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PubMed1997

Synthesis and Characterization of the Benzoylformato Ferrous Complexes with the Hindered Tris(pyrazolyl)borate Ligand as a Structural Model for Mononuclear Non-Heme Iron Enzymes.

By using a hindered tripodal ligand, hydrotris(3-tert-butyl-5-isopropylpyrazol-1-yl)borate HB(3-tBu-5-iPrpz)(3), a series of monomeric ferrous complexes having acetate, hydroxide, and benzoylformate ligands were synthesized. Reaction of KHB(3-tBu-5-iPrpz)(3) with anhydrous Fe(OAc)(2) yielded acetato complexes Fe(OAc)[HB(3-tBu-5-iPrpz)(3)] (1) and Fe(OAc)[HB(3-tBu-5-iPrpz)(3)](3-iPr-5-tBupzH) (2). A hydroxo complex Fe(OH)[HB(3-tBu-5-iPrpz)(3)] (3) was prepared by the treatment of 1 or 2 with aqueous NaOH. The geometry of Fe(II) in 3 is a slightly distorted tetrahedron as determined by X-ray crystallography. The hydroxo complex 3 reacted with benzoylformic acid to give the benzoylformato complex Fe(O(2)CC(O)Ph)[HB(3-tBu-5-iPrpz)(3)] (4), which showed thermochromism which depended on the coordination geometry of the benzoylformate ligand. The Fe(II) ion in the colorless form of 4 isolated at 4 degrees C is coordinated by a tetrahedral N(3)O(1) ligand donor set including the unidentate benzoylformato ligand. On the other hand, the bluish purple form of 4 isolated at -20 degrees C has a five-coordinate trigonal bipyramidal Fe(II) center. The benzoylformate ligand in this bluish purple form works as a chelate ligand through coordination of the unidentate carboxylate oxygen atom as well as the ketonic oxygen atom. A benzoylformato complex containing an additional pyrazole, Fe(O(2)CC(O)Ph)[HB(3-tBu-5-iPrpz)(3)](3-iPr-5-tBupzH) (5), was obtained by the reaction of 3 with benzoylformic acid in the presence of 3-tert-butyl-5-isopropylpyrazole. The iron atom in 5 is coordinated by an N(4)O(1) ligand donor set with trigonal bipyramidal geometry. A hydrogen-bonding interaction between the carboxylate oxygen atom and the additional pyrazole's NH proton in 5 is suggested from the short distance between O(carboxylate) and N(pyrazole) observed in the X-ray structure and the absence of the nuNH vibration in the IR spectrum.

Journal Article↗
PubMed1999

Coordination and Conversion of Urea at Dinuclear &mgr;-Acetato Nickel(II) Complexes with Symmetric and Asymmetric Cores.

A series of symmetric and asymmetric pyrazolate-based dinuclear Ni(II) complexes relevant to the active site of urease is reported, which have acetate ions as secondary bridges and which feature variations in the type (N or S) and number of donor sites provided within the individual coordination compartments of the primary pyrazolate ligand matrixes. X-ray crystallographic structures of the acetone adduct [L(1)Ni(2)(&mgr;-OAc)(acetone)(2)](ClO(4))(2) (1) as well as of the urea adducts [L(1)Ni(2)(&mgr;-OAc)(benzylurea)(2)](ClO(4))(2) (2c), [L(2)Ni(2)(&mgr;-OAc)(urea)](ClO(4))(2) (3a), and [L(3)Ni(2)(&mgr;-OAc)(N,N'-dimethylurea)(2)(MeOH)(2)](ClO(4))(2) (4) have been determined. They reveal that the urea substrates are tied up with the bimetallic cores by both O-coordination to the metal centers and hydrogen bonding between the urea NH and the O atoms of the bridging acetate. In a related complex [L(3)Ni(2)(&mgr;-OAc)(OAc)(2)Na]BPh(4) (5) a sodium ion is associated with the dinickel framework via binding to one O atom of each of the three acetates. The nickel(II) ions in 1 and 2a are weakly antiferromagnetically coupled (J = -2.6 and -1.9 cm(-)(1)), where the magnitude of the coupling appears to correlate with the tilting of the acetate moiety with respect to the plane of the pyrazolate. The superexchange in 3a and 4 is even weaker. The ability of the new complexes to mediate the ethanolysis of urea is examined and is found to be dependent on the number and stereochemical arrangement of the accessible coordination sites at the dinuclear core: the asymmetric species 3a is not capable of inducing any solvolysis of the substrate, and the activity of the symmetric systems 1 and 2b is less than stoichiometric, whereas 4 displays higher activity, albeit this is still very low and possibly proceeds via a one metal ion mechanism.

Journal Article↗
PubMed1995

Studies on new acidic azoles as glucose-lowering agents in obese, diabetic db/db mice.

Bioisosteric substitution was used as a tool to generate several new structural alternatives to the thiazolidine-2,4-dione and tetrazole heterocycles as potential antidiabetic agents. Among the initial leads that emerged from this strategy, a family of acidic azoles, isoxazol-3- and -5-ones and a pyrazol-3-one, showed significant plasma glucose-lowering activity (17-42% reduction) in genetically obese, diabetic db/db mice at a dose of 100 mg/kg/day x4. Structure-activity relationship studies determined that 5-alkyl-4-(arylmethyl)pyrazol-3-ones, which exist in solution as aromatic enol/iminol tautomers, were the most promising new class of potential antidiabetic agent (32-45% reduction at 20 mg/kg/d x4). Included in this work are convenient syntheses for several types of acidic azoles that may find use as new acidic bioisosteres in medicinal chemistry such as the antidiabetic lead 5-(trifluoromethyl)pyrazol-3-one (hydroxy tautomer) and aza homologs of the pyrazolones, 1,2,3-triazol-5-ones (hydroxy tautomer) and 1,2,3,4-tetrazol-5-one heterocycles. log P and pKa data for 15 potential acidic bioisosteres, all appended to a 2-naphthalenylmethyl residue so as to maintain a similar distance between the acidic hydrogen and arene nucleus, are presented. This new data set allows comparison of a wide variety of potential acid mimetics (pKa 3.78-10.66; log P -0.21 to 2.76) for future drug design.

Animals↗
PubMed1990

Growth inhibition and induction of cellular differentiation of human myeloid leukemia cells in culture by carbamoyl congeners of ribavirin.

A series of 1,2,3-triazole (2), pyrazole (3 and 5), and pyrrole (4) ribonucleosides with two adjacent carbamoyl groups have been synthesized and evaluated for cell growth inhibition and induction of cellular differentiation of HL-60 cells in culture. Glycosylation of the TMS derivatives of dimethyl 1,2,3-triazole-4,5-dicarboxylate (6) and diethyl pyrazole-3,4-dicarboxylate (7) with 1-O-acetyl-2,3,5-tri-O-benzoyl-D- ribofuranose (8) in the presence of TMS triflate gave predominantly the beta-nucleosides 9 and 14, respectively. Ammonolysis of 9 and 14 furnished 2-beta-D-ribofuranosyl-1,2,3-triazole-4,5-dicarboxamide (2) and 1-beta-D-ribofuranosylpyrazole-3,4-dicarboxamide (3), respectively. Stereoselective ring annulation of 1-deoxy-1-hydrazinyl-2,3-O-isopropylidene-D- ribose (16) with tetracyanoethylene (15) gave 5-amino-1-(2,3-O-isopropylidene-beta-D-ribofuranosyl)pyrazole-3,4- dicarbonitrile (17). Deisopropylidenation of 17, followed by oxidative hydrolysis of the reaction product (18), gave the 5-amino derivative of 3 (5). Stereospecific glycosylation of the sodium salt of preformed diethyl pyrrole-3,4-dicarboxylate (22) with 1-chloro-2,3-O-isopropylidene-5-O-(tert-butyldimethylsilyl)-alpha-D- ribofuranose (23) was accomplished to furnish blocked nucleoside 24, which on ammonolysis and deisopropylidenation gave 1-beta-D-ribofuranosylpyrrole-3,4-dicarboxamide (4). The structures of 2 and 3 were assigned by single-crystal X-ray diffraction studies, which showed extensive inter- and intramolecular hydrogen bonding. Nucleosides 2-5 are devoid of significant cytotoxic properties against L1210 and WI-L2 leukemia cells in culture. However, these compounds were found to be inducers of cellular differentiation of HL-60 cells in the range of 30-60 microM and were comparable to ribavirin in this regard.

Acetylation↗
PubMed1997

Photochemistry of Phenyl-Substituted 1-Methylpyrazoles.

Direct irradiation of 1-methyl-4-phenylpyrazole (2) in methanol results in regiospecific phototransposition to 1-methyl-4-phenylimidazole (4) and in photocleavage to (E)/(Z)-3-(N-methylamino)-2-phenylpropenenitrile (5) and (E)/(Z)-2-(N-methylamino)-1-phenylethenyl isocyanide (6). Deuterium labeling confirms that the phototransposition occurs via the P(4) permutation pathway. Separate experiments show that 5 and 6 undergo (Z) --> (E) isomerization and photocyclization to imidazole 4. Quantum yields for these reactions show that the sequence 2 --> 6 --> 4 is a major pathway for the P(4) phototransposition of 2 --> 4. Isocyanides were also detected as intermediates in the P(4) phototransposition of a variety of other pyrazoles confirming the generality of this pathway in pyrazole photochemistry. Direct irradiation of 1-methyl-5-phenylpyrazole (3) resulted in the formation of 1-methyl-5-phenylimidazole (7), 1-methyl-2-phenylimidazole (8), and 1-methyl-4-phenylimidazole (4). Deuterium labeling revealed that these products were formed by P(4), P(6), and P(7) permutation pathways, respectively. (E)/(Z)-3-(N-methylamino)-3-phenylpropenenitrile (9) and (E)/(Z)-2-(N-methylamino)-2-phenylethenyl isocyanide (10) photocleavage products were also formed in this reaction. Irradiation of 3 in furan solvent did not result in phototransposition but led to the formation of endo and exo adducts formed by Diels-Alder reaction of furan with 4-phenyl-5-methyl-1,5-diazabicyclo[2.1.0]pent-2-ene. This constitutes the first direct evidence for the formation of a 1,5-diazabicyclo[2.1.0]hex-2-ene from photolysis of a pyrazole and is consistent with the electrocyclic ring closure-heteroatom migration mechanism suggested for the P(6) and P(7) phototranspositions.

Journal Article↗
PubMed2003

Endothelium-independent relaxation to cannabinoids in rat-isolated mesenteric artery and role of Ca2+ influx.

(1) Three cannabinoid receptor agonists, anandamide (CB(1) receptor-selective) and the aminoalkyl-indoles, JWH 015(2-methyl-1-propyl-1H-indol-3-yl)-1-napthalenylmethanone; (CB(2) receptor-selective), R-(+)-WIN 55,212-2 (R-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolol[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone; slightly CB(2) receptor-selective), as well as the enantiomer S-(-)-WIN 55,212-3(S-(-)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolol[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone; inactive at cannabinoid receptors), induced endothelium-independent relaxation of methoxamine-precontracted isolated small mesenteric artery of rat. KCL (60 mM) precontraction did not affect relaxation to the aminoalkylindoles, but reduced that to anandamide. (2) SR14176A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide; 3 micro M; CB(1) receptor antagonist) inhibited relaxation only to JWH 015 and anandamide. Neither AM 251 (N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide; CB(1) antagonist) nor SR 144528 (N-[(1S)-endo-1,3,3-trimethyl bicyclo[2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide; CB(2) antagonist; both at 3 micro M) affected any of the relaxations. (3) Vanilloid receptor desensitisation with capsaicin reduced anandamide relaxation; addition of SR 141716A (3 micro M) then caused further inhibition. SR 141716A did not affect capsaicin-induced relaxation. (4) The aminoalkylindoles inhibited CaCl(2)-induced contractions in methoxamine-stimulated vessels previously depleted of intracellular Ca(2+). These inhibitory effects were greatly reduced or abolished in ionomycin-(a calcium ionophore) contracted vessels. Anandamide also caused vanilloid receptor-independent, SR 141716A- (3 micro M) insensitive, inhibition of CaCl(2) contractions. (5) In conclusion, the aminoalkylindoles JWH 015, R-(+)-WIN 55,212-2 and S-(-)-WIN 55,212-3 relax rat small mesenteric artery mainly by inhibiting Ca(2+) influx into vascular smooth muscle. Anandamide causes vasorelaxation by activating vanilloid receptors, but may also inhibit Ca(2+) entry. Relaxation to JWH 015 and anandamide was sensitive to SR 141716A, but there is no other evidence for the involvement of CB(1) or CB(2) receptors in responses to these compounds.

Animals↗
PubMed2006

Photomagnetic properties of iron(II) spin crossover complexes of 2,6-dipyrazolylpyridine and 2,6-dipyrazolylpyrazine ligands.

The photomagnetic properties of the following iron(II) complexes have been investigated: [Fe(L1)2][BF4]2, [Fe(L2)2][BF4]2, [Fe(L2)2][ClO4]2, [Fe(L3)2][BF4]2, [Fe(L3)2][ClO4]2 and [Fe(L4)2][ClO4]2 (L1 = 2,6-di{pyrazol-1-yl}pyridine; L2 = 2,6-di{pyrazol-1-yl}pyrazine; L3 = 2,6-di{pyrazol-1-yl}-4-{hydroxymethyl}pyridine; and L4 = 2,6-di{4-methylpyrazol-1-yl}pyridine). Compounds display a complete thermal spin transition centred between 200-300 K, and undergo the light-induced excited spin state trapping (LIESST) effect at low temperatures. The T(LIESST) relaxation temperature of the photoinduced high-spin state for each compound has been determined. The presence of sigmoidal kinetics in the HS --> LS relaxation process, and the observation of LITH hysteresis loops under constant irradiation, demonstrate the cooperative nature of the spin transitions undergone by these materials. All the compounds in this study follow a previously proposed linear relation between T(LIESST) and their thermal spin-transition temperatures T(1/2): T(LIESST) = T(0)- 0.3T(1/2). T(0) for these compounds is identical to that found previously for another family of iron(II) complexes of a related tridentate ligand, the first time such a comparison has been made. Crystallographic characterisation of the high- and low-spin forms, the light-induced high-spin state, and the low-spin complex [Fe(L4)2][BF4]2, are described.

Journal Article↗
PubMed1986

Biochemical properties of alcohol dehydrogenase from Drosophila lebanonensis.

Purified Drosophila lebanonensis alcohol dehydrogenase (Adh) revealed one enzymically active zone in starch gel electrophoresis at pH 8.5. This zone was located on the cathode side of the origin. Incubation of D. lebanonensis Adh with NAD+ and acetone altered the electrophoretic pattern to more anodal migrating zones. D. lebanonensis Adh has an Mr of 56,000, a subunit of Mr of 28 000 and is a dimer with two active sites per enzyme molecule. This agrees with a polypeptide chain of 247 residues. Metal analysis by plasma emission spectroscopy indicated that this insect alcohol dehydrogenase is not a metalloenzyme. In studies of the substrate specificity and stereospecificity, D. lebanonensis Adh was more active with secondary than with primary alcohols. Both alkyl groups in the secondary alcohols interacted hydrophobically with the alcohol binding region of the active site. The catalytic centre activity for propan-2-ol was 7.4 s-1 and the maximum velocity of most secondary alcohols was approximately the same and indicative of rate-limiting enzyme-coenzyme dissociation. For primary alcohols the maximum velocity varied and was much lower than for secondary alcohols. The catalytic centre activity for ethanol was 2.4 s-1. With [2H6]ethanol a primary kinetic 2H isotope effect of 2.8 indicated that the interconversion of the ternary complexes was rate-limiting. Pyrazole was an ethanol-competitive inhibitor of the enzyme. The difference spectra of the enzyme-NAD+-pyrazole complex gave an absorption peak at 305 nm with epsilon 305 14.5 X 10(3) M-1 X cm-1. Concentrations and amounts of active enzyme can thus be determined. A kinetic rate assay to determine the concentration of enzyme active sites is also presented. This has been developed from active site concentrations established by titration at 305 nm of the enzyme and pyrazole with NAD+. In contrast with the amino acid composition, which indicated that D. lebanonensis Adh and the D. melanogaster alleloenzymes were not closely related, the enzymological studies showed that their active sites were similar although differing markedly from those of zinc alcohol dehydrogenases.

Alcohol Dehydrogenase↗
PubMed2004

A beta-galactosidase gene is expressed during mature fruit abscission of 'Valencia' orange (Citrus sinensis).

beta-galactosidases have been detected in a wide range of plants and are characterized by their ability to hydrolyse terminal non-reducing beta-D-galactosyl residues from beta-D-galactosides. These enzymes have been detected in a wide range of plant organs and tissues. In a search for differentially expressed genes during the abscission process in citrus, sequences encoding beta-galactosidase were identified. Three cDNA fragments of a beta-galactosidase gene were isolated from a cDNA subtraction library constructed from mature fruit abscission zones 48 h after the application of a mature fruit-specific abscission agent, 5-chloro-3-methyl-4-nitro-1H-pyrazole (CMN-pyrazole). Based on sequence information derived from these fragments, a full-length cDNA of 2847 nucleotides (GenBank accession number AY029198) encoding beta-galactosidase was isolated from mature fruit abscission zones by 5'- and 3'-RACE approaches. The beta-galactosidase cDNA encoded a protein of 737 amino acid residues with a calculated molecular weight of 82 kDa. The deduced protein was highly homologous to plant beta-galactosidases expressed in fruit ripening. Southern blot analysis demonstrated that at least two closely related beta-galactosidase genes were present in 'Valencia' orange. Temporal expression patterns in mature fruit abscission zones indicated beta-galactosidase mRNA was detected 48 h after treatment of CMN-pyrazole and ethephon in mature fruit abscission zones. beta-galactosidase transcripts were detected in leaf abscission zones only after ethephon application. The citrus beta-galactosidase was expressed in stamens and petals of fully opened flowers and young fruitlets. The results suggest that this beta-galactosidase may play a role during abscission as well as early growth and development processes in flowers and fruitlets.

Amino Acid Sequence↗
PubMed2006

Three substituted 4-pyrazolylbenzoates: hydrogen-bonded supramolecular structures in one, two and three dimensions.

The molecules of ethyl 4-(5-amino-3-methyl-1H-pyrazol-1-yl)benzoate, C13H15N3O2, are linked by two independent N-H...O hydrogen bonds into a chain of edge-fused and alternating R(4)2(8) and R(2)2(20) rings. A combination of N-H...N and N-H...O hydrogen bonds links the molecules of methyl 4-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)benzoate, C15H19N3O2, into sheets of alternating R(2)2(20) and R(6)6(32) rings. In 4-(5-amino-3-methyl-1H-pyrazol-1-yl)benzoic acid monohydrate, C11H11N3O2.H2O, the molecular components are linked into a three-dimensional framework structure by a combination of five independent hydrogen bonds, two of O-H...N type and one each of O-H...O, N-H...O and N-H...N types.

Azo Compounds↗
PubMed1987

Characterization of three isoenzymes of rat alcohol dehydrogenase. Tissue distribution and physical and enzymatic properties.

Rat tissues contain three different isoenzymes of alcohol dehydrogenase (ADH) that we have named ADH-1, ADH-2 and ADH-3, ADH-1 is an anodic isoenzyme present in high amounts in the ocular tissues, stomach and lung. ADH-2 is also anodic and has been found in all the rat organs examined. ADH-3 is the group of cathodic ADH forms, mainly present in liver, that has been the subject of the majority of the previous studies on rat ADH. The three isoenzymes have been purified to homogeneity and characterized. All of them have similar physical characteristics: Mr 80,000, with two subunits of Mr 40,000; they contain four atoms of Zn per molecule, and prefer NAD+ as cofactor. Isoelectric points are, however, different: 5.1 for ADH-1, 5.95-6.3 for ADH-2 and 8.25-8.4 for ADH-3. ADH-3 exhibits a Km for ethanol of 1.4 mM, a broad substrate specificity and is strongly inhibited by pyrazole (Ki = 0.4 microM). ADH-2 shows substrate specificity toward long-chain alcohols and aldehydes, cannot be saturated by ethanol and is practically insensitive to pyrazole (Ki = 78.4 mM). ADH-1 has intermediate properties, with a Km for ethanol of 340 mM, a broad substrate specificity and Ki for pyrazole of 0.56 mM. Rat ADH-1, ADH-2 and ADH-3 exhibit many analogies with human ADH classes II, III and I respectively. The specific localization and kinetic properties of rat ADH isoenzymes suggest that ADH-1 and ADH-3 may act as metabolic barriers to external alcohols and aldehydes whereas ADH-2 may have a function in the metabolism of the endogenous long-chain alcohols and aldehydes.

Alcohol Dehydrogenase↗
PubMed1988

Effects of malotilate on alcoholic liver injury in rats.

Malotilate (diisopropyl 1,3-dithio-2-yldenemalonate), a hepatotrophic drug, was administered to rats with alcohol-pyrazole hepatitis, which is considered to be a suitable experimental model for alcoholic liver injury, in order to elucidate the effects of malotilate on alcoholic liver injury. The number of ballooned hepatocytes and necrotic hepatocytes were smaller in the alcohol-pyrazole hepatitis rats treated with malotilate for 12 weeks (Al-Py Mal group) than for those without malotilate treatment (Al-Py group). Immunohistochemically, the retention of transferrin, one of the secretory proteins from the liver, in the ballooned hepatocytes was inhibited by malotilate. Biochemically, transferrin content in the Golgi fraction of the hepatocytes was significantly lower in the Al-Py Mal group than in the Al-Py group. Hepatic acetaldehyde levels in the Al-Py Mal group were significantly lower than those in the Al-Py group, even though ethanol metabolic rates were not different between the two groups. These results indicated that malotilate prevented the development of hepatocytic injury in alcohol-pyrazole hepatitis by decreasing hepatic acetaldehyde levels and preventing the retention of transferrin in the hepatocytes.

Acetaldehyde↗
PubMed1991

Ethanol-induced enhancement of cocaine bioactivation and irreversible protein binding: evidence against a role of cytochrome P-450IIE1.

Chronic ethanol consumption potentiates cocaine-induced liver injury in rodents. Since cocaine has to be bioactivated by a cytochrome P-450-dependent N-oxidative pathway to exert its hepatotoxic effects, we studied the role of the ethanol-inducible P-450IIE1 for cocaine metabolism. Male Sprague-Dawley rats were pretreated with either a liquid diet containing ethanol (30% of calories) for 4 weeks or injected with pyrazole (200 mg/kg/day, ip, for 3 days). Both agents induced microsomal p-nitrophenol hydroxylation which is a probe for the catalytic activity of P-450IIE1. However, only ethanol, but not pyrazole, increased both microsomal cocaine N-demethylase activity (by 47%) and the extent of irreversible binding of [3H]-cocaine to microsomal proteins (by 100%), which was taken as a quantitative endpoint for the formation of a reactive metabolite. Cocaine N-demethylation and irreversible protein binding of cocaine were not inhibited by P-450IIE1 isozyme-selective substrates, nor was the rate of cocaine metabolism and binding decreased by functionally active polyclonal anti-rat P-450IIE1 antibodies. Furthermore, pyrazole pretreatment sensitized cultured hepatocytes to the glutathione-dependent cytotoxic effects of nontoxic concentrations of cocaine. These results indicate that (a) cocaine is not a major substrate for the ethanol-inducible P-450IIE1, (b) the enhancing effects of ethanol on cocaine bioactivation may be due to induction of other P-450 isoforms, and (c) induction of P-450IIE1 may potentiate cocaine-induced hepatocellular toxicity in vitro independently of cocaine metabolism, e.g., by P-450IIE1-dependent oxidative stress.

Animals↗
PubMedDate not supplied

Correlation between the predicted and the observed biological activity of the symmetric and nonsymmetric cyclic urea derivatives used as HIV-1 protease inhibitors. A 3D-QSAR-CoMFA method for new antiviral drug design.

The predicted inhibition constant (Ki) and the predicted inhibitor concentration (IC90) of the HIV-1 protease (HIV- 1 PR) inhibitors: symmetric and nonsymmetric - benzyl, ketone, oxime, pyrazole, imidazole, and triazole cyclic urea derivatives, were obtained by the 3D-CoMFA (Comparative Molecular Field Analysis) method. The CoMFA statistical parameters: cross-validate correlation coefficient (q2), higher than 0.5, and the fitted correlation coefficient (r2), higher than 0.90 validated the predicted biological activities. The best predictions were found for the trifluoromethyl ketoxime derivative (log 1/Ki predict = 8.42), the m-pyridineCH2 pyrazole derivative (log 1/Ki predict = 9.77) and the 1,2,3 triazole derivative (log 1/Ki predict = 7.03). We attempted to design a new potent HIV-1 protease inhibitor by addition of o-benzyl to the (p-HOPhCH2) pyrazole 12f derivative inhibitor. A favorable steric area surrounded the o-benzyl, suggesting a possible new potent HIV-1 protease inhibitor.

Drug Design↗
PubMed2005

The crystal structure and physicochemical characteristics of 2-hydroxy-N-[3(5)-pyrazolyl]-1,4-naphthoquinone-4-imine, a new antitrypanosomal compound.

This study was designed to investigate the physical characteristics and crystalline structure of 2-hydroxy-N-[3(5)-pyrazolyl]-1,4-naphthoquinone-4-imine (PNQ), a new active compound against Trypanosoma cruzi, the causative agent of American trypanosomiasis. Methods used included differential scanning calorimetry, thermogravimetry, hot stage microscopy, polarized light microscopy (PLM), Fourier-transform infrared (FTIR) spectroscopy, and high-resolution X-ray powder diffraction (HR-XRPD). According to PLM and HR-XRPD data, PNQ crystallized as red oolitic crystals (absolute methanol) or prisms (dimethyl sulfoxide [DMSO]-water) with the same internal structure. The findings obtained with HR-XRPD data (applying molecular location methods) showed a monoclinic unit cell [a = 18.4437(1) A, b = 3.9968(2) A, c = 14.5304(1) A, alpha = 90 degrees , beta = 102.71(6) degrees , gamma = 90 degrees , V = 1044.9(1) A(3), Z = 4, space group P2(1)/c], and a crystal structure (excluding H-positions) described by parallel layers in the direction of the b-axis, with molecules held by homochemical (phenyl-phenyl and pyrazole-pyrazole) van der Waals interactions. In addition, FTIR spectra displayed the NH-pyrazole stretch overlapped with the OH absorption at 3222 cm(-1), typical of -NH and -OH groups associated through H-bondings; and a carbonyl stretching absorption at 1694 cm(-1), indicating a nonextensively H-bonded quinonic C=O, which was in accordance with the solved crystal structure of PNQ. The existence of such cohesive forces shed light on the thermoanalytical data, which revealed that PNQ is a stable solid, unaffected by oxygen that decomposed without melting above 260 degrees C.

Antiprotozoal Agents↗
PubMed1997

Production of plant non-protein amino acids by recombinant enzymes of sequential biosynthetic reactions in bacteria.

We constructed the co-expression vector, pFK4, in which two cDNAs encoding serine acetyltransferase (SATase) and beta-(pyrazol-1-yl)-L-alanine/L-cysteine synthase (beta-PA/CSase) from Citrullus vulgaris (watermelon) were over-expressed under the transcriptional control of T7 promoter in Escherichia coli. Accumulation of both SATase and beta-PA/CSase in soluble extracts of E. coli was confirmed by immunoblotting. The high enzymatic activities of SATase and L-cysteine synthase (CSase) were detected in cell-free extracts of E. coli carrying pFK4. The activities of the formation of beta-PA and L-mimosine, plant non-protein amino acids, from O-acetyl-L-serine (OAS) and the precursor heterocyclic compounds, pyrazole and 3,4-dihydroxypyridine, were also found in the extracts. beta-PA was also produced in vivo from L-serine and pyrazole as precursors by E. coli cells transformed with pFK4. beta-PA was accumulated mainly in the extra-cellular culture medium. The pronounced accumulation of L-cysteine and L-methionine was observed in the cells transformed with pFK4. Additionally, we also constructed vectors which carried chimeric genes encoding fusion proteins of SATase and beta-PA/CSase. However, the fusion proteins tended to form insoluble inclusion bodies and thus to exhibit only weak enzymatic activities. The successful results of pFK4 shows the way to create a new sequential biosynthetic pathway of plant specific amino acids in bacterial cells by means of recombinant DNA technology.

Acetyltransferases↗
PubMed2000

Determination of malondialdehyde in biological samples by solid-phase extraction and high-performance liquid chromatography.

An analytical procedure for determination of malondialdehyde in tissue homogenates and blood serum was developed. A reaction with 2,4-dinitrophenylhydrazine is used followed by cleaning up of the derivative by solid-phase extraction. The samples were analyzed by isocratic high-performance liquid chromatography (HPLC) using a narrow-bore HPLC-column. A good separation of the 1-pyrazole peak from that of 2,4-dinitrophenylhydrazine was observed. A high linear dependence was established by the concentration of 1-pyrazole in the range of 10-5000 ng/ml. The detection limit of the method applied for tissue homogenates and blood serum was approximately 10 ng/ml or lower, and RSD of the method was 9% (n = 8). The peak of 1-pyrazole for these samples was well separated from the other matrix peaks. Experiments carried out evaluated that the solid-phase extraction might be an effective step of the sample preparation, significantly increasing the selectivity of the analysis and the life-time of the column. The method seems to be applicable for determination of malondialdehyde in different biological samples.

Animals↗
PubMed1981

Bacterial degradation of aminopyrine.

1. Four strains of bacteria growing with aminopyrine as sole source of carbon were isolated from soil and were identified as strains of Phenylobacterium immobilis. 2. Strain M13 and strain E, the type species of Phenylobacterium immobilis (DSM 1986), which had been isolated by enrichment with chloridazon (5-amino-4-chloro-2-phenyl-2H-pyridazin-3-one) were used to investigate the bacterial degradation of aminopyrine. 3. Three metabolites were isolated and identified as: 4-(dimethylamino)-1,2-dihydro-1,5-dimethyl-2-(2,3-dihydro-2,3-dihydroxy-4,6-cyc lohexadien-1-yl)-3H-pyrazol-3-one, 4-(dimethylamino)-1,2-dihydro-1,5-dimethyl-2-(2,3-dihydroxyphenyl)-3H-pyrazol-3 -one and 4-(dimethylamino)-1,2-dihydro-1,5-dimethyl-3H-pyrazol-3-one. 4. An enzyme extract from cells of strain m13 was shown to further metabolize the catechol derivative of aminopyrine, with the formation of 2-pyrone-6-carboxylic acid. 5. Results indicate that the benzene ring of aminopyrine is the principal site of microbial metabolism.

Aminopyrine↗