157 Acta Pharm. 56 (2006) 157–174 Original research paper 3D-QSAR CoMFA/CoMSIA studies on 5-aryl-2,2-dialkyl- -4-phenyl-3(2H)-furanone derivatives, as selective COX-2 inhibitors DEVENDRA SHARAD PUNTAMBEKAR RAJANI GIRIDHAR MANGE RAM YADAV* Pharmacy Department Faculty of Technology and Engineering, Kalabhavan The M. S. University of Baroda Vadodara-390001, India Accepted December 4, 2005 Comparative Molecular Field Analysis (CoMFA) and Com- parative Molecular Similarity Indices Analysis (CoMSIA) were performed on a series of 5-aryl-2,2-dialkyl-4-phenyl- -3(2H)-furanone derivatives, as selective cyclooxygenase- -2 (COX-2) inhibitors. Ligand molecular superimposition on the template structure was performed by the atom/ shape based root mean square fit and database alignment methods. Removal of three outliers from the initial train- ing set of 49 molecules improved the predictivity of the model. The statistically significant model was establish- ed of 36 molecules, which were validated by a test set of ten compounds. The atom and shape based root mean square alignment (IV) yielded the best predictive CoMFA model [R 2 cv = 0.664, R 2 (non-cross-validated square of correlation coefficient) = 0.916, F value = 47.341, R 2 bs = 0.947 with six components, standard error of prediction 36 = 0.360 and standard error of estimate 36 = 0.180] while the CoMSIA model yielded [R 2 cv = 0.777, R 2 (non-cross- -validated square of correlation coefficient) = 0.905, F va- lue = 66.322, R 2 bs = 0.933 with four components, standard error of prediction 36 = 0.282 and standard error of esti- mate 36 = 0.185]. The contour maps obtained from 3D- -QSAR studies were appraised for activity trends for the molecules analyzed. Results indicate that steric, electro- static, hydrophobic (lipophilic) and hydrogen bond donor substituents play a significant role in COX-2 inhibitory activity and selectivity of the compounds. The data ge- nerated from the present study will further help design novel, potent and selective COX-2 inhibitors. Keywords: 3D-QSAR, CoMFA, CoMSIA, cyclooxygenase- -2 inhibitors, anti-inflammatory agents * Correspondence, e-mail: mryadav@sify.com