A SEMINAR ON

BIOISOSTERISM AND ISOSTERISM

Presented byMr. Swapnil R. Bhalerao M.Pharm II Sem.

Guided byProf. S. V. Amrutkar

Department of Pharmaceutical Chemistry

M.G.Vs Pharmacy College, Panchvati, Nashik - 03
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Content

Introduction 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. Conclusion References
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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.

Drug Discovery, Design and Development

-Drug discovery without a Lead.

Eg. Penicillins,Librium.
Lead discovery-Random Screening. Non-random Screening. Drug Metabolism Studies. Clinical approach.

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.

Drug Development. Optimization of Lead

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

Why Lead Modification is Necessary?

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

ISOSTERISM AND BIOISOSTERISM IMPORTANT TOOL IN LEAD MODIFICATION

Isosterism and Bioisosterism

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

IsostereLangnmuir in 1919 define iosstere asCompound 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 )

Langnmuir
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Bioisostere

Dr.Alferrd Burger

. 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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Bioisosteric Replacement.Why?

-Greater selectivity
-Less side effects -Deceased toxicity -Improved pharmakokinetics -Increase stability
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Why Bioisosterism?
Me CH2OH Me

Me Si

CH2OH Me

Majantol-Strong fresh floral aq.aldegydic odour

Me Ge CH2OH Me

Sila majantol-more terpineol like odour

Germa majantol-weak and not characteric odour All lily of the valley flower

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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
1.Classical bioisosteresa.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 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 Examplesa.Halogens- Cl,F,Br b.Ethers- R-O-R,-Sc.Hydroxy group- -OH d.Carboxylic acid group- R-COOH,R-SOOH HO e.CatecholHO
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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 physicochemical 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.
OH
CH HO

OH
CH

CH2

NHCH3

CH2

NHCH3

SO2CH3HN

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.

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Bioisostere increase target interaction and selectivity

N O N N OMe EtO2S C2 H5

NEt N H OMe

Sultopride
EtO 2S 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 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 O N N Drug N Drug N O 5-Substiuted tetrazole Carboxylic acid H H
H- acidic proton
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Bioisostere 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.
Cl N OH N Me COOH
Me N N OH N N N NH Cl

a.

losartan

Repacement of COOH with tetrazole ring leads to losartan

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Monovalent 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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O HN O
Uracil

H
HN

O F N H

N H

5-Flurouracil (antineoplastic agent)

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Tetravalent isosteric replacement

Ex. Alpha tocopherol reduce cardiac damage due to myocardial infraction.
HO H3C O X

X= C14H29

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

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Replacement of Methyl by Chlorine

O Me S O H N NH(CH2)3CH3 O
Cl O S O H N NH(CH2)3CH3 O

Tolbutamide
Antidiabetics drug

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.
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Isosteric Replacement of C for O and O for X

Parent Compound
OH

Bioisostere
O O

Testesterone

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

Mammary Gland antineoplastic Actitivity of bioisostere is similar to parent compound

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Parent Compound

Bioisostere

HO

C C NH2 H2 H2

CH2ONH2
Benzyloxyamine

HO Dopamine

Activity of bioisostere not similar to parent compound

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Isosteric replacement of N for X

Parent Compound Bioisostere
H3C N CH3 N CH3

HO

HO

Cholesterol

20,25-Diazaclolesterol

Bioisostere is a potent inhibitor of cholesterol synthesis

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Isosteric replacement of S for X

Parent Compound
OH
OH

Bioisostere

17-Hydroxy-5 androst-2-ene

2-Thia-A-nor-5 androstan17-ol

Activity of parent compound- High order of androgenic activity

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Isosteric Replacement of Si for C

Parent Compound
CH2CH2CH3 C (CH2O2CNH2)2

Bioisostere
CH2CH2CH3 Si CH3 (CH2O2CNH2)2

CH3 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

Parent Compound
H N OH CH2 N C2H5 Cl N
Cl N

Bioisostere
C2H5
H N OH CH2 N

Amopyroquine

Amodiaquine

Antimalerial actvity Activity of bioisostere is similsr to parent compound

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Exchangeble gropus
N

Parent Compound
CH3 CH OCH2CH2 N CH3

Bioisostere
CH3 CH Cl OCH2CH2 N CH3

Diphenylhydramine

d-Carbinoxamine

Activity of bioisostere similar to parent compound. Drug act as a Antihistamine

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Parent Compound
O HO CH2OCOCH3 OH

Bioisostere
O HO CH2OCOCH3 OH

F
O

Hydrocortisone acetate

9--flurohydrocortisone acetate

Antiinflamatory activity
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CONCLUSION

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References
1)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 Chemistry3rd 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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