QSAR analyses of conformationally restricted 1,5-diaryl pyrazoles as selective COX-2 inhibitors: Application of connection table representation of ligands

Devi Ahilya University, Indore, Indaur, Madhya Pradesh, India
Bioorganic & Medicinal Chemistry Letters (Impact Factor: 2.42). 05/2005; 15(8):2097-102. DOI: 10.1016/j.bmcl.2005.02.035
Source: PubMed


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.

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    • "Please cite this article as: Malvar DC, et al, Antinociceptive, anti-inflammatory and antipyretic effects of 1.5-diphenyl-1H-Pyrazole-3- carbohydrazide, a new heterocyclic pyrazole derivative, Life Sci (2013), to a tricyclic structural system that is present in the structure of celecoxib (SC58125), a selective COX-2 inhibitor drug (Prasanna et al., 2005). Moreover, some heterocyclic pyrazoles have also been shown to inhibit the synthesis of pro-inflammatory cytokines, such as TNF-α (Keche et al., 2012; Townes et al., 2004). "
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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.
    Full-text · Article · Dec 2013 · Life sciences
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    • "The major finding in this area is attributed to the initial evidences of anti-inflammatory effects without ulcerogenic effects in DuP-697 (a diaryl heterocyclic). Subsequently, a number of selective COX-2 inhibitors with proven therapeutic utility for the treatment of inflammation such as celecoxib, rofecoxib, valdecoxib, and etoricoxib , have been developed [2]. However, the use of specific COX-2 selective drugs was a failure owing to their cardiovascular side effects that occurred because of the inhibition of prostaglandins secretion which is required for the normal functioning of the cardiovascular system and is produced by COX-1 isoform [3]. "
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    ABSTRACT: QSAR analyses were performed on a series of trans-stilbenoid diaryl compounds for modeling their COX-2 inhibitory activities. The multivariate regression equations were developed with the selected independent variables using various feature selection methods. In addition, model training was done using different test-train data selection methods. The applicability of each variable and the test-train selection methods was investigated through the type and number of the selected significant descriptors as well as the statistical criteria of the developed model for each pair of feature and test-train selection methods. The goodness of fit and the statistical significance of 15 developed equations were evaluated using the correlation coefficient (R), the variance ratio (F), and the standard error of estimate (S.E.). The models were validated using the leave many out and the leave one out cross-validation methods. The mean percentage deviation (MPD(+/-SD)) was used as an accuracy criterion for checking the predicted activities. It was found that the developed models could predict the COX-2 and COX-1 inhibitory activities as well as the COX-2/COX-1 selectivity ratios producing the MPD values of 1.6(+/-0.8)%, 7.7(+/-5.6)%, and 16.9(+/-9.6)%, respectively.
    Full-text · Article · Mar 2010 · European Journal of Medicinal Chemistry
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    • "Hence it was considered worthwhile to study fused heterocyclic ring systems with physicochemical and structural relevance for selective COX-2 inhibition. In view of these and as a part of our ongoing research efforts (Prasanna et al., 2004a, b, c, 2005a, b, c; Manivannan et al., 2004), we attempted to subject a series of conformationally restricted 1,5-diaryl pyrazoles (Bertenshaw et al., 1996; Prasanna et al., 2005d) reported to be selective COX-2 inhibitors to QSAR analysis. "
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    ABSTRACT: Quantitative structure–activity relationship (QSAR) analysis has been carried out on a series of conformationally restricted 1,5-diaryl pyrazoles reported as selective cyclooxygenase-2 (COX-2) inhibitors in order to explore the selectivity requirements for COX-2 inhibition among these congeners. QSAR analysis was based on regression analysis between various computed physicochemical and topological descriptors and biological activity. Derived QSAR models evinced a satisfactory correlation of COX-2 inhibitory potency with a three-dimensional (3D) spatial descriptor, std_dim3, and a two-dimensional (2D) partial charge descriptor, PEOE_VSA-1. Balaban J, a highly discriminating topological descriptor, was found to play an imperative role in governing both COX-1 inhibitory potency as well as selective inhibition of COX-2 over COX-1. The selective COX-2 inhibition could be influenced by the size, shape, and polarizability of the whole molecules and was discerned by the contribution of molar refractivity (MR), Balaban J descriptors. The findings are in good consonance with earlier X-ray crystallographic investigations of binding mode of these types of selective COX-2 inhibitors. Results discussed herein bring important structural insights to aid the design and development of novel COX-2 inhibitors.
    Full-text · Article · Jun 2009 · Medicinal Chemistry Research
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