Dimedone Derivatives Research Articles

Synthetic Methods of 1H-Pyrazolo[1,2-b]Phthalazine Derivatives

Abstract: This review deals with the synthetic methods of pyrazolo[1,2-b]phthalazine derivatives using one-pot multi-component reactions via modern and traditional methods. The synthetic methods are subdivided into groups according to the type of reactants e.g (1) one-pot three-component reaction of 2,3-dihydrophthalazine-1,4-dione, aldehydes and acetonitriles; (2) one-pot three-component reaction of 2,3-dihydrophthalazine-1,4-dione, aldehydes and aroyl acetonitriles; (3) one-pot three-component reaction of 2,3-dihydrophthalazine-1,4-dione, aldehydes and acetylacetone or 4-hydroxy-2H-chromen-2-one or acetylene derivatives; (4) one-pot four-component condensation reaction of phthalimide, hydrazine hydrate, aldehydes and acetonitriles; (5) one-pot four-component reaction of phthalic acid, hydrazine hydrate, indole-3- carbaldehyde and acetonitriles; and (6) one-pot three-component condensation reaction of 2,3- dihydrophthalazine-1,4-dione, aldehyde, and dimedone derivatives. Moreover, the various methods were reported.

LRRC8A Anion Channel Associates with Myosin Phosphatase Rho Interacting Protein (MPRIP) to Regulate Vascular Function

Volume-regulated anion channels (VRACs) are activated by tumor necrosis factor alpha (TNFα) and angiotensin II. VRACs are composed of Leucine Rich Repeat Containing 8 (LRRC8) family proteins (LRRC8A, B, C, D and E) and LRRC8A is required for all VRACs. LRRC8A associates with NADPH oxidase 1 (Nox1) and modulates production of extracellular superoxide in vascular smooth muscle cells (VSMCs). We investigated vascular reactivity in mesenteric arteries from wild type (WT) and smooth muscle-specific LRRC8A knockout (KO) mice. KO vessels displayed enhanced responsiveness to multiple vasodilator agents; acetylcholine, sodium nitroprusside, PKA (forskolin) or PKG (BAY60-2770) activators and a Rho kinase inhibitor (Y-27632), compared to WT. This was associated with decreased RhoA activity and reduced ROCK-dependent MYPT1 phosphorylation at T853. To explore the mechanism of enhanced relaxation we immunoprecipitated LRRC8A-associated proteins from WT and KO VSMCs and analyzed these by mass spectroscopy. Myosin Phosphatase Rho-Interacting protein (MPRIP) was identified only in WT lysates. MPRIP is a scaffolding protein that binds to RhoA, MYPT1, and actin and regulates activity of the myosin light chain phosphatase complex. Association of LRRC8A and MPRIP was confirmed using IP/western blot, proximity ligation assay (PLA) and immunohistochemistry. LRRC8A binds to the second plextrin homology domain of MPRIP. Knockdown of MPRIP (siRNA) increased protein expression of LRRC8A in cultured VSMCs. To explore the relationship between Nox1/LRRC8A, superoxide and intracellular redox signaling events sulfenylation of MPRIP cysteine residues (-SOH) was quantified using DCP-Bio1 (a biotin-labeled dimedone derivative) pulldown with streptavidin beads and western blotting. Sulfenylation was significantly increased 3 min following TNFα stimulation (2.3 fold, n = 3, p < 0.05). It remains to be determined how this impacts association of MPRIP with its four binding partners. Disruption of interaction between Nox1/LRRC8A and MPRIP/RhoA/MYPT1/actin may underly enhanced vasodilation in VSMC-specific LRRC8A null blood vessels. This multi-protein complex provides a potential mechanism by which oxidants produced by Nox1 impact vasomotor function, linking inflammation to increased vascular reactivity and hypertension. NIGMS (5R35GM138191-02), NIDDK (1R01DK132948-01), NHLBI (1R01HL160975-01A1) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

BioMOF-Mn: An Antimicrobial Agent and an Efficient Nanocatalyst for Domino One-Pot Preparation of Xanthene Derivatives.

In this paper, a new Mn-based metal-organic framework [UoB-6] was obtained via a one-step ultrasonic irradiation method with the ligand (H2bdda: 4,4'-(1,4-phenylenebis(azaneylylidene))bis(methaneylylidene))dibenzoic acid. The structural integrity of the synthesized BioMOF-Mn was corroborated by FT-IR, EDX, ICP, XRD, TEM, DLS, FESEM, and BET-BJH analyses. The aerobic oxidative domino reaction of benzyl alcohols or aldehydes with dimedone derivatives was performed in the presence of the UoB-6 catalyst to produce xanthene derivatives in good yields. Hot filtration and Hg poisoning tests proved the heterogeneous nature of the catalyst. Novel synthesized xanthene-based bis-aldehydes were introduced as potent HDAC1 inhibitors according to molecular docking calculations. Finally, the inhibitory activities of Mn-MOF nanoparticles were evaluated on Escherichia coli and Candida albicans. The MIC, MBC, and MFC values were determined from 2048 to 4096 μg·mL-1 according to antimicrobial susceptibility testing methods. The inhibitory effects of antimicrobial agents can be exacerbated when loaded on BioMOFs.

Synthesis, characterization and antimicrobial activity of metal complexes with N,O-bidentate ligand derived from dimedone

One N,O-bidentate dimedone derivatives ligand (1) and its Ni(II), Pd(II), and Cu(II) complexes (2,3,4) have been prepared and structurally characterized by the spectroscopic methods such as FT-IR, NMR, and X-Ray. 1,3, and 4 crystallize in the triclinic crystal system in the space group P-1, 2 crystallizes in the monoclinic crystal system in the space group C2/c. X-Ray diffraction studies showed 1 exists in enamine form, 2–4 have a square planar geometry around metal atoms which are surrounded by two nitrogen and two oxygen atoms from two ligands. Antibacterial properties of 1–4 have been examined against selected bacteria and yeast strains. Also, the minimum inhibitory concentration of 1–4 against these pathogens was compared with the selected antibiotic drugs. The result revealed that all compounds have good activity.

Benzannulation and Hydrocarboxylation Methods for the Synthesis of a Neopentylene-Fused Analogue of Ibuprofen.

Neopentylene ring fusions (ring-fused 4,4-dimethylcyclopentane polycycles) are found in many natural products, but they are largely absent from synthetic compound libraries and focused medicinal chemistry research. Here is reported a synthetic approach to one of the few non-natural product-based target compounds from medicinal chemistry that includes a neopentylene ring fusion: an analogue of ibuprofen referred to herein as “neoprofen”. The approach features ring-opening fragmentation reactions of dimedone derivatives coupled with transition metal-catalyzed benzannulation and hydrocarboxylation methods.

Deciphering the role of sulfonamides and molecular basis of thioredoxin domain dynamics through comparative simulations

DsbA, a thioredoxin periplasmic protein was prioritized based on subtractive proteomics and immunoinformatics in-depth investigation of Providencia rettgeri proteome. It is an important member of the protein family thioredoxins that catalyzes disulfide bond formation and acts as a folding catalyst for multiple categories of virulence factors. Herein, we performed the molecular dynamics (MD) simulation analysis of synthetic analogues of ubiquinone (dimedone derivatives) that inhibit disulfide bond formation (IC50 ~ 1 μM) catalyzed by E. coli DsbA: DsbB and in comparison propose a sulfonamide comprising compound from the Chembridge library. Both the structures were confined to crystal water molecules and placed in a 5-Å shell of water. The enzyme in solution underwent ligand-induced conformational changes, which appeared to correspond to position shifts in the equilibrium in the crystallographically defined thioredoxin domains. Dimedone derivative eventually drifted away from the thioredoxin domain and shifted to the conserved hydrophobic patch exposing itself to interact preferably with the solvent or the membrane protein DsbB. Comparatively, a Chembridge compound 10,005,560 exhibited strong hydrogen bonding and π- π stacking with the residues ASN155 and PHE56 while moving towards the thioredoxin domain and revealing stability till 250 ns. This positional shift relative to the thioredoxin domain was further analyzed through advanced Radial distribution function (RDF) and Axial frequency distribution (AFD) analyses to confirm the substantial collaboration of sulfonamide core like structures, which could be a starting point into the development of potential DsbA: DsbB inhibitors.

Synthesis and structural characterization of oxovanadium(IV) complexes of dimedone derivatives

We have successfully synthesized new oxovanadium (IV) complexes with dimedone derivatives and their structure were confirmed by elemental analyses, spectroscopic techniques (FT‐IR, UV–visible, EPR) and thermal analysis. The reaction of [VO (acac)2] with the azo dimedone ligands (HLn) produced mononuclear oxovanadium (IV) complexes with formula [VO (Ln)2]H2O. Results of the molar conductance proved that VO2+ complexes are non‐electrolytes and fall in the range 14–16 Ω‐1cm2mol−1. The coordination geometry of VO (IV) complexes is square‐pyramidal, where vanadium (IV) ion is coordinated by oxygen atom of the carbonyl (C=O) group, and nitrogen atom of the deprotonating hydrazone moiety (–NH–), while the fifth position is occupied by an oxo group. Moreover, the optimized structure, bond angles, bond lengths, as well as the calculated quantum chemical parameters of the complexes have been estimated. DNA binding activities of the complexes were investigated using electronic absorption titration and viscosity measurements. The obtained results showed groove binding of the complexes to CT‐DNA accompanied with a partial insertion of the ligand between the base stacks of the DNA with a binding constant of 2.07–5.51 x 105 M−1 range. Evaluation results of the synthesized complexes against the human cancer cell lines HepG‐2 and MCF‐7, as compared to the positive controls in the viability assay of vinblastine and colchicine have been reported. The in vitro anti‐oxidant activity of all the complexes is determined by DPPH free radical‐scavenging assay. Finally, the anti‐microbial activities of the complexes have been investigated against fungal (Candida albicans), gram negative bacteria (Escherichia coli), and gram positive bacteria (Staphylococcus aureus) using the disc‐diffusion method.

Synthesis and Biological Evaluation of Some Newly Synthesized Barbiturates and Their Derivatives by Using Task Specific Ionic Liquid [Bmim]OH

Eco-friendly synthesis of some selected Barbiturates, Thiobarbiturates and Dimedone derivatives has been developed by using task specific ionic liquid Bmim[OH], which not only act as catalyst but also are best solvent media for the Knoevenagel condensation reaction between heteroaryl (pyrazole, 2-chloro-quinoline and Indole) aldehydes with barbituric/ thiobarbituric acid and dimedone. High yield and less reaction time are the advantages of this methodology. All the synthesized compounds were tested for their antimicrobial activities. Most of the compounds showed very good antibacterial and antifungal activity. DOI: http://dx.doi.org/10.17807/orbital.v11i3.1175

Synthesis of 2-[3-Aryl-3-(5-phenylisoxazol-3-yl)propyl] Derivatives of 5,5-Dimethylcyclohexane- and Cyclopenthane-1,3-diones Proceeding from 2-(4-Nitro-3-arylbutyl) Precursors

Regiospecific reduction of carbonyl group of acyl chain in the previously described 4-nitro-3-arylbutanoyl derivatives of dimedone and cyclopentane-1,3-dione was performed. On the basis of nitromethyl group of the enol derivatives of the reduction products obtained from the mentioned compounds nitrile oxide intermediates were prepared, which in situ reacted with phenylacetylene to form the corresponding isoxazole derivatives.

Synthesis and in vitro evaluation of 2-(((2-ether)amino)methylene)-dimedone derivatives as potential antimicrobial agents

The study was designed with an aim to synthesize a series of 2-(((2-ether)amino)methylene)-dimedone derivatives and evaluate the synthesized compounds for antimicrobial activity. Compound library was synthesized by reaction with alkyl, alkenyl, alkynyl and alicyclic bromo-compounds. Characterization of the synthesized compounds was performed by 1H NMR, 13C NMR and mass spectral techniques. The compounds were evaluated for their antibacterial activity against Gram-positive (Staphylococcus aureus, Bacillus subtilis, Clostridium sporogenes) and Gram-negative bacteria (Pseudomonas aeruginosa, Escherichia coli). The activity of these compounds was also evaluated against fungi (Aspergillus fumigatus, Penicillium chrysogenum, Fusarium oxysporum, Candida albicans) and molds (A. niger and A. oryzae). Broth microdilution method and CLSI guidelines with minor modification were used for the determination of anti-bacterial and antifungal activity, respectively. Although four compounds (4i, 4j, 4k and 4l) showed good antibacterial activity but compound 4k was found to be most active chemotype in the series. Compound 4k was found to be active against S. aureus, B. cereus and B. subtilis bacterial strains at one dilution lower compared to the control ciprofloxacin. Antibacterial activity of compound 4k was comparable to ciprofloxacin against S. pyogenes and M. luteus. The compound 4d, 4e and 4s showed good antifungal and antimold activity compared to other chemotypes. However, in comparison to fluconazole both the compounds showed lower activity. The results merit the antimicrobial promise of the 2-(((2-ether)amino)methylene)-dimedone analogs.

A tri-functional vanadium(iv) complex to detect cysteine oxidation.

The development of effective molecular probes to detect and image the levels of oxidative stress in cells remains a challenge. Herein we report the design, synthesis and preliminary biological evaluation of a novel optical probe to monitor oxidation of thiol groups in cysteine-based phosphatases (CBPs). Following orthogonal protecting approaches we synthesised a new vanadyl complex designed to bind to CBPs. This complex is functionalised with a well-known dimedone derivative (to covalently trap sulfenic acids, SOHs) and a coumarin-based fluorophore for optical visualization. We show that this new probe efficiently binds to a range of phosphatases in vitro with nanomolar affinity. Moreover, preliminary flow cytometry and microscopy studies in live HCT116 cells show that this probe can successfully image cellular levels of sulfenic acids - one of the species resulting from protein oxidative damage.

ChemInform Abstract: Potassium‐Exchanged Zirconium Hydrogen Phosphate [α‐Zr(KPO4)2]‐Catalyzed Synthesis of 2‐Amino‐4H‐pyran Derivatives under Solvent‐Free Conditions.

AbstractThe one‐pot three component reaction between dimedone derivatives, malonitrile or cyanoacetate and aryl, alkenyl or alkyl aldehydes provides the title products in generally high yields.

Dimedone Derivative {2-[(4-Hydroxy-phenylamino)- methylene]-5,5-dimethyl-cyclohexane-1,3-dione} Plays an Important Role in Breast Cancer Treatment

Purpose: To investigate the effect of 2-[(4-hydroxy-phenylamino)-methylene]-5,5-dimethyl-cyclohex (HPDH) on mammary carcinogenesis induced by 7,12-dimethylbenz(a)anthracene in female Sprague Dawley rats.Methods: Among three groups of rats (50 each) used in the study, the control group was fed standard diet alone, ibuprofen group received standard diet containing 1200 mg/kg ibuprofen while HPDH group was administered standard diet containing 1200 mg/kg HPDH. The treatment was for 10 days for all the groups. All the animals received 20 mg of DMBA intragastrically by gavage. Clinical parameters for the rats were recorded weekly. Micrometer caliper was used to measure the diameter of all the tumors at the end of the experiment and tumor volume calculated. Histological evaluation was performed using hematoxylin and eosin (H&E) staining. High performance liquid chromatography (HPLC) was used to determine the level of HPDH and ibuprofen in the serum of the animals.Results: The data revealed a significant decrease in the number of rats with mammary tumor, number of tumors/rat and tumor volume by 54, 72 and 75 %, respectively, in HPDH group compared to control group. The ibuprofen- treated rats also showed significant decrease in the number of rats with tumor, number of tumors/rat and tumor volume by 43, 55, and 59 %, respectively. Treatment of rats with HPDH increased the latency period of tumor induction significantly (p < 0.005). Median detection period (50 % of tumors) was 92, 83 and 56 days, respectively, in HPDH, ibuprofen and control groups, respectively, after DMBA induction.Conclusion: These results demonstrate that HPDH possesses strong chemopreventive activity against mammary carcinogenesis.Keywords: Carcinogenesis, Mammary tumor, Median detection period, Tumor, Latency period, Chemopreventive activity, Ibuprofen

Mn(III)-based reaction of alkenes with quinolinones. Formation of peroxyquinolinones and quinoline-related derivatives

The reactions of 1,1-disubstituted alkenes with 4-hydroxyquinolin-2(1H)-ones under both Mn(III)-catalyzed aerobic oxidation conditions at room temperature and Mn(III)-mediated oxidation conditions at reflux temperature are described. The Mn(III)-catalyzed aerobic oxidation afforded bis(hydroperoxyethyl)quinolinones and azatrioxa[4.4.3]propellanes, while the oxidation with Mn(OAc)3·2H2O produced furo[3,2-c]quinolin-4-one analogues. The existence of a substituent at the 3-position of the 4-hydroxyquinolin-2(1H)-ones prevented a double reaction with the alkenes, and (endoperoxy)quinolinones and/or (hydroperoxyethyl)quinolinones were obtained under the Mn(III)-catalyzed aerobic conditions, while furo[3,2-c]quinolinone hemiacetals and vinylquinolinones were selectively produced under the Mn(III)-mediated oxidation conditions depending on the reaction temperature and times. Cyclic assembly of quinolinone-related 1,3-dicarbonyl compounds such as dihydropyridinones, pyranones, and dimedone derivatives was also examined under elevated temperature conditions.

Arylidene Derivatives as Synthons in Heterocyclic Synthesis

This review describes the synthetic procedures for the preparation of arylideneacetophenones, arylidenecycloalkanones, 2-arylidene-1-indanones, 2-arylidene-1-tetralones, 2-arylidene-1-benzosuberones, aurones, 1-thioaurones, 3-arylidene-4-chromanones, 3-arylidene-1-thio-4-chromanones, 3-arylideneflavanones, 3-arylidene-1-thioflavanones, arylideneanilines, arylidenemalononitriles, diethylarylidenemalonates, ethylarylidenecyanoacetates, arylidenecyanoacetamides, 5-arylidene derivatives of barbituric and thiobarbituric acids, arylidene derivatives of Meldrum’s acid and arylidene derivatives of dimedone. Also, it demonstrates the reactivity of these arylidene derivatives in heterocyclic synthesis with emphasis on the most recent findings. Some of these are the α,β-enones, viz. aurones and 3-arylidene-4-chromanones belong to the natural products. The others are synthetic substances which are convenient and important intermediates for the synthesis of a variety of useful and novel heterocyclic systems.

Reaction of Cyanoselenoacetamide with 1,3-Dicarbonyl Compound Anilinomethylene Derivatives

The reaction of cyanoselenoacetamide with a 2-anilinomethylene derivative of Meldrum’s acid (2 equiv. KOH, EtOH, 20°C) gives the 5-cyano-6-hydroseleno-2-oxo-1,2-dihydropyridine-3-carboxylic acid dipotassium salt. The latter reacts with alkyl halides to yield 5-cyano-6-(R-methylseleno)-2-oxo-1,2-dihydropyridine-3-carboxylic acids. Treatment of cyanoselenoacetamide with 2-anilinomethyl derivatives of dimedone and 1,3-cyclohexanedione is accompanied by oxidation and gives 2,2'-di-selane-1,2-diylbis(5-oxo-5,6,7,8-tetrahydroquinoline-3-carbonitriles). The obtained diselanes undergo cleavage using alkyl halides in KOH to give 2-(R-methylseleno)-5-oxo-5,6,7,8-tetrahydroquinoline-3-carbonitriles or selenopheno[2,3-b]quinolines as Thorpe–Ziegler cyclization products of the latter in low yields.

ChemInform Abstract: Unexpected Result in the Reaction of 3‐Amino‐3‐thioxopropanamides with 2‐Anilinomethylene Derivatives of 1,3‐Dicarbonyl Compounds. Synthesis of Pyrimidine‐5‐carboxamide Derivatives.

The interaction of 3-amino-3-thioxopropanamides with 2-anilinomethylene derivatives of dimedone, 1,3-cyclohexanedione and Meldrum’s acid led to the formation of 2-(2-amino-2-oxoethyl)-6-thioxo-1,6-dihydropyrimidine-5-carboxamides. The latter were alkylated in alkaline medium with the formation of 4-(alkylthio)pyrimidine-5-carboxamide derivatives.

Non-cytotoxic Dimedone Derivatives: Structure, Antiradical and UV Protective Studies

Dimedone derivatives (L1-L4) with methyl substitution at the ortho, para and meta positions were synthesized and their anti-radical, photoreactive and photostability activities were evaluated. All compounds are characterized by spectroscopic techniques and by single crystal X ray diffraction. UV exposure experiments on pBR322 showed inhibition of plasmid DNA fragmentation by UV radiation in a dose dependent manner. Radical scavenging assays and ESR spectra indicate that these compounds possess antiradical activities and do not photodegrade to form other side products as confirmed by chromatographic analysis. They are non-cytotoxic towards human keratinocyte HaCaT cell line indicates their potentiality in sunscreens.

Mechanistic aspects of the reaction of dimedone derivatives with sulfenic acids and other sulfur compounds—a computational study

Dimedone derivatives are used as highly selective test reagents for the detection of biogenic sulfenic acids. DFT-calculations have been applied to elucidate the reaction mechanism and the factors triggering the selectivity towards sulfenic acids, in the presence of other sulfur compounds, such as sulfinic acids, sulfonic acids and disulfides. The SN2-like substitution of the sulfenic OH by dimedone requires the active participation of water molecules for pre-orientation of the reactants, as a proton shuttle and depository, as well as a buttressing agent. Alternative reaction pathways could be excluded because of their unfavourable energy profiles.

ChemInform Abstract: Unusual Reaction of Thiomalonamide with 5,5‐Dimethyl‐2‐phenylaminomethylidene‐1,3‐cyclohexanedione.

β-Enaminocarbonyl compounds are commonly used in heterocyclic synthesis as convenient and readily available 1,3-dielectrophile 3C synthones [1, 2]. In previous work [3], we showed that the reaction of 5,5-dimethyl-2-phenylaminomethylidenecyclohexane-1,3-dione (1) with cyanothioacetamide gives the quinoline derivative 2. We established that the reaction of thiomalonamide 3 with dimedone derivative 1 yields 6-thioxopyrimidine-5-carboxamide 4 instead of the expected 3-carbamoyl analog of quinoline 2. Alkylation of carboxamide 4 with benzyl chloride gives benzyl derivative 5. The structures of carboxamides 4 and 5 were supported by IR, H-NMR, and C-NMR spectroscopy, HPLC/MS, elemental analysis, and the results of a H-C HMBC NMR experiment for carboxamide 4 (Fig. 1). The H NMR spectrum of carboxamide 4 shows signals for two amide groups and one methylene group, as well as singlets for protons H-4 and NH. The HPLC/MS shows a peak [M+H] with m/z 213.6. Atom H-4 in the pyrimidine ring in the H-C HMBC spectrum gives four correlation peaks: δ-8.78/127.1 (H-4/C-5), 8.78/159.6 (H-4/C-2), 8.78/163.7 (H-4/5-CONH2), and 8.78/179.7 ppm (H-4/C-6). The CH2 group protons give two cross peaks: δ-3.69/159.6 (CH2/C-2) and 3.69/167.8 ppm (CH2/CO). The finding of cross peaks at δ 7.17/41.1