Isatin Derivatives Research Articles

Probing the biological activity of isatin derivatives against human lung cancer A549 cells: Cytotoxicity, CT-DNA/BSA binding, DFT/TD-DFT, topology, ADME-Tox, docking and dynamic simulations

Probing the biological activity of isatin derivatives against human lung cancer A549 cells: Cytotoxicity, CT-DNA/BSA binding, DFT/TD-DFT, topology, ADME-Tox, docking and dynamic simulations

Pd-Catalyzed asymmetric allylic amination with isatin using a P,olefin-type chiral ligand with C-N bond axial chirality.

In this study, we implemented the P,olefin-type chiral ligand (aR)-(-)-6, which contains a cyclohexyl group and a cinnamoyl group on the nitrogen atom, in the Pd-catalyzed asymmetric allylic amination of allylic esters with isatin derivatives 11 as nucleophiles. The reaction proceeds efficiently, yielding the products (S)-13 with good-to-high enantioselectivity. A scale-up reaction was also successfully conducted at a 1 mmol scale. Additionally, when malononitrile was added to the resulting product (S)-13a in the presence of FeCl3 as the catalyst, the corresponding malononitrile derivative (S)-16 was obtained without any loss in optical purity.

3,3-Bis(hydroxyaryl)oxindoles and Spirooxindoles Bearing a Xanthene Moiety: Synthesis, Mechanism, and Biological Activity.

A facile and efficient methanesulfonic acid-catalyzed, solvent-free, microwave-assisted method was developed for the synthesis of biologically active 3,3-bis(hydroxyaryl)oxindoles and spirooxindoles bearing a xanthene moiety. The scope of the procedure was investigated with a wide range of isatin and phenol derivatives; moreover, the reaction mechanism was studied by density functional theory calculations. Both 3,3-bis(hydroxyaryl)oxindoles and spirooxindoles bearing a xanthene moiety synthesized were evaluated for their anticancer and antimicrobial activity, and most of them showed promising or significant activity on six cancer cell lines and against Gram-positive bacteria.

Synthesis of novel spiro[chromeno[2,3-d][1,3,4]thiadiazolo[3,2-a] pyrimidines via an isatin-based three-component reaction

This study presents an efficient and sustainable method for the synthesis of novel spiro[chromeno[2,3-d][1,3,4]thiadiazolo[3,2-a]pyrimidine-10,3′-indoline]-2′,9,11-trione derivatives via a three-component condensation reaction is introduced. The reaction involves dimedone, 5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-5,7(6 H)-dione, and isatin derivatives, catalyzed by the economical and highly effective Keggin heteropolyacid (H₃PW₁₂O₄₀). This protocol achieves (70–90%) yields within relatively short reaction times under mild and solvent-free conditions. Using a green, cost-effective catalyst highlights the method’s practicality and potential for broader applications in synthetic organic chemistry, offering an attractive route for spiro oxindole derivative synthesis.

From Structure to Function: Isatin Derivatives as a Promising Class of Antiviral Agents.

A range of heterocyclic compounds, including Isatin (oneH-indole-2, 3-dione) and its by-products, have been shown to represent potential unit blocks in the synthesis of potential medicinal agents. Numerous studies have been carried out on isatin, its synthesis, biological uses, and its chemical composition since when it was discovered. Functionally, these isatin-containing heterocycles have demonstrated antibacterial, antidiabetic, antiviral, antitubercular, and anticancer properties, among many others. In vitro and In vivo efficaciousness of several Isatin moieties has been assessed in recent years based on their antimicrobial qualities. Isatin has shown great promise as a flexible heterocycle in the realm of drug development in recent years. Many viruses have caused extensive epidemics during the last 50 years, which have had detrimental effects on social, economic, and health conditions. The current unprecedented SARS-CoV-2 epidemic necessitates intensive research into the development of potent antiviral medications. It has been shown that Isatin, a flexible heterocycle, has a great deal of potential for drug development. Appropriately functionalized Isatin compounds have shown noteworthy and extensive antiviral activities throughout the last fifty years. The goal of this study is to gather all known data on Isatin derivatives' antiviral activity, emphasizing their structure-activity correlations as well as research on mechanistic and molecular modelling. We think that the scientific community will find this review to be a useful tool in the development of more efficient and powerful antiviral treatments based on Isatin scaffolds.

The Isatin Scaffold: Exceptional Potential for the Design of Potent Bioactive Molecules

Since its discovery, the isatin scaffold has been recognized for its significance, but it gained particular attention after being isolated from natural sources and identified as a natural product. This discovery prompted extensive research into its synthesis, as well as its chemical and biological applications. The isatin scaffold undergoes several key chemical reactions, including oxidation, reduction, ring expansion, Friedel-Crafts reactions, and aldol condensation, resulting in the formation of biologically active compounds such as 2-oxindoles, tryptanthrin, indirubins, and others. In recent years, numerous derivatives of isatin, particularly those involving N-, C3-, and C5-positions, have been synthesized and investigated for their diverse biological activities, with some even receiving FDA approval as therapeutic agents. This account provides a concise overview of the isatin scaffold, highlighting its synthesis, reactivity, and structural features of the scaffold as well as those of its main derivatives, particularly their ability to engage in various non-covalent interactions. Finally, selected recent biological applications of isatin derivatives are discussed, with an emphasis on contributions from our own research group. The goal is to enhance the understanding of the isatin scaffold's potential as a platform for designing potent bioactive molecules, with an optimistic outlook on its future in drug development.

B(C6F5)3-Catalyzed Reductive Deoxygenation of Isatins for Indole Synthesis.

An efficient method for reductive deoxygenation of isatin derivatives using catalyst B(C6F5)3 and methylphenylsilane is described. This reaction proceeds rapidly under mild conditions, and the protocol provides a broad substrate scope. Notably, while general synthetic methods utilizing a combination of B(C6F5)3 and hydrosilanes smoothly reduce indoles to generate indolines, the present strategy represents the first reductive deoxygenation reaction for the formation of indoles without further reduction.

Isatin-modified Calixarene derivatives: A comprehensive study on synthesis, enzyme inhibition, antioxidant, antimicrobial, and Antiproliferative activities.

Isatin-modified Calixarene derivatives: A comprehensive study on synthesis, enzyme inhibition, antioxidant, antimicrobial, and Antiproliferative activities.

Synthesis and Evaluation of Thiazolidinone-Isatin Hybrids for Selective Inhibition of Cancer-Related Carbonic Anhydrases.

A small library of novel thiazolidinone-based sulfonamide derivatives was designed, synthesized and evaluated for their ability to target human carbonic anhydrase (hCA) isoforms IX and XII, which are overexpressed in malignant cells and play a key role in metastasis and therapeutic response of cancer cells. A molecular hybridization approach was employed to design the molecules by combining different moieties identified as having antitumor activity. The thiazolidinone core was functionalized with benzenesulfonamide as a zinc-binding group and different isatin derivatives to enhance the chemical profile and optimize the hydrophilic/lipophilic balance. Biological evaluation against hCA I, II, IX and XII isoforms showed promising inhibitory activities, and some compounds exhibited selectivity and high inhibitory activity against hCA IX and hCA XII while not affecting off-target hCA I and hCA II. In particular, compound 3h demonstrated high selectivity with Ki values of 57.8 nM for hCA IX and 44.3 nM for hCA XII.

Design and synthesis of isatin derivative payloaded peptide-drug conjugate as tubulin inhibitor against colorectal cancer.

Design and synthesis of isatin derivative payloaded peptide-drug conjugate as tubulin inhibitor against colorectal cancer.

Elucidating the Potential of Isatin Derivatives as Antimicrobial Agents: DFT Calculations and MD Simulations

Elucidating the Potential of Isatin Derivatives as Antimicrobial Agents: DFT Calculations and MD Simulations

An evaluation of spirooxindoles as blocking agents of SARS-CoV-2 spike/ACE2 interaction: synthesis, biological evaluation and computational analysis

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has gained significant public health attention owing to its devastating effects on lives and livelihoods worldwide. Due to difficult access to vaccines in many developing countries and the inefficiency of vaccines in providing complete protection even with fully vaccinated persons, there remains the need for the development of novel drugs to combat the disease. This study describes the in vitro activity of a library of fifty-five spiro-fused tetrahydroisoquinoline–oxindole hybrids (spirooxindoles) as potential blocking agents of the interaction between the SARS-CoV-2 viral spike and the human angiotensin-converting enzyme 2 (ACE2) receptor, essential for viral transmission. The synthesis was conducted by the Pictet-Spengler condensation of phenethylamine and isatin derivatives, while the screening against spike-ACE2 interaction was done using our previously described AlphaScreen fluorescent assay. The in vitro screening identified compound (11j) as the most active, showing a 50% inhibitory concentration (IC50) of 3.6 μM against SARS-CoV-2 spike/ACE2 interaction. Structure-activity relationships explained via molecular docking studies and the computation of binding free energy of each compound with respect to the spike/ACE2 protein-protein interaction showed that the most active compound possesses a bulky naphthyl group, which addresses voluminous hydrophobic regions of the ACE2 binding site and interacts with the hydrophobic residues of the target. Therefore, these compounds could be potentially useful in searching for SARS-CoV-2 spike/ACE2 interaction blocking agents.

In Vitro Enzymatic and Computational Assessments of Pyrazole-Isatin and Pyrazole-Indole Conjugates as Anti-Diabetic, Anti-Arthritic, and Anti-Inflammatory Agents.

Background/Objectives: Recently, the prevalence of diseases such as diabetes, arthritis, and inflammatory diseases, along with their complications, has become a significant health problem. This is in addition to the various biomedical applications of pyrazole, isatin, and indole derivatives. Accordingly, cooperation will continue between chemistry scientists, pharmaceutical scientists, and human doctors to produce hybrid compounds from pyrazole with isatin or indole possessing biological activities as anti-diabetic, anti-arthritic, and anti-inflammatory agents. Methods: The two series of pyrazole-isatin conjugates 12a-h and pyrazole-indole conjugates 14a-d were prepared from our previous works via the direct reaction of 5-amino-pyrazoles 10a-d with N-alkyl isatin 11a,b, and 1H-indole-3-carbaldehyde (13), respectively, using the previously reported procedure. The potential biological activities of 12a-h and 14a-d as anti-diabetic, anti-arthritic, and anti-inflammatory agents were assessed through estimated inhibition percentage (%) and the median inhibitory concentrations (IC50) using methods described in the literature. Further, the computational assessments of 12a-h and 14a-d such as toxic doses (the median lethal dose, LD50), toxicity classes, drug-likeness model scores (DLMS), molecular lipophilicity potential (MLP) maps, polar surface area (PSA) maps, and topological polar surface area (TPSA) values were predicted using available free websites. Results: The in vitro enzymatic assessment results showed that pyrazole-indole conjugate 14b possesses powerful activities against (i) α-amylase (% = 65.74 ± 0.23, IC50 = 4.21 ± 0.03 µg/mL) and α-glucosidase (% = 55.49 ± 0.23, IC50 = 2.76 ± 0.01 µg/mL); (ii) the protein denaturation enzyme (% = 49.30 ± 0.17) and against the proteinase enzyme (% = 46.55 ± 0.17) with an IC50 value of 6.77 ± 0.01 µg/mL; (iii) the COX-1, COX-2, and 5-LOX enzymes with an IC50 of 5.44 ± 0.03, 5.37 ± 0.04, and 7.52 ± 0.04, respectively, which is almost close to the IC50 of the indomethacin and zileuton drugs. Also, the computational assessment results showed (i) the conjugate 14b possesses lipophilic surface properties thus can cross cell membranes, and is effective for treatment; (ii) all the conjugates possess a TPSA value of more than 140 Å2 thus possess good intestinal absorption. Conclusions: The two series of pyrazole-isatin conjugates 12a-h and pyrazole-indole conjugates 14a-d were synthesized from our previous works. The results of these in vitro enzymatic and computational assessments concluded that the pyrazole-indole conjugate 14b possesses powerful activities against various studied enzymes and possesses good computational results. In the future, our research team will present in vitro, in vivo biological, and computational assessments to hopefully obtain effectual agents such as anti-diabetic, anti-arthritic, and anti-inflammatory.

Synthesis of Polyfunctional Indazoles via Novel Rearrangement of Isatin Derivatives

AbstractIn this work we present a new method for indazole synthesis through the unexpected rearrangement of various 7‐nitroisatins during the reaction with hydrazine hydrate. The new pyrazole cycle is formed via direct metal‐free C−H amination. We demonstrate the limitations of the discovered approach and several accessible methods for functionalization of the compounds to obtain novel indazole derivatives.

CsCF3B(OMe)3: A Versatile Nucleophilic Source of the Trifluoromethyl Anion

AbstractWe have identified cesium trimethoxy(trifluoromethyl)borate [CsCF3B(OMe)3] as a nucleophilic source for the trifluoromethylation of carbonyl compounds. A differentiating characteristic of CsCF3B(OMe)3 is its heightened reactivity in ethereal solvents compared to its potassium analogue, which is typically employed in dimethylformamide. Also, in contrast to the extensively studied Ruppert–Prakash reagent (TMSCF3), CsCF3B(OMe)3 does not require the addition of an exogenous activator. Described herein, we detail the synthesis of CsCF3B(OMe)3 and demonstrate its efficacy in trifluoromethylation across various scaffolds, including methyl ketones, isatin derivatives, and 1,2-acyclic dicarbonyls.

Synthetic Strategies for the Development of Novel Heterocycles as Larvicides Targeting Aedes aegypti Linn.

Owing to their extensive utilization as pesticides, heterocycles assume a fundamental role in the management of vector-borne diseases. Despite the presence of numerous heterocyclic compounds in commercial insecticides and larvicides, resistance to pesticides still demands novel strategies to current pest control methods. Considering these facts, this review aims to survey the synthesis and SAR of heterocyclic molecules with larvicidal activity against Aedes aegypti Linn. Comprehensive searches across the major databases were conducted to identify heterocyclic compounds exhibiting larvicidal efficacy against Ae. aegypti with the goal to unveil the main characteristics that are essential for exhibiting larvicidal activity. Active compounds display LC50 values varying from 0.36 to 2907 μM. Fifteen heterocyclic compounds displayed larvicidal activities below 20 μM. Five-membered ring molecules containing nitrogen and oxygen have displayed larvicidal activity according to the position of heteroatoms in the ring. Molecules bearing 1,2,4-oxadiazole and 1,2-oxazole moieties have been shown to be more active than 1,3,4-oxadiazole derivatives. Compounds possessing the indole scaffold have proven to be more potent than isatin and pyrimidine derivatives. Structural characteristics other than a heterocyclic moiety, such as the presence of halogens and less ionized and polar molecules, may also play a role in determining the final larvicidal activity. The rationale behind this review is to stimulate the discovery of innovative heterocyclic larvicides. Thus, it is important to continue synthesizing new scaffolds to comprehensively elucidate the structure-activity relationship for each heterocyclic moiety outlined in this investigation.

Computational Exploration of Isatin Derivatives for InhA Inhibition in Tuberculosis: Molecular Docking, MD Simulations and ADMET Insights.

Anti-tubercular drug discovery is a critical research area aimed at addressing the global health burden imposed by Mycobacterium tuberculosis. Nowadays, computational techniques have increased the likelihood of drug development compared to traditional, labor-intensive, and time-consuming drug design approaches. The pivotal goal of drug design is to identify compounds capable of selectively targeting protein, thereby disrupting its enzymatic activity. InhA, or NADH-dependent enoyl-acyl carrier protein reductase, stands at the forefront of targeted approaches in the battle against TB. Isatin derivatives have garnered interest for their diverse pharmacological activities. To identify novel isatin derivatives that could serve as potential chemical templates for anti-TB drug discovery by targeting InhA. The present work utilized various computational approaches, including molecular docking, binding free energy calculations, and conformational alignment studies to investigate the binding mode and interactions of carefully selected dataset of 88 isatin derivatives within InhA active site. Study also employed MD simulations of the most promising molecule to check the stability of the protein-ligand complex and in-silico ADMET profiling of the top compounds to predict their pharmacokinetic and toxicity properties. Results provided insights into the structural features contributing to InhA inhibition, assessing overall drug-like characteristics of isatin derivatives and identified compound 48 (BA= -10.4 kcal mol-1) with potential for further optimization. MD simulation analysis revealed that compound 48 binds firmly within the InhA protein, exhibiting minimal conformational fluctuations and enhanced stability. Considering the aforementioned, isatin derivatives represents a novel framework for creating targeted InhA inhibitors during anti-TB therapy. However, experimental validations and in-depth analyses are crucial to confirm efficacy and safety of these derivatives as potential InhA inhibitors for TB treatment.

Synthesis of Isatin-derived Heterocycles with Promising Anticancer Activities.

Isatin or 1H-indole-2,3-dione skeleton has been playing a significant role in drug design and development. Isatin itself and many of its derivatives are widely distributed in naturally occurring bioactive compounds. Various synthetic isatin derivatives were found to possess a broad range of significant pharmacological efficacies especially anti-cancer activity against a wide variety of cancer cell lines. Interestingly, on a few occasions, some isatin-derived scaffolds were reported as more potent than the tested reputed drug molecules. As a result, isatin-derived compounds have been gaining significant attention in cancer-based drug developments. In this review, we have summarized literature reported during the last two decades related to the synthesis of structurally diverse isatin-derived scaffolds with promising anti-cancer activities.

An Untold Story of Ionic Liquid for the Isatin Derivative Synthesis

Due to its unique features and environmental benefits, green synthesis is attracting researchers worldwide. To expand the uses of ionic liquids (ILs) in green chemistry, particularly as environmentally friendly solvents and catalysts, researchers are investigating novel methods to ILs and improving their characteristics. Due to its exceptional properties, ILs have been widely utilized as a green catalyst and solvent system in the synthesis of valuable heterocyclic compounds. Aza-heterocycle isatin derivatives are regarded for their versatility in drug development and medicinal research. Organic chemists have developed isatin-based frameworks employing ILs as solvents and catalysts aligning with one of the main goals of green synthesis, maximize synthetic efficiency while reducing environmental effects. This review provides a comprehensive summarization of reports related to the ILassisted isatin derivative synthesis.

Enantioselective Addition of 1,3,5,7-Tetramethyl-BODIPYs to Isatins by Bifunctional Quinine-Based Squaramides.

This work describes the development of the first enantioselective addition reaction between 1,3,5,7-tetramethyl-BODIPYs and isatin derivatives. The reaction utilizes bifunctional quinine/squaramide organocatalysts and affords nine novel chiral BODIPY dyes under mild conditions, with enantioselectivities reaching up to 60%. The synthesized BODIPY-oxindoles exhibit high fluorescence emissions, consistent with their parent BODIPYs, and display tunable colors. A representative example demonstrates a remarkably high quantum yield of 0.78 compared to fluorescein. Notably, the newly created carbon-stereocenter on the isatin skeleton induces detectable asymmetry in the electronically decoupled BODIPY chromophore. This is confirmed by the presence of Cotton effects in the visible region of the electronic circular dichroism (ECD) spectra. Density Functional Theory calculations suggested that the model oxindole 3aa adopts an (R) absolute stereochemical configuration, unveiling key interactions between the catalyst and substrates.