Adilson P. Sinhorin

Antinociceptive effect of novel pyrazolines in mice

The antinociceptive effect of six novel synthetic pyrazolines (3-ethoxymethyl-5-ethoxycarbonyl-1H-pyrazole (Pz 1) and its corresponding 1-substituted methyl (Pz 2) and phenyl (Pz 3) analogues, and 3-(1-ethoxyethyl)-5-ethoxycarbonyl-1H-pyrazole (Pz 4) and its corresponding 1-substituted methyl (Pz 5) and phenyl (Pz 6) analogues) was evaluated by the tail immersion test in adult male albino mice. The animals (N = 11-12 in each group) received vehicle (5% Tween 80, 10 ml/kg, sc) or 1.5 mmol/kg of each of the pyrazolines (Pz 1-Pz 6), sc. Fifteen, thirty and sixty minutes after drug administration, the mice were subjected to the tail immersion test. Thirty minutes after drug administration Pz 2 and Pz 3 increased tail withdrawal latency (vehicle = 3.4 +/- 0.2; Pz 2 = 5.2 +/- 0.4; Pz 3 = 5.9 +/- 0.4 s; mean +/- SEM), whereas the other pyrazolines did not present antinociceptive activity. Dose-effect curves (0.15 to 1.5 mmol/kg) were constructed for the bioactive pyrazolines. Pz 2 (1.5 mmol/kg, sc) impaired motor coordination in the rotarod and increased immobility in the open-field test. Pz 3 did not alter rotarod performance and spontaneous locomotion, but increased immobility in the open field at the dose of 1.5 mmol/kg. The involvement of opioid mechanisms in the pyrazoline-induced antinociception was investigated by pretreating the animals with naloxone (2.75 micro mol/kg, sc). Naloxone prevented Pz 3- but not Pz 2-induced antinociception. Moreover, naloxone pretreatment did not alter Pz 3-induced immobility. We conclude that Pz 3-induced antinociception involves opioid mechanisms but this is not the case for Pz 2.

A convenient one-pot synthesis of 5-carboxyisoxazoles: trichloromethyl group as a carboxyl group precursor

Abstract The one-pot synthesis of ten 5-carboxyisoxazoles from the cyclocondensation of β-alkoxyvinyl trichloromethyl ketones [CCl 3 C(O)C(R 2 )C(R 1 )OR, where R 1 , R 2 =H, Me and R=Me, Et] and 2-trichloroacetyl cyclohexanone with hydroxylamine is reported. This work shows that the trichloromethyl group attached to β-alkoxyvinyl trichloromethyl ketones (a heterocyclic CCC building block) is an excellent carboxyl group precursor.

Effects of the acute exposition to glyphosate-based herbicide on oxidative stress parameters and antioxidant responses in a hybrid Amazon fish surubim (Pseudoplatystoma sp).

The aim of this study was to investigate the effects of acute glyphosate (active ingredient) exposure on the oxidative stress biomarkers and antioxidant defenses of a hybrid surubim (Pseudoplatystoma sp). The fish were exposed to different herbicide concentrations for 96 h. The thiobarbituric acid-reactive substances (TBARS), protein carbonyls and antioxidant responses were verified. The 15 mg a.pL(-1) of herbicide resulted in the death of 50% of the fish after 96 h. An increase in liver and muscle TBARS levels was observed when fish were exposed to the herbicide. The protein carbonyl content was also increased in the liver (4.5mg a.pL(-1) concentration) and brain (2.25 mg a.pL(-1) concentration). The antioxidant activities decreased in the liver and brain after exposure to herbicide. Levels of ascorbic acid in the liver (2.25 mg a.pL(-1) and 4.5 mg a.pL(-1) concentrations) and brain (2.25 mg a.pL(-1) concentration) were increased post-treatment. Levels of total thiols were increased in the liver and brain (2.25 mg L(-1) and 7.5mg a.pL(-1), respectively). Glyphosate exposure, at the tested concentrations affects surubim health by promoting changes that can affect their survival in natural environment. Some parameters as TBARS and protein carbonyl could be early biomarkers for Roundup exposure in this fish species.

Antiproliferative activity of Rhinella marina and Rhaebo guttatus venom extracts from Southern Amazon

The venom of amphibians is a fascinating source of active substances. In view of their medical importance and aiming to explore the amazing Brazilian biodiversity, we conducted bioprospecting of antiproliferative activity in extracts of Rhinella marina and Rhaebo guttatus toads occurring in the Southern Amazon of Mato Grosso, Brazil. LC-MS and HPLC analysis of the venom extracts of R. marina revealed four bufadienolides (telocinobufagin, marinobufagin, bufalin and resibufogenin. R. guttatus venom extracts contained only marinobufagin. First, R. marina and R. guttatus venom extracts were evaluated for cytotoxicity against tumor cell lines by the MTT assay. All extracts revealed cytotoxicity, where R. marina extracts were comparable to doxorubicin (IC₅₀ values ranging from 0.01 to 0.23 μg/mL). Only extracts of R. guttatus toad venom caused membrane disruption of human erythrocytes. The extracts were investigated for selective activity by determining their effect on stimulated human peripheral blood mononuclear cells (PBMC) with the Alamar Blue™ assay. The extracts were up to 80-fold more selective against leukemia cells when compared to dividing leukocytes. Aiming to confirm these antiproliferative effects, BrdU incorporation into DNA was measured in HL-60 treated cells with R. marina venom extracts. These extracts decreased BrdU incorporation at both concentrations tested. In summary, nine extracts of R. marina and R. guttatus venom showed pronounced lethal and discriminating effects on tumor lines, especially those from R. marina, highlighting toad parotoid gland secretions as a promising source for novel lead anticancer chemicals.

HALOACETYLATED ENOL ETHERS. XVII.1* A CONVENIENT SYNTHESIS OF 5-TRICHLOROMETHYL-1,2-DIMETHYL- 1H-PYRAZOLIUM CHLORIDES

ABSTRACT The one-pot synthesis of nine 5-trichloromethyl-1,2-dimethyl-1H-pyrazolium chlorides 2 from the cyclocondensation of 4-alkoxy-1,1,1-trichloro-3-alken-2-ones [CCl3C(O)C(R2)= C(R1)OR, where R1 = H, Me, Et, n-Pr, (CH2)5CO2Et, CH2Br, Ph, 4-Br-C6H4; R2 = H, Me; and R = Me, Et] with 1,2-dimethylhydrazine is reported. For Part 16, see Ref. [12].

Characterization and Quantification of the Compounds of the Ethanolic Extract from Caesalpinia ferrea Stem Bark and Evaluation of Their Mutagenic Activity

Caesalpinia ferrea Martius has traditionally been used in Brazil for many medicinal purposes, such as the treatment of bronchitis, diabetes and wounds. Despite its use as a medicinal plant, there is still no data regarding the genotoxic effect of the stem bark. This present work aims to assess the qualitative and quantitative profiles of the ethanolic extract from the stem bark of C. ferrea and to evaluate its mutagenic activity, using a Salmonella/microsome assay for this species. As a result, a total of twenty compounds were identified by Flow Injection Analysis Electrospray Ionization Ion Trap Mass Spectrometry (FIA-ESI-IT-MS/MSn) in the ethanolic extract from the stem bark of C. ferrea. Hydrolyzable tannins predominated, principally gallic acid derivatives. The HPLC-DAD method was developed for rapid quantification of six gallic acid compounds and ellagic acid derivatives. C. ferrea is widely used in Brazil, and the absence of any mutagenic effect in the Salmonella/microsome assay is important for pharmacological purposes and the safe use of this plant.

Microwave assisted synthesis of 5-hydroxy-5-trichloromethyl-4,5-dihydroisoxazoles

Abstract A series of 13 5-hydroxy-5-trichloromethyl-4,5-dihydroisoxazoles have been synthesized in 78–96% yield by environmentally benign microwave induced techniques involving the cyclocondensation of 4-alkoxy-1,1,1-trichloro-3-alken-2-ones [CCl 3 C(O)C(R 2 )=C(R 1 )OR, where R 2 =H, alkyl; R 1 =H, alkyl, aryl and R=H, alkyl] with hydroxylamine using toluene as solvent. The advantages obtained by the use of microwave irradiation in relation to a classical method were demonstrated.

SYNTHESIS OF 3-METHYLISOXAZOLE- 5-CARBOXAMIDES AND 5-[(1H-PYRAZOL-1-YL)CARBONYL]- 3-METHYLISOXAZOLES

ABSTRACT The one-pot synthesis of six 3-methylisoxazole-5-carboxamides 2 [where the N-substituents are R1 = H, Me and R2 = Ph, CH2Ph, n-Bu, C(CH3)2Et, 3-methylisoxazol-5-yl] and twelve 5-[(1H-pyrazol-1-yl)carbonyl]-3-methyl isoxazoles 3 and 4 [where the pyrazole substituents are R3 (C5/C3) = CO2Et, CF3 and R5 (C3/C5) = H, Me, Et, Ph] from the 3-methyl isoxazole-5-carboxylic acid, thionyl chloride and the corresponding amine or pyrazole is reported. In the synthesis of 5-[(1H-pyrazol-1-yl)carbonyl]-3-methylisoxazoles we obtained a mixture of 1,3- and 1,5-isomers 3 and 4 in variable ratios, i.e., the substituent R3 (CO2Et and CF3) are present in position 3 or 5 on the pyrazole ring.

One‐Pot Synthesis of Pyrazole‐5(3)‐carboxyamides

Abstract A convenient one‐pot synthesis of eight pyrazole‐5(3)‐carboxyamides from the reaction of the 5(3)‐trichloromethylpyrazoles with amines, in good yield, is reported. These reactions show that the trichloromethyl group is a convenient precursor to carboxyamide groups.

Molecular Structure of Heterocycles: 6. Solvent Effects on the 17O Nmr Chemical Shifts of 5-Trichloromethylisoxazoles

A multilinear-regression analysis using the Kamlet-Abboud-Taft (KAT) solvatochromic parameters in order to elucidate and quantify the solvent effects on the 17O chemical shifts of three 5-trichloromethylisoxazoles [(1a) non-, (1b) 3-methyl- and (1c) 4-methyl-substituted] is reported. The chemical shifts of ring oxygen atom, O1, of compounds 1a-c show dependencies (in ppm) on the solvent polarity-polarizability of -4.8p*, -3.2p*, -8.9p*, on the solvent hydrogen-bond-donor (HBD) acidities 0.9a, -0.2a, -2.7a and the solvent hydrogen-bond-acceptor (HBA) basicities -0.4b, 1.9b, 0.9b, respectively. The data of net charges of O1 and dipole moment, obtained from MO calculations (AM1), are compared with the solvent effect parameters obtained for compounds 1a-c.