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PubMed2004

Problem of a wide variety of products in the Cu(hfac)2-nitroxide system.

The stereochemically flexible Cu(hfac)(2) metal-ligand system when combined with polyfunctional nitroxides leads to a variety of solids with varying structure and composition. While investigating the products of Cu(hfac)(2) interaction with spin-labeled pyrazole 4,4,5,5-tetramethyl-2-(1-methyl-1H-pyrazol-4-yl)-imidazoline-3-oxide-1-oxyl, we have isolated a family of (12) heterospin compounds differing in structure and composition in the solid state. In synthetic systems, these compounds often cocrystallize and must be separated mechanically. It is also shown that minor variation of the structure of the solid heterospin complex can substantially change the magnetic properties of compounds.

Journal Article↗
PubMed2005

Structural variety and magnetic properties of tetranuclear nickel(II) complexes with a central mu4-azide.

Using a set of pyrazolate-based dinucleating ligands with thioether sidearms and a set of different carboxylates, seven tetranuclear nickel(II) complexes of types [L2Ni4(N3)3(O2CR)2](ClO4) (1) and [L2Ni4(N3)(O2CR)4](ClO4) (2) featuring an unprecedented central mu4-1,1,3,3-azide could be isolated and fully characterized. X-ray crystal structures are discussed for 1a,b,e and 2b. The mu4-1,1,3,3-azide is symmetric in all cases except 1a but exhibits distinct binding modes with significantly different Ni-N(azide)-Ni angles and Ni-NNN-Ni torsions in type 1 and 2 complexes, which indicates high structural flexibility of this novel bridging unit. Also, IR-spectroscopic signatures and magnetic properties are distinct for type 1 and 2 complexes. Magnetic data for 1a,b,d,e and 2a,b were investigated and analyzed in a three-J approach. The only model that gave a satisfactory fit for all type 1 complexes includes one dominant antiferromagnetic coupling and two ferromagnetic interactions (one large and one smaller), indicating some degree of frustration. On the basis of magneto-structural correlations for end-on and end-to-end azide linkages, it is reasonable to assign the antiferromagnetic interaction to the intradimer exchange along the pyrazolate and the end-to-end linkage of the mu4-azide. Overall, the magnitude of the coupling constants differs significantly for the two distinct types of compounds, 1 or 2, and depends on the individual geometric details of the Ni4 array and the mu4-1,1,3,3-azide.

Journal Article↗
PubMed2005

Copper(II) mediated anion dependent formation of Schiff base complexes.

A tetranuclear mixed ligand copper(II) complex of a pyrazole containing Schiff base and a hydroxyhexahydropyrimidylpyrazole and copper(II) and nickel(II) complexes of the Schiff base having N-donor atoms have been investigated. A 2 equiv amount of 5-methyl-3-formylpyrazole (MPA) and 2 equiv of 1,3-diamino-2-propanol (1,3-DAP) on reaction with 1 equiv of copper(II) nitrate produce an unusual tetranuclear mixed ligand complex [Cu4(L1)2(L2)2(NO3)2] (1), where H2L1 = 1,3-bis(5-methyl-3-formylpyrazolylmethinimino)propane-2-ol and HL2 = 5-methyl-3-(5-hydroxyhexahydro-2-pyrimidyl)pyrazole. In contrast, a similar reaction with nickel(II) nitrate leads to the formation of a hygroscopic intractable material. On the other hand, the reaction involving 2 equiv of MPA and 1 equiv each of 1,3-DAP and various copper(II) salts gives rise to two types of products, viz. [Cu(T3-porphyrinogen)(H2O)]X2 (X = ClO4, NO3, BF4 (2)) (T3-porphyrinogen = 1,6,11,16-tetraza-5,10,15,20-tetrahydroxy-2,7,12,17-tetramethylporphyrinogen) and [Cu(H2L1)X]X x H2O (X = Cl (3), Br (4)). The same reaction carried out with nickel(II) salts also produces two types of compounds [Ni(H2L1)(H2O)2]X2 [X = ClO4 (5), NO3 (6), BF4 (7)] and [Ni(H2L1)X2] x H2O [X = Cl (8), Br (9)]. Among the above species 1, 3, and 5 are crystallographically characterized. In 1, all four copper atoms are in distorted square pyramidal geometry with N4O chromophore around two terminal copper atoms and N5 chromophore around two inner copper atoms. In 3, the copper atom is also in distorted square pyramidal geometry with N4Cl chromophore. The nickel atom in 5 is in a distorted octahedral geometry with N4O2 chromophore, where the metal atom is slightly pulled toward one of the axial coordinated water molecules. Variable-temperature (300 to 2 K) magnetic susceptibility measurements have been carried out for complex 1. The separations between the metal centers, viz., Cu(1)...Cu(2), Cu(2)...Cu(2)A, and Cu(2)A...Cu(1)A are 3.858, 3.89, and 3.858 A, respectively. The overall magnetic behavior is consistent with strong antiferromagnetic interactions between the spin centers. The exchange coupling constants between Cu(1)...Cu(2) and Cu(2)...Cu(2A) centers have turned out to be -305.3 and -400.7 cm(-1), respectively, resulting in a S = 1/2 ground state. The complexes are further characterized by UV-vis, IR, electron paramagnetic resonance, and electrochemical studies.

Journal Article↗
PubMed2006

Mono-, di-, and oligonuclear complexes of Cu(II) ions and p-hydroquinone ligands: syntheses, electrochemical properties, and magnetic behavior.

Four highly soluble square-planar Cu(II) and Ni(II) complexes of siloxy-salens (2SiCu, 2SiNi) and hydroxy-salens (2Cu, 2Ni) have been synthesized. An X-ray crystal structure analysis was performed on 2SiCu, 2SiNi, and 2Ni. The compounds have been investigated by cyclic voltammetry, UV-vis-NIR spectroelectrochemistry, and EPR spectroscopy. According to these results, the monooxidized species [2SiCu]+ and [2SiNi]+ are to be classified as Robin-Day class II and III systems, respectively. Magnetic measurements on the dinuclear (PMDTA)Cu(II) complex 1Cu2 x (PF6)2 with deprotonated 1,4-dihydroxy-2,5-bis(pyrazol-1-yl)-benzene (1) linker revealed antiferromagnetic coupling between the two Cu(II) ions thereby resulting in an isolated dimer compound. Coordination polymers [1Cu]n(H2O)(2n) of Cu(II) ions and bridging p-hydroquinone linkers were obtained from CuSO4 x 5 H2O and 1,4-dihydroxy-2,5-bis(pyrazol-1-yl)benzene. X-ray crystallography revealed linear chains running along the crystallographic a-direction and stacked along the b-axis. Within these chains, the Cu(II) ions are coordinated by two pyrazolyl nitrogen atoms and two p-hydroquinone oxygen atoms in a square-planar fashion.

Copper↗
PubMed2006

2D and 3D Cu(hfac)2 complexes with nitronyl nitroxide biradicals.

Reactions between Cu(hfac)2 and nitronyl nitroxide biradicals 1,4-bis[4-(4,4,5,5-tetramethyl-3-oxide-1-oxyl-4,5-dihydro-1H-imidazol-2-yl)pyrazol-1-yl]butane (L4) and 1,8-bis[4-(4,4,5,5-tetramethyl-3-oxide-1-oxyl-4,5-dihydro-1H-imidazol-2-yl)pyrazol-1-yl]octane (L8) gave respectively a framework compound [Cu(hfac)2]2L4 and a layered polymer compound [Cu(hfac)2]2L8. The framework of [Cu(hfac)2]2L4 consists of 66-membered condensed metallocycles. Inside the framework, the structure has macrohelixes (pitch approximately 25 A) extending along the [001] crystallographic direction. All the helixes have the same direction of winding; the crystals, therefore, are optically active, the structure corresponding either to P-isomer (P4(1)2(1)2) or to M-isomer (P4(3)2(1)2). The long distances between the Cu atoms and the O atoms of the coordinated >N-O groups (Cu-O 2.351-2.467 A) are responsible for ferromagnetic exchange interactions in Cu2+-O-N< and >N-O-Cu2+-O-N< exchange clusters.

Journal Article↗
PubMed2006

Syntheses and characterization of oxygen/sulfur-bridged incomplete cubane-type clusters, [Mo3S4Tp3]+ and [Mo3OS3Tp3]+, and a mixed-metal cubane-type cluster, [Mo3FeS4ClTp3]. X-ray structures of [Mo3S4Tp3]Cl, [Mo3OS3Tp3]PF6, and [Mo3FeS4ClTp3].

The reaction of [Mo3S4(H2O)9]4+ (1) with hydrotris(pyrazolyl)borate (Tp) ligands produced [Mo3S4Tp3]Cl x 4 H2O ([3]Cl x 4 H2O) in an excellent yield. An X-ray structure analysis of [3]Cl x 4 H2O revealed that each molybdenum atom bonded to the Tp ligand. We report four salts of 3, [3]Cl x 4 H2O, [3]tof x 2 H2O, [3]PF6 x H2O, and [3]BF4 x 2 H2O in this paper. The solubility and stability of the chloride salt in organic solvents differ completely from those of the other salts. We have also prepared a new compound, [Mo3OS3Tp3]PF6 x H2O ([4]PF6 x H2O), via the reaction of [Mo3OS3(H2O)9]4+ (2) with KTp in the presence of NH4PF6. All the molybdenum atoms bonded to Tp ligand. 1H NMR signals corresponding to nine protons bonded to three pyrazole rings in one Tp were observed in a spectrum (at 253 K) of [3]BF4 x 2 H2O. It shows that cluster 3 has a 3-fold rotation axis in CD2Cl2 solution. Twenty-one 1H NMR signals corresponding to twenty-seven protons bonded to nine pyrazole rings in three Tp ligands were observed in a spectrum (at 233 K) of [4]PF6 x H2O; obviously, 4 has no 3-fold rotation axis, in contrast to 3. The short CH...mu3S distance caused large upfield chemical shifts in the 1H NMR spectra of 3 and 4. The reaction of 3 with metallic iron in CH2Cl2 produced [Mo3FeS4XTp3] (X = Cl (5), Br (6)). X-ray structure analysis of 5 has revealed the existence of a cubane-type core Mo3FeS4. Complex 3 functions as a metal-complex ligand for preparing a novel mixed-metal complex even in nonaqueous solvents. The cyclic voltammogram of 5 shows two reversible one-electron couples (E(1/2) = -1.40 and 0.52 V vs SCE) and two irreversible one-electron oxidation processes (E(pc) = 1.54 and 1.66 V vs SCE).

Journal Article↗
PubMed1996

Dinuclear Copper(II) Complexes Incorporating a New Septadentate Polyimidazole Ligand.

The dinuclear copper(II) complexes [Cu(2)(tmihpn)(prz)](ClO(4))(2).2CH(3)CN (6) and [Cu(2)(tmihpn)(O(2)CCH(3))](ClO(4))(2).CH(3)CN (7) were prepared, where tmihpn is the deprotonated form of N,N,N',N'-tetrakis[(1-methylimidazol-2-yl)methyl]-1,3-diaminopropan-2-ol and prz is the pyrazolate anion. The crystal structures of 6 and 7 were determined and revealed that both complexes contain bridging alkoxide ligands as well as bridging pyrazolate and acetate ions, respectively. Crystal data: compound 6, triclinic, P&onemacr;, a = 18.089(2) Å, b = 22.948(3) Å, c = 9.597(2) Å, alpha = 93.37(2) degrees, beta = 94.49(2) degrees, gamma = 81.69(2) degrees, V = 3925.1 Å(3), Z = 4; compound 7, triclinic, P&onemacr;, a = 12.417(2) Å, b = 15.012(3) Å, c = 10.699(2) Å, alpha = 104.76(2) degrees, beta = 102.63(2) degrees, gamma = 99.44(2) degrees, V = 1830.1 Å(3), Z = 2. In compound 6, the coordination geometry around both copper centers resembles a distorted square pyramid, while the stereochemistry around the copper centers in 7 is best described as trigonal bipyramidal. Both complexes display well-resolved isotropically shifted (1)H NMR spectra. Selective substitution studies and integration data have been used to definitively assign several signals to specific ligand protons. Results from the solution (1)H NMR studies suggest that the basal and apical imidazole groups do not exchange rapidly on the NMR time scale and the solid state structures of the complexes are retained in solution. In addition, the magnetochemical characteristics of 6 and 7 were determined and provide evidence for "magnetic orbital switching". Antiferromagnetic coupling in 6 (J = -130 cm(-)(1)) is strong, while the copper centers in compound 7 are ferromagnetically coupled (J = +16.4 cm(-1)). Differences in the magnetic behavior of the two copper centers have been rationalized using the "ligand orbital complementary" concept. The ground state magnetic orbitals involved in spin coupling in 6 (d(x)()()2(-)(y)()()2) are different from those in 7 (d(z)()()2).

Journal Article↗
PubMed1998

A Dinuclear Nickel(II) Complex with Readily Accessible Coordination Sites and Additional N-Functional Groups in Proximity to the Bimetallic Core.

A series of pyrazolate-based dinuclear Ni(II) complexes relevant to the active site of urease are reported. Deprotonation of HL(1) [HL(1) = 3,5-bis(R(2)NCH(2))-pyzH; R(2)N = Me(2)N(CH(2))(3)NMe] by means of 1 equiv of BuLi and subsequent reaction with 2 equiv of [Ni(H(2)O)(6)](ClO(4))(2) in the presence of NEt(i)Pr(2) affords the dinuclear complex [L(1)Ni(2)(OH)(MeCN)(2)](ClO(4))(2) (1). This is shown crystallographically to contain two five-coordinate nickel ions bridged by both the pyrazolate and a hydroxide, with an acetonitrile solvent molecule bound to each metal center. When HL(2) is employed {HL(2) = 3,5-bis(R(2)NCH(2))-pyzH; R(2)N = [Me(2)N(CH(2))(3)](2)N}, the additional ligand side arms act as proton acceptors forming an intramolecular N.H.N bridge to yield the complex [HL(2)Ni(2)(OH)(MeCN)(2)](ClO(4))(3) (2), whose basic bimetallic framework is essentially identical to 1. The two Ni(II) centers in 2 exhibit strong antiferromagnetic coupling (J = -46.7 cm(-)(1)). The labile acetonitrile donors in 2 are easily replaced by either neutral ligands such as dmf or anions such as thiocyanate, giving rise to the formation of complexes [HL(2)Ni(2)(OH)(dmf)(2)](ClO(4))(3) (3) and [HL(2)Ni(2)(OH)(NCS)(2)](ClO(4)) (4), respectively, where the overall dinuclear framework of 2 remains unchanged upon the substitution reaction.

Journal Article↗
PubMed1998

Synthesis and Characterization of Palladium(II) Complexes with New Polydentate Nitrogen Ligands. Dynamic Behavior Involving Pd-N Bond Rupture. X-ray Molecular Structure of [{Pd(eta(3)-C(4)H(7))}(2)(Me-BPzTO)](4-MeC(6)H(4)SO(3)) [Me-BPzTO = 4,6-Bis(4-methylpyrazol-1-yl)-1,3,5-triazin-2-olate].

The ligands 2,4,6-tris(4-methylpyrazol-1-yl)-1,3,5-triazine (Me-TPzT), 2,4,6-tris(4-bromopyrazol-1-yl)-1,3,5-triazine (Br-TPzT), and 2-methoxy-4,6-bis(4-methylpyrazol-1-yl)-1,3,5-triazine (Me-BPzTOMe) have been synthesized and their reactions with some palladium derivatives explored. The palladium fragment [Pd(eta(3)-2-Me-C(3)H(4))(S)(2)](+), S = acetone, reacts in acetone with Me-TPzT or Br-TPzT in a 3:1 molar ratio to generate new complexes in which two allylpalladium fragments are present and the TPzT ligands have been partially hydrolyzed: [{Pd(eta(3)-C(4)H(7))}(2)(X-BPzTO)]A, X-BPzTO = 4,6-bis[4-methyl(or bromo)pyrazol-1-yl]-1,3,5-triazin-2-olate (X = Me, A = BF(4), 1; A = PF(6), 2; A = CF(3)SO(3), 3; A = p-MeC(6)H(4)SO(3), 4; X = Br, A = CF(3)SO(3), 5). When the ligand Me-BPzTOMe is made to react with only 1 equiv of the palladium solvate, compound 6, [Pd(eta(3)-2-Me-C(3)H(4))(Me-BPzTOMe)]CF(3)SO(3), is isolated. Reaction of 6 with another 1 equiv of the palladium derivative leads to 3. The intermediate 7, [{Pd(eta(3)-2-Me-C(3)H(4))}(2)(Me-BPzTOMe)]CF(3)SO(3), has been isolated as an almost pure compound. The reaction of Me-BPzTOMe with 1 equiv of [Pd(C(6)F(5))(2)(cod)] (cod = 1,5-cyclooctadiene) leads to the complex [Pd(C(6)F(5))(2)(Me-BPzTOMe)], 8. Attention has been focused on the dynamic behavior, related with metallotropic phenomena, of the new complexes. (1)H NMR variable-temperature studies of complexes 1, 6, and 8 have been carried out. For 8, only one static species is observed, while, for 1 and 6, two isomers are detected at low temperature. Different DeltaG(c)() activation energies at the coalescence temperature have been determined and are ascribed to processes implying Pd-N bond ruptures. For 6, two different barriers are detected, corresponding to Pd-N(triazine) or Pd-N(pyrazole) bond ruptures. From the DeltaG(c)() data, it is concluded that the main driving force of the hydrolysis process is the formation of a better coordinating ligand. The molecular structure of 4 has been determined by X-ray diffraction. The meso isomer, in which the two C-Me axes of the allylic groups are oriented in the same direction, is found in the solid state.

Journal Article↗
PubMed1999

Syntheses and Structures of Bis(azole)difluorosulfuranes.

Bis(imidazole)sulfur difluoride (4), bis(pyrazole)sulfur difluoride (6), and bis(1,2,4-triazole)sulfur difluoride (8) are formed in the reactions of N-(trimethylsilyl)imidazole, N-(trimethylsilyl)pyrazole, and 1-(trimethylsilyl)-1,2,4-triazole with SF(4), in high yield. The ring systems in these three molecules occupy equatorial positions in the pseudo-trigonal-bipyramidal coordination sphere of the central sulfur atoms. The angles between the planes of the ring substituents and the FSF axis for 4 and 6 are in the range 23.6-35.3 degrees, and in 8 the triazole rings are almost parallel (deviation 1.7 degrees ). The interaction between the heterocyclic substituents and the sulfur centers and their influence on the axial and equatorial bonds is discussed.

Journal Article↗
PubMed2000

Lowest electronic excited states of platinum(II) diimine complexes.

Absorption and emission spectra of Pt(diimine)L2 complexes (diimine = 2,2'-bipyridine (bpy) or 4,4'-dimethyl-2,2'-bipyridine (dmbpy); L = pyrazolate (pz-), 3,5-dimethylpyrazolate (dmpz-), or 3,4,5-trimethylpyrazolate (tmpz-)) have been measured. Solvent-sensitive absorption bands (370-440 nm) are attributed to spin-allowed metal-to-ligand charge-transfer (1MLCT) transitions. As solids and in 77 K glassy solution, Pt(bpy)(pz)2 and Pt(dmbpy)(pz)2 exhibit highly structured emission systems (lambda max approximately 494 nm) similar to those of the diprotonated forms of these complexes. The highly structured bands (spacings 1000-1400 cm-1) indicate that the transition originates in a diimine-centered 3(pi-->pi*) (3LL) excited state. The intense solid-state and 77 K glassy solution emissions from 3MLCT[d(Pt)-->pi*(bpy)] excited states of complexes with dmpz- and tmpz- ligands occur at longer wavelengths (lambda max = 500-610 nm), with much broader vibronic structure. These findings are consistent with increasing electron donation of the pyrazolate ligands, leading to a distinct crossover from a lowest 3LL to a 3MLCT excited state.

Journal Article↗
PubMed2001

Minimum energy structure of hydridotris(pyrazolyl)borato iridium(V) tetrahydride is not a C(3upsilon) capped octahedron.

Recent synthesis and NMR spectroscopy of neutral Ir(V) complexes hydridotris(3,5-dimethylpyrazol-1-yl)borato tetrahydride (Tp*IrH(4)) and hydridotris(pyrazol-1-yl)borato tetrahydride (TpIrH(4)) have been interpreted as supporting face-capped octahedral structures (C(3upsilon)) with each of three Ir-H bonds trans to an Ir-N bond and the fourth hydride capping the IrH(3) face. Here, density functional geometry optimizations and coupled cluster calculations on hydridotris(pyrazol-1-yl)borato iridium tetrahydrogen find that a C(s) edge-bridged octahedral tetrahydride structure and a C(1) eta(2)-dihydrogen, dihydride structure are local minima and find that the C(3upsilon) structure is a local maximum (second-order saddle point). Several low energy transition states connecting the local minima have been located, and these minima can be used to simulate the experimental NMR spectra. A comparison of the experimental infrared spectrum of Tp*IrH(4) and the harmonic frequency calculations on the C(s), C(1), and C(3upsilon) structures also supports the assignment of the C(s)and C(1) structures as the observed ones.

Borates↗
PubMed2000

Synthesis and fungicidal activity against Rhizoctonia solani of 2-alkyl (Alkylthio)-5-pyrazolyl-1,3,4-oxadiazoles (Thiadiazoles).

Some series of 2-alkyl (alkythio)-5-((4-chloro)-3-ethyl-1-methyl-1H-pyrazole-5-yl)-1,3, 4-oxadiazoles (thiadiazoles) were prepared as potential fungicides. Their fungicidal activity was evaluated against rice sheath blight, which is a major disease of rice in China. Structure-activity relationships for the screened compounds were evaluated and discussed. It was found that 5-(4-chloro-3-ethyl-1-methyl-1H-pyrazole-5-yl)-1,3, 4-thiadiazole-2-thione has the higher fungicidal activity.

Fungicides, Industrial↗
PubMed1995

A novel type of retinoic acid receptor antagonist: synthesis and structure-activity relationships of heterocyclic ring-containing benzoic acid derivatives.

A new series of heterocyclic ring-containing benzoic acids was prepared, and the binding affinity and antagonism of its members against all-trans-retinoic acid were evaluated by in vitro assay systems using human promyelocytic leukemia (HL-60) cells. Structure-activity relationships indicated that both an N-substituted pyrrole or pyrazole (1-position) and a hydrophobic region, with these linked by a ring system, were indispensable for effective antagonism. Among the compounds evaluated, optimal antagonism was exhibited by 4-[4,5,7,8,9,10-hexahydro-7,7,10,-10-tetramethyl-1-(3- pyridylmethyl)anthra[1,2-b]pyrrol-3-yl]benzoic acid (31), 4-[4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl-1-(3-pyridylmethyl)-5- thiaanthral[1,2-b]pyrrol-3-yl]benzoic acid (40), and 4-[4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl-1-(3- pyridylmethyl)anthra[2,1-d]pyrazol-3-yl]benzoic acid (55), all of which possess a 3-pyridylmethyl group at the five-membered ring nitrogen atom.

Benzoates↗
PubMed1977

6-aminopyrazolo[4,3-c]pyridin-4(5H)-one, a novel analogue of guanine.

Treatment of dimethyl alpha-ethoxymethylidineacetonedicarboxylate with hydrazine gave methyl 3-(methoxy-carbonylmethyl)pyrazole-4-carboxylate which, upon ammonolysis and dehydration, afforded methyl 3-(cyanomethyl)pyrazole-4-carboxylate. This compound, when heated with liquid ammonia, gave 6-aminopyrazolo[4,3-c]pyridin-4(5H)-one, a new guanine analogue, which did not possess any of the potent antiviral activity shown by 6-aminoimidazo[4,5-c]pyridin-4(5H)-one (3-deazaguanine).

Antiviral Agents↗
PubMed1977

Synthesis and biological activity of some derivatives of thiochroman-4-one and tetrahydrothiapyran-4-one.

A small series of pyrazoles and isoxazoles derived from thiochroman-4-one has been synthesized and characterized. The compounds were examined for their in vitro inhibitory activity against Bacillus subtilis and Pseudomonas fluorescens. Among the tested compounds the pyrazole derivative from thiochroman-4-one was found to be the most effective inhibitor of growth of B. subtilis. Extensive H NMR analysis was recorded for all compounds.

Animals↗
PubMed2001

Fluorosulfonyl- and bis-(beta-chloroethyl)amino-phenylamino functionalized pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine derivatives: irreversible antagonists at the human A3 adenosine receptor and molecular modeling studies.

A series of pyrazolotriazolopyrimidines was previously reported to be highly potent and selective human A(3) adenosine receptor antagonists (Baraldi et al. J. Med. Chem. 2000, 43, 4768-4780). A derivative having a methyl group at the N(8) pyrazole combined with a 4-methoxyphenylcarbamoyl moiety at N(5) position, displayed a K(i) value at the hA(3) receptor of 0.2 nM. We now describe chemically reactive derivatives which act as irreversible inhibitors of this receptor. Electrophilic groups, specifically sulfonyl fluoride and nitrogen mustard (bis-(beta-chloroethyl)amino) moieties, have been incorporated at the 4-position of the aryl urea group. Membranes containing the recombinant hA(3) receptor were preincubated with the compounds and washed exhaustively. The loss of ability to bind radioligand following this treatment indicated irreversible binding. The most potent compound in irreversibly binding to the receptor was 14, which contained a sulfonyl fluoride moiety and a propyl group at the N(8) pyrazole nitrogen. The bis-(beta-chloroethyl)amino derivatives displayed a much smaller degree of irreversible binding than the sulfonyl fluoride derivatives. A computer-generated model of the human A(3) receptor was built and analyzed to help interpret these results. The model of the A(3) transmembrane region was derived using primary sequence comparison, secondary structure predictions, and three-dimensional homology building, using the recently published crystal structure of rhodopsin as a template. According to our model, sulfonyl fluoride derivatives could dock within the hypothetical TM binding domain, adopting two different energetically favorable conformations. We have identified two amino acids, Ser247 and Cys251, both in TM6, as potential nucleophilic partners of the irreversible binding to the receptor.

Aniline Compounds↗
PubMed2002

7-Substituted 5-amino-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines as A2A adenosine receptor antagonists: a study on the importance of modifications at the side chain on the activity and solubility.

It was demonstrated in the early 1990s that adenosine exerts many physiological functions through the interaction with four different receptors, named A1, A2A, A2B, and A3. In the past few years, our group has been involved in the development of A2A antagonists, which led to the synthesis of SCH 58261 (1), the first potent and selective adenosine A2A antagonist, which has been widely used as a reference compound. In this paper, we present an extended series of pyrazolotriazolopyrimidines synthesized with the aim to investigate the influence of the substitutions on the pyrazole ring. The choice of the substituents was based on their capability to improve water solubility while retaining high affinity and selectivity at the human A2A adenosine receptor subtype. In this series, some structural characteristics that are important for activity, i.e., tricyclic structure, free amino group at 5-position, furan ring, and substituent at 7-position on the pyrazole moiety, have been maintained. We focused our attention on the nature of the phenyl ring substituent to improve water solubility. Following this strategy, we developed new compounds with good affinity and selectivity for A2A adenosine receptors, such as 8d (K(i) 0.12 nM; hA1/hA2A ratio = 1025; R(m) = 2.8), 8h (K(i) 0.22; hA1/hA2A ratio = 9818; R(m) = 3.4), 8i (K(i) 0.18 nM; hA1/hA2A ratio = 994; R(m) = 2.8), 8k (K(i) 0.13 nM; hA1/hA2A ratio = 4430; R(m) = 3.6), and 14b (K(i) 0.19 nM; hA1/hA2A ratio = 2273; R(m) = 2.7). All the new synthesized compounds have no significant interaction with either A2B or A3 receptor subtypes. This new series of compounds deeply enlightens some structural requirements to display high affinity and selectivity for the A2A adenosine receptor subtype, although our goal of identifying new compounds with increased water solubility was not completely achieved. On this basis, other strategies will be devised to improve this class of compounds with a profile that appears to be promising for treatment of neurodegenerative disorders, such as Parkinson's disease.

Binding, Competitive↗