Seturam B Katti

Publications of Seturam B Katti

• Synthesis and Pharmacological Evaluation of Novel Arginine Analogs as Potential Inhibitors of Acetylcholine-Induced Relaxation in Rat Thoracic Aortic Rings.

  Authors: Manish Jain, Manoj Kumar Barthwal, Wahajul Haq, Seturam B Katti, Madhu Dikshit

  Chemical biology & drug design. 12/2011;

  It is widely appreciated that the vascular endothelium is capable of modulating vascular smooth muscle tone suiting it well for its role as an important regulator of a number of diverse biologicalIt is widely appreciated that the vascular endothelium is capable of modulating vascular smooth muscle tone suiting it well for its role as an important regulator of a number of diverse biological processes. Endothelial dysfunction is an early manifestation of atherothrombosis and a consequence of the established disease. Although several arginine derivatives alkylated at one of the guanidino nitrogen were found to inhibit vasorelaxation induced by acetylcholine, activity of the corresponding arginine esters is not reported. The present work was therefore designed to synthesize and evaluate series of novel arginine derivatives to obtain further insight into structure-activity relationship in this series of compounds. Present study involves assessment of activity of these novel compounds on the vascular tone of rat thoracic aorta in comparison with l-arginine analog, that is, l-nitro-arginine methyl ester (l-NAME). Results from the present study showed that full reversal of phenylephrine-mediated contraction was achieved by cumulative applications of acetylcholine (3 nm-300 μm), which were abolished when the aortic rings were pretreated with l-NAME (300 μm). Results from the present study demonstrated that these novel arginine derivatives cause significant yet reversible reduction in acetylcholine-mediated relaxation, similar to that of l-NAME.

• Lead optimization at C-2 and N-3 positions of thiazolidin-4-ones as HIV-1 non-nucleoside reverse transcriptase inhibitors.

  Authors: Vanangamudi Murugesan, Vinay S Tiwari, Reshu Saxena, Rajkamal Tripathi, Ramesh Paranjape, Smita Kulkarni, Nandini Makwana, Rahul Suryawanshi, Seturam B Katti

  Bioorganic & medicinal chemistry. 11/2011; 19(22):6919-26.

  Based on rational drug design approach, a series of novel thiazolidin-4-ones bearing different aryl/heteroaryl moieties at position C-2 and N-3 are synthesized and evaluated as potent inhibitors forBased on rational drug design approach, a series of novel thiazolidin-4-ones bearing different aryl/heteroaryl moieties at position C-2 and N-3 are synthesized and evaluated as potent inhibitors for human immunodeficiency virus type-1 reverse transcriptase enzyme (HIV-1 RT). An in vitro HIV-1 RT assay showed that the compounds 4, 5, 6, 8, 12, 13, 14 and 17 have shown high inhibition of reverse transcriptase (75.41, 95.50, 98.07, 91.24, 85.27, 77.59, 84.11 & 76.49% inhibition) enzyme activity. Further, cell based assay showed that compounds 4, 5, 8 &12 are identified as the best compounds of the series (EC(50) ranged from 0.09 to 0.8 μg/ml and 0.12 to 1.06 μg/ml) against HIV-1 III(B) and HIV-1 ADA5 strains, respectively. Moreover, the compounds which were active against HIV-1 III(B) and HIV-1 ADA5 were also found to be active against primary isolates (EC(50) ranged from 0.10 to 1.55 μg/ml against HIV-1 UG070 and 0.07 to 1.1 μg/ml against HIV-1 VB59), respectively. Structure-activity relationship (SAR) studies demonstrated the importance of the lipophilic bulky substituent pattern on compact heteroaryl ring at N-3, replacement of C4' at C-2 phenyl by trivalent bioisosteric nitrogen and dihalo groups at C-2 aryl/heteroaryl of thiazolidin-4-ones is crucial for anti-HIV-1 activity. Molecular modeling of compounds 4, 5, 8 and 12 in complex with HIV-1 RT demonstrate that there is good correlation of results obtained from SAR studies. Therefore the compounds 4, 5, 8 and 12 may be considered as good candidates for further optimization of anti-HIV-1 activity.

• Anti-stroke profile of thiazolidin-4-one derivatives in focal cerebral ischemia model in rat.

  Authors: Ram Raghubir, Rajkumar Verma, Sheeba S Samuel, Saman Raza, Wajahul Haq, Seturam B Katti

  Chemical biology & drug design. 06/2011; 78(3):445-53.

  Recently, some PPARγ agonists like pioglitazone, rosiglitazone, and other newer thiazolidine-2, 4-dione (TZD) derivatives have been shown to be neuroprotective in experimental model of cerebralRecently, some PPARγ agonists like pioglitazone, rosiglitazone, and other newer thiazolidine-2, 4-dione (TZD) derivatives have been shown to be neuroprotective in experimental model of cerebral ischemia/reperfusion (I/R) injury. Replacement of active pharmacophore viz: thiazolidine-2,4-dione of these PPARγ agonists with biologically privileged scaffold thiazolidin-4-one derivatives have been synthesized and bioevaluated in focal cerebral ischemia model in rats with an aim to ameliorate cerebral ischemic damage. Of 20 synthesized molecules, three of the substituted compounds (2, 6 and 18) have shown significant (p < 0.001) neuroprotection even much better than rosiglitazone at same dose, when administered 1 h prior to 2/24hrI/R cerebral injury in rats, whereas compounds 10, 15, and 17 also showed significant but moderate effect on most of the parameters used in the study. Moreover, compound 2 and 6 also showed curative potential after 6 h post I/R treatment. The compound 2 has also shown significant effect on glutamate uptake by perhaps enhancing the GLT-1 activity. Thus, the present study indicates that some of the synthesized thiazolidin-4-one substituted PPARγ agonists exhibit better neuroprotection and have potential to ameliorate the ischemic damage. Therefore, this novel class of compounds could be further suitably modified to obtain potent anti-ischemic agents, warranting clinical exploitation.

• 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.

• 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.

• 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.

• New acylides: synthesis of 3-O-[gamma-(4-oxo-2-aryl-thiazolidin-3-yl)butyryl]erythromycin A derivatives.

  Authors: Deepa Pandey, Wahajul Haq, Seturam B Katti

  Beilstein journal of organic chemistry. 02/2008; 4:14.

  In search of new erythromycin derivatives 3-O-[gamma-(4-oxo-2-aryl-thiazolidin-3-yl)butyryl]erythromycin A derivatives have been synthesized. The 3-hydroxy group was derivatised to a primary amineIn search of new erythromycin derivatives 3-O-[gamma-(4-oxo-2-aryl-thiazolidin-3-yl)butyryl]erythromycin A derivatives have been synthesized. The 3-hydroxy group was derivatised to a primary amine and subsequently the thiazolidinone nucleus was generated at the amino functionality through DCC mediated one-pot three-component reaction in good yields.

• New acylides: synthesis of 3- O -[γ-(4-oxo-2-aryl-thiazolidin-3-yl)butyryl]erythromycin A derivatives

  Authors: Pandey Deepa, Haq Wahajul, Seturam B Katti

  Beilstein Journal of Organic Chemistry. 01/2008;

  In search of new erythromycin derivatives 3- O -[γ-(4-oxo-2-aryl-thiazolidin-3-yl)butyryl]erythromycin A derivatives have been synthesized. The 3-hydroxy group was derivatised to a primary amine andIn search of new erythromycin derivatives 3- O -[γ-(4-oxo-2-aryl-thiazolidin-3-yl)butyryl]erythromycin A derivatives have been synthesized. The 3-hydroxy group was derivatised to a primary amine and subsequently the thiazolidinone nucleus was generated at the amino functionality through DCC mediated one-pot three-component reaction in good yields.