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Anantoju K.K.,GVK Biosciences Pvt. Ltd. | Anantoju K.K.,Jawaharlal Nehru Technological University | Syed Mohd B.,GVK Biosciences Pvt. Ltd. | Maringanti T.C.,Jawaharlal Nehru Technological University
Tetrahedron Letters | Year: 2017

A novel total synthesis of antimicrobial prenyl indoles, Indiacen A and its chloro analogue Indiacen B has been accomplished by using Horner-Wadsworth-Emmons olefination for terminal conjugated enynes, carboalumination, chlorination and Vilsmeier-Haack formylation as the key transformations. © 2017 Elsevier Ltd


Yanamandra M.,GVK Biosciences Pvt. Ltd. | Yanamandra M.,Jawaharlal Nehru Technological University | Kole L.,VINS BIO | Giri A.,Jawaharlal Nehru Technological University | Mitra S.,GVK Biosciences Pvt. Ltd.
Analytical Biochemistry | Year: 2014

The phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that regulate the cellular signal transduction pathways involved in cell growth, proliferation, survival, apoptosis, and adhesion. Deregulation of these pathways are common in oncogenesis, and they are known to be altered in other metabolic disorders as well. Despite its huge potential as an attractive target in these diseases, there is an unmet need for the development of a successful inhibitor. Unlike protein kinase inhibitors, screening for lipid kinase inhibitors has been challenging. Here we report, for the first time, the development of a radioactive lipid kinase screening platform using a phosphocellulose plate that involves transfer of radiolabeled [γ-32P]ATP to phosphatidylinositol 4,5-phosphate forming phosphatidylinositol 3,4,5-phosphate, captured on the phosphocellulose plate. Enzyme kinetics and inhibitory properties were established in the plate format using standard inhibitors, such as LY294002, TGX-221, and wortmannin, having different potencies toward PI3K isoforms. ATP and lipid apparent Km for both were determined and IC50 values generated that matched the historical data. Here we report the use of a phosphocellulose plate for a lipid kinase assay (PI3Kβ as the target) as an excellent platform for the identification of novel chemical entities in PI3K drug discovery. © 2013 Elsevier Inc. All rights reserved.


Channagiri L.S.,GVK Biosciences Pvt. Ltd. | Reddy V.K.R.,Vijayanagara Sri Krishnadevaraya University
Der Pharma Chemica | Year: 2015

The Gewald Reaction is a synthesis of 2-aminothiophenes via a multi-component condensation between sulfur, an α-methylene carbonyl compound and an α-cyanoester. Green chemistry encourages the design of synthetic processes that minimize the use and generation of hazardous substances. The application of microwave assisted organic synthesis to conduct Gewald reaction has been demonstrated by the microwave assisted transformation of ethylcyanoacetate, cyclohexanone, anisidines and sulphur into 2-Amino-3-o/p-anisidyl-carboxamido-4,5,6,7-tetrahydro-benzo (b) thiophenes. The transformation has been confirmed by conventional synthesis.


Kothapalli Y.,GVK Biosciences Pvt. Ltd | Puthukanoori R.K.,GVK Biosciences Pvt. Ltd | Alapati S.R.,GVK Biosciences Pvt. Ltd
Tetrahedron Letters | Year: 2012

An enantiospecific first total synthesis of metabolite 7a(S)-p- hydroxyphenopyrrozin 2, isolated from the cultured fungi Chromocleista sp. has been achieved starting from readily and abundantly available l-proline. The strategy of synthesis utilizes base mediated cyclization and base mediated oxygenation as the key steps. © 2011 Elsevier Inc. All rights reserved.


Southan C.,Astrazeneca | Boppana K.,GVK Biosciences Pvt. Ltd. | Jagarlapudi S.A.R.P.,GVK Biosciences Pvt. Ltd. | Muresan S.,Astrazeneca
Journal of Cheminformatics | Year: 2011

Background: Since the classic Hopkins and Groom druggable genome review in 2002, there have been a number of publications updating both the hypothetical and successful human drug target statistics. However, listings of research targets that define the area between these two extremes are sparse because of the challenges of collating published information at the necessary scale. We have addressed this by interrogating databases, populated by expert curation, of bioactivity data extracted from patents and journal papers over the last 30 years. Results: From a subset of just over 27,000 documents we have extracted a set of compound-to-target relationships for biochemical in vitro binding-type assay data for 1,736 human proteins and 1,654 gene identifiers. These are linked to 1,671,951 compound records derived from 823,179 unique chemical structures. The distribution showed a compounds-per-target average of 964 with a maximum of 42,869 (Factor Xa). The list includes non-targets, failed targets and cross-screening targets. The top-278 most actively pursued targets cover 90% of the compounds. We further investigated target ranking by determining the number of molecular frameworks and scaffolds. These were compared to the compound counts as alternative measures of chemical diversity on a per-target basis. Conclusions: The compounds-per-protein listing generated in this work (provided as a supplementary file) represents the major proportion of the human drug target landscape defined by published data. We supplemented the simple ranking by the number of compounds assayed with additional rankings by molecular topology. These showed significant differences and provide complementary assessments of chemical tractability. © 2011 Southan et al; licensee Chemistry Central Ltd.


Kamal A.,Indian Institute of Chemical Technology | Rahim A.,Indian Institute of Chemical Technology | Riyaz Sd.,Indian Institute of Chemical Technology | Poornachandra Y.,Indian Institute of Chemical Technology | And 5 more authors.
Organic and Biomolecular Chemistry | Year: 2015

2-Styryl quinolines (9a-l) have been synthesized regioselectively from 2-methyl-quinoline by using NaOAc in water acetic acid binary solvents and evaluated for their antibacterial activity against both Gram-positive and Gram-negative strains. Among these, the compounds 12 and 8 were found to be active against both bacterial strains. Compounds 9b, 9f, 9g, 9i, 9j and 9k were the most active among the series exhibiting MIC values ranging between 1.9 and 31.2 μg ml-1 against different bacterial strains. Compounds 9j and 9k were found to be as potent as the standard drug ciprofloxacin against Micrococcus luteus, Klebsiella planticola and Staphylococcus aureus. In addition, the compounds showed bactericidal activity; compound 9j was found to be better than ciprofloxacin, with an MBC value of 0.9 μg ml-1 against both M. luteus and K. planticola. The compounds also inhibited biofilm formation, and compound 9j was found to be equipotent to erythromycin against M. luteus and S. aureus MLS16. Further, theoretical studies such as those on druggable properties and PMI plot have been carried out. © The Royal Society of Chemistry 2015.


Kansal N.,Punjabi University | Silakari O.,Punjabi University | Ravikumar M.,GVK Biosciences Pvt. Ltd.
European Journal of Medicinal Chemistry | Year: 2010

Three Dimensional Pharmacophore model was developed based on 24 currently available c-Kit inhibitors. The best pharmacophore model (Hypo1) consists of four features namely one hydrogen bond acceptor, one hydrophobic point and two ring aromatics. The correlation coefficient, root mean square deviation and cost difference were 0.973, 0.729 and 100.989 respectively, suggesting that a highly predictive pharmacophore model was successfully obtained. The application of the model shows great success in predicting the activities of 40 known c-Kit inhibitors in our test set with a correlation coefficient of 0.709 with a cross validation of 95% confidence level. Accordingly, our model is reliable in identifying new compounds as c-Kit inhibitors. © 2009 Elsevier Masson SAS. All rights reserved.


Suneel Kumar B.V.S.,GVK Biosciences Pvt. Ltd | Malik S.,GVK Biosciences Pvt. Ltd | Grandhi P.,National Institute of Pharmaceutical Education and Research | Dayam R.,GVK Biosciences Pvt. Ltd | Sarma J.A.R.P.,GVK Biosciences Pvt. Ltd
Current Topics in Medicinal Chemistry | Year: 2014

Anthrax Lethal Factor (LF) is a zinc-dependent metalloprotease, one of the virulence factor of anthrax infection. Three forms of the anthrax infection have been identified: cutaneous (through skin), gastrointestinal (through alimentary tract), and pulmonary (by inhalation of spores). Anthrax toxin is composed of protective antigen (PA), lethal factor (LF), and edema factor (EF). Protective antigen mediates the entry of Lethal Factor/Edema Factor into the cytosol of host cells. Lethal factor (LF) inactivates mitogen-activated protein kinase kinase inducing cell death, and EF is an adenylyl cyclase impairing host defenses. In the past few years, extensive studies are undertaken to design inhibitors targeting LF. The current review focuses on the small molecule inhibitors targeting LF activity and its structure activity relationships (SAR). © 2014 Bentham Science Publishers.


Burns R.N.,Mercer University | Hendrix C.W.,Johns Hopkins University | Chaturvedula A.,Mercer University | Chaturvedula A.,GVK Biosciences Pvt. Ltd.
Journal of Clinical Pharmacology | Year: 2015

The objective of this analysis was to develop and qualify a population pharmacokinetic model describing plasma tenofovir (TFV) concentrations and tenofovir-diphosphate (TFV-DP) concentrations in peripheral blood mononuclear cell (PBMC) in healthy women volunteers from the MTN-001 clinical trial, an open label 3-way crossover study of oral tenofovir disoproxil fumarate 300 mg tablet, TFV 1% vaginal gel, or both. TFV pharmacokinetics were best described by a 2-compartment, first-order absorption/elimination model with absorption lag time. TFV was linked to PBMC TFV-DP by first-order uptake with first-order elimination. An adherence adjustment was included to account for nonadherence by explicitly modeling a bioavailability parameter on the previous day's dose. The final model included weight as a covariate on central compartment volume (Vc) with estimates as follows: absorption rate constant (Ka) 9.79 h-1, absorption lag time 0.5 hours, Vc 385.71-2.16∗(73-WT(kg)), and apparent TFV clearance of 56.7 L/h ((K20 + K24)∗Vc). TFV-DP's half-life was 53.3 hours. All diagnostic plots and bootstrap confidence intervals were acceptable. Model validation was conducted using simulations compared to data from the MTN-001 oral + vaginal period and other clinical trial data. The resulting model closely predicted the disposition of TFV and TFV-DP when compared to healthy participant data from another clinical trial. © 2015 The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.


Ravi Kumar P.,GVK Biosciences Pvt. Ltd. | Ravi Kumar P.,Jawaharlal Nehru University | Behera M.,GVK Biosciences Pvt. Ltd. | Raghavulu K.,GVK Biosciences Pvt. Ltd. | And 2 more authors.
Tetrahedron Letters | Year: 2012

An efficient method for the preparation of novel 2-(5-arylisoxazol-3-yl) cyclohexa-2,5-diene-1,4-dione hybrids via 1,3-dipolar cycloaddition followed by an oxidation reaction using ceric ammonium nitrate (CAN) has been described. Using this method, various aryl as well as alkyl substituted isoxazole-benzoquinone hybrids were synthesized in high yields. © 2012 Elsevier Ltd. All rights reserved.

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