The document discusses isosteres and bioisosteres, which are functional groups or molecules that have similar chemical and physical properties and broadly produce similar biological properties. It covers the introduction of isosteres by Langmuir and Grimm, the definition and utility of bioisosteres, strategies for molecular modification using bioisosteres, classification of classical and nonclassical bioisosteres, and applications of isosteres in drug design including examples of fluorine, carboxylic acid, and amide isosteres. The significance of bioisosterism in improving drug properties like potency, stability, and toxicity is also highlighted.

1. ISOSTERS & BIO-ISOSTERES:
ROLE IN MEDICINAL
CHEMISTRY
SUBMITTED BY- INDRAJIT SAMANTA
M.PHARMA, 1ST YEAR, 1ST SEM, DEPARTMENT OF
PHARMACEUTICAL CHEMISTRY, SPER, JAMIA
HAMDARD

2. CONTENTS
 INTRODUCTION
 UTILITY OF BIOISOSTERES
 STRATEGIES FOR MOLECULAR
MODIFICATION OF THE LEAD
COMPOUND
 CLASSIFICATION
 CHANGES OCCURS IN BIO-
ISOSTERS REPLACEMENT
 Application of Isosteres in Drug Design
 SUMMARY
 REFERENCE

3. INTRODUCTION
Isosterism is of vital importance to the medicinal chemists because the
biological characteristics of isosteres appear to be similar; more frequently
than physical or chemical characteristics.
Langmuir (1919):Compounds or groups of atoms having the same number of
atoms and electrons Examples: N2 and CO, N2O and CO2, N3 - and NCO-
Grimm(1925):“Hydride DisplacementLaw” additionof hydride to an atom
givesto the resultingpseudo atom' the properties of the atom with the next highest
atomic number.
22/09/202
2
ISOSTERES & BIOISOSTERES 3

4. BIOISOSTERES
IN MEDICINAL CHEMISTRY,
Bioisosteres are functional groups or molecules that have
 Similar chemical and physical properties
 Broadly produce similar biological properties
 Can attenuate toxicity, modify activity of lead, and/or alter pharmacokinetics of lead.
According to Burger bioisosteres are compounds or groups that possess
 Near equal molecular shapes and volumes
 Approximately similar distributionof electrons
 Exhibit similar physical and chemical properties
 Produce similar biological activities.
 Targeted similar biological target.
22/09/202
2
ISOSTERES & BIOISOSTERES 4

5. BIOISOSTERES
• Friedman (1951): Bio-isosteres are atoms or molecules that fit the broadest
definition for isosteres and have the same type of biological activity.
• Thornber (1979): Groups or molecules which have chemical and physical
similarities producing broadly similar biological effects.
• Parameters affected with bioisosteric replacements:
• Size, conformation,inductiveandmesomeric effects, polarizability, H-bond
formation capacity,pKa,solubility, hydrophobicity, reactivity, stability.
20XX presentation title 5

6.  Bio-isosteric replacements: Why?
• Greaterselectivity
• Lesssideeffects
• Decreasedtoxicity
• Improvedpharmacokinetics(solubility-hydrophobicity)
• Increasedstability
• Simplifiedsynthesis
•Patented lead compounds
UTILITY OF BIOISOSTERES
The utility of bio-isosteres is extending to
Improving potency
Enhancing selectivity
Alteringphysicalproperties
Reducingor redirecting metabolism
Eliminationor modifying toxico-phores
Acquiringnovel intellectualproperty

7. STRATEGIES FOR MOLECULAR
MODIFICATION OF THE LEAD COMPOUND
22/09/202
2
ISOSTERES & BIOISOSTERES 7
Analog
design
Isosteres, bioisosteres
Homolog
Ring
modification
Homo and
heterodimers
Conformational
restriction
Optical isomers

8. Aim-1.toimproveitspharmacodynamic&pharmacokineticproperties.
2.toboostthephysical,biological&pharmacologicalproperties aswellasrectifythetoxicityofleadmolecule.
22/09/202
2
ISOSTERES & BIOISOSTERES
8

9. In order to develop a new drug the structure
of the drug is considered to consist of two
parts,
• 1) Non-critical or non-essential:
• The non-critical part allows sufficient changes without a considerable change in the
biological activity. The various molecular modifications done on this non critical part
are classified as follows.
• (a) Selectophores, (b) Contactophores, (c) Carrier moieties or conducting moieties.
• Thus, non-critical part of a drug molecule is not involved in drug receptor interactions
but is involved in passive transport of the drug.
• (2) Critical or essential:
• While any change or modification of critical part of the drug molecule will result in the
change of its biological activity, only those groups having similar steric, electronic and
solubility characteristics can be interchanged.
• The study of such groups (bio-isoster) and their application in medicinal chemistry is
known as Bio-isosterism.
20XX presentation title 9

10. CLASSIFICATION
Bio-isosteres are classified into the
followingtwotypes:
1.Classicalbio-isosteres
2.Nonclassicalbio-isosteres
22/09/202
2
ISOSTERES & BIOISOSTERES
10

11. Classical bioisosteres
22/09/202
2
ISOSTERES & BIOISOSTERES 11
1) monovalent atomsor groups:
F, H ,OH, NH, F, OH, NH, or CH3 for H, SH, OH, Cl, Br, and CF3
2)divalent atomsor groups:
C=C,C=N,C=O, C=S–CH2–,–NH–,–O–,–S–
3) trivalentatomsor groups:
–CH=, –N= Nonclassical bio-isosteres are structurally distinct, usually comprise different number of
atomsandexhibitdifferentstericandelectronic properties.
4)tetrasubstitutedatoms:
=N+=, =C=, =P+=, =As+=,R4C,R4Si,R4N +
5)ringequivalent

12. 20XX presentation title 12
Classical bioisosteres
MONOVALENT ATOMS OR GROUPS EXAMPLE:
• Substitution of hydrogen with fluorine is one of the most common type of
monovalent isosteric replacement.
• Sterically hydrogen and fluorine are quite similar with Vander Waal's radius 1.2 and
1.35 A respectively.
• An example of replacement of hydrogen by fluorine is development of the
antineoplastic agent 5- Fluorouracil from uracil.
• In hypoxanthine6th positionhydroxyl . group is replaced with thiol group gives 6-
Mercaptopurine with anticancer activity.

13. 20XX presentation title 13
DIVALENT ATOMS OR GROUPS
• The replacement of -O- by -NH- group
in procaine gives procainamide.
• Procaine - Local anaesthetic
• Procainamide – antiarrhythmic
TRIVALENT ATOMS OR GROUPS:
Substitution of the pyridinyl amino -N=
by -CH= in Mepyramine produces
Chlorpheniramine valued for its short,
powerful and freedom from sedation,
which is an undesirable side effect of
antihistaminic drugs.

14. 20XX presentation title 14
 TETRASUBSTITUTED
ATOMS
In case of acetyl choline,
replacement of quaternary
ammonium group with the
phosphonium and arsonium
analogues has resulting in greater
toxicity

15. Nonclassical bio isosteres
22/09/202
2
ISOSTERES & BIOISOSTERES 15
• Nonclassicalbio isosteres are structurally distinct, usually comprise different number of atoms
and exhibit different steric and electronic properties.
Exchangeable groups:
Cyclic versus noncyclic structure:

16. 20XX presentation title 16
•Ring vs. noncyclic structures
• Estradiol isanaturallyoccurringhormone. Inthisdoublebond isplacedat aposition thatis
essential fortheparticularspatialconfigurationcriticalfortheactivity.
• Thissubstitution leadto formationof diethylstilbestrol asynthetic analogueofestradiol.
Transformhassamepotency asthatof estradiolwhereas cis-isomeris only1/14thas
activeas estradiol.

17. 20XX presentation title 17
APPLICATION OF NON- CLASSICAL
BIOISOSTERES IN DRUG DESIGN
• In the catecholamine Phenylephrine, phenolic hydroxyl group takes
part in H bonding with bioactive site on the receptor.
• The hydroxyl group can be replaced by other group having ability
to undergo H bonding.
• Hence alkyl sulphonamido derivative of Phenylephrine was found
to retain activity.

18. 20XX presentation title 18
FUNCTIONAL GROUP MODIFICATION -
Scaffold Hopping
• Bioisosterism include the replacement of the initial molecular scaffold
by a different one, keeping the same biological activity. This
approach, called scaffold hopping, is well illustrated by molecules like
diazepam, zolpidem, zaleplon, and zopiclone which exert the same
biological response acting as full agonists of GABA-A (g-aminobutyric
acid) receptor at the benzodiazepine site though being structurally
different.

19. 20XX presentation title 19
Example:

20. 20XX presentation title 20
SIGNIFICANCE OF BIOISOTERISM
• Bioisosterism is used for
Improving biological and physical properties of
the drug
Improving potency of the drug
Enhancing stability of the drug
Reducing toxicity of the drug
Improving bioavailability of the drug
Altering the metabolism on lead compound.

21. 22/09/202
2
ISOSTERES & BIOISOSTERES 21
Application of Isosteres in Drug Design
• Fluorine as an Isostere of Hydrogen:
The unique properties of fluorine have led to its widespread application in drug design as an
isostere for hydrogen, since incorporation of fluorine can productively modulate a range of
properties of interest to medicinal chemists.
Metabolic stability: block the metabolically labile site with a fluorine substituent,
hoping that the small fluorine atom will not impair the binding to the target protein.
The effect on molecular lipophilicity: A survey of 293 pairs of molecules
that differed only by a F-for-H exchange revealed that the average lipophilicity(logD) increased by
0.25 log units. But there are quite a number of cases (shown below) for which an H to F
substitution decreases lipophilicity. Metabolic stability block the metabolically labile site with a
fluorine substituent, hoping that the small fluorine atom will not impair the binding to the target
protein The effect on the pKa As the most electronegative atom, fluorine has a very strong effect
on the acidity or basicity of nearby functional groups.

22. 22/09/202
2
ISOSTERES & BIOISOSTERES 22
A close inspection of these cases revealed that all compounds were found to have at least one low-
energy conformer with an O F distance smaller than 3.1 Å.
The effect on molecular conformation:
α-fluorinated carbonyl derivatives favour a conformation in which the C-F and C=O bonds adopt a
trans orientation to align the dipoles in an antiperiplanar.
The modestly preferred(~0.4 kcal/mol) conformation of benzyl fluoride projects the C-F bond
orthogonal to the aryl ring, stabilized by donation of electron density from the aryl π-orbital into the
σ*C-F antibonding orbital

23. 22/09/202
2
ISOSTERES & BIOISOSTERES 23
Carboxylic Acid Isosteres
• Isosteres of carboxylic acid have been studied extensively. These studies have typically focused on...
• enhancing potency
• reducing polarity
• increasing lipophilicity (improve membrane permeability)
• enhancing pharmacokinetic properties
• reducing the potential for toxicity

24. 22/09/202
2
ISOSTERES & BIOISOSTERES 24
Phenol Isosteres
• Phenol and catechol isosteres were typically designed to overcome pharmacokinetic and toxicological
limitations.
• A range of useful surrogates are well-established. The structural diversity, electronic properties, lipophilicity,
and size of these functionalities varies widely, providing ample flexibility to customize for a special
application.

25. 22/09/202
2
ISOSTERES & BIOISOSTERES 25
Amide and Ester Isosteres
• Amide isosteres have typically been of interest as a means of modulating polarity and bioavailability, while
ester isosteres have frequently been developed to address metabolism issues since esters can be rapidly
cleaved in vivo.

26. 20XX presentation title 26

27. 22/09/202
2
ISOSTERES & BIOISOSTERES 27
Trifluoroethylamines As Amide Isosteres
• Amide isosteres have been focused on in the context of peptidomimetics. Many amide replacements are
known which retain the geometry of the amide bond or maintain the hydrogen bond-accepting properties
of the amide. However, there are few functional groups, which are capable of preserving the hydrogen
bond-donating properties of the amide. In this situation, trifluoroethylamines were identified as amide
isosteres.
• reducing the basicity of the amine without compromising the ability of the NH to function as a H-bond
donor
• CF3CH(R)NHR' bond is close to the 120o observed with an amide
• C-CF3 bond is as polar as C=O bond.
• application (inhibitors of cathepsin K):
The replacement of an amide with a trifluoroethylamine leads to high potency, high selectivity and metabolic
stability. The role of the CF3 group was explored in a brief SAR study.

28. 22/09/202
2
ISOSTERES & BIOISOSTERES 28
Phenyl Ring Isosteres
• Application of the bicyclo[1.1.1]pentane as a nonclassical phenyl ring bio-isostere in the design of a
potent and orally active γ-secretase inhibitor.
• SAR studies into other fluorophenyl replacements indicate the intrinsic advantage of the
bicyclo[1.1.1]pentane moiety over conventional phenyl ring isosteres with respect to achieving an optimal
balance of properties.
For further application of bicyclo[1.1.1]pentane skeleton to drug discovery:

29. 22/09/202
2
ISOSTERES & BIOISOSTERES 29
Oxetanes in Drug Discovery
• Oxetanes have recently gained attention as attractive, stable, and less lipophilic molecular for drug
discovery.

30. summary
The design and application of isosteres have inspired medicinal
chemists for almost 80 years, fostering creativity directed
toward solving a range of problems in drug design, including
understanding and optimizing drug — target interactions and
specificity, improving drug permeability, reducing or redirecting
metabolism, and avoiding toxicity.
As an established and powerful concept in medicinal
chemistry, the application of bioisosteres will continue to play an
important role in drug discovery.
Isosterism can also contribute to the productive application in
the design and optimization of catalysts in organic chemistry.
22/09/202
2
ISOSTERES & BIOISOSTERES 30

31. REFERENCES:
o Foye's Principles of medicinal chemistry- Thomas L. Lemkey, David A. Williams, Victoria F. Roche
and S. William Zito
o Berger's medicinal chemistry and drug discovery. volume 1. Drug Discovery
o Wilson and Gisvold's textbook of organic medicinal and pharmaceutical chemistry, 12th edition,
edited by John. M. Beale, Jr., John H. Block. P. Review of bioisosteres: J. Med. Chem. 2011, 54,
2529 Chem. Rev. 1996, 96, 3147
o Fluorine in medicinal chemistry: ChemBioChem 2004, 5, 637 oxetanes in drug discovery: Angew.
Chem. Int. Ed. 2010, 49, 9052
o Burger, A. A Guide to the Chemical Basis of Drug Design, NY, EUA,. Wiley, 1983; p. 24-29.
o Gaikwad PL et al., The Use of Bioisosterism in Drug Design and Molecular Modification. American
Journal of PharmTech Research 2012
o Stenlake, J. B. Fondations of Molecular Pharmacology 1979, Vol The Chemical Basis of Drug Action,
Londres, Inglaterra,Athlone Press, p. 213-290.
o www.tubakhanslideshare//slideshare.com
22/09/202
2
ISOSTERES & BIOISOSTERES 31

32. Thank you