Acridinedione Derivatives Research Articles

Potential acridinedione derivatives for the development of a heterobifunctional PROTAC for targeted degradation of PCSK9 protein

Proprotein convertase substilisin-like/kexin type 9 (PCSK9) interacts with the low-density lipoprotein (LDL) receptor by protein-protein interaction (PPI). The inhibition of this PPI lowers the LDL cholesterol levels, thereby reducing the risks of cardiovascular diseases. We identified in-house synthesized acridinedione scaffolds as binders of PCSK9 through microsecond timescale conventional and biased molecular dynamics (MD) simulations. The free energy of binding was calculated by the Molecular Mechanics Poisson-Boltzmann Surface Area and umbrella sampling methods for acridinedione molecules and compared with reference molecules (co-crystallized inhibitors). Three acridinedione molecules (DSPD-2, DSPD-4, and DSPD-6) were identified as potential binders of the PCSK9 allosteric binding site from preliminary docking and steered MD simulations. The stability of molecules inside the allosteric pocket was established by the low values of root mean square deviations of backbone C-α atoms. The acridinedione derivatives also showed a shorter distance of hydrogen bonds as compared to the standard molecules. The molecule DSPD-6 showed the lowest binding free energy as compared to other selected and standard molecules. The binding of the selected molecules at the allosteric binding pocket had no effect on structural parameters of LDL receptor-binding site of PCSK9 protein. Finally, a proteolysis targeting chimera (PROTAC) was developed by attaching a proteasome recruiting tag to DSPD-6 (lowest binding affinity) to achieve ligand-induced protein degradation. These results qualify the development of the DSPD-6 molecule as a heterobifunctional PROTAC for targeted degradation of PCSK9 protein. Moreover, our computational strategy provides a framework for the identification of molecules against conventionally undruggable PPI targets.

Utilizing magnetic xanthan gum nanocatalyst for the synthesis of acridindion derivatives via functionalized macrocycle Thiacalix[4]arene

An effective method for synthesizing acridinedione derivatives using a xanthan gum (XG), Thiacalix[4]arene (TC4A), and iron oxide nanoparticles (IONP) have been employed to construct a stable composition, which is named Thiacalix[4]arene-Xanthan Gum@ Iron Oxide Nanoparticles (TC4A-XG@IONP). The process used to fabricate this nanocatalyst includes the in-situ magnetization of XG, its amine modification by APTES to get NH2-XG@IONP hydrogel, the synthesis of TC4A, its functionalization with epichlorohydrine, and eventually its covalent attachment onto the NH2-XG@IONP hydrogel. The structure of the TC4A-XG@IONP was characterized by different analytical methods including Fourier-transform infrared spectroscopy, X-Ray diffraction analysis (XRD), Energy Dispersive X-Ray, Thermal Gravimetry analysis, Brunauer–Emmett–Teller, Field Emission Scanning Electron Microscope and Vibration Sample Magnetomete. With magnetic saturation of 9.10 emu g−1 and ~ 73% char yields, the TC4As-XG@IONP catalytic system demonstrated superparamagnetic property and high thermal stability. The magnetic properties of the TC4A-XG@IONP nanocatalyst system imparted by IONP enable it to be conveniently isolated from the reaction mixture by using an external magnet. In the XRD pattern of the TC4As-XG@IONP nanocatalyst, characteristic peaks were observed. This nanocatalyst is used as an eco-friendly, heterogeneous, and green magnetic catalyst in the synthesis of acridinedione derivatives through the one-pot pseudo-four component reaction of dimedone, various aromatic aldehydes, and ammonium acetate or aniline/substituted aniline. A combination of 10 mg of catalyst (TC4A-XG@IONP), 2 mmol of dimedone, and 1 mmol of aldehyde at 80 °C in a ethanol at 25 mL round bottom flask, the greatest output of acridinedione was 92% in 20 min.This can be attributed to using TC4A-XG@IONP catalyst with several merits as follows: high porosity (pore volume 0.038 cm3 g−1 and Pore size 9.309 nm), large surface area (17.306 m2 g−1), three dimensional structures, and many catalytic sites to active the reactants. Additionally, the presented catalyst could be reused at least four times (92–71%) with little activity loss, suggesting its excellent stability in this multicomponent reaction. Nanocatalysts based on natural biopolymers in combination with magnetic nanoparticles and macrocycles may open up new horizons for researchers in the field.

One Pot Efficient Synthesis of Adridinedione derivatives using Flyash-ZrO2 Catalyst under solvent free condition

An efficient one pot green methodology for the synthesis of acridinedione derivatives has been achieved by multicomponent condensation of dimedone, substituted aromatic aldehydes and ammonium acetate in the presence of Flyash-ZrO2 catalyst under solvent free condition. It is clean, eco-friendly, high-yield efficiency procedure with simple work-up, and easy purification method. The synthesized acridinedione derivatives are characterized using spectroscopic analyses like FTIR, 1H NMR, 13C NMR, and mass spectrometry techniques. The synthesized catalyst was characterized using IR, SEM, TEM, BET and X-ray diffraction techniques. The results of these analyses show the formation of highly crystalline Flyash-ZrO2. This catalyst is a most efficient catalyst which gives the high yield of products in a short time.

Selective CDK4/6 inhibition of novel 1,2,3-triazole tethered acridinedione derivatives induces G1/S cell cycle transition arrest via Rb phosphorylation blockade in breast cancer models

CDK4 & CDK6 are essential regulators of initial cell cycle phases and are always considered an exciting choice for anti-cancer therapy. In the present study, we presented the structure-based rational design & synthesis of a new class of 1,2,3-triazole tethered acridinedione derivatives (6a-l) as selective CDK4/6 inhibitors. Title molecules were prepared as a result of the rate-determining reaction between substituted derivatives of 1-Phenyl-1H-1,2,3-triazole-4-carbaldehydes and substituted dimedones, and the molecules were structurally characterized by IR, 1H,13C NMR, and MS spectral data. All molecules were screened for in-vitro cytotoxic potential against a group of human breast tumor cell lines of distinct origin with differential Rb expression status. Out of entire series of conjugated hexahydro acridinediones, 6g showed potent cytotoxic effect against MCF-7, BT-474, and SK-BR3 cell lines with IC50values 0.173 ± 0.037, 0.117 ± 0.025, and 0.136 ± 0.027 μM, respectively. Further, CDK inhibition assays revealed that the compounds 6g and 6h selectively inhibit CDK4/6 over other CDK-parter complexes of the family against the selected cell line group except for MDA-MB468 cells. Furthermore, apoptotic evaluation and cell cycle analysis determined that compound 6g successfully triggered apoptosis in all examined cell lines except MDA-MB468 through blocking G1/S cell cycle transformation. In addition, compound 6g showed the highest in-vitro selectivity towards CDK4/6 inhibition, even compared with Abemaciclib, and it was also proved for favourable in-vivo pharmacokinetic properties in male albino mice. Furthermore, molecule 6g showed promising tumor growth suppression with lower adverse effects in MCF-7 xenograft mice models, which could competently be considered as a novel chemotherapeutic candidate for a further comprehensive preclinical study involving breast cancer therapy.

Synthesis and Biological Evaluation of m-PEG Attached Acridinedione Derivatives as Antimicrobial, Antioxidant and Anticancer Agents

Among heterocycles, a wide variety of nitrogen heterocycles have been exploited to develop pharmaceutically important molecules. Particularly, acridines are clinically used potential drug candidates showing various pharmacological activities. Some of the novel m-PEG attached acridinediones 4(a-j) were synthesized with the readily available starting materials such as dimedone, glycine and aldehydes. Structures of the synthesized compounds were characterized by spectral techniques. The synthesized compounds (4a-j) were evaluated for in vitro antimicrobial, antioxidant and anticancer activities. Compounds 4d, 4e and 4g were found to produce potent antimicrobial activities against Gram-positive and Gram-negative organisms while 4c active against only Gram-positive organisms when compared with the standard, ciprofloxacin. On the other side, 4d and 4i produced potent antioxidant activity and 4a, 4d and 4g exhibited comparable anticancer properties.

Photophysical and molecular docking studies of photoinduced electron transfer (PET) and non-PET based fluorophores of acridinedione derivatives with a glycoprotein: Ovalbumin

Photophysical studies of resorcinol-based family of acridinedione (ADR) dyes with a glycoprotein, ovalbumin (OVA) were carried out in water. Addition of OVA to photoinduced electron transfer (PET) based dye (ADR1) resulted in a considerable red shift of emission maxima with a slight increase in the fluorescence intensity, whereas no significant variation in the fluorescence intensity or shift of emission maxima results in the case of a non-PET dye. Fluorescence lifetime studies illustrates that the PET lifetime component enhances by several fold on the introduction of OVA which is accompanied with the formation of multi lifetime components in the aqueous phase of varying distribution as observed in well-known globular protein, bovine serum albumin (BSA). Interestingly, a decrease in the fluorescence lifetime of non-PET dye (ADR2) with the evolution of more than one distinct lifetime species results with OVA. This behaviour ascertains the presence of at least two different micro environment of dye residing in aqueous phase on the addition of OVA. The introduction of OVA induces the formation of several distinguishable micro environments around the close vicinity of the dye molecule that are subjected to various binding forces. Further, the dye bound to several amino acid residues through conventional and non-conventional hydrogen-bonding interactions accompanied with hydrophobic interactions, pi-pi, pi-alkyl interactions and weak van der Waals forces also coexist. The variation in binding energies of various dye-OVA conformations are established from molecular docking (MD) techniques. The combination of docking techniques validates and authenticates the origin of multi decay characteristics of dye-OVA complex that correlates dye bound to different binding sites in protein. A combined approach of fluorescence techniques along with MD methods and Isothermal Calorimetric Titration (ITC) studies provides an excellent approach in determining the nature of interaction and binding stability of dye-protein system in a micro heterogeneous environment.

Retraction: Pt NPs@GO as a highly efficient and reusable catalyst for one-pot synthesis of acridinedione derivatives.

Retraction for ‘Pt NPs@GO as a highly efficient and reusable catalyst for one-pot synthesis of acridinedione derivatives’ by Handan Pamuk et al., RSC Adv., 2015, 5, 49295–49300, DOI: 10.1039/C5RA06441D.

Structural and energetics of weak non-covalent interactions in two chemically distinct classes of O/N-heterocycles: X-ray and theoretical exploration

Two different classes of compounds namely xanthenedione and acridinedione derivatives have been synthesized and crystal structures of these compounds (9-(p-tolyl)-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione, C20H20O3, 1 and 9-(p-tolyl)-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione, C20H21NO2, 2) are reported. The X-ray analysis reveals that the central heterocyclic ring exhibits boat conformation and the cyclohexene rings have envelope conformations in both structures. The Hirshfeld surface analysis suggests that the relative contribution of H···H, H···O and H···C contacts have not changed due to the positional isomers (ortho and para) of 1. The same is true when NH group replaces the O atom in the central ring as well. The PIXEL energy analysis suggests that the intermolecular C–H···O and C–H···C(π) interactions stabilize the crystal structure of 1. In 2, the intermolecular N–H···O, C–H···O and C–H···C(π) interactions existing in different dimers. The isostructurality analysis indicates that the structure 1 shares 2D isostructurality with one of its closely related structure, whereas structure 2 shares only 0D isostructurality with its closely related structure. The lattice energy calculation for 1 and its ortho isomer and compound 2 is reported. The energy frameworks analysis was performed in order to visualize the topology of the energy frameworks for these crystals. The topological analysis is presented for intermolecular interactions existing in 1 and 2. The frontier molecular orbital analysis suggests that the HOMO orbital's localization shows distinct features for 1 and 2.

New Hydrogen-Bond-Enriched 1,3,5-Tris(2-hydroxyethyl) Isocyanurate Covalently Functionalized MCM-41: An Efficient and Recoverable Hybrid Catalyst for Convenient Synthesis of Acridinedione Derivatives.

A new nano-ordered 1,3,5-tris(2-hydroxyethyl) isocyanurate-1,3-propylene covalently functionalized MCM-41 (MCM-41-Pr-THEIC) was designed and prepared at room temperature through a simple procedure. According to various microscopic, spectroscopic, or thermal methods and techniques, the correlation of the catalytic performance of the hybrid mesoporous MCM-41-Pr-THEIC to its structural characteristics was fully confirmed. The new MCM-41-Pr-THEIC organosilica nanomaterials were successfully investigated as a solid mild nanocatalyst through hydrogen-bonding activation provided by its organic moiety, for the pseudo-four-component condensation of dimedone, aldehydes, and ammonium acetate or p-toluidine to afford the corresponding acridinedione derivatives under green conditions. Furthermore, the introduced nanocatalyst could be reused at least four times with negligible loss of its activity, indicating the good stability and high activity of the new hybrid organosilica.

Highly Efficient and Reusable Pd/AlO(OH) Catalyzed Synthesis of Acridinedione Derivatives

Background: Synthesis of acridinedione derivatives via one-pot multi-component approaches using highly active and reusable Pd/AlO(OH) heterogenous catalyst was studied. This process provided a convenient method to obtain various acridinediones with potential biological activities. The reactions were performed in mild conditions such as low temperature and short reaction time with desirable yields. Methods: Commercially available Pd/AlO(OH) nanoparticles characterized by XRD and SEM methods were afforded for the synthesis of acridinedione derivatives with high yields. Crude products were analyzed by GC and 1H NMR. The reactions were completed within 1h at 40°C by the assistance of ultrasound system. Results: Optimization of reaction conditions is of critical case for successful synthesis. Solvent, temperature, time and amount of catalyst were studied. At the end of the experiments, the synthesis of 1 mmol of acridinedione was optimized by using 25 mg of Pd/AlO(OH) NPs, 3 ml of DMF for 60 min at 40°C in the ultrasound system. An experimental work to check the reusability of the catalyst was also studied. Pd/Al(O)OH catalyst in the first run was higher than that of the reused catalyst in the fifth run. ICP-OES analyses showed palladium leaching into the reaction medium was only 1.1% which is negligible. Nanocatalyst employed a high activity and good reusability. Conclusion: A convenient and versatile method was developed for the synthesis of acridinediones in a mild condition with absolute conversion and high yield using ultrasound system in the presence of nanocatalyst.

An AIE based fluorescent probe for digital lifting of latent fingerprint marks down to minutiae level

Abstract Acridinediones, a new addition to the family of dyes having aggregation induced emission characteristics have been reported. Facile hydrophobic interactions between the acridinedione aggregates and fingerprint residues were exploited to lift the latent fingerprint marks on a non-porous substrate. By employing this preferential adhesion approach, a portable wet method for the enhancement and visualization of latent fingerprint marks using hand held UV light and mobile camera was demonstrated. Using this simple, rapid, cost effective, eco and user friendly method the latent fingerprints, its primary and secondary level of information’s can be easily decoded. These acridinedione derivatives also show strong blue luminescence in solid state with high fluorescence quantum yield.

Microwave-assisted SiO2-H2SO4-catalyzed Synthesis of 3,4,6,7-Tetrahydro-3,3,6,6-Tetramethyl-9,10-diphenylacridine-1,8-dione Derivatives as Cholesterol Esterase Inhibitors

A library of 3,4,6,7-tetrahydro-3,3,6,6-tetramethyl-9,10-diphenylacridine-1,8-dione derivatives were synthesized via microwave-assisted three-component reaction employing silica supported sulphuric acid under solvent free conditions and tested for in vitro cholesterol esterase inhibitory activity. All synthesized compounds exhibited moderate to good inhibition of cholesterol esterase enzyme. Among all the synthesized acridinedione derivatives, compound HSM-1a showed the most promising activity with IC50 value of 1.53 µM against cholesterol esterase enzyme. Enzyme kinetic studies carried out for HSM-1a, revealed its mixed-type inhibition approach. Molecular protein–ligand docking studies were also performed to figure out the key binding interactions of HSM-1a with the amino acid residues of the enzyme’s active site. Furthermore, acquiescence of some potent compounds to the Lipinski rule was also determined.

Functionalized Multi‐Walled Carbon Nanotubes (f‐MWCNT) as Highly Efficient and Reusable Heterogeneous Catalysts for the Synthesis of Acridinedione Derivatives

AbstractAddressed herein, carboxylic acid groups were immobilized onto carbon nanotubes and their catalytic properties were examined for the first time for the synthesis of acridinedione derivatives, opening new paths in the investigation of catalysis and their comparison with carbon‐based materials. An efficient methodology for the synthesis of acridinedione derivatives has been achieved by one‐pot, multi‐component condensation of dimedone, substitute aromatic aldehydes, various aromatic amines and, in the presence of the easily available, inexpensive, and nontoxic f‐MWCNTs as versatile biodegradable catalysts. At this method, f‐MWCNTs carrying simple carboxylic acid functionalities catalyze the model reaction in ethanol providing the product in a quantitative yield. This highly monodisperse catalyst is one of the most efficient catalysts which gives the highest yield of products in the shortest time. Its high‐yield efficiency, clean, eco‐friendly, simple work‐up procedure, and easy purification are regarded to be the main advantages of this method. The synthesized compounds are characterized using spectroscopic (IR, 1H‐NMR, 13C‐NMR and HRMS) techniques.

Graphene Oxide as Highly Effective and Readily Recyclable Catalyst Using for the One-Pot Synthesis of 1,8-Dioxoacridine Derivatives.

Graphene oxide as a highly stable, reusable, isolable, and efficient catalyst has been used for the first time for the synthesis of acridinedione derivatives from dimedone, aromatic aldehydes and various amines with great catalytic performance. One pot synthesis of acridinedione compounds were performed using highly efficient graphene oxide.

ChemInform Abstract: One‐Pot, Efficient and Green Synthesis of Acridinedione Derivatives Using Highly Monodisperse Platinum Nanoparticles Supported with Reduced Graphene Oxide.

AbstractThe title compounds are prepared by multicomponent cyclocondensation of dimedone, benzaldehydes, and anilines in short times and high yields.

Synthesis of 8,16-diarylacridino[4,3-c]acridine-1,9-dione derivatives

A number of new acridino[4,3-c]acridinedione derivatives have been synthesized for the first time by condensation of N1,N5-bis(arylmethylidene)naphthalene-1,5-diamines with cyclic 1,3-diketones (cyclohexane-1,3-dione and dimedone). The product structure has been determined by two-dimensional NMR spectroscopy, and a probable reaction mechanism has been proposed.

ChemInform Abstract: Magnetically Separable Recyclable Nano‐Ferrite Catalyst for the Synthesis of Acridinediones and Their Derivatives under Solvent‐Free Conditions.

AbstractA facile and green protocol for the synthesis of acridinedione derivatives (III) (19 examples) via Fe‐catalyzed condensation of dimedone with aldehydes and NH4OAc is developed.

Synthesis of 1,8-Dioxo-Decahydroacridines using Pyridinium Hydrogen Sulfate Ionic Liquid as an Green, Efficient and Reusable Catalyst

Background: In this research, pyridinium hydrogen sulfate ionic liquid (PHSIL) was employed as a green, efficient and reusable catalyst for the synthesis of 1,8-dioxo-decahydroacridines. Different primary amines and aromatic aldehydes were subjected to the reaction with 5,5-dimethyl- 1,3-cyclohexanedione (dimedone) in the presence of this catalyst and the corresponding products were achieved in excellent yields and short reaction times. Two important advantages of the study were easily separation of ionic liquid from the reaction mixture by water extraction and a high recycling capability of up to six times. Methods: Different primary amines and aromatic aldehydes were subjected to the reaction with 5,5-dimethyl-1,3- cyclohexanedione (dimedone) in the presence of, pyridinium hydrogen sulfate ionic liquid (PHSIL) catalyst and the corresponding 1,8-dioxo-decahydroacridines derivatives were achieved in excellent yields and short reaction times. Results: Having established optimum conditions as follows: aldehyde (1 mmol), amine (1 mmol), PHSIL (0.65 mmol), CH3CN (3 mL) at 80°C, a series of 1,8-dioxo-decahydroacridines were synthesized via the one-pot three component reaction between various aromatic aldehydes and amines with dimedone. The aromatic aldehydes containing electrondonating and electron-withdrawing groups afforded 1,8-dioxo-9-aryl-10-aryl-decahydroacridines with high yields within short reaction times in comparison with other conventional procedures. The presence of substituent on the amine has the same effect. All compounds were identified by melting point (in some cases), IR spectra, 1H- and 13C-NMR and elemental analysis. Conclusion: In summary, pyridinium hydrogen sulfate ionic liquid was used as a green catalyst for the synthesize of 1,8- dioxo-decahydroacridines. Various derivatives of acridinediones were synthesized in high yield. Short-time reaction, high yield, stability, reusability up to six times, relatively non-toxicity of the catalyst, economically viable and one-pot synthesis of acridinedione derivatives are the important advantages of the reported method. Keywords: 1, 8-dioxo-decahydroacridines, green chemistry, ionic liquid, pyridinium hydrogen sulfate, reusability.

One-pot, efficient and green synthesis of acridinedione derivatives using highly monodisperse platinum nanoparticles supported with reduced graphene oxide

An efficient, high yielding, quick method has been developed for the synthesis of acridinedione derivatives using highly monodisperse Pt NPs@rGO.

One-Pot, Facile, Highly Efficient, and Green Synthesis of Acridinedione Derivatives Using Vitamin B1

An efficient methodology for the synthesis of acridinedione derivatives 4a–o has been achieved by one-pot, multicomponent condensation of dimedone 1, various amines 2a–d, and substitute aromatic aldehydes 3a–k, in the presence of the easily available, inexpensive, and nontoxic catalyst vitamin B1 (VB1) as a versatile biodegradable. Synthesis of acridine-type compounds was performed in good yields in water as green solvent. Its high-yield efficiency; clean, ecofriendly, simple workup procedure; and easy purification are regarded as the main advantages of this method besides its green solvent. The synthesized compounds are characterized using spectroscopic analyses (FTIR, 1H NMR, 13C NMR, and high-resolution mass spectrometry) techniques.