Chemistry Reference
In-Depth Information
Though bioisosteres are classically used by medicinal chemists to improve
potency, selectivity, bioavailability and/or metabolic stability, to decrease side
effects or even to achieve patentability. Bioiosteric replacements can also result in
compounds with reduced structural complexity and, consequently, better synthetic
accessibility. This can be achieved by improving structural stability, for example,
when an ester group is replaced by an amide (Fig.
7
), which is more resistant to
chemical hydrolysis, or when a methyl group of an ethanoate ester is replaced
with NH
2
(Fig.
4
), thus generating an urethane functional group [40].
O
O
O
O
R
2
R
2
R
2
R
2
A)
B)
R
1
O
R
1
H
H
3
C
O
H
2
N
O
Ester
Amide (isostere)
Methyl
Amino (isostere)
Figure 7:
Isosteric replacement of (
A
) an ester with an amide and (
B
) a methyl with an amino group.
Bioisosterism also can be helpful to adapt the structure of a compound to a more
feasible or commercially convenient synthesis. In the synthesis of pteridine
analogues designed as anticancer agents, the authors synthesized analogue
I
in
three steps from commercial 2,4-dihydroxy-5,6-diaminopyrimidine (Fig.
8
). To
obtain its bioisostericsurrogate
II
(that in fact proved to be more active than
I
itself), the synthesis was accomplished in only one step starting from
commercially available 2,4-diamino-6,7-dimethylpteridine [41].
OH
OH
N
N
N
N
HN
HN
ON
N
H
HN
N
N
H
I
II
S
NH
N
N
HN
HN
OH
OH
+
+
H
2
N
H
2
N
ON
H
HN
N
H
Commercial
S
NH
2
OO
HN
+
O
N
H
NH
2
O
NH
2
HN
O
H
NH
2
Commercial
Figure 8:
Syntheses of pteridine analogues designed as anticancer agents [41].
