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IIIM-CSIR Challenges in new drug discovery in South Asia Ram Vishwakarma Indian Institute of Integrative Medicine (Council of Scientific & Industrial Research)

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Presentation on theme: "IIIM-CSIR Challenges in new drug discovery in South Asia Ram Vishwakarma Indian Institute of Integrative Medicine (Council of Scientific & Industrial Research)"— Presentation transcript:

1 IIIM-CSIR Challenges in new drug discovery in South Asia Ram Vishwakarma Indian Institute of Integrative Medicine (Council of Scientific & Industrial Research) Jammu and Srinagar, India

2 IIIM-CSIR Drug Discovery and Development (Current Business Model) New drugs: Small organic molecules and therapeutic proteins (biologics) Big Pharma and Biotech companies (US, Europe, Japan) Generic drugs: API formulation of off-patent drugs for domestic/world market Indian and Chinese companies Contract research, API manufacturing and Clinical trials services Indian and Chinese companies

3 IIIM-CSIR Time tested model for new drug discovery Natural products (plants and microbial species) and traditional system of medicine and ethno-biology (Opiates, statins, antibiotics, rapamycin, ephedrine, quinine, artemisinin, amphotericin, vincritine, taxol, podophyllotoxin (almost all anticancer and anti- infective drugs are natural products derived) Medicinal chemistry of know bioactive compounds (drugs) to decipher structure-activity relationship (SAR) and discovery of new pharmacological activity A single chemical motif gave rise to antibiotics, hypoglycemic agents, diuretics, and antihypertensive drugs

4 IIIM-CSIR Random screening of compound libraries by HTS against clinically validated targets (enzymes, receptors etc) relevant to the disease Hits – lead – drug candidate (medicinal chemistry) Mechanism based drug design and discovery (antimetabolites, methotrexate, trimethoprim, antidepressants, steroids like contraceptives and anti-inflammatory drugs) Structure based drug design (X-ray crystallography, NMR spectroscopy, molecular modeling) (Imatinib) Observational pharmacology (off-target optimization) Sidnafil citrate (Viagra), Cialis and other PDE5 blocker)

5 IIIM-CSIR Most Successful Biological Targets

6 IIIM-CSIR Lead Discover y Pre- clinical Regulatory approval Marketing Marketing Phase I IND Phase II Phase III NDA Target Id 14 Years Drug discovery & development process Key Milestone

7 IIIM-CSIR New Drug Safety Pharmacology/ Toxicology Natural Product Chemistry Intellectual Property Regulation ADME-PK Medicinal Chemistry Cheminformatics Structural Biology Formulation Expertise required in the area of drug discovery & development

8 IIIM-CSIR Uniqueness of drug discovery Most regulated industry FDA and country-specific multiple agencies Risk of post-approval failure (Vioxx and Glitazones) Balance between profits and public-health Patent expiry and generic competition (India) Goal-posts keep changing Current state of knowledge in Science & Technology Biological targets and approaches change significantly and R&D has to rapidly change (stem cells, RNAi, antibodies) Entirely new opportunities are created by new Science

9 IIIM-CSIR Key discovery “ecosystem” issues ! Drug discovery is a team work (chemistry, pharmacology, clinical sciences) with moments of brilliant thinking and months of painstakingly detailed work Spotting, inspiring, nurturing and retaining leaders who are also accomplished scientists Segregation of “first-in-class” and “best-in-class’ drug discovery teams (cultural issues) with appropriate goals and reward system Outsourcing non-essential functions to remain focused on key core objectives and expertise Partnership with innovator pharma companies in clinical development phases Identify areas of strategic and future interests and initiate collaboration with leading academic groups (new ideas) Answers to public health problems are “drugs” not “publications”

10 IIIM-CSIR Our efforts in new drug discovery Targets: clinically validated kinases

11 IIIM-CSIR Phosphatidylinositol 3-kinase (PI3K) pathway Inhibition of PI-3K kinase (isoform specific inhibitors) PI3K  for cancer and PI3K  for inflammation Up-regulation of PTEN phosphatase Inhibition of AKT isoforms Inhibition of mTOR

12 IIIM-CSIR Central role of PI3K pathway in cell

13 IIIM-CSIR Regulation of PI3K activity by phosphatases (PTEN and SHIP)

14 IIIM-CSIR Both the RTK and GPCR pathways are involved in PI3K activation

15 IIIM-CSIR PI3K signaling: the big picture

16 IIIM-CSIR Discovery of Preclinical candidates using target based discovery In house validation of PI3K isoforms ( , , ,  ) assay

17 IIIM-CSIR Target-Product Profile of PI3K for discovery of preclinical candidate Criteria/ParametersIdeal Anticancer PI3K drug candidate (NVPBEZ-235 Clinical trial Phase II)) Proposed candidate (IIIM) Enzyme Potency (IC 50 )PI3K/m-TOR/Dual Inhibitor (IC 50 <1nM ; all isoforms) <25nM Isoform SelectivityPan-PI3K PI3K-α 0.004; β 0.076; ү 0.007; δ fold against other isoforms Kinase selectivityNot known20-30 fold against other isoforms Cell based Assay (IC 50 ) μM (HCT116, DLD-1 and SW480 cells)0.1-10μM Solubility<1mg/ml in water≥ 4 and 7.8; In vitro ADMENA; Proposed Candidate: All Cyp’s ≥ 10uM Stable in HLM, MLM Permeability: High No HERG liability at 10uM No Cyp 10uM Stable in HLM, MLM Permeability: High No HERG liability at 10uM In vivo PKBioavailability ≥ 30%, Half life ≥ 3hrs (mice, rat & dog) Bioavailability ≥ 30%, Half life ≥ 3hrs (mice, rat & dog) In vivoMurine tumor models 40–50 mg/kg body weight-treats effectively without side effects Murine model-tumor regression SafetyNo cardiac/Hepatotoxicity IPNCE’sPatentable NCE’s MW<500<500 (<500 )

18 IIIM-CSIR  A meroterpenoid isolated from marine sponge Aka coralliphaga Inhibitory activity against PI3Kα (10 fold selectivity)  More selective than the synthetic LY and Wortmanin.  IC 50 : 100 nM Medicinal chemistry of Liphagane scaffold (Isoform selective PI3K inhibitors) K. A. Arvinda Cell based data: LoVo (human colon)0.58 µM CaCo (human colon), 0.67 µM MDA-468 (human breast) 1.58 µM

19 IIIM-CSIR Synthesis of Liphagal

20 IIIM-CSIR NCEs based on Liphagal scaffold (first series)

21 IIIM-CSIR S. No.Code % inhibition of Pi3K α at 0.5 μM 1IIIM-264 (Standard) IIIM IIIM IIIM IIIM IIIM IIIM IIIM IIIM IIIM IIIM IIIM-1070 Medicinal chemistry of Liphagane scaffold S. No.Code % inhibition of Pi3K α at 0.5 μM 13IIIM IIIM IIIM IIIM IIIM IIIM IIIM IIIM IIIM Sample % 0.5 μM SD IIIM IIIM

22 IIIM-CSIR Events or TargetsSample code SIP-1003SIP1004 Enzyme based IC 50 PI3Kα- 140 nM β nM γ  D  D PI3Kα- 102 nM β - 30 µM γ   Cell based IC 50 Caco-2 =10.0µM HCT-116 =8.12µM Caco-2 =7.6µM HCT-116 =5.2µM Annexin-V35-57% (1-9 µM) 50-58% (1-9 µM) Cell Cycle50-60% G 1 arrest (1-9 µM) 64-70% G 1 arrest (1-9 µM) Wound HealingEffectiveHighly effective Phospho-Akt50-55% Down-regulation60-68% Downregulation IC 50 of two best IIIM compounds from Liphagal scaffold

23 IIIM-CSIR Isoform selective: PI3K-α IC 50 : 66nM Six-membered analog : PI3K-α IC 50 : nM K. A. Aravinda Medicinal chemistry of Liphagane (Six-membered ring) scaffold

24 IIIM-CSIR Source: Science (2007) 318: N C KINASE DOMAIN Hinge region N-Lobe C-Lobe Activation Loop Kinase domain: N lobe: Residues * C lobe: Residues * Activation Loop: Molecular Docking on 3D crystal structure of Pi3K-α Analysis of the Kinase Domain of Pi3K-α

25 IIIM-CSIR Interaction of liphagal on Pi3K-α - Molecular Docking studies on 3D crystal structure of Pi3K-α - Liphagal

26 IIIM-CSIR 4-amino quinazolines as PI3K-α inhibitors PI3K & mTOR activity p110α4 nM p110β76 nM p110δ5 nM p110γ7 nM mTOR21 nM New series: 25 analogs synthesized All screened for cytotoxicity against 5 cell lines All screened for PI3K-  inhibition Isoform-selectivity determined for selected analogs Rammohan Mol. Cancer. Ther. 2009, 8, Patent filed

27 IIIM-CSIR S.NoCode % inhibition of PI3K α at 0.5 µM IC 50 against PI3K isoforms (µM) αβγδ 1 NVP-BEZ IIIM-MCD IIIM-MCD na IIIM-MCD IIIM-MCD IIIM-MCD IIIM-MCD IIIM-MCD IIIM-MCD IIIM-MCD IIIM-MCD IIIM-MCD Rammohan Medicinal chemistry of 4-amino quinazolines as PI3K-α inhibitors S. No.Code % inhibition of PI3K α at 0.5 µM 13 IIIM-MCD IIIM-MCD IIIM-MCD IIIM-MCD IIIM-MCD IIIM-MCD IIIM-MCD IIIM-MCD IIIM-MCD IIIM-MCD IIIM-MCD IIIM-MCD IIIM-MCD-2850

28 IIIM-CSIR IND in clinical trials from this scaffold One IND filed and Phase I/II is under progress in India (Piramal) S. Kumar, R. Vishwakarma, R. Mundada, V. Deore, P. Kumar, S. Sharma (Piramal Life Sciences Ltd, Mumbai), Preparation of imidazo[4,5-c]-quinoline derivatives and their use in the treatment of tumors and/or inflammation, PCT Int. Appl. (2011) WO

29 IIIM-CSIR Criteria/ParametersIdeal: anticancer molecule (pre-clinical candidate) Enzyme Potency (IC 50 ) CDK inhibitor (IC 50 <100nM) 100 nM (CDK2–CYCA and CDK2–CYCE), Proposed candidate: <25nM Selectivity~100 fold more over other kinases (Lipid kinases, VEGFR, IGFR, etc) Cell based Assay (IC 50 )~ nM; Proposed Candidate 5-10 nM Solubility≥ 2 4 and 7.8, Storage at (2-8 o C); Proposed Candidate ≥ mg/ml; Storage at room temperature In vitro ADMEAll Cyp’s ≥ 10µM Stable in HLM, MLM Permeability: High No HERG liability at 10µM In vivo PKOral bioavailability ≥ 20%, Half life ≥ 2.5-3hrs (rat/mice) Proposed Candidate: Oral bioavailability >40% and Half life >5-6hrs. In vivoMouse xenograft model-tumor regression SafetyNo cardiac/Hepatotoxicity IPPatentable Initial SAREstablished MWLess than 500 In Silico Predicted ToxNIL Cytotoxicity10 fold Rohitukine Isolated from Indian medicinal plant Dysoxylum binectariferum Hook P Nicholas Piramal Phase II Flavopiridol Sanofi-FDA approved orphan drug for CLL TPP as CDK inhibitor Shreyans Discovery of natural products CDK inhibitors

30 IIIM-CSIR Rohitukine is a flavone alkaloid isolated from plant Dysoxylum binectariferum (Meliaceae) This flavone led to discovery of two clinical candidates – Flavopiridol and P These flavones are potent inhibitors of CDKs – 1,2,4 and 9 Patent filed Medicinal chemistry of Rohitukine scaffold Series of NCEs have been synthesized by functionalization at these three positions This scaffold has shown promising activity against several kinases implicated in pathogenesis of cancer/ Alzheimers disease/ diabetes Contd.. Shreyans

31 IIIM-CSIR Medicinal chemistry of Rohitukine scaffold

32 IIIM-CSIR S.N o Code % Inhibition at 0.5 μM CDK-2/ACDK-9/T1 1 5d (IIIMNPC-290) 89.9 (IC50 =0.015 μM) 92.3 (IC50 = μM) 25g e h c751 65a b f033 S.No.Code% Inhibition at 0.5 μM CDK-2/ACDK-9/T1 1IIIMNPC IIIMNPC IIIMNPC IIIMNPC IIIMNPC IIIMNPC IIIMNPC IIIMNPC IIIMNPC IIIMNPC IIIMNPC-3705 Medicinal chemistry of Rohitukine scaffold Contd.. Shreyans

33 IIIM-CSIR S.No.Code % Inhibition at 0.5 μM CDK-2/A CDK-9/T1 1IIIMNPC IIIMNPC IIIMNPC IIIMNPC IIIMNPC IIIMNPC IIIMNPC IIIMNPC IIIMNPC Contd.. Medicinal chemistry of Rohitukine scaffold Shreyans Entry IC 50, µMIC 50, nM HL-60PC-3 MiaPaca2MCF-7A431Caco-2 CDK-2/ACDK-9/T1 NPC N.D NPC NPC N.D.310 NPC NPC2914> nt NPC

34 IIIM-CSIR Docking of Flavopiridol (pan CDK inhibitor) on crystal structure of CDK2 (2DUV) - FBDD for designing CDK2 inhibitors - Source : Bioorg.Med.Chem.Lett. (2007) 17 p.1284

35 IIIM-CSIR C1 C2 C5 C1 C2 C5 The site for modifications identified through the FTMap analysis of the binding site matches with the SAR carried out on the flavopiridol structure Superimposed docked conformation on the cluster information of the binding site of CDK2 List of 132 structures designed using this approach Modeling on Flavopiridol structure for lead optimisation Molecular Weight range of the fragment library used: FBDD for designing CDK2 inhibitors -

36 IIIM-CSIR Mechanistic studies of two optimized hits: IIIM-NPC-288 and IIIM-NPC-290 Caspase-8 c-MYC CDK-1 PARP Cleaved PARP γH2AX β actin NPC-290, µM NPC-288, µM Western blots from MiaPaca-2 cells Western blots from HL-60 cells Control ApopG1SG2 1%43%56%1% NPC290-3 µM ApopG1SG2 98%53%43%4% ApopG1SG2 98%57%40%3% NPC µM VEGF-R2 NPC-290, µM β- actin

37 IIIM-CSIR Sr.No.ParameterIIIM-NPC-290 1Mol. wt.461 2Solubility 1.PBS = 5 µM 2.SGF = 26 µM 3.SIF = 141 µM 3In-vitro cytotoxicity IC 50 (µM) 1.HL-60 = 0.9 µM 2.PC-3 = 41 µM 3.A431 = 8 µM 4.MIAPaCa = 0.6 µM 5.MCF-7 = 4 µM 6.Caco-2 = 7 µM 4Target IC 50 (nM) 1.CDK9/T1 = 1.92 nM 2.CDK2/ A = 15.5 nM 5 Protein binding 1.Fraction unbound = % Bound = CYP liability (% inhibition at 10 uM) 1.CYP3A4 = CYP2D6 = CYP2C9 = CYP1A2 = CYP2C19 = Caco-2 permeabilityA to B: 2.1; B to A: 3.9; Efflux ratio: Log P PKa5.4 Preclinical data of IIIM-NPC-290

38 IIIM-CSIR Medicinal chemistry of Meriolins Sites for modification Contd.- Co-crystal structure of CDK-2 with Meriolin  Lower Log P  Orally not available PK 30 mg/Kg No plasma level observed Nanomolar CDK potency Acceptable Log P Umed Singh

39 IIIM-CSIR Synthesis of analogs as per approach 3 Medicinal chemistry of Meriolins Patent filing under process Confidential Sr.No.CodeCDK2 %activity CDK9 %activity IC 50 CDK2IC 50 CDK9 1IIIM IIIM IIIM IIIM IIIM IIIM IIIM IIIM IIIM IIIM IIIM IIIM IIIM IIIM Umed Singh

40 IIIM-CSIR ParametersMeriolin 1IIIM-293IIIM-368 In vitro enzyme and cell based activity( nm) Kinase activityCDK2: IC 50 = 250 nM CDK9 : IC 50 = 150 nM CDK2: IC 50 = 10 nM CDK9 IC 50 = 20 nM CDK2: IC 50 = 6 nM CDK9 : IC 50 = 24 nM Cell line activityHCT116 = 1.2 PC-3 = 1.5 PANC1 = 1.0 KMS-11 =1.1 A549 = 0.4 MCF-7 = 1.56 THP-1 = 0.99 HCT-116 = 0.56 PC-3 = 2.7 Hep-2 = 2.67 (Growth inhibition at 10 µM) T47D = 73 A549 = 93 PC-3 = 86 NCI-H322 = 95 IC 50 is in progress Solubility (µg/ml) WaterPBSSGFSIF In progress < 5 >1500< 5 cLogP In progress PK propertiesIn progress Medicinal chemistry of Meriolins: Preclinical Candidates

41 IIIM-CSIR Identification of modification sites Molecular docking studies of Meriolin analogs on CDK2 contd. - FBDD for designing CDK2 inhibitors -

42 IIIM-CSIR Creation of virtual library XP Gscore: MMGBSA DG Bind: QP logo/w: Hbdonor: 3 Hbacceptor: 7.5 XP Gscore: MMGBSA DG Bind: QP logo/w: Hbdonor: 3 Hbacceptor: 6.5 XP Gscore: MMGBSA DG Bind: QP logo/w: Hbdonor: 4 Hbacceptor: 6 XP Gscore: MMGBSA DG Bind: QP logo/w: Hbdonor: 3 Hbacceptor: 3.5 XP Gscore: MMGBSA DG Bind: QP logo/w:1.124 Hbdonor: 3 Hbacceptor: 6.5 XP Gscore: MMGBSA DG Bind: QP logo/w: 1.53 Hbdonor: 4 Hbacceptor: 5 XP Gscore: MMGBSA DG Bind: QP logo/w: 1.77 Hbdonor: 3 Hbacceptor: 5.2 XP Gscore: MMGBSA DG Bind: QP logo/w: Hbdonor: 3 Hbacceptor: 6.5 Molecular docking studies of Meriolin analogs on CDK2 contd. - FBDD for designing CDK2 inhibitors -

43 IIIM-CSIR Hits identified (4 for PI3K and 3 for CDK) taken forward for lead optimization and preclinical development Optimization of lead PK profile, in vivo animal studies Cyp liabilities, Pre-formulation studies Kinase profiling Ongoing studies NCEs in preclinical development

44 IIIM-CSIR Kinase Inhibitors of Marine Origin Chem. Rev. 2013, 113, 6761−6815

45 IIIM-CSIR 1.R. A. Vishwakarma, S. D. Sawant, P. P. Singh, A.H. Dar, P. R. Sharma, A. K. Saxena, A. Nargotra, A. A. K. Kollaru, R. Mudududdla, A. K. Qazi et.al. Bororic acid bearing liphagane compounds as inhibitors of PI3Ka and/or b PCT Int. Appl. (2012) WO 2013/ A1 2.R. A. Vishwakarma, S. D. Sawant, P. P. Singh, A. H. Dar, A. Nargotra, P. R. Sharma, D. M. Mondhe; Isoform selective C-ring substituted purinyl, tetrazolyl, isatinyl-quinazolinone analogs as anticancer agents and inhibitors of PI3K-a/b; PCT Application: 150NF/ S. K. Jain, T. Sidiq, S. Meena, A. Khajuria, R. A. Vishwakarma, S. Bharate BibishanTetrahydro-2H-Pyrano [3,2-C] Isochromene-6-Ones for the treatment of inflammatory Disorders; PCT Appl. Filed, 1565DEL D. M. Mondhe, S.C. Taneja, S.Koul, J.K. Dhar, A.K. Saxena, R.K. Johri, Z.A. Wani, S.A. Andotra, S.C. Sharma, S. Singh, P. N. Gupta, R.A. Vishwakarma; A novel formulation useful in Cancer chemotherapy; PCT Appl. Filed. 2554/DEL/ R. A. Vishwakarma, S. B. Bharate, S. Bhushan, S. K. Jain, S. Meena, S. K Guru, A. S. Pathania, S. Kumar; Cyclin-Dependent Kinase Inhibition by 5,7-Dihydroxy-8-(3-Hydroxy-1-MethylPiperidin-4-Yl)-2-Methyl-4H-Chromen-4-One Analogs; PCT Appl. Filed 1142DEL P. P. Singh, R. A. Vishwakarma; 6-Nitro-2,3-Dihydroimidazo [2,1-b] oxazoles for the treatment of M. tuberculosis and a process for the preparation thereof ; PCT Appl. Filed 0225NF R. A. Vishwakarma, S. B. Bharate, S. Bhushan, S. K. Jain, S. Meena, A. Khajuria, S. K. Bhola et. al. New Chromone alkaloid dysoline for the treatment of cancer and inflammatory disorders.; PCT Appl. Filed 1077DEL Deepika Singh, Jai Parkash Sharma, Sundeep Jaglan, Abid Hamid Dar, Varun Partap Singh, Ram A. Vishwakarma; Brachiatins: Novel anticancer agents from an endophytic fungus Trichoderma longibrachiatum, process for their production and use thereof; PCT Appl. Filed 2563DEL S. D. Sawant, G. Lakshma Reddy, M. Srinivas, S. S. Hussain, D M Ishaq, A. Nargotra, P. Mahajan, R. A. Vishwakarma; Novel Pyrazolopyrimidies for treatment of impotence and process for the preparation thereof; PCT Appl. Filed 0106NF R. A. Vishwakarma, S. B. Bharate, S. Bhushan, RR Yadav, S. K. Guru, P. Joshi, 6-Aryl-3-phenylamino-quinazoline analogs as phosphoinositide- 3-kinase inhibitors; PCT Appl. Filed 0117/NF/2013 Patent filed on 23-May S. Balachandran, C. J. Dinsmore, A. Roychowdhury, R. Sharma, R. A. Vishwakarma. Preparation of morpholinosulfonyl indole compounds as modulators of insulin-like growth factor I receptors and insulin receptors for treating cancer, PCT Int. Appl. (2012), WO A1 Our Patents ( )

46 IIIM-CSIR Byproducts of discovery projects: Publications ( ) 1.V. Venkateswarlu, KA Arvinda Kumar, S. Balgotra, G. L. Reddy, M. Srinivas, R. A. Vishwakarma, S.D. Sawant, Chemistry, Eur. J., 20, 1-6, (2014) 2.N. Mupparapu, S. Khan, S. Battula, M. Kushwaha, A. P. Gupta, Q. N. Ahmed, R. A. Vishwakarma, Organic Letters, 16, (2014) 3.P. Kannaboina, K. Anilkumar, S. Aravinda, R. A. Vishwakarma, P. Das, Organic Letters, 15, (2013) 4.S. B. Bharate, S. D. Sawant, P. P. Singh and R. A. Vishwakarma, Chemical Reviews, 113, (2013). 5.Singh, P.P.; Aithagani, S.K.; Yadav, M.; Singh, V.P.; Vishwakarma, R.A.. J. Org. Chem., 2013, 78, 2639– R. Mudududdla, S. K. Jain, J. B. Bharate, A. P. Gupta, B. Singh, R. A. Vishwakarma, S. B. Bharate, J. Org. Chem. 77, (2012) 7.P. P. Singh, T. Thatikonda, K. A. Kumar, Aravinda; S. D. Sawant, B. Singh, A. K. Sharma, P. R. Sharma, D. Singh, R. A. Vishwakarma, J. Org. Chem., 77, (2012) 8.S. B. Bharate, R. Mudududdla, J. B. Bharate, N. Battini, S. Battula, R. R.Yadav, B.Singh, R. A. Vishwakarma, Org. Biomol. Chem. 10, (2012) 9.P. P. Singh, S. Gudup, H. Ayuri, S. Ambala, M. Yadav, S. D. Sawant and R. A. Vishwakarma, Org. Biomol. Chem., 10, (2012) 10.P. P. Singh, S. Gudup, S. Ambala, U. Singh, S. Dadhwal, B. Singh, S. D. Sawant and R. A. Vishwakarma, Chem. Commun., 47, (2011) 11.S. Manda, B, Singh, S. B. Bharate, R. A. Vishwakarma, Med. Chem. Commun., 3, (2012) 12.Bharate, S.B.; Yadav, R.R.; Khan, S. I.; Tekwani, B. L.; Jacob, M. R.; Khan, I.A.;. Med. Chem. Commun. 2013, 4,

47 IIIM-CSIR Publications ( ) 13.S. B. Bharate, A. K. Padala, B. A. Dar, R. R. Yadav, B. Singh and R. A. Vishwakarma, Tetrahedron Lett., 54, (2013) 14.S. B. Bharate, R. Mudududdla, R. Sharma and R. A. Vishwakarma, Tetrahedron Lett., 54, (2013) 15.S. K. Jain, S. Meenaa,b, A. K. Qazi, A. Hussain, S. K. Bhola, R. Kshirsagar, K. Pari, A. Khajuria, A. Hamid, R. Uma Shaanker, S. B. Bharate and R. A. Vishwakarma, Tetrahedron Lett., In Press B. Singh, R. Parshad, R.K. Khajuria, S. K. Guru, A. S. Pathania, R. Sharma, R. Chib, S. Aravinda, V. K. Gupta, I. A. Khan, S. Bhushan, Sandip B. Bharate, R. A. Vishwakarma, Tetrahedron Lett. In Press: S. D. Sawant, M. Srinivas, K. A. Aravinda Kumar, G. Lakshma Reddy, P. P. Singh, B. Singh, A. K. Sharma, P. R. Sharma and R. A. Vishwakarma, Tetrahedron Lett., 54, (2013) 18.R. M. Yadav, R. A. Vishwakarma and S. B. Bharate, Tetrahedron Lett, 53, (2012) 19.S. D. Sawant, M. Srinivas, G. Lakshma Reddy, P. P. Singh, R. A. Vishwakarma, Tetrahedron Lett., 53, (2012) 20.R. R. Yadav, N. Battini, R. Mudududdla, J. B. Bharate, N. Muparappu, S. B. Bharate and R. A. Vishwakarma, Tetrahedron Lett., 53, (2012) 21.S. Mohammed, A. K. Padala, B. A. Dar, B. Singh, B. Sreedhar, R. A. Vishwakarma and S. B. Bharate, Tetrahedron 68, (2012) 22.S. K. Jain, A. S. Pathania, S. Meena, R. Sharma, A. Sharma, B. Singh, B. D. Gupta, S. Bhushan, S. B. Bharate, and R. A. Vishwakarma, J. Nat. Prod. In Press, 2013:DOI: /np400433g 23.M. K. Zilla, M. Qadri, A. S. Pathania, G. A. Strobel, Y. Nalli, S. Kumar, S. K. Guru, S. Bhushan, S. K. Singh, R. A. Vishwakarma et al; Phytochemistry, In Press, 2013; DOI: /j.phytochem M. Sen, B. Shah, S. Rakshit, V. Singh, B. Padmanabhan, M. Pomusamy, K. Pari, R. A. Vishwakarma, D. Nandi and P. P. Sadhale, PloS Pathogens, 7, e (2011)

48 IIIM-CSIR Acknowledgements Parvinder Pal Singh S.D. Sawant Sandip B. Bharate Parthasarathi Das Naveed Qazi Ajay Kumar S.C. Sharma Shashi Bhushan Amit Nargotra K.A. Aravind Kumar M. Srinivas M. Ramesh V. Venkateshwaralu Rammohan R. Yadav T. Thanusha Umed Singh Prashant Joshi D. Saidulu Collaborators: Jubilant Biosys, Bangalore Vimta Labs, Hyderabad International Center for Kinase Profiling (ICKP), University of Dundee, UK Dr. Raj Hirwani and Team, URDIP, Pune (for patentability search) M. Nagaraju Sudhakar Manda Mohammed Shabbir Shreyans K. Jain Baljinder Singh Abubakar Wani


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