Yenamandra S Prabhakar

Publications of Yenamandra S Prabhakar

• CP-MLR/PLS directed QSAR study on the glutaminyl cyclase inhibitory activity of imidazoles: rationales to advance the understanding of activity profile.

  Authors: Viney Kumar, Manish K Gupta, Gagandip Singh, Yenamandra S Prabhakar

  Journal of enzyme inhibition and medicinal chemistry. 02/2012;

  The glutaminyl cyclase inhibitory activity of a series of imidazoles has been analyzed through combinatorial protocol in multiple linear regressions (CP-MLR) and partial least square using differentThe glutaminyl cyclase inhibitory activity of a series of imidazoles has been analyzed through combinatorial protocol in multiple linear regressions (CP-MLR) and partial least square using different topological and structural descriptors. The QC activity was found to be correlated with 2D-autocorrelation (2DAUTO) and atom centered fragments (ACF) descriptors. The descriptor from 2DAUTO class showed that molecular structure frames of one, six and seven path length associated with atomic van der Waals volumes and polarizability hold scope for modulating QC inhibitory activity. The ACF descriptors suggested that the unsubstituted alkyl fragments and methyl substituted imidazole ring are favorable, while unsaturation in the same and C=N-C≡N are unfavorable for activity. The molar refractivity (MR) is conducive for activity. The descriptors identified in the study collectively highlight the significance of molecular volume and polarizability to the QC inhibitory activity of imidazoles. The models are statistically significant and showed good predictivity.

• Cypermethrin induces astrocyte apoptosis by the disruption of the autocrine/paracrine mode of epidermal growth factor receptor signaling.

  Authors: Shailendra Kumar Maurya, Asit Rai, Nagendra Kumar Rai, Shreekant Deshpande, Rajeev Jain, Mohana Krishna Reddy Mudiam, Yenamandra S Prabhakar, Sanghamitra Bandyopadhyay

  Toxicological sciences : an official journal of the Society of Toxicology. 11/2011; 125(2):473-87.

  Cypermethrin is reported to affect astrocytes in rat brain; however, its mechanism of action is obscure. Here, we observed an increase in apoptosis in the cortical astrocytes upon treatment of ratsCypermethrin is reported to affect astrocytes in rat brain; however, its mechanism of action is obscure. Here, we observed an increase in apoptosis in the cortical astrocytes upon treatment of rats with cypermethrin. We then characterized the mechanism governing the apoptosis. Because the epidermal growth factor receptor (EGFR) signaling regulates the survival of astrocytes, we investigated the effect of cypermethrin on EGFR activation. The astrocytes exhibited an early and irreversible attenuation in the basal EGFR phosphorylation. Supportively, molecular docking studies revealed considerable homology in the docking mode of cypermethrin and the known EGFR inhibitors, erlotinib and AG1478, to the kinase domain of EGFR. Furthermore, treatment with cypermethrin demonstrated a downregulation in the intracellular and secreted levels of heparin-binding epidermal growth factor (HB-EGF), an EGFR ligand. AG1478 reduced the synthesis of HB-EGF, suggesting the dependence of HB-EGF on EGFR activation. In addition, a neutralizing antibody against HB-EGF diminished the basal EGFR levels, indicating ligand-dependent expression of EGFR. Likewise, cypermethrin caused irreversible suppression in the basal EGFR levels, which induced apoptosis in astrocytes. The apoptosis was prevented by exogenous HB-EGF. These data imply an autocrine/paracrine mode of action of HB-EGF-EGFR in astrocyte survival. Consequently, cypermethrin induced a mitochondria-mediated apoptosis, characterized by rise in Bax/Bcl-2 ratio and cleavage of caspase-9, -3, and -7, and the effect was prevented by HB-EGF. HB-EGF activated the extracellular signal-regulated kinases and AKT pathways that protected against apoptosis. Together, these data demonstrate that cypermethrin induces astrocyte apoptosis by disrupting the autocrine/paracrine mode of HB-EGF-EGFR signaling at two levels, irreversible loss of basal EGFR and downregulation of HB-EGF.

• CoMFA and CoMSIA of diverse pyrrolidine analogues as dipeptidyl peptidase IV inhibitors: active site requirements.

  Authors: Vanangamudi Murugesan, Nidhi Sethi, Yenamandra S Prabhakar, Seturam B Katti

  Molecular diversity. 05/2011; 15(2):457-66.

  The inhibition of dipeptidyl peptidase IV (DPP-IV) has emerged as an attractive target in the treatment of type 2 diabetes. In view of this development, a critical analysis of structural requirementsThe inhibition of dipeptidyl peptidase IV (DPP-IV) has emerged as an attractive target in the treatment of type 2 diabetes. In view of this development, a critical analysis of structural requirements of the DPP-IV inhibitors is envisioned to identify the significant features toward design of selective inhibitors. The comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) contour plots of pyrrolidine based analogues are used to analyze the structural requirements of a DPP-IV active site. The CoMFA model has shown a cross-validated q (2) of 0.651 with a non-cross-validated r (2) of 0.882 and explained 70.6% variance in the activity of external test compounds. In this, the steric and electrostatic fields have respectively contributed 59.8 and 40.2%, respectively, to the explained activity of the compounds. The CoMSIA model has shown optimum predictivity (cross-validated q (2) = 0.661; non-cross-validated r (2) = 0.803; external test set's predictive r (2) = 0.706) with four molecular fields namely, steric, electrostatic, hydrogen bond (HB)-donor, and HB-acceptor. The contour plots of molecular fields resulting from these studies have suggested: (i) steric restriction with small electron rich substituent at 2- and 3-position of pyrrolidine ring, (ii) presence of electropositive ring linker between the pyrrolidine head and aryl tail, (iii) presence of electron-rich groups around the aryl tail moiety, and (iv) presence of sulfonamide between the ring linker and aryl tail which would increase DPP-IV binding affinity of the compounds. These findings will help in the design of structurally related/new compounds as potential DPP-IV inhibitors.

• Specific targeting of insulin-like growth factor 1 receptor signaling in human estrogen dependent breast cancer cell by a novel tyrosine-based benzoxazepine derivative.

  Authors: Bandana Chakravarti, Jawed A Siddiqui, Shailendra K Dhar Dwivedi, Shreekant Deshpande, Krishnanda Samanta, Rabi S Bhatta, Gautam Panda, Yenamandra S Prabhakar, Rituraj Konwar, Sabaysachi Sanyal, Naibedya Chattopadhyay

  Molecular and cellular endocrinology. 03/2011; 338(1-2):68-78.

  The present study sought to investigate the in vitro and in vivo effects of a tyrosine-based benzoxazepine, 4-[4-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-3-ylmethyl]-phenol)The present study sought to investigate the in vitro and in vivo effects of a tyrosine-based benzoxazepine, 4-[4-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-3-ylmethyl]-phenol) [THBP] in human breast cancer cells, with a focus on determining its molecular target. THBP had growth inhibitory effect on MCF-7 and MDA-MD-231 cells. At IC(50) value (∼20 μM), THBP resulted in G1 arrest, decrease in cyclin D1 levels and induction of apoptosis of MCF-7 cells. Mechanistically, activation of caspase 8 contributes critically to the induction of apoptotic cell death as copresence of selective inhibition of caspase 8 effectively abrogates the cytotoxic effect of THBP in MCF-7 cells. Further, THBP increased pro-apoptotic protein, Bax; decreased anti-apoptotic protein, Bcl-2; and decreased mitochondrial membrane potential in MCF-7 cells, indicating involvement of an intrinsic pathway of apoptosis following caspase 8 activation. Out of the various growth factors/hormones, THBP selectively abrogated increased viability of MCF-7 cells by insulin-like growth factor 1 (IGF-1). Molecular docking studies revealed that THBP occupied the ATP binding pocket of IGF-1 receptor (IGF-1R). Accordingly THBP was found to inhibit IGF-1-induced phosphorylation of IGF-1R and insulin receptor substrate-1 (IRS-1) without inhibiting insulin signaling in MCF-7 cells. In athymic nude mice, compared with vehicle, THBP treatment significantly reduced the growth of MCF-7 xenograft tumors through inhibition of cancer cell proliferation as well as promotion of cell death that correlated with reduced phospho-IGF-1R levels. We suggest that interfering with the IGF-1R signaling by the benzoxazepine THBP offers a novel and selective therapeutic strategy for estrogen receptor-positive, postmenopausal breast cancer patients.

• CP-MLR/PLS directed QSAR study on apical sodium-codependent bile acid transporter inhibition activity of benzothiepines.

  Authors: Brij Kishore Sharma, Prithvi Singh, Pradeep Pilania, Kirti Sarbhai, Yenamandra S Prabhakar

  Molecular diversity. 02/2011; 15(1):135-47.

  The apical sodium-codependent bile acid transporter (ASBT) inhibition activity of benzothiepine derivatives have been analyzed based on topological and molecular features. Analysis of the structuralThe apical sodium-codependent bile acid transporter (ASBT) inhibition activity of benzothiepine derivatives have been analyzed based on topological and molecular features. Analysis of the structural features in conjunction with the biological endpoints in Combinatorial Protocol in Multiple Linear Regression (CP-MLR) led to the identification of 21 descriptors for modeling the activity. The study clearly suggested that the role of Randic shape index (path/walk ratio 3) and topological charges of 2-, 5-, and 6-orders to optimize the ASBT inhibitory activity of titled compounds. The influence of atomic van der Waals volumes, masses, Sanderson electronegativities, and polarizabilities are indicated via different lags of Moran and Geary autocorrelations. Presence of tertiary aromatic amine functionality in molecular structure has also shown its relevance in rationalizing the biological actions of benzothiepines. The PLS analysis has confirmed the dominance of information content of CP-MLR identified descriptors for modeling the activity when compared to those of the leftover ones.

• Consensus features of CP-MLR and GA in modeling HIV-1 RT inhibitory activity of 4-benzyl/benzoylpyridin-2-one analogues.

  Authors: Shreekant Deshpande, Rinki Singh, Mohammad Goodarzi, Seturam B Katti, Yenamandra S Prabhakar

  Journal of enzyme inhibition and medicinal chemistry. 02/2011; 26(5):696-705.

  The HIV-1 reverse transcriptase (RT) inhibitory activity of benzyl/benzoylpyridinones is modeled with molecular features identified in combinatorial protocol in multiple linear regression (CP-MLR)The HIV-1 reverse transcriptase (RT) inhibitory activity of benzyl/benzoylpyridinones is modeled with molecular features identified in combinatorial protocol in multiple linear regression (CP-MLR) and genetic algorithm (GA). Among the features, nDB and LogP are found to be the most influential descriptors to modulate the activity. Although the coefficient of nDB suggested in favor of benzylpyridinones skeleton, the coefficient of LogP suggested the favorability of hydrophilic nature in compounds for better activity. The partial least squares analysis of the descriptors common to CP-MLR and GA has displayed their predictivity over the total descriptors identified in both the approaches. The back-propagation artificial neural networks model from the five most significant common descriptors (nDB, T(O..O), MATS8e, LogP, and BELp4) has explained 93.2% variance in the HIV-1 RT activity of the training set compounds and showed a test set r(2) of 0.89. The results suggest that the descriptors have the ability to identify the patterns in the compounds to predict potential analogues.

• Arylpiperazines for management of benign prostatic hyperplasia: design, synthesis, quantitative structure-activity relationships, and pharmacokinetic studies.

  Authors: Amit Sarswat, Rajeev Kumar, Lalit Kumar, Nand Lal, Smriti Sharma, Yenamandra S Prabhakar, Shailendra K Pandey, Jawahar Lal, Vikas Verma, Ashish Jain, Jagdamba P Maikhuri, Diwakar Dalela, Kirti, Gopal Gupta, Vishnu L Sharma

  Journal of medicinal chemistry. 12/2010; 54(1):302-11.

  A series of 27 aryl/heteroaryl/aralkyl/aroyl piperazines were synthesized, and most of these compounds reduced prostate weight of mature rats by 15-47%. Three compounds, 10, 12, and 18, had betterA series of 27 aryl/heteroaryl/aralkyl/aroyl piperazines were synthesized, and most of these compounds reduced prostate weight of mature rats by 15-47%. Three compounds, 10, 12, and 18, had better activity profile (reduced prostate weight by 47%, 43%, and 39%, respectively) than the standard drug flutamide (24% reduction). QSAR suggested structures with more cyclic and branched moieties, increased topological separation of O and N therein, and reduced solvation connectivity index for better activity. Pharmacokinetic study with compound 10 at an oral dose of 10.0 mg/kg indicated good absorption, negligible extrahepatic elimination, and rapid distribution to the target organ (prostate) but restricted entry through the blood-brain barrier. A 10-fold decrease in PSA and 15-fold increase in ER-β gene expressions of human prostate cancer cells (LNCaP) by compound 10 in vitro indicated AR and ER-β mediated actions. The findings may stimulate further explorations of identified lead for the management of benign prostatic hyperplasia.

• A QSAR study on 2-(4-methylpiperazin-1-yl)quinoxalines as human histamine H4 receptor ligands.

  Authors: Brij K Sharma, Pradeep Pilania, Prithvi Singh, Yenamandra S Prabhakar

  Journal of enzyme inhibition and medicinal chemistry. 10/2010; 26(3):412-21.

  The histamine H(4) receptor binding affinity of 2-(4-methylpiperazin-1-yl)quinoxaline derivatives has been quantitatively analyzed in terms of Dragon descriptors. The derived QSAR models haveThe histamine H(4) receptor binding affinity of 2-(4-methylpiperazin-1-yl)quinoxaline derivatives has been quantitatively analyzed in terms of Dragon descriptors. The derived QSAR models have provided rationales to explain the activity of titled derivatives. The descriptors identified in CP-MLR analysis have highlighted the role of path/walk 4-Randic shape index (PW4), mean square distance (MSD) index, topological charges (GGI9, JGI2, and JGI7), atomic properties in respective lags of 2D-autocorrelations (MATS7e, GATS7e, and MATS8p), and Burden matrix (BELm1) to explain the binding affinity. Certain structural fragments (C-002 and C-027) have also shown prevalence to optimize the H(4)R binding affinity of titled compounds. The PLS analysis has also confirmed the dominance of information content of CP-MLR-identified descriptors for modelling the activity.

• Synthesis and biological evaluation of 2,3,4-triarylbenzopyran derivatives as SERM and therapeutic agent for breast cancer.

  Authors: Shailesh Kumar, Shreekant Deshpande, Vishal Chandra, Shakti Kitchlu, Anila Dwivedi, Vadithe Lakshma Nayak, Rituraj Konwar, Yenamandra S Prabhakar, Devi Prasad Sahu

  Bioorganic & medicinal chemistry. 09/2009;

  A novel class of 2,3,4-triarylbenzopyrans has been synthesized and were evaluated for their selective estrogen receptor modulation activity and as a therapeutic agent for breast cancer. Among theA novel class of 2,3,4-triarylbenzopyrans has been synthesized and were evaluated for their selective estrogen receptor modulation activity and as a therapeutic agent for breast cancer. Among the compounds synthesized, compounds 11a and 12c exhibited 73.91% and 69.24% inhibition as estrogen antagonistic activity, respectively. Compound 12a showed the lowest IC(50) at 6.97muM against MCF-7 and 11f showed the lowest IC(50) value of 5.6muM against MDA-MB-231 cell line in spite of their low receptor binding affinity implicating these compounds probably act through ER independent mechanism.

• Juglone derivatives as antitubercular agents: A rationale for the activity profile.

  Authors: Smriti Sharma, Brij K Sharma, Yenamandra S Prabhakar

  European journal of medicinal chemistry. 01/2009;

  The antitubercular activity and cytotoxicity of juglone derivatives were analyzed with the topological and molecular surface features from a web-based server, MODEL (MOlecular DEscriptor Lab).The antitubercular activity and cytotoxicity of juglone derivatives were analyzed with the topological and molecular surface features from a web-based server, MODEL (MOlecular DEscriptor Lab). Analysis of the structural features in conjunction with the biological endpoints in Combinatorial Protocol in Multiple Linear Regression led to the identification of seven descriptors for modeling the activity and six descriptors for that of the toxicity of the compounds. Analysis of these descriptors in PLS highlighted their relative significance in modulating the biological response. They suggested that structures with compact molecular arrangement, partial positive surface areas and increased autocorrelation with small lag values may lead to better antitubercular activity.

• CoMFA and CoMSIA studies on thiazolidin-4-one as anti-HIV-1 agents.

  Authors: Vanangamudi Murugesan, Yenamandra S Prabhakar, Seturam B Katti

  Journal of molecular graphics & modelling. 12/2008;

  Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on thiazolidin-4-one class of compounds as HIV-1 reverse transcriptaseComparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on thiazolidin-4-one class of compounds as HIV-1 reverse transcriptase (HIV-1 RT) inhibitors using global minima and crystal structure conformations. Results obtained from the crystal structure-based model yielded superior statistical data (r(cv)(2) values of 0.683 for CoMFA and 0.678 for CoMSIA) when compared to those obtained by the global minima-based model (r(cv)(2) values of 0.625 and 0.654 for CoMFA and CoMSIA, respectively). The models were validated using an external test set of 47 compounds. The predictive r(2) values for the crystal-based CoMFA and CoMSIA models were 0.735 and 0.739, respectively, while the corresponding predictive r(2) values for the global minima-based CoMFA and CoMSIA models were 0.654 and 0.635, respectively. 3D contour maps generated from these models provide the regions in space where interactive fields may influence the activity. The superimposition of contour maps on the active site of HIV-1 reverse transcriptase additionally helped in understanding the structural requirements of these inhibitors. The results provide insight for predictive and diagnostic aspects of this class of HIV-1 RT inhibitors for better activity.

• Topological descriptors in modeling the agonistic activity of human A(3) adenosine receptor ligands: The derivatives of 2-chloro-N(6)-substituted-4'-thioadenosine-5'-uronamide.

  Authors: Susheela Sharma, Brij K Sharma, Sanjeev K Sharma, Prithvi Singh, Yenamandra S Prabhakar

  European journal of medicinal chemistry. 10/2008;

  The human A(3) adenosine receptor agonistic activity of 2-chloro-N(6)-substituted-4'-thioadenosine-5'-uronamides has been analyzed through Combinatorial Protocol in Multiple Linear RegressionThe human A(3) adenosine receptor agonistic activity of 2-chloro-N(6)-substituted-4'-thioadenosine-5'-uronamides has been analyzed through Combinatorial Protocol in Multiple Linear Regression (CP-MLR) using 488 topological descriptors obtained from DRAGON software for the energy minimized 3D-structures of these molecules. Among the various descriptor classes considered in the study, the human A(3) adenosine receptor agonistic activity is correlated with simple topological descriptors (TOPO), Modified Burden eigenvalues (BCUT) and functional group (FUNC) classes of descriptors. The average valence connectivity index of order zero, X0Av, the sum of topological distances between O and Cl, T (Ocdots, three dots, centeredCl) from the TOPO class, the lowest eigenvalue n.2 of Burden matrix/weighted by atomic masses, BELm2, from the BCUT class and the number of secondary aliphatic amides, nCONHR, from FUNC class have contributed significantly in the development of a statistical sound models. The models developed and the participating descriptors suggest that the substituent groups at N(6)-position and/or 5'-uronamide of 2-chloro-N(6)-substituted-4'-thioadenosine-5'-uronamide derivatives hold scope for structural modification in the optimization of activity.

• QSAR studies on benzoylaminobenzoic acid derivatives as inhibitors of beta-ketoacyl-acyl carrier protein synthase III.

  Authors: Satyakam Singh, Love K Soni, Manish K Gupta, Yenamandra S Prabhakar, S G Kaskhedikar

  European journal of medicinal chemistry. 06/2008; 43(5):1071-80.

  Fatty acid biosynthesis is essential for most of the bacterial survival. Components of this biosynthetic pathway have been identified as attractive targets for the development of new antibacterialFatty acid biosynthesis is essential for most of the bacterial survival. Components of this biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. FabH, beta-ketoacyl-ACP synthase III, is a attractive target since it is central to the initiation of fatty acid biosynthesis. Quantitative structure-activity relationship (QSAR) studies have been carried out on a series of benzoylaminobenzoic acid derivatives as potent inhibitors of FabH and antibacterial activity against Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, Neisseria meningitidis and Escherichia coli, which demonstrate FabH inhibitory activity in cell free and whole cell system. The QSAR studies revealed that inhibitory activity increases with increase in hydrophobicity, molar refractivity, aromaticity, and presence of OH group (on x position of the nucleus). On the other side presence of hetero-atoms like N, O, or S at R(1) position of the nucleus decreases the inhibitory activity. The comparison of QSAR between the FabH inhibitory activity and antibacterial activity against S. aureus, S. pneumoniae, S. pyogenes, E. faecalis, N. meningitidis also demonstrates that the hydrophobicity, aromaticity and presence of OH group (on x position of the nucleus) are conducive for the inhibitory activity.

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• QSAR study on tetrahydroquinoline analogues as plasmodium protein farnesyltransferase inhibitors: A comparison of rationales of malarial and mammalian enzyme inhibitory activities for selectivity.

  Authors: Manish K Gupta, Yenamandra S Prabhakar

  European journal of medicinal chemistry. 03/2008;

  The quantitative structure-activity relationships of Plasmodium falciparum and Rat protein farnesyltransferase (PFT) inhibitory activities ofThe quantitative structure-activity relationships of Plasmodium falciparum and Rat protein farnesyltransferase (PFT) inhibitory activities of 6-cyano-1-(3-methyl-3H-imidazoly-4-ylmethyl)-3-substituted-1,2,3,4-tetrahydroquinoline (THQ) analogues are investigated in order to explore the similarities/deviations between the two enzymes for these analogues. The structure space of a ligand (BMS-214662) bound to Rat-PFT (PDB code 1SA5) has been used as the conformational space of the compounds under investigation. The study has been carried out using the combinatorial protocol in multiple linear regression with several 2D- and 3D-descriptors from molecular operating environment (MOE) representing the physicochemical and electronic features of the compounds. The molecular potential energy and partially charged van der Waals surface areas have taken part in the PFT models. They suggested in favor of molecular arrangement with minimum energy and low positively/negatively charged surfaces for optimum Pf-PFT inhibitory activity. Furthermore, less hydrophobic compounds are preferred for the activity. The Rat-PFT inhibitory activity models suggested in favor of more negatively as well as more positively charged surface area descriptors for the better activity. The PLS analysis carried out on the descriptors of the Pf-PFT and Rat-PFT models suggested that among the parameters, the partially charged surface areas in the range -0.20 to -0.15 (PEOE_VSA-3) and -0.30 to -0.25 (PEOE_VSA-5), hydrophobicity (a_hyd, logP(o/w) and SlogP_VSA4), and electronic energy (PM3_Eele) of the molecules hold promise for modulating the Pf-PFT/R-PFT inhibitory activities of the compounds. This suggested the possibility of modulating the Pf-PFT/R-PFT inhibitory activities and bringing about selectivity in the THQ analogues for the malarial parasite enzyme.

• QSAR study about ATP-sensitive potassium channel activation of cromakalim analogues using CP-MLR approach.

  Authors: Susheela Sharma, Yenamandra S Prabhakar, Prithvi Singh, Brij Kishore Sharma

  European journal of medicinal chemistry. 02/2008;

  The structure-activity models of the myorelaxant activity of the cromakalim analogues have been investigated with nearly 470 topological descriptors from DRAGON software using Combinatorial ProtocolThe structure-activity models of the myorelaxant activity of the cromakalim analogues have been investigated with nearly 470 topological descriptors from DRAGON software using Combinatorial Protocol in Multiple Linear Regression (CP-MLR). Among the descriptor classes considered in the study, the binding affinity is correlated with simple functional (FUN), topological (TOPO), atom centered fragments (ACF), empirical (EMP), modified Burden eigenvalues (BCUT), Galvez topological charge indices (GVZ), 2D-autocorrelation (2D-AUTO) and constitutional (CONS) descriptors. The models developed, and the participating descriptors suggest that the substituent groups of 4,6-disubstituted-2,2-dimethylchromans hold scope for further modification in the optimization of activity. The higher path lengths rich in polarizability and lower path length rich in atomic mass in addition to the lower charge indices of the molecule are beneficiary to the activity. The participating descriptors also suggested that certain structural features such as carbon atoms attached to the heteroatom by single or multiple bonding, and lesser or 'no' branching in a molecule are helpful to augment the activity.

• C-3 alkyl/arylalkyl-2,3-dideoxy hex-2-enopyranosides as antitubercular agents: synthesis, biological evaluation, and QSAR study.

  Authors: Mohammad Saquib, Manish K Gupta, Ram Sagar, Yenamandra S Prabhakar, Arun K Shaw, Rishi Kumar, Prakas R Maulik, Anil N Gaikwad, Sudhir Sinha, Anil K Srivastava, Vinita Chaturvedi, Ranjana Srivastava, Brahm S Srivastava

  Journal of medicinal chemistry. 07/2007; 50(13):2942-50.

  A series of C-3 alkyl and arylalkyl 2,3-dideoxy hex-2-enopyranoside derivatives were synthesized by Morita-Baylis-Hillman reaction using enulosides 4, 5, and 6 and various aliphatic and aromaticA series of C-3 alkyl and arylalkyl 2,3-dideoxy hex-2-enopyranoside derivatives were synthesized by Morita-Baylis-Hillman reaction using enulosides 4, 5, and 6 and various aliphatic and aromatic aldehydes. The compounds were evaluated in vitro for the complete inhibition of growth of Mycobacterium tuberculosis H37Rv. They exhibited moderate to good activity in the range of 25-1.56 mug/mL. Among these, 4d, 4h, 5c, and 4hr showed activity at minimum inhibitory concentrations, 3.12, 6.25, 1.56, and 1.56 mug/mL, respectively. These compounds were safe against cytotoxicity in VERO cell line and mouse macrophage cell line J 744A.1. A QSAR analysis by CP-MLR with alignment-free 3D-descriptors indicated the relevance of structure space comparable to the minimum energy conformation (from conformational analysis) of 5c to the activity. The study indicates that the compounds attaining the conformational space of 5c and reflecting some symmetry, minimum eccentricity, and closely placed geometric and electronegativity centers therein are favorable for activity.

• Molecular Surface Features in Modeling the HIV-1 RT Inhibitory Activity of 2-(2, 6-Disubstituted phenyl)-3-(substituted pyrimidin-2-yl)-thiazolidin-4-ones

  Authors: Ravindra K. Rawal, Yenamandra S. Prabhakar, S.B. Katti

  QSAR & Combinatorial Science. 01/2007; 26(3):398-406.

• 2-(Aryl)-3-furan-2-ylmethyl-thiazolidin-4-ones as selective HIV-RT inhibitors.

  Authors: Ravindra K Rawal, Yenamandra S Prabhakar, S B Katti, E De Clercq

  Bioorganic & medicinal chemistry. 01/2006; 13(24):6771-6.

  A series of 4-thiazolidinones were evaluated as selective inhibitors of the HIV-RT enzyme. Our attempt in correlating the derived physicochemical properties with the HIV-RT inhibitory activityA series of 4-thiazolidinones were evaluated as selective inhibitors of the HIV-RT enzyme. Our attempt in correlating the derived physicochemical properties with the HIV-RT inhibitory activity resulted in some statistically significant QSAR models with good predictive ability. The QSAR studies indicated the role of lipophilicity, dipole moment and out-of-plane potential energy of the compounds in rationalizing the activity. One of the compounds, 1, inhibited the enzyme at 0.204 microM concentration with minimal toxicity to MT-4 cells.

• Synthesis and QSAR studies on thiazolidinones as anti-HIV agents.

  Authors: Ravindra K Rawal, V Raja Solomon, Yenamandra S Prabhakar, S B Katti, E De Clercq

  Combinatorial chemistry & high throughput screening. 09/2005; 8(5):439-43.

  Selected 4-thiazolidinone have been synthesized and tested as anti-HIV activity. The results of the in vitro tests showed that one of the compounds, 5, inhibited the enzyme at 0.204 microMSelected 4-thiazolidinone have been synthesized and tested as anti-HIV activity. The results of the in vitro tests showed that one of the compounds, 5, inhibited the enzyme at 0.204 microM concentration with minimal toxicity to MT-4 cell. Furthermore, the QSAR studies indicated the role of PMIZ, Ovality and Total energy content of the compounds in rationalizing the activity.

• CP-MLR directed QSAR studies on the antimycobacterial activity of functionalized alkenols--topological descriptors in modeling the activity.

  Authors: Manish K Gupta, Ram Sagar, Arun K Shaw, Yenamandra S Prabhakar

  Bioorganic & medicinal chemistry. 02/2005; 13(2):343-51.

  The antimycobacterial activity of nitro/acetamido alkenol derivatives and chloro/amino alkenol derivatives has been analyzed through combinatorial protocol in multiple linear regression (CP-MLR)The antimycobacterial activity of nitro/acetamido alkenol derivatives and chloro/amino alkenol derivatives has been analyzed through combinatorial protocol in multiple linear regression (CP-MLR) using different topological descriptors obtained from Dragon software. Among the topological descriptor classes considered in the study, the activity is correlated with simple topological descriptors (TOPO) and more complex 2D autocorrelation descriptors (2DAUTO). In model building the descriptors from other classes, that is, empirical, constitutional, molecular walk counts, modified Burden eigenvalues, and Galvez topological charge indices have made secondary contribution in association with TOPO and/or 2DAUTO classes. The structure-activity correlations obtained with the TOPO descriptors suggest that less branched and saturated structural templates would be better for the activity. For both the series of compounds, in 2DAUTO the activity has been correlated to the descriptors having mass, volume and/or polarizability as weighting component. In these two series of compounds, however, the regression coefficients of the descriptors have opposite arithmetic signs with respect to one another. Outwardly these two series of compounds appear very similar. But in terms of activity they belong to different segments of descriptor-activity profiles. This difference in the activity of these two series of compounds may be mainly due to the spacing difference between the C1 (also C6) substituents and rest of the functional groups in them.