Dione Ring Research Articles

A rapid synthesis of 5-substituted 7-amino-6-cyano-1,5-dihydro-1H-pyrano[2,3-d]pyrimidine-2,4(3H)-diones and their in silico / in vitro evaluation against SIRT1

The 5-substituted 7-amino-6-cyano-1,5-dihydro-2H-pyrano[2,3-d]pyrimidine-2,4(3H)-diones were explored for their potential inhibitory properties against SIRT1 (Sirtuin 1). The rapid access to this class of compounds was achieved via a sonochemical approach involving the Wang-OSO3H catalyzed three component reaction of barbituric acid, aromatic aldehyde and malononitrile in water. A range of desired products was prepared by using this methodology in good to acceptable yields. The potential of all the synthesized compounds against SIRT1 was initially assessed in silico when three of them e.g. 4i, 4k and 4m emerged as the possible hits. The compound 4i participated in interactions nearly comparable to that of the native ligand Ex527a that involved three hydrogen bonds (H-bonds) (two via its -N-C = O moiety with ILE347 and ASP348 and one via its CN group with HIS363) and interactions via its 3-bromophenyl moiety with ILE411 and PHE297. Further, the docking of 4i, 4k and 4m into the hSIRT2 in silico revealed their weaker interactions with this protein thereby their probable selectivity towards SIRT1 over SIRT2. A majority of the synthesized compounds including 4i, 4k and 4m showed > 50% inhibition when tested against SIRT1 in vitro. The SAR within the current series of compounds suggested a key role of the group present at the C-5 position of the 7-amino-6-cyano-1,5-dihydro-2H-pyrano[2,3-d]pyrimidine-2,4(3H)‑dione ring. Based on SIRT1 IC50 values the compound 4i was identified as the most potent among all the compounds tested and was several fold more potent than nicotinamide. The compound 4i also showed effects on MCF7 and HEK 293T cell lines and the in silico assessment predicted its favorable pharmacokinetic properties. Thus, 4i emerged as an initial hit for further pharmacological studies.

Hyperbeanone A, a 5,6-seco-spirocyclic polycyclic polyprenylated acylphloroglucinol derivative with an unprecedented skeleton from Hypericum beanii

Hyperbeanone A (1), a novel 5,6-seco-polycyclic PPAP derivative characterized by an undescribed benz[f]indene-1,9(4H)-dione ring system fused to a tricyclic γ-lactone unit via a ketone carbonyl, was isolated from the aerial parts of Hypericum beanii.

Crystal structure, Hirshfeld surface analysis and DFT studies of 5-bromo-1-{2-[2-(2-chloro-eth-oxy)eth-oxy]eth-yl}indoline-2,3-dione.

The title compound, C14H15BrClNO4, consists of a 5-bromo-indoline-2,3-dione unit linked to a 1-{2-[2-(2-chloro-eth-oxy)eth-oxy]eth-yl} moiety. In the crystal, a series of C-H⋯O hydrogen bonds link the molecules to form a supramolecular three-dimensional structure, enclosing R 2 2(8), R 2 2(12), R 2 2(18) and R 2 2(22) ring motifs. π-π contacts between the five-membered dione rings may further stabilize the structure, with a centroid-centroid distance of 3.899 (2) Å. The Hirshfeld surface analysis of the crystal structure indicates that the most important contributions for the crystal packing are from H⋯H (28.1%), H⋯O/O⋯H (23.5%), H⋯Br/Br⋯H (13.8%), H⋯Cl/Cl⋯H (13.0%) and H⋯C/C⋯H (10.2%) inter-actions. Hydrogen bonding and van der Waals inter-actions are the dominant inter-actions in the crystal packing. Density functional theory (DFT) optimized structures at the B3LYP/6-311G(d,p) level are compared with the experimentally determined mol-ecular structure in the solid state. The HOMO-LUMO behaviour was elucidated to determine the energy gap. The chloro-eth-oxy-ethoxyethyl side chain atoms are disordered over two sets of sites with an occupancy ratio of 0.665 (8):0.335 (6).

Kinetics and mechanism of the oxidative degradation of sofosbuvir by N-bromosuccinimide in aqueous medium

The kinetics of the electron transfer in sofosbuvir (Sofo) using N-bromosuccinimide (NBS) in aqueous medium has been studied spectrophotometrically over the (10–30) °C range, (0.1–0.5) mol dm−3 ionic strength, pH = 6.0–8.0 range over a range of NBS and Sofo concentrations. The rate of reaction was first order dependence on both [NBS] and [Sofo] and decreased with increasing [H+] over the range studied suggesting that the deprotonated form of sofosbuvir is more reactive than its conjugate acid. The hydrogen atom attached to the nitrogen atom of pyrimidine dione ring has a highly acidic character due to withdrawing effect of the adjacent two carbonyl groups and so the sofosbuvir acted as an acid. The rate decreased with increasing the ionic strength of the reaction mixture and supported that the reaction took place between two ions of different charges.

6-Methyl-1,4-bis[(pyridin-2-yl)methyl]quinoxaline-2,3(1H,4H)-dione

The title compound, C21H18N4O2, crystallizes with one independent molecule in the asymmetric unit. The 6-methylquinoxaline-2,3(1H,4H)-dione unit is essentially planar. The dihedral angles between the mean plane of the 6-methylquinoxaline-2,3(1H,4H)-dione ring and its pendant pyridin-2-yl rings are 85.1 (3) and 73.8 (4)°. The pyridin-2-yl rings are inclined pointing away from the 6-methylquinoxaline-2,3(1H,4H)-dione ring system. In the crystal, molecules are linked by weak C—H...O interactions, forming a three-dimensional network structure.

6-Chloro-1,4-diethylquinoxaline-2,3(1H,4H)-dione

In the title compound, C12H13ClN2O2, the terminal C atoms of the ethyl groups deviate from the mean plane of the quinoxaline-2,3(1H,4H)-dione ring (r.m.s. deviation = 0.016 Å) in opposite directions by −1.451 (2) and 1.472 (2) Å. In the crystal, weak C—H...O interactions link the molecules into [100] chains and aromatic π–π stacking interactions [shortest centroid–centroid separation = 3.6631 (9) Å] are also observed.

Mechanism of resistance to mesotrione in an Amaranthus tuberculatus population from Nebraska, USA.

Amaranthus tuberculatus is a troublesome weed in corn and soybean production systems in Midwestern USA, due in part to its ability to evolve multiple resistance to key herbicides including 4-hydroxyphenylpyruvate dioxygenase (HPPD). Here we have investigated the mechanism of resistance to mesotrione, an important chemical for managing broadleaf weeds in corn, in a multiple herbicide resistant population (NEB) from Nebraska. NEB showed a 2.4-fold and 45-fold resistance increase to mesotrione compared to a standard sensitive population (SEN) in pre-emergence and post-emergence dose-response pot tests, respectively. Sequencing of the whole HPPD gene from 12 each of sensitive and resistant plants did not detect any target-site mutations that could be associated with post-emergence resistance to mesotrione in NEB. Resistance was not due to HPPD gene duplication or over-expression before or after herbicide treatment, as revealed by qPCR. Additionally, no difference in mesotrione uptake was detected between NEB and SEN. In contrast, higher levels of mesotrione metabolism via 4-hydroxylation of the dione ring were observed in NEB compared to the sensitive population. Overall, the NEB population was characterised by lower levels of parent mesotrione exported to other parts of the plant, either as a consequence of metabolism in the treated leaves and/or impaired translocation of the herbicide. This study demonstrates another case of non-target-site based resistance to an important class of herbicides in an A. tuberculatus population. The knowledge generated here will help design strategies for managing multiple herbicide resistance in this problematic weed species.

1,4-Dibenzyl-6-chloroquinoxaline-2,3(1H,4H)-dione

The title compound, C22H17ClN2O2, crystallizes with two independent molecules (AandB) in the asymmetric unit. The 6-chloroquinoxaline-2,3(1H,4H)-dione ring system is essentially planar. The dihedral angles between the mean planes of the 6-chloroquinoxaline-2,3(1H,4H)-dione ring and the phenyl rings of the benzyl substituents in the two molecules are 68.34 and 73.8 (7)° forA, and 73.8 (5) and 80.7 (1)° forB, so that these rings point away from the quinoxaline ring system. In the crystal, weak C—H...O hydrogen bonds and π–π stacking interactions link the molecules into a three-dimensional network.

On the origin of chloride-induced emission enhancement in ortho substituted squaramides

Abstract There is significant current interest in the development of fluorescent sensors for the physiologically relevant chloride ion. In this study we report a new squaramide-based chloride sensor, derived from ethyl ortho aminobenzoate, whose emission intensity increases by nearly 40% upon chloride binding. The intramolecularly hydrogen bonded squaramide exhibited a blue-shifted excitation spectrum relative to its absorption spectrum, and its emission displayed excitation wavelength dependence. These unusual characteristics were attributed to the existence of two ground state conformers for the unbound squaramide; an intramolecular hydrogen bonded conformer which undergoes non-radiative decay and a non-hydrogen bonded non-planar conformer from which emission occurs. Using computational investigations we identified two nearly degenerate excited states arising from two different charge transfer pathways with the squaramide nitrogen atom as the donor and either the cyclobutene dione ring or the ortho substituted N-phenyl ring functioning as acceptors. In the unbound squaramide, this competition between the two charge transfer pathways decreases fluorescence intensity. Chloride binding, suppresses charge transfer into the cyclobutene dione ring thereby enhancing emission intensity. Our study contributes to an increased understanding of the excited states of squaramides and could facilitate their use in the development of new sensors.

ChemInform Abstract: (+)‐ and (‐)‐Ganodilactone, a Pair of Meroterpenoid Dimers with Pancreatic Lipase Inhibitory Activities from the Macromycete Ganoderma leucocontextum.

Abstract(+)‐ and (‐)‐Ganodilactone (I) from the fruiting bodies of Ganoderma leucocontextum are a pair of novel meroterpenoid dimers possessing a unique 5′H‐spiro[chroman‐4,2′‐furan]‐2,5′‐dione ring system.

(+)- and (−)-ganodilactone, a pair of meroterpenoid dimers with pancreatic lipase inhibitory activities from the macromycete Ganoderma leucocontextum

(+)- and (−)-ganodilactone (1), a pair of novel meroterpenoid dimers possessing a unique 5′H-spiro[chroman-4,2′-furan]-2,5′-dione ring system were discovered from the fruiting bodies of Ganoderma leucocontextum.

A Novel Synthesis of Disubstituted Quinazoline Diones with Differential N-Substitution via a Copper-Catalysed Cross-Coupling of Acyl Ureas

An efficient method for the synthesis of disubstituted quinazoline diones with differential N-substitution is reported. A wide range of substitutions on the aromatic and dione rings are tolerated, and the reaction proceeds in high yields under mild conditions.

A Rational Design, Synthesis, Biological Evaluation and Structure--Activity Relationship Study of Novel Inhibitors against Cyanobacterial Fructose-1,6-bisphosphate Aldolase.

In the present study, a series of novel maleimide derivatives were rationally designed and optimized, and their inhibitory activities against cyanobacteria class-II fructose-1,6-bisphosphate aldolase (Cy-FBA-II) and Synechocystis sp. PCC 6803 were further evaluated. The experimental results showed that the introduction of a bigger group (Br, Cl, CH3, or C6H3-o-F) on the pyrrole-2',5'-dione ring resulted in a decrease in the Cy-FBA-II inhibitory activity of the hit compounds. Generally, most of the hit compounds with high Cy-FBA-II inhibitory activities could also exhibit high in vivo activities against Synechocystis sp. PCC 6803. Especially, compound 10 not only shows a high Cy-FBA-II activity (IC50 = 1.7 μM) but also has the highest in vivo activity against Synechocystis sp. PCC 6803 (EC50 = 0.6 ppm). Thus, compound 10 was selected as a representative molecule, and its probable interactions with the surrounding important residues in the active site of Cy-FBA-II were elucidated by the joint use of molecular docking, molecular dynamics simulations, ONIOM calculations, and enzymatic assays to provide new insight into the binding mode of the inhibitors and Cy-FBA-II. The positive results indicate that the design strategy used in the present study is very likely to be a promising way to find novel lead compounds with high inhibitory activities against Cy-FBA-II in the future. The enzymatic and algal inhibition assays suggest that Cy-FBA-II is very likely to be a promising target for the design, synthesis, and development of novel specific algicides to solve cyanobacterial harmful algal blooms.

Crystal structure of 4,4'-[(1,3,5,7-tetra-oxo-1,3,3a,4,4a,5,7,7a,8,8a-deca-hydro-4,8-etheno-pyrrolo-[3,4-f]iso-indole-2,6-di-yl)bis-(methyl-ene)]bis-(pyridin-1-ium) dinitrate.

In the title salt, C24H22N4O4 2+·2NO3 −, the cation is U-shaped with the two iso­indole dione rings inclined to one another by 60.41 (13)°, while the two outer pyridine rings are inclined to one another by 2.77 (12)°. The dihedral angles between the pyridine ring and the adjacent iso­indole dione ring are 71.82 (12) and 86.44 (13)°. In the crystal, each nitrate anion is linked to a protonated pyridine ring by N—H⋯O hydrogen bonds. These units are linked by a series of C—H⋯O hydrogen bonds, forming a three-dimensional structure.

Thermal degradation of biocidal organic N-halamines and N-halamine polymers

Novel biocidal organic N-halamines (based on imidazoline dione rings) were used as a substituents for poly(p-methyl styrene). The biocidal polymers and substituents have been investigated using thermogravimetric analysis. The thermal resistance of investigated compounds was compared to those of non-halogenated precursors. The introduction of chlorine atoms to polymers decreases their thermal resistance comparing to precursors but efficient stabilization is possible by using octyl tin mercaptide. The complex mechanism of thermal decomposition of polymers has been discussed.

Synthesis and X-Ray Crystal Structure of Two Acridinedione Derivatives

The two acridinedione derivatives 1 [3,3,6,6-tetramethyl-9-(4-methoxyphenyl)-3,4,6,7,9,10-hexahydro-2H,5H-acridine-1,8-dione (C24H29NO3)] and 2 [3,3,6,6-tetramethyl-9-(4-methylphenyl)-3,4,6,7,9,10-hexa-hydro-2H,5H-acridine-1,8-dione (C24H29NO2)] were synthesized and their crystal structures were determined by direct methods. The asymmetric unit of compound 1 contains two independent molecules. The 1,4-dihydropyridine (DHP) ring adopts boat conformation in both 1 and 2. In 1 the dione rings exist in sofa conformation (for both the crystallographically independent molecules) while the corresponding rings in 2 adopt half chair and sofa conformations, respectively. The crystal packing is stabilized by intermolecular N–H⋯O and C–H⋯O interactions in compound 1 and N–H⋯O interactions in compound 2.

Novel Monoterpenoid from Cornus Controversa and their Biological Activities

Five new monoterpenoid iridolactones, cornosides A – E (1 – 5) have been isolated from Cornus controversa. The structures of 1 – 5 were elucidated on the basis of extensive spectroscopic analysis. Cornoside A (1) is the first natural cis-fused tricyclic dilactone iridoid possessing a 4S-methyl-1H-2,6-dioxahexahydorcyclopent [c, d]indene-1,7 (2 H)-dione ring system. Cornoside B (2) exhibited potent liver X receptor (LXR) agonistic activity.

ChemInform Abstract: Syntheses and 5-HT2 Antagonist Activity of Bicyclic 1,2,4-Triazol-3(2H) -one and 1,3,5-Triazine-2,4(3H)-dione Derivatives.

A series of bicyclic 1,2,4-triazol-3(2H)-one and 1,3,5-triazine-2,4(3H)-dione derivatives with a 4-[bis(4-fluoro-phenyl)methylene]piperidine or 4-(4-fluorobenzoyl)piperidine group has been prepared and tested for 5-HT2 and alpha 1 receptor antagonist activity. Among the compounds prepared, 2-[2-[4-[bis(4-fluorophenyl)methylene]-piperidin-1-yl]ethyl]- 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one (7b) had the most potent 5-HT2 antagonist activity, which was greater than ritanserin (2), while 7b did not show alpha 1 antagonist activity in vivo. The central 5-HT2 receptor antagonism was approximately 1/30 that of 2 when tested for the ability to block head twitches induced by 5-hydroxytryptophan. Compound 21b, 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-6,7,8,9-tetrahydro- 2H- pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione also displayed potent 5-HT2 antagonist activity. The compound had moderate alpha 1 receptor antagonism, and the potency inhibiting head twitches was about one-third that of ketanserin (1). These results indicate that 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrimidin-3(2H)-one and 6,7,8,9-tetrahydro-2H-pyrido-[1,2-a]-1,3,5-triazine-2,4(3H)-dione ring systems are useful components of 5-HT2 antagonists.

Naphthospironone A: An Unprecedented and Highly Functionalized Polycyclic Metabolite from an Alkaline Mine Waste Extremophile

Bring in the new: Naphthospironone A (1), a novel polycyclic metabolite with an unprecedented spiro[bicyclo[3.2.1]octene-pyran]dione ring system, was isolated from alkalophilic Nocardiopsis sp. (YIM DT266). Its complete structural assignment with the absolute stereochemistry was elucidated by spectroscopic data, X-ray crystal diffraction, and calculation of optical rotation by using DFT methods. Naphthospironone A exhibited moderate cytotoxic and antibiotic bioactivities.

4'-(4-Methoxy-phen-yl)-1,1',1''-trimethyl-dispiro-[indoline-3,2'-pyrrolidine-3',3''-pyrrolidine]-2,2'',5''-trione.

In the title compound, C24H25N3O4, the pyrrolidine ring adopts an envelope conformation while the pyrrolidine-2′′,5′′-dione ring adopts a twist conformation. The indoline unit is planar [maximum deviation of −0.050 (9) Å] and forms a dihedral angle of 40.36 (4)° with the methoxy­phenyl ring. Intra­molecular C—H⋯O hydrogen bonds are observed. In the crystal, mol­ecules are linked into a two-dimensional network parallel to the ab plane by inter­molecular C—H⋯O hydrogen bonds and C—H⋯π inter­actions.