Benzoyl Ring Research Articles

Synthesis and properties of shape memory polyurethanes generated from schiff-base chain extender containing benzoyl and pyridyl rings

In this study, 4,4′-diphenylmethane diisocyanate and polytetramethylene glycol were used to prepare a prepolymer; N,N′-bis(4-hydroxybenzylidene)-2,6-diaminopyridine (BHBP) was used as a chain extender; and these elements were combined to prepare a novel polyurethane, BHBP/PU. Gel permeation chromatography revealed that the molecular weight of the BHBP/PU samples increased as the BHBP content was increased. Fourier transform infrared spectroscopy demonstrated that high BHBP content facilitated strong hydrogen bonding in the samples. Differential thermogravimetry indicated that the initial decomposition temperature of BHBP/PU-3 was approximately 10 °C higher than that of BHBP/PU-1. Differential scanning calorimetry and dynamic mechanical analysis revealed that increasing the BHBP content substantially increased both the glass transition and dynamic glass transition temperatures of the BHBP/PU samples. The tensile strengths of BHBP/PU-1, BHBP/PU-2, and BHBP/PU-3 were 7.7, 10.9, and 21.6 MPa, respectively, with corresponding Young’s moduli of 0.7, 1.9, and 3.3 MPa. These results demonstrated that both the tensile strength and Young’s modulus of the BHBP/PU samples increased as the BHBP content was increased. Moreover, the BHBP/PU samples exhibited excellent shape recovery of >90%.

Characterization of the biodegradation, bioremediation and detoxification capacity of a bacterial consortium able to degrade the fungicide thiabendazole.

Thiabendazole (TBZ) is a persistent fungicide used in the post-harvest treatment of fruits. Its application results in the production of contaminated effluents which should be treated before their environmental discharge. In the absence of efficient treatment methods in place, biological systems based on microbial inocula with specialized degrading capacities against TBZ could be a feasible treatment approach. Only recently the first bacterial consortium able to rapidly transform TBZ was isolated. This study aimed to characterize its biodegradation, bioremediation and detoxification potential. The capacity of the consortium to mineralize 14C-benzyl-ring labelled TBZ was initially assessed. Subsequent tests evaluated its degradation capacity under various conditions (range of pH, temperatures and TBZ concentration levels) and relevant practical scenarios (simultaneous presence of other postharvest compounds) and its bioaugmentation potential in soils contaminated with increasing TBZ levels. Finally cytotoxicity assays explored its detoxification potential. The consortium effectively mineralized the benzoyl ring of the benzimidazole moiety of TBZ and degraded spillage level concentrations of the fungicide in aqueous cultures (750mg L-1) and in soil (500mgkg-1). It maintained its high degradation capacity in a wide range of pH (4.5-7.5) and temperatures (15-37°C) and in the presence of other pesticides (ortho-phenylphenol and diphenylamine). Toxicity assays using the human liver cancer cell line HepG2 showed a progressive decrease in cytotoxicity, concomitantly with the biodegradation of TBZ, pointing to a detoxification process. Overall, the bacterial consortium showed high potential for future implementation in bioremediation and biodepuration applications.

N′-[Bis(methylsulfanyl)methylidene]-2-methoxybenzohydrazide

In the title compound, C11H14N2O2S2, the diethyl dithioate groups are inclined slightly to the benzoyl ring, making a dihedral angle of 14.0 (3)°. A short intramolecular N—H...O contact generates anS(6) ring. In the crystal, C—H...O contacts generate aC(8) chain motif along [010].

Characterization of Benzoyl Saxitoxin Analogs from the Toxigenic Marine Dinoflagellate Gymnodinium catenatum by Hydrophilic Interaction Liquid Ion-Chromatography-Tandem Mass Spectrometry

The chain-forming marine dinoflagellate Gymnodinium catenatum Graham has a remarkable capacity to produce a wide array of neurotoxic alkaloids associated with Paralytic Shellfish Poisoning (PSP). More than a decade ago, a completely new group of benzoyl saxitoxin analogs produced exclusively by this species was discovered, but the exact structural assignments and diversity among global population has remained elusive and nconfirmed in most cases. In the current study, fifteen among eighteen hypothetical benzoyl analogs were partially purified and identified from cultured isolates of G. catenatum from the Pacific coast of Mexico. Combined serial application of flash chromatography, preparative liquid chromatography and tandem mass spectrometry (LC-MS/MS) in multiple steps yielded a richness of benzoyl analogs that has not been reported nor confirmed before. Two sub-fractions were analyzed by 1H-NMR; results from one fraction showed a probable AMX pattern for three protons, consistent with the presence of a 3,4-dihydroxylated benzoyl ring. These findings could be interpreted to correct the 2,4-dihydroxylated structure previously proposed for the GCa benzoyl analog series. The revised and enhanced structural information on proposed benzoyl derivatives is necessary to provide further insights into biogeographical diversity of these potentially potent toxins produced by marine dinoflagellates and their role in seafood safety.

Crystal structure and computational studies of (3Z)-4-benzoyl-3-[(2,4-di-nitro-phen-yl)hydrazinyl-idene]-5-phenyl-furan-2(3H)-one.

In the mol-ecular structure of the title compound, C23H14N4O7, the furan, di-nitro-phenyl and phenyl rings are almost in the same plane (r.m.s. deviation = 0.127 Å), with the benzoyl ring inclined by a dihedral angle of 56.4 (1)° to the three-ring system. A bifurcated intra-molecular N-H⋯(O,O) hydrogen bond is present. In the crystal, adjacent mol-ecules are linked by C-H⋯O hydrogen bonds into chains parallel to [001]. A π-π stacking inter-action between the benzoyl and di-nitro-phenyl moieties contributes to the crystal packing. Theoretical calculations using DFT(B3YLP) methods were used to confirm the mol-ecular structure.

Crystal structures of 2'-benzoyl-1'-(4-methyl-phenyl)-1,1',2,2',5',6',7',7a'-octa-hydro-spiro-[indole-3,3'-pyrrolizin]-2-one and 2'-(4-bromo-benzoyl)-1'-(2-chloro-phen-yl)-1,1',2,2',5',6',7',7a'-octa-hydro-spiro-[indole-3,3'-pyrrolizin]-2-one.

The two title compounds, C28H26N2O2, (I), and C27H22BrClN2O2, (II), differ in their substituents, viz.4-methyl-phenyl and benzoyl rings in (I) replaced by 2-chloro-phenyl and 4- bromo-benzoyl, respectively, in (II). A significant difference between the two mol-ecules is found in the deviation of the benzoyl O atom from the least-squares plane of the ring to which it is attached [0.593 (4) and 0.131 (3) Å, respectively], a fact which may be attributed to the different participation of the benzoyl O atoms as acceptors in their inter-molecular C-H⋯O inter-actions. The chemical modifications in (I) and (II) do not seem to affect the type nor strength of the inter-molecular N-H⋯N and C-H⋯O hydrogen bonds responsible for the two crystal structures, such that the aggregation of mol-ecules appears similar in spite of the mol-ecular changes.

5-Benzoyl-2-(5-bromo-1H-indol-3-yl)-4-(4-methoxyphenyl)-1H-pyrrole-3-carbonitrile

In the title compound, C27H18BrN3O, the indole and central pyrrole ring systems are inclined to one another by 13.15 (15)°. The carbonitrile group is almost coplanar with its attached pyrrole ring, the C[triple-bond]N bond making a dihedral angle of 1.9 (2)° with the ring plane. The 4-methoxybenzene ring and the benzoyl ring are inclined to the central pyrrole ring by 55.1 (2) and 51.5 (2)°, respectively. The dihedral angle between these two benzene rings is 37.68 (17)°. In the crystal, molecules are linked by pairs of N—H...N hydrogen bonds, forming inversion dimers with anR22(16) ring motif. The dimers are linked by offset π–π interactions [intercentroid distance = 3.614 (2) Å], which leads to the formation of chains propagating in the [010] direction.

Synthesis of 9-O-3-(1-piperazinyl/morpholinyl/piperidinyl)pentyl-berberines as Potential Antioxidant and Cytotoxic Agents

A new series of 9-O-3-(1-piperazinyl/morpholinyl/piperidinyl)pentyl-berberines has been efficiently formulated via coupling 1,5-dibromopentane with berberrubine which was obtained by treating berberine in a vacuum oven at optimum temperature and pressure. Nucleophilic substitution of a variety of substituted piperazines, morpholine, carbazole and piperidine furnished analogues 5a-i. Final compounds were evaluated for their in vitro antioxidant activity using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6- sulphonic acid) (ABTS) bioassays. Also, cancer cell inhibitory potential of titled compounds was screened for cervical cancer, HeLa and CaSki employing SRB assay in terms of cytotoxicity. A minimum inhibitory concentration of 5a-i towards normal cells was studied using Madin-Darby canine kidney (MDCK) cell line. Final compounds with carbazole and 1-(naphthalen-2-yl)piperazine showed excellent free radical scavenging efficacies in DPPH and ABTS bioassays, respectively. The presence of naphthyl, benzhydryl, benzoyl, furoyl and heterocyclic rings on the piperazine system was essential to exert anticipated cytotoxic effects against cancer cell lines. The structure of the final compounds was adequately confirmed via spectroscopic techniques, elemental analysis analysis and characterization of physical properties.

5-Benzoyl-2-(1H-indol-3-yl)-4-(naphthalen-2-yl)-1H-pyrrole-3-carbonitrile

In the title compound, C30H19N3O, the indole and the naphthalene ring systems are inclined to the central pyrrole ring (r.m.s. deviation = 0.012 Å) by 29.09 (9) and 49.92 (9)°, respectively. The naphthalene ring system and the indole ring are inclined to one another by 73.57 (6) and by 42.58 (10) and 74.12 (10)°, respectively, to the benzoyl ring. In the crystal, molecules are linked by pairs of Np—H...O (p = pyrrole) hydrogen bonds, forming inversion dimers withR22(10) loops. These dimers are linkedviapairs of Ni—H...Nc(i = indole and c = carbonitrile) hydrogen bonds, enclosingR22(16) loops, which leads to the formation of chains propagating in [101]. The chains are linked by C—H...π interactions, forming slabs lying parallel to (10-1).

Synthesis and antiproliferative activity of benzophenone tagged pyridine analogues towards activation of caspase activated DNase mediated nuclear fragmentation in Dalton’s lymphoma

A series of benzophenones possessing pyridine nucleus 8a–l were synthesized by multistep reaction sequence and evaluated for antiproliferative activity against DLA cells by in vitro and in vivo studies. The results suggested that, compounds 8b with fluoro group and 8e with chloro substituent at the benzoyl ring of benzophenone scaffold as well as pyridine ring with hydroxy group exhibited significant activity. Further investigation in mouse model suggests that compounds 8b and 8e have the potency to activate caspase activated DNase (endonuclease) which is responsible for DNA fragmentation, a primary hallmark of apoptosis and thereby inhibits the Dalton’s lymphoma ascites tumour growth.

Supra-molecular hydrogen-bonding patterns in the N(9)-H protonated and N(7)-H tautomeric form of an N(6) -benzoyl-adenine salt: N (6)-benzoyl-adeninium nitrate.

In the title molecular salt, C12H10N5O(+)·NO3 (-), the adenine unit has an N (9)-protonated N(7)-H tautomeric form with non-protonated N(1) and N(3) atoms. The dihedral angle between the adenine ring system and the phenyl ring is 51.10 (10)°. The typical intra-molecular N(7)-H⋯O hydrogen bond with an S(7) graph-set motif is also present. The benzoyl-adeninium cations also form base pairs through N-H⋯O and C-H⋯N hydrogen bonds involving the Watson-Crick face of the adenine ring and the C and O atoms of the benzoyl ring of an adjacent cation, forming a supra-molecular ribbon with R 2 (2)(9) rings. Benzoyl-adeninum cations are also bridged by one of the oxygen atoms of the nitrate anion, which acts as a double acceptor, forming a pair of N-H⋯O hydrogen bonds to generate a second ribbon motif. These ribbons together with π-π stacking inter-actions between the phenyl ring and the five- and six-membered adenine rings of adjacent mol-ecules generate a three-dimensional supra-molecular architecture.

A New Molecular Design Based on Thermally Activated Delayed Fluorescence for Highly Efficient Organic Light Emitting Diodes.

Two benzoylpyridine-carbazole based fluorescence materials DCBPy and DTCBPy, bearing two carbazolyl and 4-(t-butyl)carbazolyl groups, respectively, at the meta and ortho carbons of the benzoyl ring, were synthesized. These molecules show very small ΔEST of 0.03 and 0.04 eV and transient PL characteristics indicating that they are thermally activated delayed fluorescence (TADF) materials. In addition, they show extremely different photoluminescent quantum yields in solution and in the solid state: in cyclohexane the value are 14 and 36%, but in the thin films, the value increase to 88.0 and 91.4%, respectively. The OLEDs using DCBPy and DTCBPy as dopants emit blue and green light with EQEs of 24.0 and 27.2%, respectively, and with low efficiency roll-off at practical brightness level. The crystal structure of DTCBPy reveals a substantial interaction between the ortho donor (carbazolyl) and acceptor (4-pyridylcarbonyl) unit. This interaction between donor and acceptor substituents likely play a key role to achieve very small ΔEST with high photoluminescence quantum yield.

Crystal structure of N'-[bis-(ethyl-sulfan-yl)methyl-idene]-2-hy-droxy-4-meth-oxy-benzohydrazide.

In the title compound, C13H18N2O3S2, the amide group is in the plane of the ­benzoyl ring with a C—N—N—C torsion angle of 177.63 (12)°. The two di­thio­ate groups are in an anti conformation [torsion angles = 173.68 (8) and −9.98 (10)°]. An intra­molecular N—H⋯O hydrogen bond is observed. In the crystal, an O—H⋯O hydrogen bond and a weak C—H⋯O contact involving the same acceptor atom generate an S(6) ring motif and give rise to chains along [010].

Crystal structure of (2-methyl-4-phenyl-4H-benzo[4,5]thia-zolo[3,2-a]pyrimidin-3-yl)(phen-yl)methanone.

In the title compound, C24H18N2OS, the pyrimidine ring has a flat envelope conformation with the methine C atom as the flap. The attached phenyl and benzoyl rings are inclined to the mean plane of the pyrimidine ring by 84.87 (8) and 75.33 (9)°, respectively. The benzo­thia­zolo group is planar (r.m.s. deviation = 0.009 Å) and inclined to the mean plane of the pyrimidine ring by 3.27 (6)°. In the crystal, mol­ecules are linked by pairs of C—H⋯N hydrogen bonds, forming inversion dimers.

Abstract 2706: Tumor-targeting with novel pyridyl 6-substituted pyrrolo[2,3-d]pyrimidine antifolates via cellular uptake by folate receptor (FR) α and the proton-coupled folate transporter (PCFT) and inhibition of de novo purine nucleotide biosynthesis

Abstract Recent interest has focused on exploiting non-reduced folate carrier (RFC) uptake processes including FRα and PCFT for delivering cytotoxic folate-based therapeutics to solid tumors. FRα is highly expressed in certain tumors, including ovarian and non-small cell lung cancers, whereas PCFT is expressed in most solid tumors and is active at pHs characterizing the tumor microenvironment. Although FRα is present in normal epithelial tissues, this is restricted to apical membranes and is inaccessible to the circulation. PCFT is essentially inactive at neutral pH characterizing most normal tissues. Selectivity of FR-targeted agents would be enhanced if these were also poor substrates for RFC. We previously demonstrated potent antiproliferative activities for a novel 6-substituted-pyrrolo[2,3-d]pyrimidine benzoyl antifolate with a 4-carbon bridge length (AG23). With KB human tumor cells, AG23 inhibited cell proliferation via FRα uptake and inhibition of de novo purine biosynthesis at β-glycinamide ribonucleotide formyltransferase (GARFTase), resulting in ATP depletion. We replaced the side-chain benzoyl ring of AG23 with a pyridine to generate region-isomeric pyridyl 6-substituted-pyrrolo[2,3-d]pyrimidine antifolates, AG105 (3N, 6N), AG107 (2N, 5N), and AG109 (2N, 6N). AG105, AG107, and AG109 were tested in proliferation assays with isogenic Chinese hamster ovary (CHO) sublines expressing RFC (PC43-10), FRα (RT16), or PCFT (R2/PCFT4) and the results compared to those for AG23. Additional testing was performed with KB cells. All analogs were inactive with RFC-expressing CHO cells. For FRα-expressing RT16 and KB cells, growth inhibition was in the order, AG107>AG23>AG105>>AG109. For AG107, the IC50 toward KB cells was ∼0.6 nM, slightly exceeding that for AG23. Drug effects were abolished with excess folic acid, confirming FR uptake. Inhibition of cell proliferation was reflected in high affinity binding to FRα, measured by competition with [3H]folic acid. AG107, but not AG105 or AG109, inhibited proliferation of R2/PCFT4 CHO cells expressing PCFT without FRα (IC50∼58 nM; ∼4-fold lower than for AG23). AG107 bound to PCFT, as reflected in inhibition of [3H]methotrexate uptake at pH 5.5 and 6.8; AG105 and AG109 were also inhibitory, albeit less than AG107. By protection experiments with excess thymidine or adenosine, de novo purine biosynthesis was confirmed as the targeted pathway. GARFTase was inhibited in KB cells in situ at concentrations approximating those for AG23 and which inhibited cell proliferation. Our results establish an interesting structure-activity relationship for inhibitory pyridyl 6-substituted-pyrrolo[2,3-d]pyrimidine antifolates which promotes efficacy toward FRα- and PCFT-expressing cells. Citation Format: Christina Cherian, Lei Wang, Adrianne Wallace, Steven Orr, Zhanjun Hou, Aleem Gangjee, Larry H. Matherly. Tumor-targeting with novel pyridyl 6-substituted pyrrolo[2,3-d]pyrimidine antifolates via cellular uptake by folate receptor (FR) α and the proton-coupled folate transporter (PCFT) and inhibition of de novo purine nucleotide biosynthesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2706. doi:10.1158/1538-7445.AM2014-2706

Novel Piperazine-based Compounds Inhibit Microtubule Dynamics and Sensitize Colon Cancer Cells to Tumor Necrosis Factor-induced Apoptosis

We recently identified a series of mitotically acting piperazine-based compounds that potently increase the sensitivity of colon cancer cells to apoptotic ligands. Here we describe a structure-activity relationship study on this compound class and identify a highly active derivative ((4-(3-chlorophenyl)piperazin-1-yl)(2-ethoxyphenyl)methanone), referred to as AK301, the activity of which is governed by the positioning of functional groups on the phenyl and benzoyl rings. AK301 induced mitotic arrest in HT29 human colon cancer cells with an ED50 of ≈115 nm. Although AK301 inhibited growth of normal lung fibroblast cells, mitotic arrest was more pronounced in the colon cancer cells (50% versus 10%). Cells arrested by AK301 showed the formation of multiple microtubule organizing centers with Aurora kinase A and γ-tubulin. Employing in vitro and in vivo assays, tubulin polymerization was found to be slowed (but not abolished) by AK301. In silico molecular docking suggests that AK301 binds to the colchicine-binding domain on β-tubulin, but in a novel orientation. Cells arrested by AK301 expressed elevated levels of TNFR1 on their surface and more readily activated caspases-8, -9, and -3 in the presence of TNF. Relative to other microtubule destabilizers, AK301 was the most active TNF-sensitizing agent and also stimulated Fas- and TRAIL-induced apoptosis. In summary, we report a new class of mitosis-targeting agents that effectively sensitizes cancer cells to apoptotic ligands. These compounds should help illuminate the role of microtubules in regulating apoptotic ligand sensitivity and may ultimately be useful for developing agents that augment the anti-cancer activities of the immune response.

Relationship Between Structure of Conjugated Oxime Esters and Their Ability to Cleave DNA

The size and geometry of polycycles are critical to intercalation into DNA. This work involves the establishment of a new compound library that includes 35 O-benzoyl oxime esters with intercalators of five types. These conjugated compounds were synthesized by the condensation of substituted benzoyl chlorides (XC6H4COCl; X = H, Me, CN, F, and NO2) or naphthoyl chlorides with oximes of fluoren-9-one, 9,10-anthraquinone, xanthen-9-one, thioxanthen-9-one, and 9H-thioxanthen-9-one 10,10-dioxide to give the corresponding esters in 80-99% yields. All of these compounds could cleave DNA when photolyzed by UV light. Of these conjugates, 9,10-anthraquinone-O-9-(4-fluorobenzoyl)oxime with a binding constant of 4.49 × 10(4) M(-1) cleaved DNA most efficiently. Examination of the structure-activity relationship supports a conclusion that two factors affect DNA-cleaving potency. These are (1) the planarity of the intercalating moiety, and (2) the size and substituents of the benzoyl ring. The DNA-cleaving ability followed the order 9,10-anthraquinone > fluoren-9-one ≥ xanthen-9-one ∼ thioxanthen-9-one > 9H-thioxanthen-9-one 10,10-dioxide. The benzoyl-containing oxime ester conjugates were more active than the corresponding naphthoyl-containing conjugates. The potency that was associated with the different substituents on the benzoyl ring followed the order F > CN ≥ NO2 > Me ∼ H.

Synthesis, angiopreventive activity, and in vivo tumor inhibition of novel benzophenone–benzimidazole analogs

AimThe development of anticancer drugs with specific targets is of prime importance in modern biology. This study investigates the angiopreventive and in vivo tumor inhibition activities of novel synthetic benzophenone–benzimidazole analogs. Main methodsThe multistep synthesis of novel benzophenone–benzimidazole analogs (8a–n) allowing substitution with methoxy, methyl and halogen groups at different positions on the identical chemical backbone and the variations in the number of substituents were synthesized and characterized. The newly synthesized compounds were further evaluated for cytotoxic and antiproliferative effects against Ehrlich ascites carcinoma (EAC) cells. The potent lead compounds were further assessed for antiangiogenic effects in a CAM model and a tumor-induced vasculature in vivo model. The effect of angioprevention on tumor growth was verified in a mouse model. Key findingsThe cytotoxicity studies revealed that compounds 8f and 8n are strongly cytotoxic. Analyzing the structure–activity relationship, we found that an increase in the number of methyl groups in addition to methoxy substitution at the para position of the benzoyl ring in compound 8n resulted in higher potency compared to 8f. Furthermore, neovessel formation in in vivo systems, such as the chorioallantoic membrane (CAM) and tumor-induced mice peritoneum models, was significantly suppressed and reflected the tumor inhibition observed in mice. SignificanceThese results suggest the potential clinical application of compound 8n as an antiangiogenic drug for cancer therapy.

Synthesis of (4-benzoyl-phenoxy)-acetic acid derivatives and their efficacy as antioxidant agents

Aim & background: To study the synthesis of a series of (4-benzoyl-phenoxy)-acetic acid derivatives (6aek) and to test their antioxidant activity. Methods: The newly synthesized compounds were characterized by IR, 1H NMR and LCeMS analyses. All these compounds were screened for their in vitro antioxidant activity by employing 1,1-diphenyl-1- picrylhydrazyl (DPPH), nitric oxide (NO) and hydrogen peroxide (H2O2) radical scavenging assays. Results: Compounds 6h with chloro substituent in benzoyl ring and 6f with no substituent in benzoyl ring showed good radical scavenging activity in all the three methods compared to the standard drug ascorbic acid. Whereas compound 6k with methoxy substituent in benzoyl ring showed good antioxidant activity only in hydrogen peroxide method and remaining compounds showed moderate to mild radical scavenging activity. Conclusion: Compounds 6f, 6h and 6i showed excellent activity, almost equivalent to that of standard and the remaining compounds showed moderate to mild scavenging activity.

4-{5-[(2-Bromobenzyl)sulfanyl]-1H-tetrazol-1-yl}benzoic acid

In the title compound, C15H11BrN4O2S, the tetra­zole ring makes dihedral angles of 45.97 (10) and 75.41 (1)°, respectively, with the benzoyl and bromo­benzene rings while the dihedral angle between the benzene rings is 73.77 (1)°. In the crystal, mol­ecules are linked through O—H⋯ N and C—H⋯ O hydrogen bonds, giving infinite chains in both the [110] and [1-10] directions. These chains are further connected by C—Br⋯π and C—O⋯π inter­actions and also by π–π stacking between tetra­zole rings [centroid–centroid distance = 3.312 (1) Å], generating a three-dimensional network.