Design and synthesis of some new tri-substituted pyrazole derivatives as anticancer agents

A new series of tri-substituted pyrazole derivatives were designed as anti-cancer agents and synthesized, starting with the formylation of semicarbazone via the Vilsmeier–Haack reaction to give 3-(4-bromophenyl)-1H-pyrazole-4-carbaldehyde I which was the precursor of compounds 1–9. The new chemical entities were screened for their anti-cancer activity on various human cancer cell lines, namely: hepatocellular carcinoma HepG2, breast cancer MCF-7, lung carcinoma A549 and prostatic cancer PC3. Most of the synthesized compounds showed remarkable activity on the tested cell lines, while compound 2 had the highest potency against the HepG2 cell line with an IC₅₀ of 9.13 µM compared with doxorubicin (IC₅₀ = 34.24 µM), the reference standard used in this study, and compound 7 was the most active on the rest of the three cell lines; MCF-7, A549 and PC3 (IC₅₀ = 16.52, 6.52 and 9.13 µM, respectively) relative to IC₅₀ = 20.85, 5.93 and 38.02 µM of the standard. Thus, some of the synthesized tri-substituted pyrazole derivatives, specially 2 and 7, have the potential to be developed into potent anticancer agents.     

Synthesis and biological evaluation of peptidyl organotrifluoroborates and their corresponding boron analogs

Six peptidyl organotrifluoroborates and their corresponding boronate esters and/or boronic acid analogs were designed and synthesized. Their anti-proliferative activity against hepatocellular carcinoma cells (HepG2) and human metastatic breast cancer cells (MDA-MB231) were evaluated by use of an MTT assay. Potassium {4-[(3S,6S,9S)-3,6-dibenzyl-9-isopropyl-4,7,10-trioxo-11-oxa-2,5,8-triazadodecyl]phenyl}trifluoroborate (B6) was potent (IC₅₀ = 29.9 μM) against MDA-MB231, and {4-[(3S,6S,9S)-6-benzyl-3-((benzyloxy)methyl)-9-isopropyl-4,7,10-trioxo-11-oxa-2,5,8-triazadodecyl]phenyl}boronic acid (B9) and Potassium {4-[(3S,6S,9S)-6-benzyl-3-((benzyloxy)methyl)-9-isopropyl-4,7,10-trioxo-11-oxa-2,5,8-triazadodecyl]phenyl}trifluoroborate (B10) had broad anti-proliferative activity against HepG2 (IC₅₀ = 24.7 and 21.8 μM, respectively) and MDA-MB231 (IC₅₀ = 24.5 and 18.9 μM, respectively).     

fac-Cobalt(III)-azido complexes derived from substituted pyridyl-based tridentate amines

Four new mononuclear triazido-cobalt(III) complexes [Co(L ^1/2/4 )(N₃)₃] and [Co(L ³ )(N₃)₃]·CH₃CN where L ¹  = [(2-pyridyl)-2-ethyl]-(2-pyridylmethyl)-N-methylamine, L ²  = [(2-pyridyl)-2-ethyl]-[6-methyl-(2-pyridylmethyl)]-N-methylamine, L ³  = [(2-pyridyl)-2-ethyl]-[3,5-dimethyl-4-methoxy-(2-pyridylmethyl)]-N-methylamine, and L ⁴  = [(2-pyridyl)-2-ethyl]-[3,4-dimethoxy-(2-pyridylmethyl)]-N-methylamine, respectively, were synthesized and structurally characterized. The four complexes were characterized by elemental microanalyses, IR and UV–VIS spectroscopy and X-ray single crystal crystallography. The complexes display two strong IR bands over the frequency region 2,020–2,050 cm^?1 assigned for the asymmetric stretching frequency, ν_a(N₃) of the coordinated azides indicating facial geometry. The molecular structure determinations of the complexes were in complete agreement with fac-[Co(L)(N₃)₃] conformation in distorted octahedral Co(III) environment.     

Nucleic Acid Binding Behavior and Cytotoxicity Properties of a Ruthenium(II) Polypyridyl Complex

The binding of [Ru(IP)₂(dppz-11-CO₂Me)]²⁺ (1) {IP = imidazo[4,5-f][1,10]phenanthroline, dppz-11-CO₂Me = dipyrido[3,2-a:2′,3′-c]phenazine-11-carboxylic acid methyl ester} to calf thymus DNA and yeast tRNA has been investigated by UV–Vis spectroscopy, fluorescence spectroscopy, viscosity, as well as equilibrium dialysis and circular dichroism. In addition, the antitumor activities of complex 1 have been evaluated by the MTT method. On the basis of the spectroscopic results, the binding mode of complex 1 to CT-DNA and yeast tRNA is intercalation. However, DNA binding with complex 1 is stronger than RNA binding with complex 1, and complex 1 is a better candidate for an enantioselective binder to CT-DNA than to yeast tRNA. These results indicate that the structures of DNA and RNA have significant effects on the binding behaviors of complex 1. Furthermore, complex 1 demonstrates different antitumor activities against selected cancer cell lines in vitro.     

Synthese von (5,10)-(7,8)-Bisepoxiden aus α- und β-4-Phenyl-1,2,4-triazolin-3,5-dion-Addukten von Vitamin D3 und Röntgenstrukturanalyse eines der Benzoylderivate

Oxidation of the α- and β-4-phenyl-1,2,4-triazolin-3,5-dione adducts of vitamin D₃ (2 and1) withMCPBA yields two diastereomeric mixtures of the (5,10)-(7,8)-dioxiranes3 a,3 b,3 c and4 a,4 b respectively. The corresponding benzoates5 a,5 b,6 a and6 b were prepared and the X-ray crystal structure of5 b was determined. This analysis proved5 b to be the (5R, 1 OS)-(7R, 8R)-dioxirane of the β-resp. (6S)-4-phenyl-1,2,4-triazolin-3,5-dione adduct1 of vitamin D₃.     

Two palladium(II) complexes based on Schiff base ligands: synthesis, characterization, luminescence, and catalytic activity

Two Pd(II) complexes involving Schiff base ligands, namely, [Pd(L1)₂] (1), [Pd₂(L₂)Cl₂] (2) [HL1 = 2-((2,6-diisopropylphenylimino)methyl)-4,6-dibromophenol, L2 = N-(4-isopropylbenzylidene)-2,6-diisopropylbenzenamine] have been synthesized using solvothermal methods and characterized by elemental analysis, IR-spectroscopy, thermogravimetric analysis, powder X-ray diffraction, UV–vis absorption spectra, and single-crystal X-ray diffraction. Complex 1 is a mononuclear cyclometalated Pd(II) complex, whereas complex 2 is a μ-chloro-bridged dinuclear. Both 1 and 2 display photoluminescence in the solid state at 298 K and possess fluorescence lifetimes (τ ₁ = 86.40 ns, τ ₂ = 196.21 ns, τ ₃ = 1,923.31 ns at 768 nm for 1, τ ₁ = 69.92 ns, τ ₂ = 136.40 ns, τ ₃ = 1,714.26 ns at 570 nm for 2). The Suzuki reactions of 4-bromotoluene with phenylboronic acid by complexes 1–2 have also been studied.     

A novel view of modelling interactions between synthetic and biological polymers via docking

Multipoint interactions between synthetic and natural polymers provide a promising platform for many topical applications, including therapeutic blockage of virus-specific targets. Docking may become a useful tool for modelling of such interactions. However, the rigid docking cannot be correctly applied to synthetic polymers with flexible chains. The application of flexible docking to these polymers as whole macromolecule ligands is also limited by too many possible conformations. We propose to solve this problem via stepwise flexible docking. Step 1 is docking of separate polymer components: (1) backbone units (BU), multi-repeated along the chain, and (2) side groups (SG) consisting of functionally active elements (SG _F ) and bridges (SG _B ) linking SG _F with BU. At this step, probable binding sites locations and binding energies for the components are scored. Step 2 is docking of component-integrating models: [BU] _m , SG = SG _F –SG _B , BU–SG, BU–BU(SG)–BU, BU(SG)–[BU] _m –BU(SG), and [BU _var (SG _var )] _m . Every modelling level yields new information, including how the linkage of various components influences on the ligand—target contacts positioning, orientation, and binding energy in step-by-step approximation to polymeric ligand motifs. Step 3 extrapolates the docking results to real-scale macromolecules. This approach has been demonstrated by studying the interactions between hetero-SG modified anionic polymers and the N-heptad repeat region tri-helix core of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp41, the key mediator of HIV-1 fusion during virus entry. The docking results are compared to real polymeric compounds, acting as HIV-1 entry inhibitors in vitro. This study clarifies the optimal macromolecular design for the viral fusion inhibition and drug resistance prevention.     

Two lignans,one alkaloid,and flavanone from the twigs of Feroniella lucida

Four new compounds, two lignans; lucidenal and lucidanin (1 and 2), one alkaloid (3), and one flavanone (4) together with 26 known compounds (5–30), were isolated from the twigs of Feroniella lucida. The structures of the new compounds were determined on the basis of spectroscopic analyses. Lucidenal 1 showed cytotoxicity against HuCCA-1, A549, MOLT-3 and HepG2 cancer cell lines with IC₅₀ values of 4.27, 9.59, 2.31, and 6.50 μg/mL, respectively. A plausible biosynthetic pathway of 1 was proposed.     

Guest inclusion in cyclic imides containing flexible tethers

Guest inclusion properties of two cyclic imides which have carboxylic acids connected through flexible tether, namely, 4-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-cyclohexanecarboxylic acid (1) and 4-(1,3-dioxo-1H,3H-benzo[de]isoquinolin-2-ylmethyl)-cyclohexanecarboxylic acid (2) are studied. The crystals of host 1 containing one molecule of 1, the crystals of 4,4′-bipyridine (bpy) cocrystal of 1 containing one molecule of 1 and half molecule of bpy (1a), the crystals of 1,4-dioxane solvate of 1 containing two molecule of 1 and one and half molecule of 1,4-dioxane (1b) and the crystals of quinoline solvate of 1 containing one molecule of 1 and one molecule of quinoline (1c) in their crystallographic asymmetric units are investigated. Intermolecular hydrogen bonded two dimensional (2D) sheet structure of 1 and 3D channel network of 1b are comprised of cyclic R ₂ ² (8) hydrogen bond motifs; whereas cleavage of dimeric carboxylic acid R ₂ ² (8) motifs occurs in the structures of 1a and 1c in which 3D host–guest networks are comprised of discrete O–H···N and cyclic R ₂ ² (7) interactions, respectively. Various types of weak interactions between the two symmetry nonequivalent host molecule are found to be responsible for the formation of channels (14 × 11 Å) filled by guest 1,4-dioxane molecules in the crystal lattice of 1b. Two different solvates of 2 containing one molecule of 2 with a water molecule (2a) and one molecule of 2 with a quinoline molecule (2b) in their crystallographic asymmetric units, respectively, are also crystallized in different space groups. The quinoline molecules are held with host molecules by discrete O–H···N and C–H···O interactions and reside inside the voids formed by 3D repeated hexameric assemblies of host molecules in the crystal lattice of 2b.     

Thermal studies of some biological active oxadiazoles

A series of new unsymmetrical 2,5-disubstituted 1,3,4-oxadiazoles (3a–d) has been synthesized to evaluate their antibacterial and thermal properties. All compounds have been tested for their in vitro antibacterial activity against two Gram-positive bacteria namely, Staphylococcus aureus and Bacillus subtilis. Among the tested compounds, compound 2-(4-chlorophenyl)-5-(thiophen-2-yl)-1,3,4-oxadiazole (3c) has been found to be most potent member having minimum inhibitory concentration. Thermal stability and melting point of compounds have been studied by TG and DSC analysis in air atmosphere at heating rate of 10 °C min^?1. Thermal degradation kinetics of the most potent antibacterial compound 3c has been carried out by multiple heating rate model free kinetic methods namely, Ozawa–Flynn–Wall, modified Coats-Redfern, and Kissinger.     

Two efficient methods for the synthesis of novel indole-based chalcone derivatives

Two powerful methods for the synthesis of indole-based chalcone derivatives, namely (E)-1-(2-chloro-1-(4-chlorobenzyl)-1H-indol-3-yl)-3-aryl(hetaryl)prop-2-en-1-ones (3a–l), are described, involving the ultrasound-assisted or solvent-free Claisen–Schmidt condensation reaction of 3-acetyl-2-chloro-1-(4-chlorobenzyl)indole (1) and various aromatic aldehydes (2a–l). The ultrasound-assisted Claisen–Schmidt condensation reaction was carried out using 1,4-dioxane as solvent and KOH as base at room temperature to give the corresponding products (3a–l) in yields ranging from 75 to 88 %. Alternatively, the Claisen–Schmidt condensation reaction could also be conducted under solvent-free conditions to obtain the products (3a–l) in comparable yields. The two procedures offer easy access to indole-based chalcone derivatives in short reaction times and good yields under mild conditions. Particularly, the advantageous aspect of the solvent-free method could avoid the use of environmentally hazardous and toxic solvents, and also reduced costs. The structures of all the newly synthesized indole-based chalcones 3a–l were confirmed by spectral data and elemental analyses.     

Synthesis and antiproliferative activity in vitro of new 2-aminobenzimidazole derivatives. Reaction of 2-arylideneaminobenzimidazole with selected nitriles containing active methylene group

A series of pyrimido[1,2-a]benzimidazole and α-cyanocinnamic acid derivatives have been synthesized in the reactions of Schiff bases 2–7 with selected nitriles containing an active methylene group: malononitrile 8–12, cyanoacetamide 13–16, benzyl cyanide 17–21, benzoylacetonitrile 22–24, cyanoacetate methyl ester 25–28 and benzylacetamide 29. The structures 8–29 were confirmed by the results of elementary analysis and their IR, ¹H-, ¹³C-NMR and MS spectra. The products 8–29 of various chemical structure pyrimido[1,2-a] benzimidazole 8–12, 14–16, 17–21, 23–24, 26 and α-cyanocinnamic acid derivatives 13, 22, 25, 27, 28 were obtained, which are of interest for biological studies or which can be substrates for further synthesis. The selected compounds 10, 13, 14, 17, 19, 21, 23–25 and 28 were screened for their antiproliferative activity in vitro against neoplastic and normal cell lines. The most active two compounds were: 2-(o-bromophenylene)-3-cyano-4-phenyl-1,2-dihydropyrimido[1,2-a]benzimidazole (24) and 3-cyano-4-phenyl-2-(2,4-dimethoxyphenyl)-1,2-dihydropyrimido[1,2-a]benzimidazole (23). However, similarly like cisplatin used as the control, they showed no selectivity towards cancer cells, by inhibiting proliferation of normal mouse fibroblasts in similar manner.      

New copper(II) 2-(alkylamino)troponates

The copper aminotropones Cu[ON(R′)C₇H₄R-4]₂ [R = H, R′ = Me (13), Et (14), n-Pr (15), n-Bu (16), Bz (17), MenOCH₂CH₂ (20); R = i-Pr, R′ = Me (18), n-Pr (19), MenOCH₂CH₂ (21)] have been prepared from the corresponding aminotropones HN(R′)OC₇H₄R-4 (1–7) by reacting with copper(II) acetate in aqueous ethanol. 20, 21 contain the flavourant, menthol, as part of the ligand. The structures of 5 (R = H, R′ = Bz), a hydrogen-bonded dimer, 14 and 20, both incorporating square-planar, four-coordinate copper centres, have been determined by X-ray crystallography. The antibacterial activities of complexes 13, 17, 20 and 21 have been assayed against Staphylococcus waneri, an in vitro model of plaque inhibition effects, and found to be more active than a commercial toothpaste formulation, but less active than the O,O-chelated copper(II) complex of ethylmaltol.     

LC Method for Analysis of Three Flavonols in Rat Plasma and Urine after Oral Administration of Polygonum aviculare Extract

A high-performance liquid chromatographic method has been developed for the simultaneous analysis of the flavonols myricitrin (1), avicularin (2), and juglanin (3) in rat plasma and urine after oral administration of the total flavonoids from Polygonum aviculare. Samples were prepared by solid-phase extraction then separated on a C₁₈ reversed-phase column by use of a mobile-phase gradient prepared from methanol and aqueous formic acid solution. The flow rate was 1 mL min^?1. Detection was performed at 254 nm. The calibration range was 11–1,100 μg mL^?1 for both 2 and 3 in plasma; in urine the calibration ranges for 1, 2, and 3 were 32–1,600, 11–1,100, and 22–1,100 μg mL^?1, respectively. Intra-day and inter-day RSD were less than 4.33 and 3.62% for 2 and 3, respectively, in plasma, and no more than 4.03 and 2.22% for all the analytes in urine. The analytical sensitivity and selectivity of the assay enabled successful application to pharmacokinetic studies of flavonols 1–3 in rats.     

Zur Kenntnis der Substitutionsprodukte der (2H)-Imidazol-4(3H)-thione und 2H-Imidazol-4(3H)-one

2H-Imidazole-4(3H)-thiones (a), available from methyl alkyl and methyl aryl ketones with sulfur and ammonia, react via their corresponding N-sodium compounds or in presence of tert. amines with alkyl and aryl carboxylic acid chlorides to give the corresponding intensely coloured (orange to violett) cryst. 3-acyl-2H-imidazole-4(3H)-thiones4 a-q and6–26. With dicarboxylic acid dichlorides the colourless cryst. N,N′-diacyl-bis-3-imidazoline-5-thiones5 a-d and27–32 are obtained. With carbamic acid chlorides and chloroformic acid esters the corresponding urea (33–35) and urethane derivatives36, 37 are formed. In an analogous way 2H-imidazol-4(3H)-ones react with acid chlorides to 3-acyl-2-imidazol-4(3H)-ones (44–50), which can also be obtained by treating the corresponding 3-acyl-2H-imidazole-4(3H)-thione with KMnO₄.     

Thioimidazolate versus pyrazolate-zinc(II)-bound hydroxo complex as structural model for the active site of hydrolytic enzyme: the crystal structure of the inclusion complex TtZn–O–C6H4–p-NO2, Tt?=?hydrotris(N-xylyl-2-thioimidazolyl)borate

The reaction of the tripod ligand hydrotris(N-(2-methylphenyl)-2-thioimidazol-1-yl)borate, Tt with zinc(II) chloride yielded the chloro complex [TtZn–Cl] 1. The hydrolytic reactivity of its hydroxo complex [TtZn–(μ-OH)ZnTt]Cl 2 towards p-nitrophenyl acetate was hampered due to the formation of the stable phenolate complex [TtZn–O–Ar–p-NO₂] 3 as a product inhibition. The X-ray structure analysis of complex 3 was determined and showed that its Zn[S₃O] coordination sphere includes three thione donors from the ligand Tt and one oxygen donor from the hydrolysed product p-nitrophenolate in an ideally tetrahedral arrangement around the zinc(II) centre.     

Theoretical study on the mechanism of C2Cl3 + NO2 reaction

The radical-molecule reaction of C₂Cl₃ with NO₂ is explored at the B3LYP/6-311G(d,p) and CCSD(T)/6-311+G(d,p) (single-point) levels. On the singlet potential energy surface (PES), the association between C₂Cl₃ and NO₂ is found to be carbon-to-nitrogen attack forming the adduct C₂Cl₃NO₂ (1) without any encounter barrier, followed by isomerization to C₂Cl₃ONO (2). Starting from 2, the most feasible pathway is the N–O1 bond cleavage which lead to P ₁ (C₂Cl₃O + NO). Much less competitively, 2 transforms to the three-membered ring isomer c-OCCl₂C–ClNO (4 ^a ) which can easily interconvert to c-OCCl₂C–ClNO 4 ^b . Then 4 (4 ^a , 4 ^b ) takes direct C1–C2 and C2–O1 bonds cleavage to give P ₂ (COCl₂ + ClCNO). The lesser competitive channel is the 4 ^a isomerizes to the four-membered ring intermediate O-c-CNClOCCl₂ (5) followed by dissociation to P₃ (CO + ClNOCCl₂). The concerted 1,2-Cl shift along with C1–O1 bond rupture of 4 ^b to form ONC(O)CCl₃ (6) followed by dissociation to P ₄ (ClNO + OCCCl₂) is even much less feasible. Moreover, some of P ₃ and P ₄ can further dissociate to P ₅ (ClNO + CO + CCl₂). Compared with the singlet pathways, the triplet pathways may have less contribution to the title reaction. Our results are in marked difference from previous theoretical studies which showed that two initial adducts C₂Cl₃–NO₂ and C₂Cl₃–ONO are obtained. Moreover, in the present paper we focus our main attentions on the cyclic isomers in view of only the chain-like isomers are considered by previous studies. The present study may be helpful for understanding the halogenated vinyl chemistry.     

Synthesis and in vitro and in vivo antitumor/anticancer activity of novel O-Mannich bases of 4,6-diaryl-3,4-dihydropyrimidine-2(1H)-ones

A new series of [4,6 substituted diaryl-1,6-dihydropyrimidin-2-yl-oxymethyl]-amines 5a–o have been synthesized by the Mannich condensation on the respective 4,6-diaryl-3,4-dihydropyrimidine-2(1H)-ones 4, in basic medium using formaldehyde along with three secondary amines, viz., dimethylamine, piperidine and morpholine. The dihydropyrimidinones 4 in turn were synthesized by the cyclocondensation of chalcones 3 with urea. Alternatively, compounds 4 were also prepared directly by one-pot 3-component cyclocondensation reaction starting from acetophenone, benzaldehyde and urea. The structures of all the newly synthesized compounds have been confirmed by their spectral and analytical data. All the O-Mannich bases 5 have been evaluated for their in vitro cytotoxic and antitumor activities, and based on the results, the potent compounds were selected for in vivo activity, as well. Only one compound 5m of the series has been found to be relatively more effective.     

The Synthesis and Characterization of Re2(Xap)4Cl2 Compounds

Five dirhenium(III) compounds, Re₂(3,5-(CH₃)₂ap)₄Cl₂ (1), Re₂(ap)₄Cl₂ (2), Re₂(3-MeOap)₄Cl₂ (3), Re₂(3-Clap)₄Cl₂ (4), and Re₂(3,5-Cl₂ap)₄Cl₂ (5), were synthesized and characterized, where 3,5-(CH₃)₂ap, ap, 3-MeOap, 3-Clap and 3,5-Cl₂ap are 2-(3,5-dimethylanilino)pyridinate, 2-anilinopyridinate, 2-(3-methoxyanilino)pyridinate, 2-(3-chloroanilino)pyridinate and 2-(3,5-dichloroanilino)pyridinate, respectively. Structural studies revealed the Re–Re bond lengths ranging from 2.2214(4) to 2.2262(11) Å, signifying that the dirhenium core maintains its quadruple bond. The asymmetric nature of 2-anilinopyridinate ligands resulted in several possible regioisomers: compounds 1 and 4 adopt a cis-(2,2) arrangement, while compounds 2 and 5 assume trans-(2,2) and (3,1) arrangements, respectively. All five compounds display three (quasi)reversible one electron couples, two oxidations and one reduction, and their electrode potentials correlate linearly with the Hammett constant of the aniline substituent.     

One-pot microwave-assisted solvent-free synthesis,theoretical and experimental studies on barrier rotation of C–N bond of N-alkenyl-1,2,3-triazoles

The reactions on benzotriazoles continue to happen to reach interesting varieties of their derivatives. This study reports a fast one-pot microwave-assisted solvent-free synthesis of N-alkenyl-1,2,3-benzotriazole (3, 5, and 7) and 1-(2-Alkyloxycarbonyl-vinyl)-1H-[1–3] triazole-4-carboxylic acid methyl ester (8 and 9) derivatives by nucleophilic addition reactions of 1,2,3-benzotriazole (C₆H₅N₃) (1) and 1H-[1–3] triazole-4-carboxylic acid methyl ester (C₄H₄N₃O₂) (1′) with R-propiolates (R = Me, Et; 2 & 4) and phenylacetylene 6 in good yields. The values of activation energy for rotation around C–N bond in the synthesized N-alkenyl-1,2,3-triazole compounds were studied by DFT-B3LYP/6-31G* method.