The relationship between bioisosteres, substituents or group with physical or chemical properties that impart similar biological properties to a chemical structure

1. BIOISOSTERISM

2. Bioisosterism Introduction
• Bioisosteric replacement is the principle guide followed by medicinal
chemists in developing analogues of the lead compound, whether as
agonists or antagonists of biological effects.
• The parameters being changed are molecular size, steric shape, bond
angles, hybridization, electron distribution, lipid solubility, pKa, the
chemical reactivity to cell components and metabolizing enzymes and
the capacity to undergo H-bonding
• keeping in view the numerous advantageous application of
isosterism in resolving biological problems effectively.

3. BIOISOSTERISM
The relationship between bioisosteres, substituents or groups
with similar physical or chemical properties that impart similar
biological properties to a chemical compound.
 Example is aromatic rings, a phenyl -C6H5 ring can often be
replaced by a different aromatic ring such as thiophene or
naphthalene which may improve efficacy, change specificity of
binding, or reduce metabolically labile sites on the molecule,
resulting in better pharmacokinetic properties.

4. Friedman
• He proposed that bioisosterism is the phenomenon by which
compunds usually fit the broadest definition of isosteres and
possess the same type of biological activity.
• Bioisosteres are functional groups or molecules that have
chemical and physical similarities producing broadly similar
biological properties.
• In order to develop new drug, the structure of the drug is
considered to consists of two parts.

5. 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 parts are classified as follows.
• SELECTOPHORES: Those modifications which support selectivity in
action of the drug by regulating drug distribution.
• CONTACTOPHORES: The modification which by increasing penetraton,
help the drug to reach the receptor site.
• CARRER MOIETIES OR CONDUCTING MOIETIES: These moieties
increase the affinity of the drug.
• Note: The non-critical part of the drug molecule is not involved in drug
receptor interactions but is involved in passive transport of the drug

6. Critical or essential
• This happens when change or modification of the critical part of
the drug molecule will result in the change of its biological
activity.
• Note: only those groups having similar steric , electronic and
solubility characteristics can be interchanged. The study of such
group in medicinal chemistry is known as Bioisosterism.
• Example: Among antihistamines, it is always preferable to have
small compact substituents on the terminal nitrogen.

7. •Bioisosteres are classified into the
following two types
•1. Classical bioisosterism
•2. Non-classical bioisosterism

8. Classical bioisosterism
Classical bioisosteres have similarities in shape and
electronic configuration of atoms, groups, and molecules,
which they replace.
 Actual applications of bioisosteres in the successful design
of a specific given molecule interacting with particular
receptor is one glaring example, and very often either fails
or negates the biological characteristics in another

9. • Therefore, it is pertinent to state that the logical use of biological
replacement (classical or nonclassical) in the design of a new target
drug molecules is solely and significantly depend on the specific
biological system under critical investigation.
• Hence, there are no predetermined, well-established, predictable
hard and fast guidelines, or laid generalized rules that may be
useful to a medicinal chemist to affect biosteric replacement
gainfully towards improved biological activity.

10. Monovalent atoms and groups
• F, H
• OH, NH
• F, OH, NH, or CH3 for H
• SH, OH
• Cl, Br, and CF3

13. Divalent atoms an groups
• A. –O-, -NH-, -CH2-, -S-, -Se-, -Te-
• B. –COCH2-, -CONH-, -COOR, -COSR

14. Trivalent atoms and groups
A. -CH=, -N=
B. -P=, As=, -Sb=
C. The trivalent substitution of –CH= with –N= is commonly used
in the modern drug design.Substitution of the pyridinyl amino
–N= by –CH= in Mepyramine produces Chlorpheniramne
valued for its short, powerful and freedom from sedation
which is an undesirable side effects of antihistamines drugs

15. Tetravalent atoms and groups
• =N=, =C=, =P=, =As=
• In case of Acetyl choline, replacement of the quanternary
ammonium group with the phosphonium and arsonium
analogues has resulted in greater toxicity

16. Non classical bioisosterism
they do not obey the steric and electronic definition of classical
isosteres.
Also, they do not have the same number of atoms as replacement.
 Although, many of these functional moieties practically just behave as
one, they have one of the following characteristic features, such as
electronic properties
physicochemical properties
spatial arrangements
functional moiety critical for biological activity

17. Exchangeable groups

18. Cyclic vs noncyclic structure

19. Application of Non-classical Bioisosterism 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
• Alkyl sulphonamido derivatives of phenylephrine was found to retain
activity
• In a search for improved anti-hyperlipidemic agents the tetrazoyl
analogue of nicotinic acid was found to be three times as active in the
lowering blood cholesterol.
• The local anaesthetics Bupivacaine has arisen from a similar
modification of the side chain of lignocaine. The considerably
increased lipophilic properties give a product which injected between
the third and fourth lumber vertebrae produces a long lasting spinal

20. Advantages of bioisosterism
• It is used to reduce toxicity
• Change bioavailability
• Modify the activity of the lead compound
• May alter the metabolism of the lead compound
• It allows the improvement of the stability; oral absorption; membrane
permeability; absorption, distribution, metabolism and excretion
(ADME) of drug candidate, while retaining their biological properties

21. Problems in using bioisosterism replacement
in a lead compound
• Variation of alkyl substituents.
• Variation of chain length.
• Extension of structure.
• Change in ring substitution pattern.
• Variation in ring size.
• Variation in ring structure.
• Simplification.
• Rigidification