RESUMEN

In this paper, we describe the antinociceptive activity, molecular modeling and in silico ADMET screening of a series of sulphonyl-hydrazone and sulphonamide imidobenzene derivatives. Among these compounds, the sulphonyl-hydrazones 9 and 11 showed the most potent analgesic activity (ID(50) = 5.1 and 6.8 µmol/kg, respectively). Interestingly, all derivatives evaluated in this study have a better analgesic profile than the control drugs, acetyl salicylic acid and acetaminophen. Derivative 9 was the most promising compound; with a level of activity that was 24 times higher than the control drugs. Our SAR study showed a relationship among the distribution of the frontier orbital HOMO coefficients, HOMO-LUMO energy gap of these molecules and their reactivity. The best analgesic compounds (including 6, 9, 10, 11 and 12) fulfilled the Lipinski "rule-of-five", which is theoretically important for good drug absorption and permeation.

Asunto(s)

Analgésicos/farmacología , Diseño de Fármacos , Hidrazonas/farmacología , Imidas/farmacología , Sulfonamidas/farmacología , Analgésicos/síntesis química , Analgésicos/química , Analgésicos/uso terapéutico , Animales , Modelos Animales de Enfermedad , Hidrazonas/síntesis química , Hidrazonas/química , Hidrazonas/uso terapéutico , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Imidas/síntesis química , Imidas/química , Imidas/uso terapéutico , Ratones , Modelos Moleculares , Estructura Molecular , Dolor/tratamiento farmacológico , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/uso terapéutico

RESUMEN

The fluorescence-based solvatochromism (fluorosolvatochromism) of 4-[(1-methyl-4(1H)-pyridinylidene)-ethylidene]-2,5-cyclohexadien-1-one (Brooker's merocyanine) was studied. The results revealed that the fluorescence emission band of the dye was dependent on the medium (lambda(fl)(max)= 573 nm in water and lambda(fl)(max)=622 nm in DMF). The fluorescence quantum yields (phi (f)) were calculated for the dye in the solvents investigated. Low phi (f) values ( < 10%) were obtained for the dye and in order to better comprehend the radiative and nonradiative decay processes of this dye, its fluorescence lifetime in methanol was measured and was found to be very short (230 ps). The results suggest that the dye in the excited state decays rapidly through nonradiative processes. The behavior of the probe in binary mixtures including a hydrogen-bond accepting solvent (acetonitrile, N,N-dimethylformamide, and dimethylsulfoxide) and a hydroxylic solvent (water, methanol, ethanol, propan-2-ol, and butan-1-ol) was also investigated. All data were successfully fitted to a model based on solvent exchange equilibria, which allowed the separation of the different contributions of the solvent species in the solvation shell of the dye. The data obtained for the mixed solvents were explained based on solute-solvent and solvent-solvent interactions.

RESUMEN

The UV-vis spectroscopic behavior of dyes: 2,6-diphenyl-4-(2,4,6-triphenylpyridinium-1-yl)phenolate (1) and 4-[(1-methyl-4(1H)-pyridinylidene)-ethylidene]-2,5-cyclohexadien-1-one (2) was investigated in solutions of methyl- beta-cyclodextrin (methyl-beta-CyD), using water, methanol, ethanol, propan-2-ol, butan-1-ol, acetone, acetonitrile, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N,N-dimethylacetamide (DMA), chloroform and dichloromethane as solvents. In aqueous solutions of dye (2) the addition of M-beta-CD leads to a bathochromic shift (of the maximum absorption), showing that the probe was transferred to a microenvironment of lower polarity and suggesting the formation of a 1 : 1 dye (2) : CyD inclusion complex, with a binding constant of 128.5 +/- 3.5 dm(3) mol(-1). Data for dye 2 in alcohols showed hypsochromic shifts, which increased in the following order: methanol < ethanol < propan-2-ol < butan-1-ol. These observations appear to reflect dye-solvent interactions through hydrogen bonding. If dye-solvent interactions are strong, the CyD-dye interactions are consequently weak, but the latter increase in importance when the dye-solvent interaction becomes weaker. With hydrogen-bond accepting solvents, data for both dyes showed clearly increasing hypsochromic shifts following the order: DMSO < DMA < DMF < acetone < acetonitrile. This order is exactly the inverse of the increasing order of basicity of the medium. This indicates that the dominant factor for the observed effects in these solvents is the solvent-CyD interaction through hydrogen bonding involving the hydroxyl groups of the CyD and the basic groups of the solvents. These interactions diminish in intensity if the basic character of the medium is reduced, increasing the capability of the dye to interact with the CyD using its phenoxide donor moiety. The largest hypsochromic shifts were obtained in chloroform (66.0 nm) and dichloromethane (67.5 nm) with dye after addition of methyl-beta-CyD. In these specific situations, solvents display weak basic and acid properties, that enhanced CyD-dye interactions to such an extent that association complexes formed through hydrogen bonding could be detected (K11) values of 24.8 +/- 4.9 dm3 mol(-1) in dichloromethane and 66.1 +/- 8.0 dm3 mol(-1) in chloroform).