Devendra S Puntambekar

The Maharaja Sayajirao University of Baroda, Vadodara, State of Gujarat, India

Are you Devendra S Puntambekar?

Claim your profile

Publications (8)13.16 Total impact

  • Devendra S Puntambekar, Rajani Giridhar, Mange Ram Yadav
    [Show abstract] [Hide abstract]
    ABSTRACT: A three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed on three different chemical series reported as selective farnesyltransferase (FTase) inhibitors employing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA) techniques to investigate the structural requirements for substrates and derive a predictive model that may be used for the design of novel FTase inhibitors. Removal of outliers improved the predictive power of models developed for all three structurally diverse classes of compounds. 3D-QSAR models were derived for 3-aminopyrrolidinone derivatives (training set N=38, test set N=7), 2-amino-nicotinonitriles (training set N=46, test set N=13) and 1-aryl-1'-imidazolyl methyl ethers (training set N=35, test set N=5). The CoMFA models with steric and electrostatic fields exhibited r(2)(cv) 0.479-0.803, r(2)(ncv) 0.945-0.993, r(2)(pred) 0.686-0.811. The CoMSIA models displayed r(2)(cv) 0.411-0.814, r(2)(ncv) 0.923-0.984, r(2)(pred) 0.399-0.787. 3D contour maps generated from these models were analyzed individually, which provide the regions in space where interactive fields may influence the activity. The superimposition of contour maps on the active site of farnesyltransferase additionally helps in understanding the structural requirements of these inhibitors. 3D-QSAR models developed may guide our efforts in designing and predicting the FTase inhibitory activity of novel molecules.
    European Journal of Medicinal Chemistry 02/2008; 43(1):142-54. · 3.50 Impact Factor
  • Devendra S Puntambekar, Rajani Giridhar, Mange Ram Yadav
    [Show abstract] [Hide abstract]
    ABSTRACT: This article presents in brief the development of farnesyltransferase inhibitors (FTIs) and their preclinical and clinical status. In this review the mechanism of action of FTIs is discussed and their selectivity issue towards tumor cells is also addressed. The significant efficacy of FTIs as single or combined agents in preclinical studies stands in contrast with only moderate effects in Clinical Phase II-III studies. This suggests that there is a need to further explore and understand the complex mechanism of action of FTIs and their interaction with cytotoxic agents.
    Journal of Enzyme Inhibition and Medicinal Chemistry 05/2007; 22(2):127-40. · 1.50 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A series of 3,4-diaryl-1,2,5-oxadiazoles and 3,4-diaryl-1,2,5-oxadiazole N-oxides were prepared and evaluated for COX-2 and COX-1 binding affinity in vitro and for antiinflammatory activity by the rat paw edema method. p-Methoxy (p-OMe) substituted compounds 9, 21, 34, 41, 42 showed COX-2 enzyme inhibition higher than that showed by compounds with other substituents. 3,4-Di(4-methoxyphenyl)-1,2,5-oxadiazole N-oxide (42) showed COX-2 enzyme inhibition of 54% at 22 micromol L(-1) and COX-1 enzyme inhibition of 44% at 88 micromol L(-1) concentrations, but showed very low in vivo anti-inflammatory activity. Its deoxygenated derivative (21) showed lower COX-2 enzyme inhibition (26% at 22 pmol L(-1)) and higher COX-1 enzyme inhibition (53% at 88 micromol L(-1)) but, marked in vivo anti-inflammatory activity (71% at 25 mg kg(-1)) vs. celecoxib (48% at 12.5 mg kg(-1)). Molecular modeling (docking) studies showed that the methoxy group is positioned in the vicinity of COX-2 secondary pocket and it also participates in hydrogen bonding interactions in the COX-2 active site. These preliminary studies suggest that p-methoxy (p-OMe) group in one of benzene rings may give potentially active leads in this series of oxadiazole/N-oxides.
    Acta Pharmaceutica 03/2007; 57(1):13-30. · 1.16 Impact Factor
  • D S Puntambekar, R Giridhar, M R Yadav
    [Show abstract] [Hide abstract]
    ABSTRACT: 3D-QSAR studies of some tricyclicpiperazinyl derivatives as farnesyltransferase inhibitors were performed by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA) methods to rationalize the structural requirements responsible for the inhibitory activity of these compounds. The global minimum energy conformer of the template molecule 35, the most active and pharmacokinetically stable molecule of the series, was obtained by simulated annealing method and used to build structures of the molecules in the dataset. The CoMFA model obtained after the removal of outliers produced statistically significant results with cross-validated and conventional correlation coefficients of 0.550 and 0.969, respectively. The combination of steric, electrostatic, hydrogen bond acceptor and hydrophobic fields in CoMSIA gave the best results with cross-validated and conventional correlation coefficients of 0.611 and 0.986, respectively. The predictive ability of CoMFA and CoMSIA were determined using a test set of 24 tricyclicpiperazinyl derivatives giving predictive correlation coefficients of 0.543 and 0.663, respectively, indicating good predictive power. Further the robustness of the model was verified by bootstrapping analysis. Based on the CoMFA and CoMSIA analysis we have identified some key features in the tricyclicpiperazinyl series that are responsible for farnesyltransferase inhibitory activity that may be used to design more potent tricyclicpiperazinyl derivatives and predict their activity prior to synthesis.
    European Journal of Medicinal Chemistry 12/2006; 41(11):1279-92. · 3.50 Impact Factor
  • Source
    Devendra Sharad Puntambekar, Rajani Giridhar, Mange Ram Yadav
    [Show abstract] [Hide abstract]
    ABSTRACT: Comparative Molecular Field Analysis (CoMFA) and Comparative 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 training set of 49 molecules improved the predictivity of the model. The statistically significant model was established 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 [R2(cv) = 0.664, R2 (non-cross-validated square of correlation coefficient) = 0.916, F value = 47.341, R2(bs) = 0.947 with six components, standard error of prediction36 = 0.360 and standard error of estimate36 = 0.180] while the CoMSIA model yielded [R2(cv) = 0.777, R2 (non-cross-validated square of correlation coefficient) = 0.905, F value = 66.322, R2(bs) = 0.933 with four components, standard error of prediction36 = 0.282 and standard error of estimate36 = 0.185]. The contour maps obtained from 3D-QSAR studies were appraised for activity trends for the molecules analyzed. Results indicate that steric, electrostatic, hydrophobic (lipophilic) and hydrogen bond donor substituents play a significant role in COX-2 inhibitory activity and selectivity of the compounds. The data generated from the present study will further help design novel, potent and selective COX-2 inhibitors.
    Acta Pharmaceutica 07/2006; 56(2):157-74. · 1.16 Impact Factor
  • Devendra Puntambekar, Rajani Giridhar, Mange Ram Yadav
    [Show abstract] [Hide abstract]
    ABSTRACT: 3D-QSAR analysis has been performed on a series of previously synthesized benzonitrile derivatives, which were screened as farnesyltransferase inhibitors, using comparative molecular field analysis (CoMFA) with partial least-square fit to predict the steric and electrostatic molecular field interactions for the activity. The CoMFA study was carried out using a training set of 34 compounds. The predictive ability of the model developed was assessed using a test set of eight compounds (r(pred)(2) as high as 0.770). The analyzed 3D-QSAR CoMFA model has demonstrated a good fit, having r(2) value of 0.991 and cross-validated coefficient q(2) value as 0.619. The analysis of CoMFA contour maps provided insight into the possible modification of the molecules for better activity.
    Bioorganic & Medicinal Chemistry Letters 05/2006; 16(7):1821-7. · 2.34 Impact Factor
  • DEVENDRA SHARAD PUNTAMBEKAR, Rajani Giridhar, Mange Ram Yadav
    [Show abstract] [Hide abstract]
    ABSTRACT: Comparative Molecular Field Analysis (CoMFA) and Comparative 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 training set of 49 molecules improved the predictivity of the model. The statistically significant model was established 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 R2cv = 0.664, R2 (non-cross-validated square of correlation coefficient) = 0.916, F value = 47.341, R2bs = 0.947 with six components, standard error of prediction36 = 0.360 and standard error of estimate36 = 0.180 while the CoMSIA model yielded R2cv = 0.777, R2 (non-cross-validated square of correlation coefficient) = 0.905, F value = 66.322, R2bs = 0.933 with four components, standard error of prediction36 = 0.282 and standard error of estimate36 = 0.185. The contour maps obtained from 3D-QSAR studies were appraised for activity trends for the molecules analyzed. Results indicate that steric, electrostatic, hydrophobic (lipophilic) and hydrogen bond donor substituents play a significant role in COX-2 inhibitory activity and selectivity of the compounds. The data generated from the present study will further help design novel, potent and selective COX-2 inhibitors.
    Acta pharmaceutica (hfd-fg-ap@zg.htnet.hr); Vol.56 No.2.
  • [Show abstract] [Hide abstract]
    ABSTRACT: A series of 3,4-diaryl-1,2,5-oxadiazoles and 3,4-diaryl-1,2,5-oxadiazole N-oxides were prepared and evaluated for COX-2 and COX-1 binding affinity in vitro and for anti-inflammatory activity by the rat paw edema method. p-Methoxy (p-OMe) substituted compounds 9, 21, 34, 41, 42 showed COX-2 enzyme inhibition higher than that showed by compounds with other substituents. 3,4-Di(4-methoxyphenyl)-1,2,5-oxadiazole N-oxide (42) showed COX-2 enzyme inhibition of 54% at 22 µmol L-1 and COX-1 enzyme inhibition of 44% at 88 µmol L-1 concentrations, but showed very low in vivo anti-inflammatory activity. Its deoxygenated derivative (21) showed lower COX-2 enzyme inhibition (26% at 22 µmol L-1) and higher COX-1 enzyme inhibition (53% at 88 µmol L-1) but marked in vivo anti-inflammatory activity (71% at 25 mg kg-1) vs. celecoxib (48% at 12.5 mg kg-1). Molecular modeling (docking) studies showed that the methoxy group is positioned in the vicinity of the COX-2 secondary pocket and it also participates in hydrogen bonding interactions in the COX-2 active site. These preliminary studies suggest that the p-methoxy (p-OMe) group in one of benzene rings may give potentially active leads in this series of oxadiazole/N-oxides.
    Acta pharmaceutica (hfd-fg-ap@zg.htnet.hr); Vol.57 No.1.