A pyrazolyl-thiazole derivative causes antinociception in mice

The present study investigates the antinociceptive effect of the pyrazolyl-thiazole derivative 2-(5-trichloromethyl-5-hydroxy-3-phenyl-4,5-dihydro-1 H-pyrazol-1-yl)-4-(4-bromophenyl)-5-methylthiazole (B50) in mice. Male albino Swiss mice (30-40 g) were used in the acetic acid-induced abdominal writhes and tail-immersion tests. B50 caused dose-dependent antinociception (8, 23 and 80 µmol/kg, sc) in the acetic acid writhing assay (number of writhes: vehicle: 27.69 ± 6.15; B50 (8 µmol/kg): 16.92 ± 3.84; B50 (23 µmol/kg): 13.85 ± 3.84; B50 (80 µmol/kg): 9.54 ± 3.08; data are reported as means ± SEM for 9 animals per group). On the other hand, B50 did not cause antinociception in the tail immersion assay. Naloxone (2.75 µmol/kg, sc) prevented B50-induced antinociception (number of writhes: vehicle-saline: 31.11 ± 3.15; vehicle-naloxone: 27.41 ± 3.70; B50 (80 µmol/kg)-saline: 8.70 ± 3.33; B50 (80 µmol/kg)-naloxone: 31.84 ± 4.26; morphine-saline: 2.04 ± 3.52; morphine-naloxone: 21.11 ± 4.26; 8-9 animals per group). The removal of the methyl group of the thiazole ring of B50 or substitution of the bromo substituent with the methyl at position 4 of the phenyl group, which is attached to the thiazole ring of B50, resulted in loss of activity, suggesting that these substituents are important for antinociceptive activity. B50 had no effect on spontaneous locomotion or rotarod performance, indicating that the antinociceptive effect of B50 is not related to nonspecific motor effects. The antinociceptive profile of B50 seems to be closer to nonsteroidal anti-inflammatory drugs than to classic opioid agents, since it had no analgesic effect in a thermally motivated test

Structural investigations of 5-hydroxy-4,5-dihydroisoxazoles

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)The X-ray diffraction data determined for eight 3-(R-3), 4-(R-4), 4,4-(R-4/R-4') and/or 5-(R-5) 5-hydroxy-4,5-dihydroisoxazoles [where R-3 = Ph, R-4/R-4' = H/H, R-5 = CCl3 (1); R-3 = 4-Br-C6H4, R-4/R-4' = H/H, R-5 = CCl3 (2); R-3 = thien-2-yl, R-4/R-4' = H/H, R-5 = CCl3 (3); R-3 = Ph, R-4 = Ph, R-4' = OH, R-5 = Me (4); R-3 = Me, R-4/R-4' = N-OH, R-5 = Me (5); R-3 = CF3, R-4/R-4' = H/H, R-5 = CMe2CH2OH (6); R-3 = H, R-4 = 4-I-C6H4, R-4' = H, R-5 = 4-I-C6H4 (7): R-3/R-4 = -(CH2)(3)-, R-4' = H, R-5 = CF2CF2H (8);] are discussed. The crystalline structure of compounds 1-3 is described for the first time and crystalline structure of compounds 4-8 has already been described in literature. It was found that the supramolecular auto-organization of 1-8 is characterized by hydrogen bonds invariably involving the hemiacetal hydroxyl group. Compound 5 is the only exception, where the hydroxyl oxime group is the participant in the hydrogen bond. Compounds 4 and 8 present intermolecular contact between the hydroxyl group of the hemiacetal and the nitrogen atom of the 4,5-dihydroisoxazole ring. Compound 7 presents similar interaction, where the hydroxyl contact is with the oxygen atom of the 4,5-dihydroisoxazole ring. Moreover, the crystal structure of compound 6 was stabilized by O-H center dot center dot center dot O interaction between the hydroxyl group of hemiacetal and the hydroxyl group of the alcohol function attached at the 5-position of 4,5-dihydroisoxazole. The crystal structure of compounds 1-3, as described here for the first time, was similar to that of compounds 4 and 7, showing a hydrogen bond O(51)-H(51)center dot center dot center dot N(2) between the hydroxyl group and the nitrogen atom of the isoxazoline ring. This means that the crystal structure of these compounds was governed by hydrogen bonds O-H center dot center dot center dot N, involving the hydroxyl of the hemiacetal group and the nitrogen atom of the 4,5-dihydroisoxazole ring. This interaction is relatively robust, showing a pattern in the crystal packing. Compounds 1-3 also have their crystal stabilized by more weak interactions of type Cl center dot center dot center dot Cl, involving the chlorine atom of the trichloromethyl group. (C) 2011 Elsevier B.V. All rights reserved.100641699462468Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundacao de Amparo a Pesquisa do Estado do Rio Grande do Sul - FAPERGS [PRONEX/Proc. 10/0037-8]Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)FAPERGSConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)CNPq [Universal/Proc. 485893/2007-0, Universal/Proc. 471519/2009-0, MAPA/Proc. 578426/2008-0]Fundacao de Amparo a Pesquisa do Estado do Rio Grande do Sul - FAPERGS [PRONEX/Proc. 10/0037-8]CAPES [PRODOC/Proc. 2684-32/2010