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Synthesis, anti-inflammatory, analgesic, COX1/2-inhibitory activity, and molecular docking studies of hybrid pyrazole analogues.

ABSTRACT: This article reports on the design, synthesis, and pharmacological activity of a new series of hybrid pyrazole analogues: 5a-5u. Among the series 5a-5u, the compounds 5u and 5s exhibited potent anti-inflammatory activity of 80.63% and 78.09% and inhibition of 80.87% and 76.56% compared with the standard drug ibuprofen, which showed 81.32% and 79.23% inhibition after 3 and 4 hours, respectively. On the basis of in vivo studies, 12 compounds were selected for assessment of their in vitro inhibitory action against COX1/2 and TNF?. The compounds 5u and 5s showed high COX2-inhibitory activity, with half-maximal inhibitory concentrations of 1.79 and 2.51 ?M and selectivity index values of 72.73 and 65.75, respectively, comparable to celecoxib (selectivity index =78.06). These selected compounds were also tested for TNF?, cytotoxicity, and ulcerogenicity. Docking studies were also carried out to determine possible interactions of the potent compounds (5u and 5s), which also showed high docking scores of -12.907 and -12.24 compared to celecoxib, with a -9.924 docking score. These selective COX2 inhibitors were docked into the active site of COX2, and showed the same orientation and binding mode to that of celecoxib (selective COX2 inhibitor). Docking studies also showed that the SO2NH2 of 5u and 5s is inserted deep inside the selective pocket of the COX2-active site and formed a hydrogen-bond interaction with His90, Arg513, Phe518, Ser353, Gln192, and Ile517, which was further validated by superimposed docked pose with celecoxib.

SUBMITTER: Alam MJ

PROVIDER: S-EPMC5096746 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Synthesis, anti-inflammatory, analgesic, COX1/2-inhibitory activity, and molecular docking studies of hybrid pyrazole analogues.

Alam Md Jahangir MJ Alam Ozair O Khan Suroor Ahmad SA Naim Mohd Javed MJ Islamuddin Mohammad M Deora Girdhar Singh GS

Drug design, development and therapy 20161031

This article reports on the design, synthesis, and pharmacological activity of a new series of hybrid pyrazole analogues: 5a-5u. Among the series 5a-5u, the compounds 5u and 5s exhibited potent anti-inflammatory activity of 80.63% and 78.09% and inhibition of 80.87% and 76.56% compared with the standard drug ibuprofen, which showed 81.32% and 79.23% inhibition after 3 and 4 hours, respectively. On the basis of in vivo studies, 12 compounds were selected ...[more]

PMID: 27826185

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Project description:PIP4K2A is a type II lipid kinase that catalyzed the rate-limiting step of the conversion of phosphatidylinositol-5-phosphate (PI5P) into phosphatidylinositol 4,5-bisphosphate (PI4,5P2). PIP4K2A has been intricately linked to the inhibition of various types of tumors via reactive oxygen species-mediated apoptosis, making it an important therapeutic target. In the quest of finding biologically active substances with efficient PIP4K2A inhibitory activity, machine learning algorithms were used to investigate the quantitative relationship between structures and inhibitory activities of 1,7-naphthyridine analogues. Three machine learning algorithms (MLR, ANN, and SVM) were used to develop QSAR models that can effectively predict the PIP4K2A inhibitory activity of a library of 1,7-naphthyridine analogues. The cascaded feature selection method was performed by sequential application of GFA and MP5 algorithms to identify a molecular descriptor subset that can best describe the PIP4K2A inhibitory activity of 1,7-naphthyridine analogues. PIP4K2A inhibitory activities predicted by the ML models were strongly correlated with the experimental values. The QSAR Modelling indicates that the best-performing ML model was SVM with the RBF kernel function. The SVM model performed very well in predicting PIP4K2A inhibitory activity of the 1,7-naphthyridine analogues with RTR and QEX values of 0.9845 and 0.8793 respectively. To further gain more structural insight into the origin of PIP4K2A inhibitory activity of 1,7-naphthyridine analogues, molecular docking studies were performed. The results indicate that five compounds; 15, 25, 13, 09, and 28 were found to have a high binding affinity with the receptor molecules. Hydrogen bonding, pi-pi interaction, and pi-cation interactions were found to modulate the binding interaction of the inhibitors. Although the SVM gives essentially a black-box model which cannot be readily interpreted, using SVM in tandem with MLR and ANN provides a unique perspective in building robust QSAR predictive models. The superior predictive performance of the ML models and the explanatory power of MLR models were combined to provide a unique insight into the structure-activity relationship of 1,7-naphthyridine inhibitors. This is relevant in that it provides information that can be invaluable as guidelines for the design of novel PIP4K2A inhibitors.

Dataset Information

Synthesis, anti-inflammatory, analgesic, COX1/2-inhibitory activity, and molecular docking studies of hybrid pyrazole analogues.

Publications

Synthesis, anti-inflammatory, analgesic, COX1/2-inhibitory activity, and molecular docking studies of hybrid pyrazole analogues.

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