Dione Derivatives Research Articles

Synthesis, structure, DFT study and molecular docking inspection of spirobi[hexahydropyrimidine]-diones derivative

It has been established that three-component condensation of benzaldehyde, acetone and urea catalyzed H2SO4 leads to the formation of spirobi[hexahidropyrimidine]-dione derivatives. The structure of the synthesized compound has been proved by X-ray method. The results of the quantum theory of atom-in-molecule and noncovalent interaction index analysis showed no intramolecular hydrogen bonds in the molecule studied. However, it contains four N-H bonds and two C=O groups. Based on the result of the DFT-NBO analysis, it was the lone pairs of oxygen on the C=O group which are forming strong orbital interactions with the antibonding orbital of the C-N single bond. The molecular docking was performed to investigate potential binding interactions of the compound with four target proteins including 5I4T (HIV-1), 5R7Z, 6M71 and 6VYB (SARS-Cov-2). Additionally, in-silico drug-likeness and ADME studies suggested oral activity (violations ≤ 1) of scaffold and predicted to be actively effluxed by P-gp (PGP+).

Discovery of Novel 5-(Pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione Derivatives as Potent and Orally Bioavailable Inhibitors Targeting Ecto-5'-nucleotidase.

Ecto-5-nucleotidase (CD73) is overexpressed in a variety of cancers and associated with the immunosuppressive tumor microenvironment, making it an attractive target for cancer immunotherapy. Herein, we designed and synthesized a series of novel (pyridazine-3-yl)pyrimidine-2,4(1H,3H)-dione derivatives as CD73 inhibitors. These compounds exhibited remarkable inhibitory activity against CD73 in both enzymatic biochemical and cellular assays. Among them, compound 35j proved to be one of the most potent inhibitors and an uncompetitive inhibitor with no obvious cytotoxicity. This compound showed high metabolic stability in rat liver microsomes and favorable pharmacokinetic profiles in rats (T1/2 = 3.37 h, F = 50.24%). Importantly, orally administered 35j significantly inhibited tumor growth in the triple-negative breast cancer 4T1 mouse model (TGI = 73.6%, 50 mg/kg). Immunoassays suggested that 35j remarkably increased the infiltration of positive immune cells, thereby reinvigorating antitumor immunity. These results demonstrate that 35j is a potent CD73 inhibitor worthy of further development.

Tetrabutylammonium Hydrogen Sulfate (TBAHS) Catalyzed Microwave-Assisted Synthesis of 3,4,5,6,7,9-Hexahydro-1H-xanthene-1,8-(2H)-dione Derivatives and its Biological Study

In this study, a facile and eco-friendly synthesis of novel 3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione derivatives using tetrabutylammonium hydrogen sulfate (TBAHS) as a catalyst in the microwave reactor is presented. The reaction involved the condensation of aromatic aldehydes with 1,3-cyclohexanedione in ethanol as solvent, offering significant advantages in terms of reaction rate, yield and purity. The use of TBAHS as catalyst in conjunction with microwave irradiation facilitated the formation of the target xanthene derivatives in remarkably short reaction times. Moreover, Monowave 50 microwave reactor provided precise control over reaction parameters, enabling rapid optimization of reaction conditions. Further these synthesized compounds were systematically evaluated for their antibacterial, antituberculosis and antioxidant activities.

Et3NH][HSO4]-Catalyzed Synthesis of Chromenoquinoline-10,12(6H)-dione Derivatives via Mortar-Pestle Grinding Approach and Their Docking Studies

Et3NH][HSO4]-Catalyzed Synthesis of Chromenoquinoline-10,12(6H)-dione Derivatives via Mortar-Pestle Grinding Approach and Their Docking Studies

Design and synthesis of spiro[pyrrolidine-3,3′-quinoline]-2,2′-dione derivatives as novel antifungal agents targeting chitin synthase

A novel spiro [pyrrolidine-3′,3′-quinoline]-2,2′-dione scaffold was constructed using fragments of quinoline and pyrrolidine. Subsequently, two series of derivatives were designed based on this scaffold. The enzyme inhibition experiments revealed that all designed compounds had moderate to good inhibitory activity against chitin synthase (CHS). The inhibitory effects of compounds 5i, 5j, 8i and 8n were approximately equal to that of control drug polyoxin B (PB, IP = 86.4 ± 2.9 %, IC50 = 0.082 ± 0.013 mM) which is a well-established CHS inhibitor. The results from enzyme kinetic parameters assays proved that these compounds act as non-competitive inhibitors of CHS. The sorbitol protection experiments demonstrated the tested compounds disrupted the synthesis of cell wall, which further verified that the target of these compounds is CHS. The experiments of antimicrobial showed that compounds 5b, 5f, 5i, 5j, 8f, 8i, 8m, 8n and 8o had strong antifungal activity against the four tested pathogenic fungi strains frequently emerging in clinical setting, with MIC values ranging from 4 to 32 μg/mL, which were either superior to or comparable with those of PB or fluconazole. Furthermore, these compounds displayed synergistic or additive effects when combined with fluconazole and these active compounds also showed promising activity against fluconazole-resistant and micafungin-resistant fungi variants. The result of antimicrobial experiments indicated that these compounds had minimal activity to tested bacterial strains. This suggests that they had selective antifungal activity. The results of ADME prediction, in conjunction with the cytotoxicity assay results, indicated that these compounds had favorable pharmacokinetic profiles and low toxicity. In addition, molecular docking studies illustrated that the compound had a strong affinity with the CHS, which was consistent with the results of enzymatic assays. These findings indicated that the designed compounds are non-competitive inhibitors of CHS with good selectivity and broad-spectrum antifungal activity, and possess significant antifungal activity against drug-resistant fungi, suggesting their potential as lead compounds for the development of novel drugs against drug-resistant fungi.

4+2] Cycloaddition Mediated Stereoselective Synthesis of Tetrahydro‐1H‐Isobenzofuro Chromene Dione Derivatives: Antibacterial Evaluation and Molecular Docking Investigation

AbstractAn efficient stereoselective synthesis of tetrahydro‐1H‐isobenzofuro[4,5‐c]chromene‐1,3(3aH)‐dione derivatives were achieved through a novel [4+2] cycloaddition reaction of 4‐styryl‐2H‐chromenes with cheaply available maleic anhydride. A series of new tetrahydro‐1H‐isobenzofuro[4,5‐c]chromene‐1,3(3aH)‐dione derivatives 21(a–p) were synthesized in good to excellent yield under mild reaction condition with no chromatographic purification. In this reaction, the generation of four new consecutive stereogenic centers were determined by single crystal X‐ray analysis. All the synthesized compounds were investigated further in silico and in vitro for antibacterial activities using two bacterial strain of DNA gyrase. Compounds 21 b and 21 j showed excellent docking score −9.3 kCal/mol and −8.6 kCal/mol with gram negative bacterial strain Escherichia coli (E. coli) with protein data bank (PDB ID) 3G7E. Out of all the tested molecules, 21 b and 21 j displayed good results with minimum inhibitory concentration 10 μg/ml, 10 μg/ml against the bacterial strain Escherichia coli(E. coli) and 10 μg/ml, 20 μg/ml against Staphylococcus aureus (S. aureus) respectively.

Flexible green synthesis of 2-benzyl-3‑hydroxy-1H-pyrazolo([1,2-b]phthalazine and [1,2-a]pyridazine)‑dione derivatives using CuI@KSF nanocatalyst under solvent-free conditions

In the frame of research that examines the use of task CuI@KSF nanoparticles as an efficient catalyst, new 1H-pyrazolo[1,2-b]phthalazine-5,10‑dione (HPPhD) and 1H-pyrazolo[1,2-a]pyridazine-5,8‑dione (HPPyD) derivatives were prepared. Using the four-multicomponent condensation reaction (4MCRs) of phthalic anhydride, hydrazine monohydrate, aromatic aldehydes, and ethyl 3-oxo-3-phenylpropanoate under solvent free conditions at 80 °C. This method has several advantages, including, operational, simplicity, mild conditions, and maximum product yield. To monitor the progress of the reactions, new organic salty catalysts were used. New catalysts are cheap, benign, recyclable, and environmentally friendly. In addition, they are easy to prepare and use. They also showed good catalytic activity, which in conclusion led to the synthesis of new phthalazine derivatives with good to excellent yields. The new catalysts were characterized by X-ray diffraction (XRD), Fourier transform infrared (FT-IR), thermal gravimetric analysis (TGA), and scanning electron microscopy (SEM). To check the possible effect of these compounds in anticancer therapy, two types of proteins were selected and examined through docking calculations. In the case of 1DHT as an oxidoreductase enzyme compound 7e with the score of amount -8.99 represent the highest tendency toward interaction with the desired enzyme, while in the case of 6LQA by the dominance hydrophobic character, compound 7c seems likely to be more efficient.

Novel Pyrazino[1,2-a]indole-1,3(2H,4H)-dione Derivatives Targeting the Replication of Flaviviridae Viruses: Structural and Mechanistic Insights.

Infections with Flaviviridae viruses, such as hepatitis C (HCV), dengue (DENV), and yellow fever (YFV) viruses, are major public health problems worldwide. In the case of HCV, treatment is associated with drug resistance and high costs, while there is no clinically approved therapy for DENV and YFV. Consequently, there is still a need for new chemotherapies with alternative modes of action. We have previously identified novel 2-hydroxypyrazino[1,2-a]indole-1,3(2H,4H)-diones as metal-chelating inhibitors targeting HCV RNA replication. Here, by utilizing a structure-based approach, we rationally designed a second series of compounds by introducing various substituents at the indole core structure and at the imidic nitrogen, to improve specificity against the RNA-dependent RNA polymerase (RdRp). The resulting derivatives were evaluated for their potency against HCV genotype 1b, DENV2, and YFV-17D using stable replicon cell lines. The most favorable substitution was nitro at position 6 of the indole ring (compound 36), conferring EC50 1.6 μM against HCV 1b and 2.57 μΜ against HCV 1a, with a high selectivity index. Compound 52, carrying the acetohydroxamic acid functionality (-CH2CONHOH) on the imidic nitrogen, and compound 78, the methyl-substituted molecule at the position 4 indolediketopiperazine counterpart, were the most effective against DENV and YFV, respectively. Interestingly, compound 36 had a high genetic barrier to resistance and only one resistance mutation was detected, T181I in NS5B, suggesting that the compound target HCV RdRp is in accordance with our predicted model.

A Series of Novel 1-H-isoindole-1,3(2H)-dione Derivatives as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: In Silico, Synthesis and In Vitro Studies.

The derivatives of isoindoline-1,3-dione are interesting due to their biological activities, such as anti-inflammatory and antibacterial effects. Several series have been designed and evaluated for Alzheimer's therapy candidates. They showed promising activity. In this work, six new derivatives were first tested in in silico studies for their inhibitory ability against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. Molecular docking and molecular dynamic simulation were applied. Next, these compounds were synthesized and characterized by 1H NMR, 13C NMR, FT-IR, and ESI-MS techniques. For all imides, the inhibitory activity against AChE and BuChE was tested using Ellaman's method. IC50 values were determined. The best results were obtained for the derivative I, with a phenyl substituent at position 4 of piperazine, IC50 = 1.12 μM (AChE) and for the derivative III, with a diphenylmethyl moiety, with IC50 = 21.24 μM (BuChE). The compounds tested in this work provide a solid basis for further structural modifications, leading to the effective design of potential inhibitors of both cholinesterases.

Synthesis and Reactions of Pentacycloundecane Derivatives Related to Cookson’s Dione

AbstractIn this study, a pentacyclic keto-olefin was treated with thallium(III) nitrate trihydrate, resulting in the formation of mono ring-expanded product. However, when the corresponding dialkene was treated with thallium(III) nitrate trihydrate, an unexpected ring-closure product was obtained instead of the expected double ring-expanded product. The use of the Tebbe reagent facilitated the olefination of hindered and enolizable cage dione derivatives, converting both keto moieties into methylene groups and forming the desired diolefin. Notably, conventional Wittig reagents proved to be ineffective in the olefination sequence with cage diones.

Synthesis and Biological Evaluation of 3-(2-Benzoyl-4-chlorophenyl)-4H-spiro [indole-3,2-[1,3]thiazolidine]-2,4(1H)- dione Derivatives for Anti-tubercular and Antimicrobial Activities

Objectives: To synthesize a new scaff fold of 3'-(2-Benzoyl-4-chlorophenyl)-4'H-spiro [indole-3,2'-[1,3] thiazolidine]-2,4'(1H)-dione derivatives and to assess the compounds for anti-tubercular and antimicrobial activities. Methods : A new series of 3'-(2-Benzoyl-4-chlorophenyl)-4'H-spiro [indole-3,2'- [1,3] thiazolidine]-2,4'(1H)-dione derivatives were prepared by synthesizing schiff’s bases followed by condensing schiff base with 2-mercaptopropanoic acid in the presence of zinc chloride. Synthesized compounds were characterized by IR, NMR and Mass spectral data. Their antimicrobial, antitubercular and also docking simulations were evaluated. Findings : Compound 3c (floro substituent) showed potent activity against Mycobacterium tuberculosis H37Rv with MIC value of 3.125 µg/ml when compared with standard Isoniazid. Compound 3c, 3d and 3f displayed better antimicrobial activity against used bacterial and fungal species with MIC range of 3-20µg/ml comparable to standard drugs ciprofloxacin and ketoconazole respectively. In silico studies revealed that compound 3c, 3f and 3d had a better binding affinity with M. tuberculosis enoyl-CoA hydratase EchA6 with ΔG values of -9.6kcal/mol, -9.4kcal/mol, and -8.6kcal/mol respectively comparable to isoniazid of -5.4kcal/mol. Compound 3c, 3f and 3d also displayed good binding affinity with DNA gyrase and lanosterol methylase. Novelty : Introducing benzoyl moiety to the thiazolidine ring potentiates the antitubercular and antimicrobial activity of spiro indole derivatives. Keywords: AntiTB, Antimicrobial, Molecular Docking, Spiro indole, Thiazolidine

Reversed-phase thin-layer chromatography and ultra-performance liquid chromatography/mass spectrometry to estimate the drug likeness of phosphodiesterase 10A inhibitors with phthalimide core

Lipophilicity is a physicochemical parameter well known as a decisive factor for predicting the successful development of a drug. Thus, a balance between potency and physicochemical properties during medicinal chemistry optimization is needed. In this study, the lipophilicity of isoindole-1,3(2H)-dione derivatives designed as phosphodiesterase 10A (PDE10A) inhibitors was determined by chromatographic [reversed-phase thin-layer chromatography (RP-TLC) and ultra-performance liquid chromatography/mass spectrometry (UPLC/MS)] and in silico methods. To assess the correlation between the obtained lipophilicity parameters, principal component analysis (PCA) was performed. logP values obtained by chromatographic (logPRP-TLC and logPUPLC/MS) and in silico methods were compared using the PCA method. The results of PCA revealed that logPUPLC/MS and in silico clogP provided by the ChemDraw program were highly correlated. Compounds’ drug likeness was screened, and the pharmacokinetic properties were predicted. All the investigated compounds displayed drug-likeness properties, and they met the criteria of Lipinski’s rule of five, which predicted the oral bioavailability of drug candidates. Analysis of the influence of physicochemical properties on the biological activity showed that the compounds with increased potency on PDE10A had significantly higher topological polar surface area (TPSA) values. The blood‒brain barrier permeability and the hemolytic activity of model compound 18 were examined. The model compound 18 displayed no toxicity effect on erythrocytes in the hemolytic assay and good parallel artificial membrane permeability. The results showed that phthalimide compounds with benzimidazole moiety are a source of compound-targeted inhibition of PDE10A with balanced physicochemical and drug-likeness properties.

Synthesis of Pyrano[2,3-d]Pyrimidine Diones Catalyzed by Cobalt-Doped Iron Tartrate Nanomaterial: A Sustainable and Efficient Approach

This study presents a novel and environmentally sustainable approach for the one-pot multicomponent green synthesis of pyrano[2,3-d]pyrimidine dione derivatives. The devised procedure involves a three-component condensation of aldehydes, malononitrile, and barbituric acid, employing a nanomaterial catalyst in the form of cobalt-doped iron tartrate. This catalyst, characterized by its nanoscale dimensions, demonstrates exceptional reusability and water solubility, contributing to its eco-friendly profile. The synthesis is conducted under reflux conditions, optimizing the reaction efficiency. Key attributes of the proposed protocol include the use of a non-toxic, cost-effective, and readily available catalyst. The high atom economy of the reaction signifies minimal waste generation, enhancing the sustainability of the synthetic process. Additionally, the reaction features a short duration, aligning with the principles of efficiency and resource conservation. Notably, the utilization of water as the solvent further enhances the green approach, minimizing the environmental impact. This innovative synthesis protocol not only addresses the growing demand for environmentally conscious methodologies but also showcases the potential for scalable and practical applications in organic synthesis. The integration of a reusable nanomaterial catalyst, coupled with the adoption of water as a solvent, positions this approach as a promising advancement in the pursuit of sustainable and green chemical practices. The study provides valuable insights into the development of efficient and environmentally benign synthetic routes for the production of pyrano[2,3-d]pyrimidine dione derivatives, paving the way for the exploration of greener alternatives in the realm of organic chemistry.

Design, synthesis and biological evaluation of novel 2-hydroxy-1 H-indene-1,3(2 H)-dione derivatives as FGFR1 inhibitors

Fibroblast growth-factor receptor (FGFR) is a potential target for cancer therapy. We synthesised a novel series of FGFR1 inhibitors bearing quinoline, quinoxalin and isoquinoline using a synthetic strategy employing a one pot reaction, yielding 2-hydroxy-1H-indene-1,3(2H)-dione. Structural elucidation via IR, NMR and HRMS analyses is complemented by a proposed mechanistic pathway. All newly-synthesised compounds were evaluated in vitro for their inhibitory activities against FGFR-1. The most potent derivatives were 9a, 9b, 9c and 7b with IC50 = 5.7, 3.3, 4.1 and 3.1 μM, respectively, supported by molecular docking studies which probed the binding interactions of these compounds within the active site of the kinase.

Synthesis, Characterization, Docking Studies, and In-vitro Cytotoxic Activity of Some Novel 2, 3 Disubstituted Naphthalene 1,4 Dione Derivatives

Synthesis, Characterization, Docking Studies, and In-vitro Cytotoxic Activity of Some Novel 2, 3 Disubstituted Naphthalene 1,4 Dione Derivatives

Ru- and Co-Catalyzed Intermolecular Carbonyl-Alkyne Metathesis Reactions of 1H-Indene-1,2,3-triones with Internal Alkynes.

The catalyst-dependent intermolecular carbonyl-alkyne metathesis (CAM) reaction of 1H-indene-1,2,3-triones with internal alkynes was realized using Ru and Co catalysts. 2-(2-Oxo-1,2-diphenylethylidene)-1H-indene-1,3(2H)-dione derivatives were obtained using a Ru catalyst, whereas S-alkyl 2-(1,3-dioxo-1,3-dihydro-2H-inden-2-ylidene)-2-phenylethanethioates were prepared using a Co catalyst. These transformations led to the synthesis of α,β-unsaturated carbonyl compounds with a broad substrate scope, excellent regiocontrol, and gram-scale amenability. This catalytic strategy using a Co or Ru catalyst has rarely been described for other established CAM catalysts.

Innovative and sustainable synthesis and structure of novel N‐substituted hexahydroacridine derivatives

AbstractAn efficient and green synthesis of tetramethyl‐10‐(phenylamino)‐3,4,6,7,9,10‐hexahydroacridine‐1,8(2H,5H)‐dione derivatives has been achieved from various substituted aryl aldehydes, 5,5‐dimethyl‐3‐(2‐phenylhydrazinyl)cyclohex‐2‐enone and dimedone in aqueous ethanol medium. Environment‐friendly reaction, excellent yields, operational simplicity and shorter reaction times are the significant features of the present protocol. All the synthesized compounds were characterized by various spectroscopic techniques and X‐ray crystal diffraction studies.

Design of Cyclobut-3-Ene-1,2 Dione Derivatives as Anti-tubercular Agents

Introduction: Recent studies have shown modified cyclobutene derivatives as potent anti- tubercular agents, and the discovery of drugs against strains of Mycobacterium tuberculosis is still a crucial challenge in the modern world. Objective: The objective of the present study is to design and perform molecular docking studies and in-silico analysis of some novel cyclobut-3-ene-1,2 Dione derivatives with the aim of creating new, potential Mtb ATP synthase inhibitors. Materials and Methods: The structures of 24 compounds of diamino-substituted cyclobut-3-ene-1,2 Dione derivatives against Mtb ATP synthase were drawn using ChemSketch. Further, molecular docking and in-silico studies for the prediction of drug-likeness and pharmacokinetic parameters were carried out. Results: The docking studies of the novel compounds were done, and they had a better docking score with a good binding affinity towards the protein molecule. The synthesized compounds also comply with the in-silico prediction of drug-likeness and pharmacokinetic parameters and have shown good activity against Mtb ATP synthase. Conclusion: The current study shows that the cyclobut-3-ene-1,2 Dione derivatives can serve as a better lead molecule against Mtb ATP synthase and can be involved in further drug discovery

Visible-light-induced decarboxylative cascade cyclization of acryloylbenzamides with N-hydroxyphthalimide esters via EDA complexes.

A visible-light-induced decarboxylative cascade reaction of acryloylbenzamides with alkyl N-hydroxyphthalimide (NHP) esters for the synthesis of various 4-alkyl isoquinolinediones mediated by triphenylphosphine (PPh3) and sodium iodide (NaI) was developed. This operationally simple protocol proceeded via the photoactivation of electron donor-acceptor (EDA) complexes between N-hydroxyphthalimide esters and NaI/PPh3, resulting in multiple carbon-carbon bond formations without the use of precious metal complexes or synthetically elaborate organic dyes, which provided an alternative practical approach to synthesize diverse isoquinoline-1,3(2H,4H)-dione derivatives.

Design, Synthesis, Characterization, and Docking Studies of Some 3,3,6,6-Tetramethyl-9-phenyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione Derivatives

Design, Synthesis, Characterization, and Docking Studies of Some 3,3,6,6-Tetramethyl-9-phenyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione Derivatives