A novel isatin Schiff based cerium complex: synthesis, characterization, antimicrobial activity and molecular docking studies.

In this work, a novel isatin-Schiff base L2 had been synthesized through a simple reaction between isatin and 2-amino-5-methylthio-1,3,4-thiadiazole. The produced Schiff base L2 was then subjected to a hydrothermal reaction with cerium chloride to produce the cerium (III)-Schiff base complex C2. Several spectroscopic methods, including mass spectra, FT-IR, elemental analysis, UV-vis, 13C-NMR, 1H-NMR, Thermogravimetric Analysis, HR-TEM, and FE-SEM/EDX, were used to completely characterize the produced L2 and C2. A computer simulation was performed using the MOE software program to find out the probable biological resistance of studied compounds against the proteins in some types of bacteria or fungi. To investigate the interaction between the ligand and its complex, we conducted molecular docking simulations using the molecular operating environment (MOE). The docking simulation findings revealed that the complex displayed greater efficacy and demonstrated a stronger affinity for Avr2 effector protein from the fungal plant pathogen Fusarium oxysporum (code 5OD4) than the original ligand. The antibacterial activity of the ligand and its Ce3+ complex were applied in vitro tests against different microorganism. The study showed that the complex was found to be more effective than the ligand.

Novel mitochondrial and DNA damaging fluorescent Calix[4]arenes bearing isatin groups as aromatase inhibitors: Design, synthesis and anticancer activity.

Breast cancer causes a high rate of mortality all over the world. Therefore, the present study focuses on the anticancer activity of new lower rim-functionalized calix[4]arenes integrated with isatin and the p-position of calixarenes with 1,4-dimethylpyridinium iodine against various human cancer cells such as MCF-7 and MDA-MB-231 breast cancer cell lines, as well as the PNT1A healthy epithelial cell line. It was observed that compound 6c had the lowest values in MCF-7 (8.83 µM) and MDA-MB-231 (3.32 µM). Cell imaging and apoptotic activity studies were performed using confocal microscopy and flow cytometry, respectively. The confocal imaging studies with 6c showed that the compound easily entered the cell, and it was observed that 6c accumulated in the mitochondria. The Comet assay test was used to detect DNA damage of compounds in cells. It was found that treated cells had abnormal tail nuclei and damaged DNA structures compared with untreated cells. In vitro human aromatase enzyme inhibition profiles showed that compound 6c had a remarkable inhibitory effect on aromatase. Compound 6c displayed a significant inhibition capacity on aromatase enzyme with the IC50 value of 0.104 ± 0.004 µM. Thus, not only the anticancer activity of the new fluorescent derivatives, which are the subject of this study, but the aromatase inhibitory profiles have also been proven.

Identification of new anti-mycobacterial agents based on quinoline-isatin hybrids targeting enoyl acyl carrier protein reductase (InhA).

Tuberculosis (TB) is a global issue that poses a significant economic burden as a result of the ongoing emergence of drug-resistant strains. The urgent requirement for the development of novel antitubercular drugs can be addressed by targeting specific enzymes. One such enzyme, Mycobacterium tuberculosis (MTB) enoyl-acyl carrier protein (enoyl-ACP) reductase (InhA), plays a crucial role in the survival of the MTB bacterium. In this research study, a series of hybrid compounds combining quinolone and isatin were synthesized and assessed for their effectiveness against MTB, as well as their ability to inhibit the activity of the InhA enzyme in this bacterium. Among the compounds tested, 7a and 5g exhibited the most potent inhibitory activity against MTB, with minimum inhibitory concentration (MIC) values of 55 and 62.5 µg/mL, respectively. These compounds were further evaluated for their inhibitory effects on InhA and demonstrated significant activity compared to the reference drug Isoniazid (INH), with IC50 values of 0.35 ± 0.01 and 1.56 ± 0.06 µM, respectively. Molecular docking studies investigated the interactions between compounds 7a and 5g and the target enzyme, revealing hydrophobic contacts with important amino acid residues in the active site. To further confirm the stability of the complexes formed by 5g and 7a with the target enzyme, molecular dynamic simulations were employed, which demonstrated that both compounds 7a and 5g undergo minor structural changes and remain nearly stable throughout the simulated process, as assessed through RMSD, RMSF, and Rg values.

Isatin-indoloquinoxaline click adducts with a potential to overcome platinum-based drug-resistance in ovarian cancer.

Herein, a series of isatin tethered indolo[2,3-b]quinoxaline hybrids was synthesized by considering the pharmacophoric features of known DNA intercalators and topoisomerase II inhibitors. The anti-proliferative properties of the synthesized compounds were evaluated against ovarian cancer cell lines (SKOV-3 and Hey A8). Four of the compounds exhibited promising anti-proliferative activities, with one of them being 10-fold more potent than cisplatin against drug-resistant Hey A8 cells. Further investigations were carried out to determine the DNA intercalating affinities of the most active compounds as potential mechanisms for their anti-proliferative activities. ADMET in silico studies were performed to assess the physicochemical, pharmacokinetics, and toxicity parameters of active compounds. This study, to the best of our knowledge, is the first report on the potential of isatin-indoloquinoxaline hybrids as structural blueprints for the development of new DNA intercalators. Additionally, it explores their potential to circumvent platinum-based resistance in ovarian cancer.

Design, synthesis, in vitro and in silico evaluations of new isatin-triazine- aniline hybrids as potent anti- Alzheimer multi-target directed lead compounds.

Multi target directed ligands (MTDLs) are one of the promising tools for treatment of complex disease like Alzheimer's disease (AD). In this study, using rational design, we synthesized new 15 hybrids of the s-triazine, isatin and aniline derivatives as anti- AD compounds. The design was as way as that new compounds could had anti cholinesterase (ChE), antioxidant and biometal chelation ability. In vitro biological evaluation against ChE enzymes showed that these molecules were excellent inhibitors with IC50 values ranging from 0.2 nM to 734.5 nM for acetylcholinesterase (AChE), and 0.02 µM to 1.92 µM for butyrylcholinesterase (BChE). Among these compounds, 8 l with IC50 AChE = 0.7 nM, IC50 BChE = 0.09 µM and 8n with IC50 AChE = 0.2 nM, IC50 BChE = 0.03 µM were the most potent compounds. In silico studies showed that these molecules had key and effective interactions with the corresponding enzymes residues. The molecules with hydroxyl group on aniline moiety had also good antioxidant activity with EC50 values ranging from 64.2 µM to 103.6 µM. The UV-Vis spectroscopy study revealed that molecule 8n was also able to chelate biometals such as Zn2+, Cu2+and Fe2+ properly. It was concluded that these molecules could be excellent lead compounds for future studies.

Unveiling the potential of isatin-grafted phenyl-1,2,3-triazole derivatives as dual VEGFR-2/STAT-3 inhibitors: Design, synthesis and biological assessments.

The use of VEGFR-2 inhibitors as a stand-alone treatment has proven to be ineffective in clinical trials due to the robustness of cellular response loops that lead to treatment resistance when only targeting VEGFR-2. The over-activation of the signal transducer/activator of transcription 3 (STAT-3) is expected to significantly impact treatment failure and resistance to VEGFR-2 inhibitors. In this study, we propose the concept of combined inhibition of VEGFR-2 and STAT-3 to combat induced STAT-3-mediated resistance to VEGFR-2 inhibition therapy. To explore this, we synthesized new isatin-grafted phenyl-1,2,3-triazole derivatives "6a-n" and "9a-f". Screening on PANC1 and PC3 cancer cell lines revealed that compounds 6b, 6 k, 9c, and 9f exhibited sub-micromolar ranges. The most promising molecules, 6b, 6 k, 9c, and 9f, demonstrated the highest inhibition when tested as dual inhibitors on VEGFR-2 (with IC50 range 53-82 nM, respectively) and STAT-3 (with IC50 range 5.63-10.25 nM). In particular, triazole 9f showed the best results towards both targets. Inspired by these findings, we investigated whether 9f has the ability to trigger apoptosis in prostate cancer PC3 cells via the assessment of the expression levels of the apoptotic markers Caspase-8, Bcl-2, Bax, and Caspase-9. Treatment of the PC3 cells with compound 9f significantly inhibited the protein expression levels of VEGFR-2 and STAT-3 kinases compared to the control.

Formation of bis-spiropyrrolidines from isatin, secondary amines, and alkylidene Meldrum's acids.

A catalyst-free synthesis of stable bis-spiropyrrolidines from isatin, secondary amines, and alkylidene Meldrum's acids in MeCN in 75-95% yield is described. The antioxidant and antimicrobial properties of the synthesized compounds are investigated. For this purpose, the radical scavenging activities of four derivatives were studied by radical trapping of diphenylpicrylhydrazine and ferric reduction power experiments. Disk diffusion test on Gram-positive and Gram-negative bacteria was employed to investigate antibacterial activities of five derivatives.

Evaluation of N-alkyl isatins and indoles as acetylcholinesterase and butyrylcholinesterase inhibitors.

Two series of N-alkyl isatins and N-alkyl indoles varying in size of the alkyl group were synthesised and evaluated for inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Among the N-alkyl isatins 4a-j, the addition of the N-alkyl group improved inhibition potency towards AChE and BChE compared to isatin. Selectivity towards inhibition of BChE was observed, and the increase in size of the N-alkyl group positively correlated to improved inhibition potency. The most potent inhibitor for BChE was 4i (IC50 = 3.77 µM, 22-fold selectivity for BChE over AChE). N-alkyl indoles 5a-j showed similar inhibition of AChE, the most potent being 5g (IC50 = 35.0 µM), but 5a-j lost activity towards BChE. This suggests an important role of the 3-oxo group on isatin for BChE inhibition, and molecular docking of 4i with human BChE indicates a key hydrogen bond between this group and Ser198 and His438 of the BChE catalytic triad.

Synthesis biological evaluation and molecular docking of isatin hybrids as anti-cancer and anti-microbial agents.

Isatin, known as 1H-indole-2,3-dione, was originally recognised as a synthetic molecule until its discovery in the fruits of the cannonball tree, Couroupita guianensis. It is naturally occurring in plants of the genus Isatis and serves as a metabolic derivative of adrenaline in humans. Isatin possesses significant pharmacological importance, and its synthetic versatility has prompted extensive interest in its derivative compounds due to their diverse biological and pharmacological properties. These derivatives represent a valuable class of heterocyclic compounds with potential applications as precursors for synthesizing numerous valuable drugs. In the pursuit of advancing our research on isatin hybrids, we investigate the utilisation of readily available hydrazonoindolin-2-one and isatin as starting materials for the synthesis of a wide range of analogues. Characterisation of the synthesized compounds was carried out through various analytical techniques. Furthermore, the obtained compounds were subjected to extensive testing to evaluate their anticancer and antimicrobial activities. Specifically, their efficacy against key proteins, namely Staphylococcus aureus protein (PDB ID: 1JIJ), Escherichia coli protein (PDB ID: 1T9U), Pseudomonas aeruginosa protein (PDB ID: 2UV0), and Acinetobacter baumannii protein (PDB ID: 4HKG), was examined through molecular docking calculations. Several molecules, such as 3, 4, 6, 16, and 19, displayed remarkable activity against the renal cancer cell line UO-31. Additionally, the results of antimicrobial activity testing revealed that compound 16 exhibited significant cytotoxicity against Candida albicans and Cryptococcus neoformans. Subsequently, ADME/T calculations were performed to gain insights into the potential effects and reactions of these molecules within human metabolism. This comprehensive study provides valuable insights into the potential pharmacological applications of isatin derivatives and underscores their significance in drug development.

A Comprehensive Review of the Diverse Spectrum Activity of 1,2,3-Triazole-linked Isatin Hybrids.

Heterocyclic compounds containing 1,2,3-triazole and isatin as core structures have emerged as promising drug candidates due to their diverse biological activities such as anti-cancer, antifungal, antimicrobial, antitumor, anti-epileptic, antiviral, and more. The presence of 1,2,3-triazoles and isatin heterocycles in these hybrids, both individually known for their medicinal significance, has increasingly piqued the interest of drug discovery researchers, as they seek to delve deeper into their extensive pharmacological potential for enhancing therapeutic efficacy. Moreover, these hybrid compounds are synthetically accessible using readily available materials. Therefore, there is a pressing need to provide a comprehensive overview of the existing knowledge in this field, offering valuable insights to readers and paving the way for the discovery of novel 1,2,3-triazole-linked isatin hybrids with therapeutic potential.

Synthesis, Characterization, Antimicrobial and In Silico Studies of Isatin Schiff Base Linked 1,2,3-Triazole Hybrids.

A new series of isatin-Schiff base linked 1,2,3-triazole hybrids has been synthesized using CuAAC approach from (E)-3-(phenylimino)-1-(prop-2-yn-1-yl)indolin-2-one derivatives in high yield (73-91 %). These synthesized derivatives were characterized using FT-IR, 1H NMR, 13C NMR, 2D-NMR and HRMS spectral techniques. The in vitro antimicrobial activity assay demonstrated that most of the tested hybrids exhibited promising activity. Compound 5 j displayed significant antibacterial efficacy against P. aeruginosa and B. subtilis with MIC value of 0.0062 µmol/mL. While, 5 j also showed better antifungal potency against A. niger with MIC value of 0.0123 µmol/mL. The docking studies of most promising compounds were performed with the well-known antibacterial and antifungal targets i. e. 1KZ1, 5TZ1. Molecular modelling investigations demonstrated that hybrids 5 h and 5 l exhibited good interactions with 1KZN and 5TZ1, with binding energies of -9.6 and -11.0 kcal/mol, respectively. Further, molecular dynamics studies of the compounds showing promising binding interactions were also carried out to study the stability of complexes of these hybrids with both the targets.

One Pot Synthesis and Biological Activity Studies of New Spirooxindoles.

This article reports one-pot synthesis of ten novel spirooxindoles using 5-methyl-2-thiohydantoin, isatin derivatives, and malononitrile in good to high yields (65-90 %). The structures of the synthesized compounds were deduced by 1H-NMR, 13C NMR, FT-IR, and Mass spectral data. The antibacterial activity of the compounds was evaluated against two Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis) and two Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) based on the Kirby-Bauer method. According to the obtained data, the synthesized compounds show more activity against Gram-positive bacteria than Gram-negative bacteria. Also, the antioxidant activity of these compounds was measured using the DPPH radical scavenging test method, which showed good to excellent activity (59.65-94.03 %). Among them, the chlorinated derivatives (4 f-j) exhibited more antioxidant activity (84.85-94.03 %) than the other compounds (4 a-e) (56.65-74.4 %) and even ascorbic acid as a standard antioxidant compound (82.3 %).

Design and synthesis of benzo[b]thiophene-based hybrids as novel antitubercular agents against MDR/XDR Mycobacterium tuberculosis.

In an effort to support the global fight against tuberculosis (TB), which is widely recognized as the most lethal infectious disease worldwide, we present the design and synthesis of new benzo[b]thiophene-based hybrids as promising candidates for the management of multidrug-resistant (MDR)/extensively drug-resistant (XDR) Mycobacterium tuberculosis. The isatin motif was incorporated into the target hybrids as it represents a privileged scaffold in antitubercular drug discovery. Since lipophilicity plays a pivotal role in the anti-TB agents' activity, the lipophilicity of the target hybrids was manipulated via the development of two series of N-1 methyl and N-1 benzyl substituted isatins (6a-h and 9a-h, respectively). Screening of the target hybrids was first performed against drug-sensitive M. tuberculosis (ATCC 25177). The structure-activity relationship outputs highlighted that incorporation of 3-unsubstituted benzo[b]thiophene and 5-methoxy isatin moieties was favorable for the antimycobacterial activity. Thereafter, the most potent molecules (6b-h, 9c-e, and 9h) were evaluated against the resistant strains MDR-TB (ATCC 35822) as well as against XDR-TB (RCMB 2674) where they displayed promising activity. To evaluate the safety of the target hybrids, an sulforhodamine B assay was conducted to determine their possible cytotoxic effects on VERO cells.

Design, synthesis, and biological evaluation of 3-benzenesulfonamide-linked 3-hydrazinoisatin derivatives as carbonic anhydrase inhibitors.

A new series of isatin-linked benzenesulfonamide derivatives (9a-w) were synthesized using the tail approach and assayed for their inhibitory potency against four different human carbonic anhydrase (hCA) isoforms, hCA I, II, IX, and XII. Most of these synthesized compounds exhibited interesting inhibition potency against isoforms hCA I, IX, and XII in the nanomolar range and by taking the standard drug acetazolamide. The most potent compounds in the case of hCA I were 9c (435.8 nM) and 9s (956.4 nM), for hCA IX, 9a (60.5 nM), 9d (95.6 nM), 9g (92.1 nM), and 9k (75.4 nM), and for hCA XII, 9p (84.5 nM). However, these compounds showed more selectivity toward hCA IX over hCA I, II, and XII. Thus, these compounds can be further developed as potential lead molecules for the development of isoform-selective hCA IX inhibitors with further structural modifications.

Privileged Scaffold Hybridization in the Design of Carbonic Anhydrase Inhibitors.

Human Carbonic Anhydrases (hCA) are enzymes that contribute to cancer's development and progression. Isoforms IX and XII have been identified as potential anticancer targets, and, more specifically, hCA IX is overexpressed in hypoxic tumor cells, where it plays an important role in reprogramming the metabolism. With the aim to find new inhibitors towards IX and XII isoforms, the hybridization of the privileged scaffolds isatin, dihydrothiazole, and benzenesulfonamide was investigated in order to explore how it may affect the activity and selectivity of the hCA isoforms. In this respect, a series of isatin thiazolidinone hybrids have been designed and synthesized and their biological activity and selectivity on hCA I, hCA II, hCA IX, and hCA XII explored. The new compounds exhibited promising inhibitory activity results on isoforms IX and XII in the nanomolar range, which has highlighted the importance of substituents in the isatin ring and in position 3 and 5 of thiazolidinone. In particular, compound 5g was the most active toward hCA IX, while 5f was the most potent inhibitor of hCA XII within the series. When both potency and selectivity were considered, compound 5f appeared as one of the most promising. Additionally, our investigations were supported by molecular docking experiments, which have highlighted the putative binding poses of the most promising compound.

Identification of Novel Isatin Derivative Bearing a Nitrofuran Moiety as Potent Multi-Isoform Aldehyde Dehydrogenase Inhibitor.

Aldehyde dehydrogenases (ALDHs) are a family of enzymes that aid in detoxification and are overexpressed in several different malignancies. There is a correlation between increased expression of ALDH and a poor prognosis, stemness, and resistance to several drugs. Several ALDH inhibitors have been generated due to the crucial role that ALDH plays in cancer stem cells. All of these inhibitors, however, are either ineffective, very toxic, or have yet to be subjected to rigorous testing on their effectiveness. Although various drug-like compounds targeting ALDH have been reported in the literature, none have made it to routine use in the oncology clinic. As a result, new potent, non-toxic, bioavailable, and therapeutically effective ALDH inhibitors are still needed. In this study, we designed and synthesized potent multi-ALDH isoform inhibitors based on the isatin and indazole pharmacophore. Molecular docking studies and enzymatic tests revealed that among all of the synthesized analogs, compound 3 is the most potent inhibitor of ALDH1A1, ALDH3A1, and ALDH1A3, exhibiting 51.32%, 51.87%, and 36.65% inhibition, respectively. The ALDEFLUOR assay further revealed that compound 3 acts as an ALDH broad spectrum inhibitor at 500 nM. Compound 3 was also the most cytotoxic to cancer cells, with an IC50 in the range of 2.1 to 3.8 µM for ovarian, colon, and pancreatic cancer cells, compared to normal and embryonic kidney cells (IC50 7.1 to 8.7 µM). Mechanistically, compound 3 increased ROS activity due to potent multi-ALDH isoform inhibition, which increased apoptosis. Taken together, this study identified a potent multi-isoform ALDH inhibitor that could be further developed as a cancer therapeutic.

Design, synthesis, insilco study and biological evaluation of new isatin-sulfonamide derivatives by using mono amide linker as possible as histone deacetylase inhibitors.

OBJECTIVE: Aim: To evaluate the cytotoxic activity of newly synthesized a series of novel HDAC inhibitors comprising sulfonamide as zinc binding group and Isatin derivatives as cap group joined by mono amide linker as required to act as HDAC inhibitors. PATIENTS AND METHODS: Materials and Methods: The utilization of sulfonamide as zinc binding group joined by N-alkylation reaction with ethyl-bromo hexanoate as linker group that joined by amide reaction with Isatin derivatives as cap groups which known to possess antitumor activity in the designed of new histone deacetylase inhibitors and using the docking and MTT assay to evaluate the compounds. RESULTS: Results: Four compounds have been synthesized and characterized successfully by ART-FTIR, NMR and ESI-Ms. the compounds were synthesized and characterized by successfully by ART-FTIR, NMR and ESI- Ms. Assessed for their cytotoxic activity against human colon adenocarcinoma MCF-7 (IC50, I=105.15, II=60.00, III=54.11, IV=56.57, vorinostat=28.41) and hepatoblastoma HepG2 (IC50, I=63.91, II=135.18, III=118.85, IV=51.46, vorinostat=37.50). Most of them exhibited potent HDAC inhibitory activity and significant cytotoxicity. CONCLUSION: Conclusions: The synthesized compounds (I, II, III and IV) showed cytotoxicity toward MCF-7 and HepG2 cancer cell lines and their docking analysis provided a preliminary indication that they are viable [HDAC6] candidates.

Isatin-pyrimidine hybrid derivatives as enoyl acyl carrier protein reductase (InhA) inhibitors against Mycobacterium tuberculosis.

Tuberculosis is a worldwide problem that impose a burden on the economy due to continuous development of resistant strains. The development of new antitubercular drugs is a need and can be achieved through inhibition of druggable targets. Mycobacterium tuberculosis enoyl acyl carrier protein (ACP) reductase (InhA) is an important enzyme for Mycobacterium tuberculosis survival. In this study, we report the synthesis of isatin derivatives that could treat TB through inhibition of this enzyme. Compound 4l showed IC50 value (0.6 ± 0.94 µM) similar to isoniazid but is also effective against MDR and XDR Mycobacterium tuberculosis strains (MIC of 0.48 and 3.9 µg/mL, respectively). Molecular docking studies suggest that this compound binds through the use of relatively unexplored hydrophobic pocket in the active site. Molecular dynamics was used to investigate and support the stability of 4l complex with the target enzyme. This study paves the way for the design and synthesis of novel antitubercular drugs.

Synthesis, antimicrobial, antibiofilm and computational studies of isatin-semicarbazone tethered 1,2,3-triazoles.

In present era, heterocyclic compounds containing two or three nitrogen atoms play a vital role in drug discovery. In this context, a new class of isatin-semicarbazone tethered 1,2,3-triazole hybrids was synthesized via Cu(I)-mediated azide alkyne cycloaddition reaction. Structural characteristics of the newly derived compounds were identified by various spectral techniques like FTIR, 1H NMR, 13C NMR, HRMS and single crystal X-ray crystallography. Synthesized derivatives were also screened for in vitro antimicrobial and antibiofilm activity against different microbial species. Triazole hybrid 7e showed significant efficacy towards E. coli having MIC of 0.0063 µmol/mL, whereas 6a, 6b, 7a, 7c, 7e, and 7f showed highest percentage of biofilm inhibition against P. aeruginosa. Bioassay results suggested that these triazole hybrids could act as biomaterial for antimicrobial and antibiofilm applications and may constitute a new promising class of antimicrobial and antibiofilm agents. These results were further supported by in silico docking, DFT calculations and ADME studies.

A diastereoselective three-component reaction for the assembly of succinimide and isatin hybrid molecules with potent anticancer activities.

A Rh2(OAc)4 catalyzed three-component reaction of vinyl diazosuccinimides with alcohols and isatins has been reported, which provides a practical assess to the direct assembly of succinimide and isatin hybrid molecules in good-to-high yields with excellent stereoselectivity. The antiproliferation activity of these synthesized succinimide and isatin hybrid products has been tested via the CCK8 assay in different cancer cell lines, and compounds 4g (SJSA-1, IC50 = 3.82 µM) and 4r (HCT-116, IC50 = 9.02 µM) exhibit higher anticancer potency than other tested compounds.