Fundamentals of Medicinal Chemistry

Table 4.3 Examples of isosteres. Each horizontal row represents a group of structures that are

isosteric. Classical isosteres were originally defined by Erlenmeyer as atoms, ions and molecules

with identical shells of electrons. Bioisosteres are groups with similar structures that usually exhibit

similar biological activities

Classical isosteres Bioisosteres

–CH 3 , –NH 2 , –OH, –F, –Cl

NH R NH

C

NH

C

O

R NH 2

O

O O

S

N

NO 2

N

RNR 2

C

O O O

S S

O

C C C

NH NH NH

S

NH NH

CN

N

NH

N

NO 2

+

–Cl, –SH –PH 2

–Br, Isopropyl CH

CH 3

CH 3

–CH 2 –, –NH–, –O–, –S–

–COCH 2 R, –CONHR, –COOR, –COSR

–HC¼,–N¼

In rings:–CH¼CH–, –S–
–O–, –S–, –CH 2 –, –NH–
–CH¼, –N–

in their chemical and/or physical properties (Table 4.3). As a result, they may

exhibit similar pharmacokinetic and pharmacodynamic properties. In other

words, the replacement of a substituent by its isostere is more likely to result

in the formation of an analogue with the same type of activity as the lead than

the totally random selection of an alternative substituent. However, luck still

plays a part, and an isosteric analogue may have a totally different type of

activity from its lead (see section 2.3 and Figure 4.4).

A large number of drugs have been discovered by isosteric interchanges

(Figure 4.4).

OH H

N

N

N

N

H

N

N

N

N

SH

Hypoxanthine 6-Mercaptopurine

(Antitumour agent)

Dibenzazepine drugs

(Neuroleptics)

Phenothiazine drugs

(Neuroleptics)

S

N

R

N

R

Figure 4.4 Examples of drugs discovered by isosteric replacement

INTRODUCTION OF NEW SUBSTITUENTS 77