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A SEMINAR ON

BIOISOSTERISM AND ISOSTERISM

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Presented by-

Mr. Swapnil R. Bhalerao

M.Pharm II – Sem.

Guided by-

Prof. S. V. Amrutkar

Department of Pharmaceutical Chemistry

M.G.V’s Pharmacy College, Panchvati, Nashik - 03

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ContentContentIntroduction to drug design.Drug discovery, Design and modification.Introduction to Lead compound.Method of Lead discovery.Optimization of Lead.Bioisosterism and isosterisn.Classification of Bioisostere.Application of Bioisosterism in Drug design.ConclusionReferences

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DRUG DESIGN.

Drug design is an integrated developing discipline which portends an era of ‘tailored drug’.

It involves the study of effects of biologically active compounds on the basis of molecular structures or its physico-chemical properties.

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Drug Discovery, Design and DevelopmentDrug Discovery, Design and Development

-Drug discovery without a Lead.

Eg. Penicillins,Librium.

Lead discovery-Random Screening. Non-random Screening. Drug Metabolism Studies. Clinical approach.

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What is Lead? What is Lead?

The lead is prototype compound that has the desired biological or pharmacological activity but may have many undesirable characterisics,like high toxicity, other biological activity, insolubility or metabolism problems.

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Drug Drug DevelopmentDevelopment. Optimization of Lead. Optimization of Lead

-Identification of the active part.-Functional group optimization.-SAR studies.-Bioisosterism and Isosterism

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Why Why LeadLead Modification is Modification is Necessary?Necessary?

For fine tune of biological activity in order to--Minimize toxicity-Modify the activity-Alter metabolism-Maximize bioavailability

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ISOSTERISM AND BIOISOSTERISMIMPORTANT TOOL IN LEAD MODIFICATION

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Isosterism and BioisosterismIsosterism and Bioisosterism

Replacement or modification of functional group with other group having similar properties is known as isosteric and bioisosteric replacement.

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Isostere-

Langnmuir in 1919 define iosstere as-Compound or group of atom having same number

of atom and electron.

(e.g. CO2 and N2O)

CO2(O=C=O) and N2O (- N=N+=O )

10Langnmuir

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BioisostereBioisostere

.Burger define Bioisosteres as substituent's or groups

that have similar chemical and physical properties and which produce broadly similar biological properties.

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Dr.Alferrd Burger

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Bioisosteric Replacement.Why?Bioisosteric Replacement.Why?

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-Greater selectivity

-Less side effects

-Deceased toxicity

-Improved pharmakokinetics

-Increase stability

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MeCH2OH

MeSi

Me

Me

CH2OH

Majantol-Strong fresh floral aq.aldegydic odour

Sila majantol-more terpineol like odour

Me

GeCH2OHMe

Germa majantol-weak and not characteric odour

Why Bioisosterism?

All lily of the valley flower

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Why Bioisosterism?Why Bioisosterism?

- The size, shape ,electronic effect lipid solubility, water solubility,pka,chemical reactivity, hydrogen bonding are the parameter that influences the potency, selectivity and the duration of drug action.

- Bioisosterism is effective because it affect all above parameters to less or more extents.

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Clasification Of Bioisosteres Clasification Of Bioisosteres

1.Classical bioisosteres-

a.Univalent atoms and groups. (C,N,O,S,-Cl,-Br)

b.Bivalent atom or groups. (R-O-R,R-S-R,R-NH-R)

c.Trivalent atom and groups. (-CH=,-N=,-P=,R-N=R)

d.Tetravalent atoms . (=c=,=N=,=P=)

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2.Non classical bioisosteres2.Non classical bioisosteres

Do not have same number of atom and do not fit the steric and electronic rules of classical isosteres, but they produce similar biological activity

Examples-a.Halogens- Cl,F,Brb.Ethers- R-O-R,-S-c.Hydroxy group- -OHd.Carboxylic acid group- R-COOH,R-SOOHe.Catechol-

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OH

OH

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Changes resulting from bioisosteric replacements.

Size, shape, electronic distribution, lipid solubility, water solubility, pKa, chemical reactivity, hydrogen bonding

Effects of bioisosteric replacement:

1. Structural (size, shape, H-bonding are important)

2. Receptor interactions ( lipid/H2O solubility are important)

3. Pharmacokinetics (lipophilicity, hydrophilicity, pKa, H-bonding are important)

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Bioisosterism allows modification of Bioisosterism allows modification of physicochemical parametersphysicochemical parameters

-Multiple alterations may be necessary:

-If a bioisosteric modification for receptor binding decreases lipophilicity, modify a different part of the molecule with a lipophilic group

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Examples Of Bioisosteric Replacement

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Adrenergic Drug.

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OH

CH CH2NHCH3

OH

Phenylephrine(pka=9.6) Alkylsulphonamidophenethanolamine (pka=9.6)

Phenylephirine-phenolic OH group take parts in Hydrogen bonding,with bioactive site of rceptor.The OH group is replaced by other group having ability to undergo H-bonding.Hence alkylsulphonamido derivative of phenylepherine was found to retain activity.

SO2CH3HN

CH CH2NHCH3

OH

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Bioisostere increase target interaction and Bioisostere increase target interaction and selectivityselectivity

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EtO2S

N

NC2H5

OMe

O N

H

NEt

N

OMe

EtO2SSultopride

DU122290

-Pyrrole ring has used as a non-classical isostere for an amide -Sultopride Dopamine antagonist leads to its antagonist activity as selectivity towards the D3 receptor over the D2 receptor.

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Bioisosteres for polar groupBioisosteres for polar group

For example carboxylic acid is a highly polar group which can ionize and hindered the absorption of any drug containing it.

To overcome this problem, replacement of carboxylic acid with bioisostere which has similar physicochemical properties.

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5-Substituted tetrazole – Most popular bioisostere for the carboxylic acid.

tetrazole contain an acidic proton and are ionized at pH 7.4.

Tetrazole anaion is 10 times more lipophilic than a carboxylic acid and drug absorption is enhanced as a result

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Drug

O

O

H

NN

NN

Drug

HCarboxylic acid 5-Substiuted tetrazole

H- acidic proton

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Bioisostere to increase absorptionBioisostere to increase absorption

-Biphenyl structure a. inhibit the angiotensin II receptor and had potential as an antihypertensive agent.

-It shows poor absorption through gut wall.

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N

N

COOH

Cl

OH

MeNH

NN

N

N

NCl

OH

Me

Repacement of COOH with tetrazole ring leads to losartan

a. losartan

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Monovalent isosteric replacementMonovalent isosteric replacement

- Substitution of hydrogen with fluorine is one of the most common isosteric replacements.

- Sterically H and F are quite similar with their vanderwalls reddi being 1.2 and 1.35 respectively.

- F is most elecronegative- H replace with F alter the biological activity- Ex.development of 5 flurouracil from uracil

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Uracil 5-Flurouracil (antineoplastic agent)

NH

NH

O

H

O

NH

NH

O

F

O

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Tetravalent isosteric replacementTetravalent isosteric replacement

Ex. Alpha tocopherol –reduce cardiac damage due to myocardial infraction.

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O

XOH

CH3

X= C14H29

Replacement of X with X= N(CH3)3 Shows similar activity

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Replacement of Methyl by ChlorineReplacement of Methyl by Chlorine

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Me S NH

NH(CH2)3CH3

O

O

O

Cl S NH

NH(CH2)3CH3

O

O

O

Tolbutamide Chlorpropamide

-In tolbutamide methyl group oxidized and compound may have a shorter half life.

-In chlorpropamide Chlorine may block metabolic hydroxylation and may have longer lasting.

Antidiabetics drug

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Isosteric Replacement of C for O and O for X

O

OHO

O

O

Testesterone 17α-Oxa-D-fomo-1,4 androstadine-3,17-dione

Parent Compound Bioisostere

Mammary Gland antineoplastic

Actitivity of bioisostere is similar to parent compound

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OH

OH

CH2

CH2

NH2 CH2ONH2

Dopamine Benzyloxyamine

Parent Compound Bioisostere

Activity of bioisostere not similar to parent compound

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Isosteric replacement of N for X

N

OH

NCH3

CH3

CH3

Bioisostere

OH

Parent Compound

Cholesterol 20,25-Diazaclolesterol

Bioisostere is a potent inhibitor of cholesterol synthesis

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Isosteric replacement of S for X

OH

S

H

2-Thia-A-nor-5α –androstan17β-ol

BioisostereOH

H

Parent Compound

Activity of parent compound- High order of androgenic activity

17β-Hydroxy-5 α-androst-2-ene

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Isosteric Replacement of Si for C

Si

CH2CH2CH3

CH3

(CH2O2CNH2)2C

CH2CH2CH3

CH3

(CH2O2CNH2)2

Parent Compound Bioisostere

Meprobamate

Silameprobamate

Activity of bioisostere is similar to parent compound

Drug act as a Tranquilizer

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Isosreric replacement involving cylic vs noncylic analog

NCl

N

H OH

CH2N

NCl

N

H OH

CH2N

C2H5

C2H5

Amodiaquine

Amopyroquine

Antimalerial actvity

Activity of bioisostere is similsr to parent compound

Parent Compound Bioisostere

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Exchangeble gropus

CH

Cl

OCH2CH2N

CH3

CH3

N

CH OCH2CH2N

CH3

CH3

Parent Compound Bioisostere

Diphenylhydramine d-Carbinoxamine

Activity of bioisostere similar to parent compound.

Drug act as a Antihistamine

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CH2OCOCH3O

OHOH

O

F

CH2OCOCH3O

OHOH

O

Hydrocortisone acetate 9-α-flurohydrocortisone acetate

Parent Compound Bioisostere

Antiinflamatory activity

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CONCLUSIONCONCLUSION

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ReferencesReferences1)Pratrick,Graham.L., “An Introduction to Medicinal

Chemistry”, 3rd End., (International student edition) Oxford University Press 2005

2)Ashutosh Kar, “Medicinal Chemistry”, 3rd End.,New Age International Publishers,New Delhi,2005.

3)Dr.kulculkarni, V.M.,Dr. Bothara K.G., “Drug Design“,4th Edn., Nilrali Prakashan 2006.

4)William Foye ‘Princiople Of Medicinal Chemistry’3rd End.Varghese Publication.Bombay.

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5)www.springerLink.com

6)www.interscienceWilly.com

6)www.science direct.com

8)www. www.disat.unimib.it/

9) www.wikipedia.com

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