about severe acute coronaviral syndrome 2 (SARS-CoV-2). The global coronavirus disease 2019 (COVID-19) pandemic in 2020 resulted in an extremely high potential for dissemination. No drugs are validated in large-scale studies for significant effectiveness in the clinical treatment of COVID-19 patients, despite the worsening trends of COVID-19. This study aims to design a simple and efficient cyclo-condensation reaction of 6-aminouracil derivatives 2a-e and isatin derivatives 1a-c to synthesize spiro-oxindoles 3a-d, 4a-e, and 5a-e. All compounds were tested in vitro against the SARS-CoV-2. Four spiro[indoline-3,5'-pyrido[2,3-d:6,5-d']dipyrimidine derivatives 3a, 4b, 4d, and 4e showed high activities against the SARS-CoV-2 in plaque reduction assay and were subjected to further RNA-dependent-RNA-polymerase (RdRp) and spike glycoprotein inhibition assay investigations. The four compounds exhibited potent inhibitory activity ranging from 40.23 ± 0.09 to 44.90 ± 0.08 nM and 40.27 ± 0.17 to 44.83 ± 0.16 nM, respectively, when compared with chloroquine as a reference standard, which showed 45 ± 0.02 and 45 ± 0.06 nM against RdRp and spike glycoprotein, respectively. The computational study involving the docking studies of the binding mode inside two proteins ((RdRp) (PDB: 6m71), and (SGp) (PDB: 6VXX)) and geometrical optimization used to generate some molecular parameters were performed for the most active hybrids.

Theoretical molecular properties prediction, docking and antimicrobial studies on Anisidine-Isatin Schiff bases

The continuous intake of a specific antibiotic for diseases is continuously reducing the immunity of the human in course of time, which includes Covid-19 treatment. Recent research on Schiff bases shows the promising biological activities and good antibacterial results. In this study, three Schiff bases with lactam ring using isatin and three different anisidines in presence of acetic acid were synthesized and characterized. Drug likeness was examined using Molsoft and docking against the target proteins such as 5J6R, 3L9L, 5HVY, covid main protease and 3ZBO proteins for drug suitability. The experimental antibacterial activity against Gram-positive strains like Staphylococcus aureus, Bacillus subtilis and Staphylococcus epidermidis. Among the synthesized compounds, three Schiff bases ortho and meta substituted compounds exhibited good results when compared to para compound, where the methoxyl group position effect was observed. © 2021 Chemical Publishing Co.. All rights reserved.

Isatin-based virtual high throughput screening, molecular docking, DFT, QM/MM, MD and MM-PBSA study of novel inhibitors of SARS-CoV-2 main protease.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a rapidly growing health care emergency across the world. One of the viral proteases called main protease or Mpro, plays a crucial role in the replication of SARS-CoV-2. As the structure of Mpro of SARS-CoV-2 is similar to the Mpro of SARS-CoV-1 (responsible for SARS outbreak between 2002 and 2004), we hypothesize that the inhibitors of SARS-CoV-1 Mpro can also inhibit the Mpro of SARS-CoV-2. To test this hypothesis, a total of 79 isatin derivatives, which inhibited Mpro activity under in vitro conditions, were selected from the literature, and then screened through AutoDock Vina. The chemical features of the top 5 isatin derivatives with low binding energies (-8.5 to -8.2 kcal/mol) were used to screen similar types of compounds from several small-molecule libraries containing 15856508 compounds. A total of 1,609 compounds with similarity score ≥ 6 were screened and then subjected to docking as well as ADME analysis. Among the compounds screened, 4 ligands form Zinc drug-like library (ZINC000008848565, ZINC000009513563, ZINC000036759789 and ZINC000046053855) showed good ADMET properties, low binding energy (-8.4 to -8.6 kcal/mol), low interaction energy (-72.62 to -50.01 kcal/mol) and high structural stability with Mpro. Hence, the selected ligands might serve as the lead candidates for further wet laboratory validation, optimization and development.Communicated by Ramaswamy H. Sarma.

In silico evaluation of isatin-based derivatives with RNA-dependent RNA polymerase of the novel coronavirus SARS-CoV-2.

Isatin (1H-indole-2,3-dione)-containing compounds have been shown to possess several remarkable biological activities. We had previously explored a few isatin-based imidazole derivatives for their predicted dual activity against both inflammation and cancer. We explored 47 different isatin-based derivatives (IBDs) for other potential biological activities using in silico tools and found them to possess anti-viral activity. Using AutoDock tools, the binding site, binding energy, inhibitory constant/Ki and receptor-ligand interactions for each of the compounds were analyzed against SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). The partition coefficient (logP) values were predicted using MedChem Designer tool. Based on the best Ki, binding energy and the ideal range of logP (between 1.0 and 3.0), 10 out of total 47 compounds were deemed to be prospective RdRp inhibitors. Some of these compounds gave better Ki, binding energy and logP values when compared to standard RdRp inhibitors, such as remdesivir (REM) (Ki = 15.61 µM, logP = 2.2; binding energy = -6.95), a clinically approved RdRp inhibitor and nine other RdRp inhibitors. The results showed that the 10 selected IBDs could be further explored. Molecular dynamics simulations (MDSs) showed that the selected RdRp-IBD complexes were highly stable compared to the native RdRp and RdRp-REM complex during 100 ns time periods. DFT studies were performed for the compounds 16a, 24a, 28a, 38a and 40a, to evaluate the charge transfer mechanism for the interactions between the IBDs and the RdRp residues. Among these, ADME profiling revealed that 28a is a possible lead compound which can be explored further for anti-RdRp activity in vitro. Communicated by Ramaswamy H. Sarma.

Advances in Synthesis, Derivatization and Bioactivity of Isatin: A Review.

BACKGROUND: Isatin (IST) is a crucial pharmacologically active compound, chemically known as indole- 1H-2,3-dione. Development of different IST based analogues acquired significant awareness because of its pronounced therapeutic importance such as analgesic, anticancer, anti-inflammatory, antitubercular, antimicrobial, antifungal, antiviral (effective against SARS coronavirus 3C protease) and many other activities, and represents an important class of heterocyclic compounds that can be used as a precursor for the synthesis of many useful drugs. OBJECTIVE: Previously, many articles were reported on IST synthesis and its different pharmacological activities but herein, we mentioned 59 different synthesis schemes of several IST derivatives/hybrids derived from the substitution of the nitrogen, aromatic ring, the second and third position of IST along with most potent molecule among each of synthesized libraries with their structural activity relationship (SAR). Using these standardized approaches, several biologically important compounds were developed like sunitinib, nintedanib, indirubin, etc and several studies have been carried out nowadays to develop newer compounds having fewer side effects and also overcome the problem of resistance. CONCLUSION: This report critically reviews the different strategies for the designs and synthesis of several IST based compounds having different biological activities with SAR, which can favour further investigation and modification for the development of new and more potent entities.

Potent inhibitors of SARS-CoV-2 3C-like protease derived from N-substituted isatin compounds.

SARS-CoV-2 3C-like protease is the main protease of SARS-CoV-2 and has been considered as one of the key targets for drug discovery against COVID-19. We identified several N-substituted isatin compounds as potent SARS-CoV-2 3C-like protease inhibitors. The three most potent compounds inhibit SARS-CoV-2 3C-like protease with IC50's of 45 nM, 47 nM and 53 nM, respectively. Our study indicates that N-substituted isatin compounds have the potential to be developed as broad-spectrum anti-coronavirus drugs.