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Indian Ayurvedic System of Medicine: Scope forNew Drug Design and Discovery

Dr. Narshinha P. Argade

Division of Organic ChemistryNational Chemical Laboratory, Pune 411 008

INDIA

np.argade@ncl.res.in

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2Saraswati: Godess of KnowledgeMother of Vedas

Dhanwantari: Physician of GodsFather and Promulgator of Ayurveda

Guru-Shishya Tradition

INDIA / CHINA

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World of Ayurveda: Rich Repository of Original Knowledge Charak Samhita Sushruta Samhita Madhava Nidana Astanga Haridaya

Indian area: 2.4% of the world with range of geoclimatic conditions Indian biodiversity: 8.1% of the world Indian Plant Species: 45000 (3000 used in Ayurveda) Indian Ayurvedic formulations: 35000 + Bhasmas Indian Registered Ayurvedic Practitioners: 6,00,000

http://images.google.co.in/imgres?imgurl=http://lh6.ggpht.com/_PDHWS6OSLfU/R3s8yg1ApPI/AAAAAAAAEYY/Dt95rvEk1fQ/P1010218.JPG&imgrefurl=http://picasaweb.google.com/lh/photo/Y_AhgWh_zJ68TeVqAv_v3w&h=1712&w=2288&sz=175&hl=en&start=9&um=1&tbnid=fV3PCl1m-bAXkM:&tbnh=107&tbnw=143&prev=/images%3Fq%3DPicture%2Bof%2Bdense%2BIndian%2Bforest%26um%3D1%26hl%3Den%26sa%3DXhttp://images.google.co.in/imgres?imgurl=http://www.northindiatours.indianconsultancy.com/gifs/north-india-forest.jpg&imgrefurl=http://www.northindiatours.indianconsultancy.com/&h=239&w=261&sz=17&hl=en&start=15&um=1&tbnid=qW7SdaljSwWYfM:&tbnh=103&tbnw=112&prev=/images%3Fq%3DPicture%2Bof%2Bdense%2BIndian%2Bforest%26um%3D1%26hl%3Den%26sa%3DX

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Development of Ayurvedic FormulationsObservationHypothesis formulationTesting by experimentsInduction derived general principleApplication of general principle

http://www.organicindia.com/images/ayurveda.jpg

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Disease Plant species Common nameMultiresistant Tuberculosis Cyperus rotundus Motha

Obesity & heart diseases Commiphora mukul Guggulu

Cancer Rubia cordifolia Manjistha

Diabetes Petrocarpus marsupium Vijaysar

Asthma Adhatoda vasica Adhulsa

Hepatitis Peganum nigellastrum Syrian rue

Diseases and Ayurvedic Medicines

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Comparison of Ayurvedic System of Medicine with AllopathyAyurvedic System Allopathic System

Experiential Experimental

Reductionistic

Health oriented Disease oriented

Diet oriented Drug and surgery orientedGreen pharmacy Red pharmacy

Pro-nature Anti-nature

Client oriented Profession orientedActive on all humans Active on 30% humans

No side effects Side effects

Mode of action unknown Mode of action known ?

Slow effects Fast effects

Holistic

Philophical Physical

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First Institute of AyurvedicEducation: Gurukul Kangdi

Ayurvedic Colleges in India: 210

BAMS: 8000

MAMS: 600 I Desire that the Diseases andMiseries of all Living Beings areResolved

Shri Zandu Bhattji

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Natural Products Derived Drugs 1998-2004

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New Drug Discovery @ NCL

N

N

O

OH

NH

NN

O

O

OH

O

O

O

O

O

O

O

HO

HO

H

H

H

H

AssayDevelopment

High-ThroughputScreening

Separation

Parallel

Synthesis

Evaporation

Extraction

Hits & Leads

NewDrugs

Natural Products

Synthetic Products

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Dr. G. V. Satyavati

1966-Guggulu Girl

O

O

Z-Guggulsterone

(Cholesterol Lowering Agent)

G. V. Satyavati et al. Ind. J. Med. Res. 1988, 87, 327.

Commiphora mukul

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A Natural Product That Lowers Cholesterol As anAntagonist Ligand for FXRNancy L. Urizar, Amy B. Liverman, DNette T. Dodds, Frank Valentin Silva,Peter Ordentlich, Yingzhuo Yan, Frank J. Gonzalez, Richard A. Heyman, David

J. Mangelsdorf, David D. Moore*

The gum resin of Commiphora mukul (guggulu in Sanskrit)has been used in Ayurvedic medicine since at least 600 BC totreat a wide variety of ailments, including obesity and lipiddisorders.

Science 2002,296, 1703.

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(-)-Vasicine, (-)-Vasicinone and Isovasicinone

N

N

O

OH(-)-Vasicinone

N

N

OH(-)-Vasicine

Iso la t ion: A d h a t o d a v a s i c a

Act i v it y : Used in The Indian Ayurvedic Sys tem o f

Medic ine as a remedy fo r cough, co ld and

bronch i t i s

N

N

O OH

Isovasicinone

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N

N

O

N

N

O

OH

Davis reagent

-78 oC

39% (71% ee)

Earlier Approaches towards Vasicinone

Eguchi et al. J. Org. Chem. 1996, 61, 7316.

N

N

O

OHN

N

O

OAc

Amano PS, VA

THF

45% (100% ee)

Kamal et al. J. Org. Chem. 2001, 66, 997.

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NCL-Synthesis of (-)-Vasicinone

NH2

NH2

O

O

O

OOAc

+

CONH2

NH

OHOO

OAc

CONH2

NH

OO

OMe

OAc

CONH2

NH

OOH

OH

N

NHOH

O

OH

N

N

O

OH

(98%) (98%)

(92%)

(90%)

7 6

2 3 45

(-)-Vasicinone (1)

Ether CH2N2

(a) LAH(b) H2O

DEAD,TPP

S. B. Mhaske and N. P. Argade J. Org. Chem. 2001, 66, 9038.

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Synthesis of (-)-Vasicine - in Progress

TFA

NH2

NHBocO

O

OOAc

+NH

OHOO

OAc

NHBoc

NH

OO

OMe

OAc

NHBoc

NH

OOH

OH

NHBoc

N

NHOH

OH

N

N

OH

(95%) (87%)

7 6

2 3 4 5

(-)-Vasicine (1)

Ether CH2N2

LAH, THF(73%)

?X

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Batey et al. Org. Lett. 2004, 6, 4913.

Yao et al.J. Org. Chem. 2007, 72, 6270.

N

N

H

O

O

N

O

N

N

Aniline, Dy(OTf)3

(51%)

N

N

O

O

NH

Ph3PO, Tf2O

(99%)

1

2

Earlier Approaches towards Luotonin A

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An Efficient Biogenetic Total Synthesis of Luotonin F

NH2

O

NH2 +

1

O

O

O

N

NH

O

OH

N

N

O OH

Pegamine

N

N

NH

O

2

(93%)

(96%)(62%)

Deoxoluotonin F (8)

NH

CONH2O COOH

NH

CONH2O

COOMe

43

Et2O

(98%) (98%)

CH2N2

(i) LAH/THF(ii) H2O

PCC

(64%)

Isovasicinone (7)

o-Amino-benzaldehyde,KOH CrO3/H5IO6

[5]NH

CONH2O

OH

N

NH

O

CHO

[6]

N

N

NH

O

O

Luotonin F

Practical Synthesis of Luotonin A and Luotonin B & E via

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Practical Synthesis of Luotonin A and Luotonin B & E via

Novelortho-Directed Lithiation

NH2

NH2

O

NCl

ON

NH

N

O

NH

O

N

CONH2

N

N

N

O

N

NH

N

O OH

N

N

N

O

N

N

N

O OMe

N

N

N

O OH

N

NLi

N

OCHO

+

Luotonin A (1a)

Luotonin B (1b)Luotonin E (1c)

i ii

iiia

iv

iiic

iiib

v

vi

2 3 4 5

[6]7

[8]

LiLi

(96%) (98%)

(86%)

(81%)

(95%)

(61%)

(82%)

8

3`

8`

Reagents,condition and Yields: (i) TEA (2 eq.), THF, rt, 3 h (96%); (ii) 5% aq. KOH, EtOH, reflux, 5 min. (98%); (iiia) Mesityllithium (2.2 eq.), 78 oC, 1 h to 20 oC (gradually), (iiib) THF solution of HCHO (5 eq.), 30 oC, 20 min., saturated aq. solution ofNH4Cl (86%), (iiic) DMF (5 eq.),

20

o

C, 30 min., saturated aq. solution of NH4Cl (81%); (iv) PPh3 (1.3 eq.), DEAD (1.2 eq.), THF,rt, 1 h (95%); (v) PCC (1.2 eq.), powdered 4 molecular sieves, DCM, rt, 1 h (61%); (vi)p-TSA (5 eq.), MeOH, reflux, 3 h (82%).

S. B. Mhaske and N. P. ArgadeJ. Org. Chem. 2004, 69, 4563.

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NH

NH2MeO

O

O

O

CH3

+

MeON

NH

CH3

HOOC

Luotonin C (1)

N

NMeO

O

CH3

MeON

CH3

N

O

NHNH

MeOO

CH3

HOOC

2 3 4

5 6

Synthesis of Luotonins C, in Progress

P. B. Wakchaure and N. P. Argade (Unpublished results).

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Indian AyurvedicSystem of Medicine Chemist Doctor

Safe but slow Fast and moresafe

A k l d t

http://images.google.co.in/imgres?imgurl=http://www.saunalahti.fi/~marian1/gourmet/pic/s_sand.jpg&imgrefurl=http://www.saunalahti.fi/~marian1/gourmet/i_sugars.htm&h=170&w=170&sz=10&hl=en&start=245&um=1&tbnid=RvF8UWL2dGMtNM:&tbnh=99&tbnw=99&prev=/images%3Fq%3Dphoto%2Bof%2Bcoloured%2Bcrystalline%2Bcompound%26start%3D240%26ndsp%3D20%26um%3D1%26hl%3Den%26sa%3DN

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Acknowledgements

Aquapharm Ltd., PuneRecon Ltd., BangaloreGodrej Agrovet, MumbaiParke-Davis, USAYamanuchi, JapanNikem, ItalyDST, New DelhiCSIR, New DelhiICS-UNIDO, ItalyDr. G. P. Pandey, HeadDOC, NCL, PuneDr. S. Sivaram, DirectorNCL, Pune, India

Dr. S. B. DesaiDr. A. M. DeshpandeDr. S. MangaleswaranDr. S. B. MhaskeDr. Anirban KarDr. S. EaswarDr. M. MondalDr. Merajuddin BaagDr. Sanjib GogoiMr. Kishan Haval (SRF)Mr. Umesh Kshirsagar (SRF)Mr. Ramesh Patel (SRF)Mr. Prasad Wakchaure (SRF)Mr. Mandeep Singh (JRF)Mr. Prashant Deore (JRF)

Th f thi l b t i t d k l d

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www.ncl-india.org

The purpose of this laboratory is to advance knowledgeand apply chemical science for the good of the people

National Chemical Laboratory, Pune, India

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