QSAR analyses of conformationally restricted 1,5-diaryl pyrazoles as selective COX-2 inhibitors: application of connection table representation of ligands.
ABSTRACT As a part of our continuing efforts in discerning the structural and physicochemical requirements for selective COX-2 over COX-1 inhibition among the fused pyrazole ring systems, herein we report the QSAR analyses of the title compounds. The conformational flexibility of the title compounds was examined using a simple connection table representation. The conformational investigation was aided by calculating a connection table parameter called fraction of rotable bonds, b_rotR encompassing the number of rotable bonds and b_count, the number of bonds including implicit hydrogens of each ligand. The hydrophobic and steric correlation of the title compounds towards selective COX-2 inhibition was reported previously in one of our recent publications. In this communication, we attempt to calculate Wang-Ford charges of the non-hydrogen common atoms of AM1 optimized geometries of the title compounds. Owing to the partial conformational flexibility of title compounds, conformationally restricted and unrestricted descriptors were calculated from MOE. Correlation analysis of these 2D, 3D and Wang-Ford charges was accomplished by linear regression analysis. 2D molecular descriptor b_single, 3D molecular descriptors glob, std_dim3 showed significant contribution towards COX-2 inhibitory activity. Balaban J, a connectivity topological index showed a negative and positive contribution towards COX-1 and selective COX-2 over COX-1 inhibition, respectively. Wang-Ford charges calculated on C(7) showed a significant contribution towards COX-1 inhibitory activity whereas charges calculated on C(8) were crucial in governing the selectivity of COX-2 over COX-1 inhibition among these congeners.
Heterocycles 12/2010; 81(7). DOI:10.3987/COM-10-11950 · 0.91 Impact Factor
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ABSTRACT: QSAR studies on a series of 2-benzoxazolyl hydrazone derivatives against various cancer cell lines were carried out to interpret the physicochemical properties responsible for the antitumor activity. The integy moments of the molecules (vsurf_ID8 and vsurf_IW6) reveals that the active site surface or the biological membrane where these compounds bind or penetrate must have a very specific and localized hydrophobic region. These integy moments reduce the interaction energy between the molecule and the water, which improve the antitumor activity. The potential energy descriptors indicate that the flexibility of the freely rotatable bonds is important for the interaction with the chemotherapeutic target and/or barriers to reach the target. Comparing the results obtained from this study and other QSAR studies addressed to similar compounds, we concluded that the benzoxazolyl derivatives may bind to the same target. The present analysis has shown that the antitumor activity can be improved with the presence of specific hydrophobic substituents and electro-donating groups nearby the hydrazone moiety. Moreover, the formation of an intramolecular hydrogen bond has a high impact on the pharmacological activity of these compounds. The information gathered from these studies provides useful information about the binding site of these compounds.Medicinal Chemistry Research 01/2012; 21(2). DOI:10.1007/s00044-010-9510-3 · 1.61 Impact Factor
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ABSTRACT: Heterocyclic pyrazole derivative have been described for the treatment of pain and inflammatory diseases. This study evaluated the in vivo, antinociceptive, anti-inflammatory and antipyretic effects of 1.5-diphenyl-1H-Pyrazole-3-carbohydrazide (1.5-DHP) and the in vivo or in vitro mechanism of action. Acetic acid-induced writhing, hot-plate and formalin-induced nociception tests were used to evaluate the antinociceptive effect, while the rota-rod test was used to assess the motor activity. Croton oil-induced ear oedema and carrageenan-induced peritonitis tests were used to investigate the anti-inflammatory effect of 1.5-DHP. The antipyretic effect was assessed using the LPS-induced fever model. The mechanism of action was evaluated by PGE2 and TNF-α measurement and cyclooxygenase inhibition assay. Oral administration (p.o.) of 1.5-DHP (1, 3, 10mg/kg) caused a dose-related inhibition of the acetic acid-induced writhing, however the highest dose was not effective on the hot-plate and rota-rod. In the formalin-induced nociception, 1.5-DHP (10mg/kg, p.o.) inhibited only the late phase of nociception. This same dose of 1.5-DHP also reduced the croton oil-induced ear oedema. 1.5-DHP (3, 10, 30mg/kg, p.o.) produced a dose-related reduction of leukocyte migration on the carrageenan-induced peritonitis. 1.5-DHP (60mg/kg, p.o.) reduced the fever and the increase of PGE2 concentration in the cerebrospinal fluid induced by LPS. 1.5-DHP inhibited both COXs in vitro. Finally, 1.5-DHP (10mg/kg, p.o.) reduced the TNF-α concentration in peritoneal exudates after carrageenan injection. These results indicate that 1.5-DHP produces anti-inflammatory, antinociceptive and antipyretic effects by PGE2 synthesis reduction through COX-1/COX-2 inhibition and by TNF-α synthesis/release inhibition.Life sciences 12/2013; DOI:10.1016/j.lfs.2013.12.005 · 2.56 Impact Factor