Marli R. Oliveira

Hypothermic and antipyretic effects of 3-methyl- and 3-phenyl-5-hydroxy-5-trichloromethyl-4,5-dihydro-1H-pyrazole-1-carboxyamides in mice.

The effect of novel pyrazolines, 3-methyl-5-hydroxy-5-trichloromethyl-4,5-dihydro-1H-pyrazole-1-carboxyamide (MPCA) and 3-phenyl-5-hydroxy-5-trichloromethyl-4,5-dihydro-1H-pyrazole-1-carboxyamide (PPCA) on body temperature and endotoxin-induced fever was investigated in mice. The subcutaneous (s.c.) administration of 1.5 mmol/kg dipyrone, MPCA or PPCA and the intracerebroventricular (i.c.v.) administration of 225 nmol dipyrone reduced basal rectal temperature. Intracerebroventricular administration of 225 nmol MPCA or PPCA did not alter basal rectal temperature. The administration of 0.15 mmol/kg (s.c.) or 25 nmol (5 microl) dipyrone (i.c.v.), MPCA or PPCA had no effect on basal rectal temperature, but reversed lipopolysaccharide-induced fever. These results suggest that MPCA and PPCA cause antipyresis, which is similar to that caused by dipyrone, and may be useful antipyretic agents.

Baker yeast-induced fever in young rats: characterization and validation of an animal model for antipyretics screening.

In this study we describe a low-cost and reliable method for inducing fever in young male rats (28-30 days of age, 75-90 g), which seems suitable for the screening of new antipyretics. The effects of temperature measuring procedure-induced stress on the basal rectal temperature and on Baker yeast-induced hyperthermia was assessed. Rectal temperature (T) was recorded every hour for 12 h (07:00-19:00 h) with a lubricated thermistor probe. The animals were injected intraperitoneally with baker yeast (0.25, 0.135, 0.05 g/kg) or the equivalent volume of saline at 7:00 h. The administration of 0.135 g/kg baker yeast induced a sustained increase in rectal temperature for 4 h. Classical (dipyrone and acetaminophen) and novel (MPCA and FPCA) antipyretics, at doses that had no effect per se, reverted baker yeast-induced fever. The method presented induces a clear-cut fever, which is reverted by antipyretics commonly used in human beings and selected novel antipyretics in small animals. The method also allows antipyretic evaluation with low amount of drugs, due to the use of small animals and to the small variability of the pyretic response, which ultimately causes a significant reduction in the number of animals necessary for antipyretic evaluation. Therefore, this study describes an animal model of fever that is not only advantageous from the economical and technical point of view, but that also bears ethical concerns.

Synthesis and in vitro antimycobacterial activity of 3-substituted 5-hydroxy-5-trifluoro[chloro]methyl-4,5-dihydro-1H-1-(isonicotinoyl) pyrazoles

A series of 3-substituted 5-hydroxy-5-trifluoro[chloro]methyl-1H-1-isonicotinoyl-4,5-dihydropyrazoles (2a-i) were synthesised by the cyclocondensation reaction of 4-methoxy-1,1,1-trifluoro[chloro]-4-(substituted)-alk-3-en-2-ones (1a-i) and isoniazid (INH). Their in vitro antimicrobial activity was tested against INH-susceptible Mycobacterium tuberculosis H37Rv, INH-resistant clinical M. tuberculosis isolates and non-tuberculous mycobacteria. Amongst the synthesised compounds, 5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-1-(isonicotinoyl)-pyrazole (2a) and 5-hydroxy-3-(4-methylphenyl)-5-trifluoromethyl-4,5-dihydro-1H-1-(isonicotinoyl) pyrazole (2d) were found to be the two most active agents against susceptible M. tuberculosis and several INH-resistant strains. The compound 3-(2-furyl)-5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-1-(isonicotinoyl)pyrazole (2f) was active against all the INH-resistant strains regardless of the genetic background at concentrations two- to four-fold its minimum inhibitory concentration against M. tuberculosis H37Rv. These compounds were inhibitors of mycolic acid biosynthesis, in agreement with the utilisation of the INH scaffold for their design. Interestingly, the most active compound against M. tuberculosis, 5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-1-(isonicotinoyl)-pyrazole (2a), was even more potent than INH against non-tuberculous mycobacteria.

3-Methyl-5-hydroxy-5-trichloromethyl-1H-1-pyrazolcarboxyamide induces antinociception

The antinociceptive action of a novel pyrazole-derived compound, 3-methyl-5-hydroxy-5-trichloromethyl-1H-1-pyrazolcarboxyamide (MPCA) was evaluated using the formalin and tail-immersion tests in mice. Anti-inflammatory activity was assessed by paw plethysmometry in adult rats using the carrageenin-induced paw edema test. Subcutaneous administration of MPCA (22, 66, and 200 mg/kg) induced a dose-dependent decrease in the time spent licking during the neurogenic and inflammatory phases of the formalin test, and preadministration of naloxone (1 mg/kg, sc) did not prevent MPCA-induced (200 mg/kg, sc) antinociception. Naloxone decreased the spontaneous locomotor activity of mice, while MPCA had no effect on locomotion. In contrast, administration of the opioid antagonist caused a significant increase in the locomotor behavior of mice previously injected with MPCA. MPCA was devoid of antinociceptive action by the tail-immersion test and of anti-inflammatory activity. Moreover, MPCA had no effect on the motor performance of mice in the rotarod test. These results suggest that MPCA induces antinociception in the neurogenic and inflammatory phases of the formalin test, an effect that does not involve opioid receptors.

Regiospecific synthesis of new non-condensed heteropolycyclic systems from beta-heteroaryl-beta-methoxyvinyl trihalomethyl ketones

A novel series of twelve heteroaroyl-2-pyrazolines trihalomethyl and substituted heteroaryl, as non-condensed heteropolycyclic systems, have been synthesized in one-step in 50-78% yield from the regiospecific cyclocondensation reaction of 1,1,1-trifluoro(chloro)-4-methoxy-4-(2-furyl)- and 4-(2-thienyl)-3-buten-2-ones (b-alkoxyvinyl trihalometil ketones) with furoic hydrazide, 2-thiophenecarboxylic hydrazide and isonicotinic acid hydrazide (heteroaroylhydrazines) under mild conditions in methanol as solvent.

Synthesis of Tetrahydro‐2(1H)quinazolinones, Cyclopenta[d]‐2(1H)pyrimidinones, and Their Thioxo Analogs from 2‐Trifluoroacetyl‐1‐methoxycycloalkenes

Abstract A series of six (8)‐alkyl‐4‐trifluoromethyl‐5,6,7,8‐tetrahydro‐2(1H)quinazolinones, 4‐trifluoromethyl‐cyclopenta[d]‐2(1H)pyrimidinones, and their thioxo analogs from the reaction of five β‐alkoxyvinyl trifluoromethyl ketones, derived from alkylated cyclohexanones and cyclopentanone with urea and thiourea, is reported. The reactions were carried out in a single step in propan‐2‐ol as solvent and boron trifluoride diethyl etherate as catalyst in 18–65% yield.

Molecular Structure of Heterocycles: 4# NMR Spectroscopy, X-Ray Diffraction, and Semiempirical Mo Calculations of 3-Phenyl-5-Hydroxy- 5-Trichloromethyl-4,5-Dihydro-FH-Pyrazole-1-Carboxyamide

Abstract A new series of trichloromethylated- 4, 5-dihydro-1H-pyrazoles has been studied. The molecular structure of 5-hydroxy-3-phenyl-5-trichloromethyl-4,5-dihydro-7H-pyrazole-1-carboxyamide (2), synthesized from the reaction of 4-methoxy -4-phenyl-1,1,1-trichloro-3-buten-2-one (1) with semicarbazide hydrochloride, was selected and determined by NMR spectroscopy, X-ray diffraction, and semiempirical MO calculations. Proton and carbon-13 NMR data, as one set of signals, shown that only one pair of the enanfiomers was obtained. The AM1 calculations showed that 2a (1S5S/1R5R) is the more stable enantiomers pair. The x-ray diffraction data confirmed that only the structure 2a (1S5S/1R5R) was obtained. This was explained by the existence of an intramolecular hydrogen bond between the hydroxy group at C(5) and the carbonyl group at N(1), with the formation a stable six-membered ring. Compound 2 (C11H10CI3N3O2, Mr = 320.98) crystallizes in the monoclinic space group P21/c with the unit cell dimensions a = 6.49...