Substituted imidazole derivatives as novel cardiovascular agents

A series of novel substituted imidazole derivatives were synthesized and have been screened in vivo for their hypotensive and acute toxicity activities. Out of seventeen compounds eight compounds (2b, 2c, 3b, 3c, 3f, 4a, 4b and 4c) have shown good hypotensive and bradycardiac responses. Compounds 3b, 3c, 3f and 4c have shown better activity than reference drug clonidine. All the compounds have shown ALD50 >1000 mg/kg with maximum in 2e and 4c (>1200 mg/kg).     

Dopamine release and molecular modeling study of some coumarin derivatives

4-aryl-2-amino-6-(4-hydroxy-2-oxo-2H-chromen-3-yl)-pyridin-3-carbonitrile (1), 4-aryl-2-oxo-6-(4-hydroxy-2-oxo-2H-chromen-3-yl)-pyridin-3-carbonitriles (2a-2c), 3-(6-aryl-1,2,5,6- tetrahydro-2-thioxopyrimidin-4-yl)-4-hydroxy-2H-chromen-2-one (3a, 3b) and pyrazol-3-yl-4-hydroxycoumarin derivatives (4a-4c, 5, 6a, 6b, 7a, 7b, and 8a-8c) were prepared in order to measure their % change dopamine release in comparison to amphetamine as reference, using PC-12 cells in different concentrations. In addition, the molecular modeling study of the compounds into 3BHH receptor was also demonstrated. The calculated inhibition constant (k_i) implemented in the AutoDock program revealed identical correlation with the experimental results to that obtained binding free energy (ΔG_b) as both parameters revealed reasonable correlation coefficients (R²) being 0.51 involving 10 compounds; (1, 2b, 2c, 3a, 3b, 4a, 4b, 6a, and 8c).     

Mixed-ligand tris chelated complexes of Mo(IV) and W(IV): A comparative study

Two hitherto unknown mixed-ligand tris chelated complexes containing 2-aminothiophenolate, [Et₄N]₂[M^IV(NH-(C₆H₄)-S)(mnt)₂] (M = Mo, 1a; W, 2a) and two mixed-ligand tris chelate complex containing N,N-diethyldithiocarbamate, [Et₄N]₂[M^IV(Et₂NS₂)(mnt)₂] (M = Mo, 1b; W, 2b) have been synthesized and characterized structurally. Although these complexes are supposed to be quite similar to the well-known symmetric tris chelate complexes of maleonitriledithiolate (mnt), [Et₄N]₂[M^IV(mnt)₃] (M = Mo, 1c; W, 2c), but display both trigonal prismatic and distorted trigonal prismatic geometry in their crystal structure indicating the possibility of an equilibrium between these two structural possibilities in solution. Unlike extreme stability of 1b, 2b, 1c and 2c, both 1a and 2a are highly unstable in solution. In contrast to one reversible reduction in case of 1b and 2b, 1a and 2a exhibited no possible reduction up to −1.2 V and two sequential oxidation steps which have been further investigated with EPR study. Differences in stability and electrochemical behavior of 1a, 1b, 2a and 2b have been correlated with theoretical calculations at DFT level in comparison with long known 1c and 2c.     

Regioselective facile one-pot Friedländer synthesis of sugar-based heterocyclic biomolecules

Regioselective facile one-pot synthesis of 16 different sugar-based quinoline, naphthyridine, and xanthone derivatives is reported. The compounds are characterized by NMR spectroscopy and elemental analysis. The β-Anomeric form of the sugar moiety was identified from ¹H NMR studies. Antimicrobial studies of these sugar-heterocyclic derivatives, 3a, 3b, 3f, 5c, 7a, 7b, and 7c show excellent activity against different microbes.     

Diheteroarylmethyl substituted titanocenes: A novel class of possible anti-cancer drugs

From the reaction of tert-butyl lithium or n-butyl lithium with N-methylpyrrole (1a), furan (1b) or 2-bromo-thiophen (1c), 2-N-methylpyrrolyl lithium (2a), 2-furyl lithium (2b) or 2-thiophenyl lithium (2c), respectively, was obtained. When reacted with 6-(2-N-methylpyrrolyl) fulvene (3a), 6-(2-furyl) fulvene (3b) or 6-(2-thiophenyl) fulvene (3c), the corresponding lithiated intermediates were formed (4a-c). Titanocenes (5a-c) were obtained through transmetallation with titanium tetrachloride. When these titanocenes were tested against pig kidney epithelial (LLC-PK) cells, inhibitory concentrations (IC₅₀) of 32 μM, 140 μM, and 240 μM, respectively, were observed. These values represent improved cytotoxicity against LLC-PK, compared to their ansa-analogues.     

Synthesis, structure and theoretical studies of Hg(II)-NH carbene complex of annulated ligand pyridinyl[1,2-a]{2-pyridylimidazol}-3-ylidene hexaflurophosphate

Experimental and theoretical studies of a new class of novel annulated imidazolium scffords 2a, 2b, 2c and their Hg(II)-NHC complexes 3a, 3b and 3c have been synthesized and characterized by different spectroscopic techniques. Molecular structures of 3a and 3b have been determined by single crystal X-ray diffraction studies. Virtual linear geometry [C_carbene-Hg-C_carbene 176.56(17)°] around Hg of the complex 3b is observed where as in 3a and 3c its deviate a more. DFT calculations provide geometrical parameters in conformity with the experimental values in case of 3a. The molecules prefer syn configuration over the anti due to lower energy supported by theoretical studies. Attention has given paid for theoretical calculations and comparison of 3a and 3c to observe the steric effect of -CH₃ group in the scaffords where as in case of 3b the -CH₃ group remain innocent.     

Synthesis of 4,6-dideoxy-3-fluoro-2-keto-β-d-glucopyranosyl analogues of 5-fluorouracil, N-benzoyl adenine, uracil, thymine, N-benzoyl cytosine and evaluation of their antitumor activities

The synthesis of the unsaturated 4,6-dideoxy-3-fluoro-2-keto-β-d-glucopyranosyl nucleosides of 5-fluorouracil (6a), N⁶-benzoyl adenine (6b), uracil (6c), thymine (6d) and N⁴-benzoyl cytosine (6e), is described. Monoiodination of compounds 1a,b, followed by acetylation, catalytic hydrogenation and finally regioselective 2′-O-deacylation afforded the partially acetylated dideoxynucleoside analogues of 5-fluorouracil (5a) and N⁶-benzoyl adenine (5b), respectively. Direct oxidation of the free hydroxyl group at the 2′-position of 5a,b, with simultaneous elimination reaction of the β-acetoxyl group, afforded the desired unsaturated 4,6-dideoxy-3-fluoro-2-keto-β-d-glucopyranosyl derivatives 6a,b. Compounds 1c-e were used as starting materials for the synthesis of the dideoxy unsaturated carbonyl nucleosides of uracil (6c), thymine (6d) and N⁴-benzoyl cytosine (6e). Similarly a protection-selective deprotection sequence followed by oxidation of the free hydroxyl group at the 2′-position of the dideoxy benzoylated analogues 9c-e with simultaneous elimination reaction of the β-benzoyl group, gave the desired nucleosides 6c-e. None of the compounds was inhibitory to a broad spectrum of DNA and RNA viruses at subtoxic concentrations. The 5-fluorouracil derivative 6a was more cytostatic (50% inhibitory concentration ranging between 0.2 and 12 μM) than the other compounds.     

Novel benzyl-substituted molybdocene anticancer drugs

From the reaction of 6-(p-methoxyphenyl) fulvene (1a), 6-(3,4-dimethoxyphenyl) fulvene (1b) and 6-(3,4,5-trimethoxyphenyl) fulvene (1c) with LiBEt₃H, lithiated cyclopentadienide intermediates (2a-c) were synthesised. These intermediates were then transmetallated to molybdocene using MoCl₄ (synthesized in situ) to yield the benzyl-substituted molybdocenes bis-[(p-methoxybenzyl)cyclopentadienyl] molybdenum (IV) dichloride (3a), bis-[(3,4-dimethoxybenzyl)cyclopentadienyl] molybdenum (IV) dichloride (3b), and bis-[(3,4,5-trimethoxybenzyl)cyclopentadienyl] molybdenum (IV) dichloride (3c). The molybdocene 3a was characterised by single crystal X-ray diffraction. All three molybdocenes had their cytotoxicity investigated through MTT based preliminary in vitro testing on the human renal cell line Caki-1 in order to determine their IC50 values and compare them with the corresponding titanocene and vanadocene dichloride derivatives. Molybdocenes 3b-c were found to have the same IC50 values of 290 μM, while 3a yielded a value of 84 μM, respectively     

Solid-gas carbonylation of aryloxide rhodium(I) complexes: stepwise reaction forming Vaska-type complexes

Aryloxide rhodium(I) complexes Rh(OAr)(PPh₃)₃ (1a: Ar=C₆Cl₅, 1b: Ar=C₆F₅, 1c: Ar=C₆H₄-NO₂-4) react with CO in toluene solutions to produce Vaska-type complexes trans-Rh(OAr)(CO)(PPh₃)₂ (2a: Ar=C₆Cl₅, 2b: Ar=C₆F₅, 2c: Ar=C₆H₄-NO₂-4). Carbonylation of a similar complex with PMe₃ ligands, Rh(OC₆H₄-NO₂-4)(PMe₃)₃ (3c), also forms trans-Rh(OC₆H₄-NO₂-4)(CO)(PMe₃)₂ (4c). Molecular structures of the complexes are determined by X-ray crystallography and NMR spectroscopy. Complex 1a reacts with CO in the absence of solvent to produce a mixture of 2a and complex A, the latter of which shows the IR and ¹³C{¹H} signals due to the carbonyl ligand at different positions from those of 2a. Addition of Et₂O to the above mixture turns it into analytically pure 2a. Carbonylation of 1b and 1c under the solvent-free conditions produces complexes B and C as the respective products of the solid-gas reaction. Recrystallization of B and C turns them into 2b and 2c, respectively. Complex 3c also reacts with CO in the solid state to form a mixture of 4c and complex D, although the latter complex is converted slowly into 4c even in the solid state.     

Synthesis, reactivities and catalytic carbonylation of rhodium(I) carbonyl complexes containing isomeric acetylpyridine ligands

[Rh(CO)₂Cl]₂ reacts with two mole equivalent of 2-acetylpyridine (a), 3-acetylpyridine (b) and 4-acetylpyridine (c) to afford chelate [Rh(CO)Cl(η²-N∩O)] (1a) and non-chelate [Rh(CO)₂Cl(η¹-N∼O)] (1b, 1c) complexes, where, N∩O = a, N∼O = b, c. Oxidative addition (OA) of 1a-1c with CH₃I and C₂H₅I yields penta coordinate rhodium(III) complexes, [Rh(COR)ClI(η²-N∩O)] {R = -CH₃ (2a); -C₂H₅ (3a)} and [Rh(COR)(CO)ClI(η¹-N∼O)] {R = -CH₃ (2b, 2c); -C₂H₅ (3b, 3c)}. Kinetic study for the reaction of 1a-1c with CH₃I indicates a pseudo-first order reaction. The catalytic activity of 1a-1c for the carbonylation of methanol to acetic acid and its ester was evaluated at different initial CO pressures 5, 10 and 20 bar at ∼25 °C and higher turn over numbers (TON = 1581-1654) were obtained compared to commercial Monsanto’s species [Rh(CO)₂I₂]⁻ (TON = 1000) under the reaction conditions: temperature = 130 ± 1 °C, pressure = 15-32 bar, rpm = 450, time = 1 h and catalyst: substrate = 1: 1900.     

Palladium(II) complexes bearing a salicylaldiminato ligand with a hydroxyl group: Synthesis, structures, deprotonation, and catalysis

Palladium complexes with a salicylaldiminato ligand bearing a hydroxyl group (1a and 1b) have been synthesized and characterized. The structures of these complexes were confirmed by X-ray crystallography. A reversible deprotonation/protonation of the hydroxyl moiety on 1b was observed, while such behaviour was impossible with a related palladium complex (1c) bearing a methoxyl group in place of the hydroxyl group. The deprotonation affected its catalytic behaviour: the activity for polymerization of methyl acrylate catalyzed by 1b considerably decreased in the presence of 1 equiv. of ^tBuOK.     

Unsymmetric diruthenium complexes

The new diruthenium complexes trans-[(NH₃)₅Ru(L-L)Ru(NH₃)₄(bpy-Me)](PF₆)₅ (L-L are the bridging ligands pyrazine, 2a; 4,4′dipyridyl, 2b; and trans-1,2-bis(4-pyridyl)-ethylene, 2c; bpy-Me is N-methyl-pyridyl-pyridinium) are generated from the new complexes (L-L)Ru(NH₃)₄(bpy-Me)](PF₆)₃ (1a-c) and [(NH₃)₅Ru(H₂O)](PF₆)₂. Cyclic voltammetry on the new compounds in acetonitrile electrolyte reveals two quasi-reversible oxidation steps corresponding to the two Ru^II/III couples in 2b and 2c and a single oxidations for 1a-c. In addition, two reduction waves are observed for the bpy-Me ligands of 1a-c and 2a-c. All of the new compounds exhibit multiple metal-to-ligand charge transfer (MLCT) bands in the visible region of the spectrum. For compounds 1a-c the most intense absorption in the visible region decreases in energy as the length of the aromatic bridging ligands increases. By contrast the strongest absorption band of 2a is lower in energy than the most intense bands of both 2b and 2c. Single crystal X-ray analysis of 2a reveals that the bridging pyridine is coplanar with the pyridyl ring of the bpy-Me ligand that is attached to the Ru center. DFT calculations on 2a indicate that the HOMO is localized predominately on the {(NH₃)₅Ru-pyz-Ru(NH₃)₄} portion of the complex and the LUMO has slightly more contribution from the bpy-Me ligand.     

Synthesis and structural characterization of new chiral mixed phosphine phosphoramidite complexes of ruthenium

New phosphoramidite complexes of ruthenium chiral at the metal were synthesized, structurally characterized and their electrochemical and catalytic properties were studied. Reaction of the known chiral phosphoramidites (R = naphthyl, R′ = CH₃, 1a; R = naphthyl, R′ = benzyl, 1b; R = octahydronaphthyl, R′ = benzyl, 1c) with CpRu(PPh₃)₂Cl afforded the title compounds CpRu(PPh₃)(1a-c)(Cl) (2a-c) in 46-74% isolated yields. Fractional crystallization of 2b and 2c afforded the corresponding diastereopure complexes which are chiral both at the metal and at the ligand. The molecular structures of 2b and 2c were determined, revealing a pseudo octahedral coordination geometry about the ruthenium center. Electrochemical studies by cyclic voltammetry showed reversible electrochemical behavior of the metal complexes 2a-c. The new metal complexes are catalytically active in the Mukaiyama aldol reaction (24 h, room temperature, 31-53% yield), but almost no enantiomeric excesses for the products were obtained.     

Allosteric modulators of human A2B adenosine receptor

Background

Among adenosine receptors (ARs) the A_2B subtype exhibits low affinity for the endogenous agonist compared with the A₁, A_2A, and A₃ subtypes and is therefore activated when concentrations of adenosine increase to a large extent following tissue damages (e.g. ischemia, inflammation). For this reason, A_2B AR represents an important pharmacological target.

Methods

We evaluated seven 1-benzyl-3-ketoindole derivatives (7–9) for their ability to act as positive or negative allosteric modulators of human A_2B AR through binding and functional assays using CHO cells expressing human A₁, A_2A, A_2B, and A₃ ARs.

Results

The investigated compounds behaved as specific positive or negative allosteric modulators of human A_2B AR depending on small differences in their structures. The positive allosteric modulators 7a,b and 8a increased agonist efficacy without any effect on agonist potency. The negative allosteric modulators 8b,c and 9a,b reduced agonist potency and efficacy.

Conclusions

A number of 1-benzyl-3-ketoindole derivatives were pharmacologically characterized as selective positive (7a,b) or negative (8c, 9a,b) allosteric modulators of human A_2B AR.

General significance

The 1-benzyl-3-ketoindole derivatives 7–9 acting as positive or negative allosteric modulators of human A_2B AR represent new pharmacological tools useful for the development of therapeutic agents to treat pathological conditions related to an altered functionality of A_2B AR.     

5a-Carba-glycopyranoside primers: potential building blocks for biocombinatorial synthesis of glycosphingolipid analogues

Three ether-linked alkyl 5a-carba-glycopyranosides 1b,d, and 5b, and 5a′-carba-lactoside 7b were examined as potent primers in mouse B16 melanoma cells for their feasibility as building blocks for oligosaccharide biosynthesis. Uptake by B16 cells was first observed for all carba-glycoside primers, and, especially, the 5a-carba-sugar analogues of N-acetyl-β-d-glucosaminide 1b and β-d-glucoside 1d were shown to produce two-to-four-fold larger amounts of glycosylated products than the corresponding true sugar primers 1a and 1c. The carba glycoside uptake by cells resulted in β-galactosylation and subsequent sialylation of the incorporated galactose residues, giving rise to glycosylated products 3b and 3d having similar glycan structures as the ganglioside GM3. According to efficient uptake in cells, in addition to stability of the ether-linked pseudo-reducing ends of the oligosaccharides that formed, the carba glycoside primers have been demonstrated to be versatile building blocks for these biocombinatorial syntheses of glycolipid oligosaccharide mimetics. On the other hand, uptake for 5a-carba-galactopyranoside residue was found to be decreased by one-third for dodecyl 5a-carba-β-d-galactopyranoside 5b. Observation of similar levels for 5a′-carba-β-lactoside 7b under both cellular and cell-free conditions suggested that enzymes are likely to recognize the pyranose oxygen atom.     

Studies of rheniumtricarbonyl complexes of tripodal pyridyl-based ligands

The reaction of N-benzoyl and N-acetyl tris(pyridin-2-yl)methylamine 1b and 1c (LH = tpmbaH and tpmaaH) with [Re(CO)₅Br] has been investigated and shown to proceed via the initial formation of a cationic rheniumtricarbonyl complex [(LH)Re(CO)₃]Br in which coordination of the ligand occurs via the three pyridine rings. For tpmbaH 1b, but not tpmaaH 1c, this initial complex 2b readily undergoes the loss of HBr to give a neutral octahedral complex 4b [(L)Re(CO)₃] where coordination occurs via two of the pyridine rings and the deprotonated amide nitrogen. The ¹H NMR spectrum of the latter complex 4b is very unusual in that at room temperature the signals for the 3-H protons on the coordinated pyridine rings are not visible due to extreme broadening of these resonances. Comparison with the analogous complex 7 from N-benzoyl bis(pyridin-2-yl)methylamine 6b (bpmbaH) confirms that this is due to rotation of the uncoordinated pyridine ring. The structure of the cationic complex 3d [(LH)Re(CO)₃]Br formed from N-benzyl tris(pyridin-2-yl)methylamine 1d (bz-tpmaH) is also discussed. The crystal structures of complexes [(tpmba)Re(CO)₃] 4b, [(bz-tpmaH)Re(CO)₃]Br 3d and [(bpmba)Re(CO)₃] 7 have been determined. In all complexes the coordination geometry around Re is distorted octahedral with a fac-{Re(CO)₃}⁺ core.     

Synthesis and structural characterizations of para-bis(dialkyl/diarylphosphino)phenylenes built around tetrahalogenated benzene cores

Double deprotonation of 1,2-dibromo-4,5-difluorobenzene and 1-bromo-2-chloro-4,5-difluorobenzene by lithium diisopropylamide (LDA) in ethereal solutions is facile at very low temperatures (T < −90 °C). The organo-dilithium intermediates thus generated react readily with chlorophosphines ClPR₂ (R = Ph and/or ⁱPr), producing 1,2-dibromo-3,6-bis(diphenylphosphino)-4,5-difluorobenzene (1a), 1,2-dibromo-3,6-bis(diisopropylphosphino)-4,5-difluorobenzene (1b) and 1-bromo-2-chloro-3,6-bis(diphenylphosphino)-4,5-difluorobenzene (1c). Corresponding P-oxides 2a-c are obtained by oxidation of 1a-c with H₂O₂. Analogous reactions of 1,2-dibromo-4,5-difluorobenzene and 1-bromo-2-chloro-4,5-difluorobenzene with only 1 equiv. of LDA do not result in selective monodeprotonations, as 1a and 1c are formed preferentially after ClPPh₂ quench. All of the isolated new compounds were fully characterized by multinuclear NMR spectroscopy, elemental analysis and/or mass-spectrometry. In addition, 1a, 1c, 2a, and 2b were characterized by single crystal X-ray diffraction methods.     

Naphtho[2,3-d]isoxazole-4,9-dione-3-carboxylates: Potent, non-cytotoxic, antiapoptotic agents

Compounds containing a quinone moiety represent an important class of biologically active molecules that are widespread in nature, displaying anticancer, antibacterial, antimalarial, and fungicidal activities. In the course of designing 2,3-disubstituted-1,4-naphthoquinones derivatives as potential cysteine protease inhibitors, two naphtho[2,3-d]isoxazole-4,9-dione-3-carboxylates, 1a and 1b, were obtained. The antiapoptotic potential of 1a and 1b was then evaluated and compared to that of naphthoquinone 4. Primary rat hepatocytes were incubated with synthesized naphthoquinone derivatives and then exposed to the apoptotic stimulus camptothecin. Our results indicate that naphtho[2,3-d]isoxazole-4,9-dione-3-carboxylates 1a and 1b exerted a potent protective role in camptothecin-induced apoptosis in primary rat hepatocytes. Both 1a and 1b significantly increased cell viability, while reducing nuclear fragmentation, caspase-3, -8 and -9 activation, and cytochrome c release induced by camptothecin. In addition, 1a and 1b were shown to up-regulate Bcl-X_L, a pro-survival member of the Bcl-2 family of proteins, which modulates the mitochondrial pathway of apoptosis. Similar protective effects of quinone derivatives were seen in HuH-7 and PC12 cells incubated with distinct apoptotic stimuli, such as camptothecin, TGF-β1, or rotenone. Our results suggest that naphtho[2,3-d]isoxazole-4,9-dione-3-carboxylates 1a and 1b may act as potent, cytoprotective agents, through modulation of apoptotic pathways.     

Synthesis and evaluation of chromenyl barbiturates and thiobarbiturates as potential antitubercular agents

A novel series of barbiturate and thiobarbiturate analogs of 2-benzoyl-3-methyl-5-oxo-5H-furo[3,2-g]chromene-6-carbaldehydes (3a-g and 4a-d, respectively) and 6-methyl-4,8-dioxo-4,8-dihydropyrano[3,2-g]chromenes (7a-c), were synthesized and evaluated for their antitubercular activities against Mycobacterium tuberculosis H37RV, and cytotoxicity (CC₅₀) in the VERO cell MABA assay. The results indicate that the furanochromene series of compounds (3a-g and 4a-d) showed only weak to moderate antitubercular activity. However, the pyranochromene analog 7b showed good antitubercular activity (IC₉₀: 5.9 μg/mL) and cytotoxicity (CC₅₀: 14.27 μg/mL). The antitubercular activity of 7b was superior to the antituberculosis drug, pyrazinamide (PZA; IC₉₀: >20 μg/mL). Analog 7b was considered to be a lead compound for subsequent structural optimization.     

Synthesis and evaluation of antioxidant and antibacterial activities of new substituted bis(1,3,4-oxadiazoles), 3,5-bis(substituted) pyrazoles and isoxazoles

Two series of five membered heterocyclic bis(1,3,4-oxadiazole) derivatives 2(a-h) and 3,5-bis(substituted)pyrazoles, isoxazoles 3(a,b,d-i), 4(a-c) were synthesized via oxidative cyclization of some diaroylhydrazones using chloramine-T and cyclocondensation reaction with hydrazine hydrate and hydroxylamine hydrochloride, respectively. The newly synthesized compounds were screened for antioxidant and anti-microbial activities. Compounds 2(b), 3(b), and 4(a) showed higher antioxidant activity at 10 μg/ml while compounds 2(a), 3(a), 3(f), and 4(a) exhibited better anti-microbial activity at 100 μg/ml compared with standard vitamin C and ciprofloxacin, respectively. Structures of newly synthesized compounds were confirmed by elemental analysis and spectral IR, ¹H NMR, and ¹³C NMR data.