1. Challenges in new drug discovery in South Asia
Ram Vishwakarma
Indian Institute of Integrative Medicine
(Council of Scientific & Industrial Research)
Jammu and Srinagar, India
Dept. Natural Products,
Dept. Natural Products,

2. 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

3. 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. Mechanism based drug design and discovery
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. Most Successful Biological Targets

6. Drug discovery & development process
Lead Discovery
Pre-
clinical
Regulatory approval
Market i ng
Phase I
IND II
III
NDA
Target Id 14
Years 6 4 2 12 10 8
Key Milestone

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

8. 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. 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. Our efforts in new drug discovery
Targets: clinically validated kinases
Dept. Natural Products,
Dept. Natural Products,

11. Phosphatidylinositol 3-kinase (PI3K) pathway
Inhibition of PI-3K kinase (isoform specific inhibitors)
PI3Ka for cancer and PI3Kg for inflammation
Up-regulation of PTEN phosphatase
Inhibition of AKT isoforms
Inhibition of mTOR

12. Central role of PI3K pathway in cell

13. Regulation of PI3K activity by phosphatases
(PTEN and SHIP)
Dept. Natural Products,
Dept. Natural Products,

14. Both the RTK and GPCR pathways are involved in PI3K activation

15. PI3K signaling: the big picture

16. Discovery of Preclinical candidates using target based discovery
In house validation of PI3K isoforms (a,b,g,d) assay

17. Target-Product Profile of PI3K for discovery of preclinical candidate
Criteria/Parameters
Ideal Anticancer PI3K drug candidate (NVPBEZ-235 Clinical trial Phase II))
Proposed candidate (IIIM)
Enzyme Potency (IC50)
PI3K/m-TOR/Dual Inhibitor (IC50<1nM ; all isoforms)
<25nM
Isoform Selectivity
Pan-PI3K
PI3K-α 0.004; β ; ү ; δ 0.005
10 fold against other isoforms
Kinase selectivity
Not known
20-30 fold against other isoforms
Cell based Assay (IC50)
μM (HCT116, DLD-1 and SW480 cells)
0.1-10μM
Solubility
<1mg/ml in water
≥ 0.05mg/ml @pH 4 and 7.8;
In vitro ADME
NA; Proposed Candidate: All Cyp’s ≥ 10uM
Stable in HLM, MLM
Permeability: High
No HERG liability at 10uM
No Cyp 10uM
In vivo PK
Bioavailability ≥ 30%,
Half life ≥ 3hrs (mice, rat & dog)
In vivo
Murine tumor models 40–50 mg/kg body weight-treats effectively without side effects
Murine model-tumor regression
Safety
No cardiac/Hepatotoxicity IP
NCE’s
Patentable NCE’s MW
<500
<500 (<500 )

18. Medicinal chemistry of Liphagane scaffold
(Isoform selective PI3K inhibitors)
A meroterpenoid isolated from marine sponge Aka coralliphaga
Inhibitory activity against PI3Kα (10 fold selectivity)
More selective than the synthetic LY and Wortmanin.
IC50: 100 nM
Cell based data:
LoVo (human colon) 0.58 µM
CaCo (human colon), µM
MDA-468 (human breast) µM
K. A. Arvinda
Dept. Natural Products,
Dept. Natural Products,

19. Synthesis of Liphagal Dept. Natural Products, 22.01.2007

20. NCEs based on Liphagal scaffold (first series)

21. Medicinal chemistry of Liphagane scaffold
S. No.
Code
% inhibition of Pi3K α
at 0.5 μM 1
IIIM-264 (Standard)
88.9 2
IIIM-265
88.2 3
IIIM-112
15.1 4
IIIM-114
10.6 5
IIIM-109
2.4 6
IIIM-106
11.1 7
IIIM-113
7.1 8
IIIM-108
5.4 9
IIIM-115 10
IIIM-111 11
IIIM-110 12
IIIM-107
S. No.
Code
% inhibition of Pi3K α
at 0.5 μM 13
IIIM-98
10.4 14
IIIM-100
7.7 15
IIIM-105
2.6 16
IIIM-102 17
IIIM-101 18
IIIM-104
10.5 19
IIIM-97 20
IIIM-99 21
IIIM-116
8.2
Sample
% 0.5 μM SD
IIIM-345
11.1
IIIM-346
11.8

22. IC50 of two best IIIM compounds from Liphagal scaffold
Events or Targets
Sample code
SIP-1003
SIP1004
Enzyme based IC50
PI3Kα- 140 nM
β nM
γ ND
 ND
PI3Kα- 102 nM
β µM
γ mM
 mM
Cell based IC50
Caco-2 =10.0µM
HCT-116 =8.12µM
Caco-2 =7.6µM
HCT-116 =5.2µM
Annexin-V
35-57%
(1-9 µM)
50-58%
Cell Cycle
50-60% G1 arrest
64-70% G1 arrest
Wound Healing
Effective
Highly effective
Phospho-Akt
50-55% Down-regulation
60-68% Downregulation

23. Medicinal chemistry of Liphagane (Six-membered ring) scaffold
Isoform selective: PI3K-α IC50: 66nM
Six-membered analog : PI3K-α IC50: nM
K. A. Aravinda

24. Molecular Docking on 3D crystal structure of Pi3K-α
Analysis of the Kinase Domain of Pi3K-α
852
Hinge region
N-Lobe
C-Lobe
Activation
Loop N
KINASE DOMAIN C
697
851
1068
Kinase domain:
N lobe: Residues *
C lobe: Residues *
Activation Loop:
Source: Science (2007) 318:

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

26. 4-amino quinazolines as PI3K-α inhibitors
PI3K & mTOR activity
p110α
4 nM
p110β
76 nM
p110δ
5 nM
p110γ
7 nM
mTOR
21 nM
25 analogs synthesized
All screened for cytotoxicity against 5 cell lines
All screened for PI3K-a inhibition
Isoform-selectivity determined for selected analogs
Mol. Cancer. Ther. 2009, 8,
New series:
Patent filed
Rammohan

27. Medicinal chemistry of 4-amino quinazolines as PI3K-α inhibitors
S.No
Code
% inhibition of PI3K α at 0.5 µM
IC 50 against PI3K isoforms (µM) α β γ δ 1
NVP-BEZ235
97.1
0.004
0.076
0.007
0.005 2
IIIM-MCD-300
69.9
0.115
0.67
1.84
0.27 3
IIIM-MCD-287
48.8
0.150 na
8.44
0.88 4
IIIM-MCD-288
48.6 5
IIIM-MCD-307
47.5 6
IIIM-MCD-286
45.6 7
IIIM-MCD-298 44 8
IIIM-MCD-301
38.1 9
IIIM-MCD-305
36.8 10
IIIM-MCD-303
36.4 11
IIIM-MCD-308 33 12
IIIM-MCD-290
29.8
S. No.
Code
% inhibition of PI3K α at 0.5 µM 13
IIIM-MCD-296
20.3 14
IIIM-MCD-294 17 15
IIIM-MCD-306
16.4 16
IIIM-MCD-304 11
IIIM-MCD-299
8.2 18
IIIM-MCD-302
4.1 19
IIIM-MCD-291
2.7 20
IIIM-MCD-292
1.5 21
IIIM-MCD-297
1.3 22
IIIM-MCD-289 23
IIIM-MCD-295 24
IIIM-MCD-293 25
IIIM-MCD-285
Rammohan

28. 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. Discovery of natural products CDK inhibitors
Criteria/Parameters
Ideal: anticancer molecule (pre-clinical candidate)
Enzyme Potency (IC50)
CDK inhibitor (IC50<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 (IC50)
~ nM; Proposed Candidate 5-10 nM
Solubility
≥ 2 4 and 7.8, Storage at (2-8 oC);
Proposed Candidate ≥ mg/ml; Storage at room temperature
In vitro ADME
All Cyp’s ≥ 10µM
Stable in HLM, MLM
Permeability: High
No HERG liability at 10µM
In vivo PK
Oral bioavailability ≥ 20%, Half life ≥ 2.5-3hrs (rat/mice)
Proposed Candidate: Oral bioavailability >40% and Half life >5-6hrs.
In vivo
Mouse xenograft model-tumor regression
Safety
No cardiac/Hepatotoxicity IP
Patentable
Initial SAR
Established MW
Less than 500
In Silico Predicted Tox
NIL
Cytotoxicity
10 fold
TPP as CDK inhibitor
Rohitukine
Isolated from Indian medicinal plant
Dysoxylum binectariferum Hook
Flavopiridol
Sanofi-FDA approved orphan drug for CLL
P276-00
Nicholas Piramal
Phase II
Shreyans

30. Medicinal chemistry of Rohitukine scaffold
Contd..
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
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
Patent filed
Shreyans

31. Medicinal chemistry of Rohitukine scaffold

32. Medicinal chemistry of Rohitukine scaffold
Contd..
S.No
Code
% Inhibition at 0.5 μM
CDK-2/A
CDK-9/T1 1 5d
(IIIMNPC-290)
89.9
(IC50 =0.015 μM)
92.3
(IC50 = μM) 2 5g 43
83.3 3 5e 42
91.5 4 5h 21 60 5 5c 7 51 6 5a
5.2
66.5 5b
0.6
70.1 8 5f 33
S.No.
Code
% Inhibition at 0.5 μM
CDK-2/A
CDK-9/T1 1
IIIMNPC-39 14 2
IIIMNPC-40 30 3
IIIMNPC-50 12 4
IIIMNPC-33 10 5
IIIMNPC-34 6
IIIMNPC-11 7
IIIMNPC-10 8
IIIMNPC-36 9
IIIMNPC-38
IIIMNPC-35 11
IIIMNPC-37
Shreyans

33. Medicinal chemistry of Rohitukine scaffold
Contd..
S.No.
Code
% Inhibition at 0.5 μM
CDK-2/A
CDK-9/T1 1
IIIMNPC-196
16.6 2
IIIMNPC-195 10 8 3
IIIMNPC-192 4
IIIMNPC-183
9.6
5.4 5
IIIMNPC-184
7.0
4.7 6
IIIMNPC-193
4.5 7
IIIMNPC-187
3.8
IIIMNPC-201
3.5 9
IIIMNPC-185
Entry
IC50, µM
IC50, nM
HL-60
PC-3
MiaPaca2
MCF-7
A431
Caco-2
CDK-2/A
CDK-9/T1
NPC287 1 58
1.8 31
4.4
3.7
N.D.
66.76
NPC288 3 30
0.8 8
608
11.53
NPC289
1.6 49 39
5.6
310
NPC290
0.9 41
0.6 4 7
15.58
1.92
NPC291
>100
4.7
4.3 nt
466
29.62
NPC292
0.4 10
2.4 6 17
1800
350
Shreyans

34. 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. Modeling on Flavopiridol structure for lead optimisation
- FBDD for designing CDK2 inhibitors -
Superimposed docked conformation on the cluster information of the binding site of CDK2 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 C2 C1
Molecular Weight range of the fragment library used: C5
List of 132 structures designed using this approach

36. Mechanistic studies of two optimized hits:
IIIM-NPC-288 and IIIM-NPC-290
NPC-288, µM
NPC-290, µM
Western blots from MiaPaca-2 cells
Caspase-8
c-MYC
CDK-1
PARP
Cleaved PARP
γH2AX
β actin
VEGF-R2
NPC-290, µM
β- actin
Western blots from HL-60 cells
Control
NPC290-3 µM
NPC µM
Apop G1 S G2 1%
43%
56%
Apop G1 S G2
98%
53%
43% 4%
Apop G1 S G2
98%
57%
40% 3%

37. Preclinical data of IIIM-NPC-290
Sr.No.
Parameter
IIIM-NPC-290 1
Mol. wt.
461 2
Solubility
PBS = 5 µM
SGF = 26 µM
SIF = 141 µM 3
In-vitro cytotoxicity IC50 (µM)
HL-60 = 0.9 µM
PC-3 = 41 µM
A431 = 8 µM
MIAPaCa = 0.6 µM
MCF-7 = 4 µM
Caco-2 = 7 µM 4
Target IC50 (nM)
CDK9/T1 = 1.92 nM
CDK2/ A = 15.5 nM 5
Protein binding
Fraction unbound = 0.044
% Bound = 4.43 6
CYP liability
(% inhibition at 10 uM)
CYP3A4 = 38.3
CYP2D6 = 16.3
CYP2C9 = 53.6
CYP1A2 = 18.5
CYP2C19 = 70.9 7
Caco-2 permeability
A to B: 2.1; B to A: 3.9; Efflux ratio: 1.8 9
Log P
2.9 10
PKa
5.4

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

39. Medicinal chemistry of Meriolins
Sr.No.
Code
CDK2 %activity
CDK9 %activity
IC50 CDK2
IC50CDK9 1
IIIM-290
31.3
68.8
0.23
0.64 2
IIIM-291
43.5
65.8 3
IIIM-292
16.6
48.7
0.16
0.45 4
IIIM-293
10.6
13.1
0.01
0.02 5
IIIM-363
37.7
83.8 6
IIIM-364
58.9
78.4 7
IIIM-365
47.6
42.4 8
IIIM-366
16.8
50.3
0.0105
0.0525 9
IIIM-367
10.9
71.7
0.004
0.0385 10
IIIM-368
10.8
17.7
0.0055
0.024 11
IIIM-369
97.7
111.3 12
IIIM-370
15.8
29.1
0.0225
0.059 13
IIIM-384
16.9
12.9 14
IIIM-294
11.6
5.9
Synthesis of analogs as per approach 3
Patent filing under process
Confidential
Umed Singh

40. Medicinal chemistry of Meriolins: Preclinical Candidates
Parameters
Meriolin 1
IIIM-293
IIIM-368
In vitro enzyme and cell based activity( nm)
Kinase activity
CDK2: IC50 = 250 nM
CDK9 : IC50 = 150 nM
CDK2: IC50 = 10 nM
CDK9 IC50 = 20 nM
CDK2: IC50 = 6 nM
CDK9 : IC50 = 24 nM
Cell line activity
HCT = 1.2
PC = 1.5
PANC1 = 1.0
KMS-11 =1.1
A = 0.4
MCF = 1.56
THP = 0.99
HCT-116 = 0.56
PC = 2.7
Hep = 2.67
(Growth inhibition at 10 µM)
T47D = 73
A549 = 93
PC-3 = 86
NCI-H322 = 95
IC50 is in progress
Solubility (µg/ml)
Water
PBS
SGF
SIF
In progress
< 5
>1500
cLogP
0.85
2.10
PK properties

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

42. Molecular docking studies of Meriolin analogs on CDK2 contd.
- FBDD for designing CDK2 inhibitors -
Creation of virtual library
XP Gscore:
MMGBSA DG Bind:
QP logo/w: 0.535
Hbdonor: 3
Hbacceptor: 7.5
XP Gscore:
MMGBSA DG Bind:
QP logo/w: 1.898
Hbacceptor: 6.5
XP Gscore:
MMGBSA DG Bind:
QP logo/w: 1.484
Hbdonor: 4
Hbacceptor: 6
XP Gscore:
MMGBSA DG Bind:
QP logo/w: 3.496
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
Hbacceptor: 5.2
XP Gscore:
MMGBSA DG Bind:
QP logo/w: 2.438

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

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

45. Our Patents ( )
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
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/2012
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, 1565DEL2013
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/2012
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 1142DEL2013
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 0225NF2012
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 1077DEL2013
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 2563DEL2013
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 0106NF2013
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-2013
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

46. Byproducts of discovery projects: Publications (2012-13)
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)
N. Mupparapu, S. Khan, S. Battula, M. Kushwaha, A. P. Gupta, Q. N. Ahmed, R. A. Vishwakarma, Organic Letters, 16, (2014)
P. Kannaboina, K. Anilkumar, S. Aravinda, R. A. Vishwakarma, P. Das, Organic Letters, 15, (2013)
S. B. Bharate, S. D. Sawant, P. P. Singh and R. A. Vishwakarma, Chemical Reviews, 113, (2013).
Singh, P.P.; Aithagani, S.K.; Yadav, M.; Singh, V.P.; Vishwakarma, R.A.. J. Org. Chem., 2013, 78, 2639–2648
R. Mudududdla, S. K. Jain, J. B. Bharate, A. P. Gupta, B. Singh, R. A. Vishwakarma, S. B. Bharate, J. Org. Chem. 77, (2012)
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)
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)
P. P. Singh, S. Gudup, H. Ayuri, S. Ambala, M. Yadav, S. D. Sawant and R. A. Vishwakarma, Org. Biomol. Chem., 10, (2012)
P. P. Singh, S. Gudup, S. Ambala, U. Singh, S. Dadhwal, B. Singh, S. D. Sawant and R. A. Vishwakarma, Chem. Commun., 47, (2011)
S. Manda, B, Singh, S. B. Bharate, R. A. Vishwakarma, Med. Chem. Commun., 3, (2012)
Bharate, S.B.; Yadav, R.R.; Khan, S. I.; Tekwani, B. L.; Jacob, M. R.; Khan, I.A.;. Med. Chem. Commun , 4,

47. Publications ( )
S. B. Bharate, A. K. Padala, B. A. Dar, R. R. Yadav, B. Singh and R. A. Vishwakarma, Tetrahedron Lett., 54, (2013)
S. B. Bharate, R. Mudududdla, R. Sharma and R. A. Vishwakarma, Tetrahedron Lett., 54, (2013)
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48. 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
M. Nagaraju
Sudhakar Manda
Mohammed Shabbir
Shreyans K. Jain
Baljinder Singh
Abubakar Wani
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)