THE OVERVIEW OF STUDIES ON HUPERZINE A: A NATURAL DRUG FOR THE TREATMENT OF ALZHEIMER’S DISEASE - Medicinal Chemistry of Bioactive Natural Products - page 161

4.6.3 Studies on the Structure-Activity Relationship

4.6.3.1 Synthetic ( )-HA Analogs
The powerful bioactivities of HA attracted the attention of scientists for its SAR.
Series of HA analogs were generated by adding, omitting, or modifying substituents
of HA by Kozikowski et al., 98,108-113 He et al., 114,115 Kaneko et al., 116 Zeng
et al., 117 Zhou and Zhu, 118 and Hogenauer et al. 119,120 These HA analogs are listed
in Figure 4-2, which were modified on the quinolinone ring (19a-e, 20-22),
exocyclic ethylidene (23a-i, 24a-d), primary amino (25a-k), three-carbon bridge
ring (26a-f, 27a-f), and multiplicate moieties (28a-h). AChE IC 50 value tests on
many HA analogs disclosed that they were far less active than racemic HA. Further-
more, although C-10 axial methyl (27b), C-10 dimethyl (27a), and ( )-C-10

a . R=H
b . R=Et
c . R=Cl (0.8 µM)
d . R=CH 2 OH (8.1 µM)
e . R=CO 2 Et (400

a . R 1 =R 2 =H
b . R 1 =R 2 =OH
c . R 1 =H, R 2 =OH;
d . R 1 =H, R 2 =NH 2 ;
e . R 1 =NH 2 , R 2 =H;

R 1

H

N

O R 2

R µ M)

NH 2

NH 2

f . R=CN (489 M)

g . R=CH 2 NH 2 (17.2 µM)
h . R=CF 3 (2

µ

(racemic)- 19

H

(racemic)- 23

H

M)
i . R=CH 2 F (0.6

µ

H

µ M) N

N O

H

N

S

a . R 1 =H, R 2 =Me (6 µM)
b . R 1 =H, R 2 =Et
c . R 1 =R 2 =F
d . R 1 + R 2 =(CH 2 ) 2

O

N NH 2 NH 2

O

( racemic)- 21

R 2 (racemic)- 20

NH 2

H a . X=Y=Me

b . X=H, Y=Me
c . X=Me, Y=H
d . X=H, Y=Et
e . X=H, Y=n-Pr
f . X+Y=CH 2

R 1

X

N

(racemic)- 24

O

a . R=CH 2 NH 2
b . R=CH 2 N 3
c . R=CH 2 OH
d . R=CH 2 NHCOOMe (200 µM)
e . R=Me
f . R=NMe 2 (0.8 µM)
g . R=NHCOOMe (8.1 µM)
h . R=OH
i . R=F
j . R=H (2.0 µM)
k . R=H, E-isomer (12.3 µM)

Y

NH 2

H

(racemic)- 27

N

O

NH 2

S

R

N

(racemic)- 25

NH 2

(racemic)- 22

a . R 1 =H, R 2 =Me
b . R 1 =Et, R 2 =Me
c . R 1 =Ph, R 2 =Me (800 µM)
d . R 1 =CN, R 2 =Me
e . R 1 =CH 2 F, R 2 =Me (0.2 µM)
f . R 1 =CF 3 , R 2 =Me (0.4 µM)
g . R 1 =R 2 =CF 3 (4 µM)
h . R 1 =R 2 =H (282 µM)

R 2

R 1

R 1

R 3 H

H

a . R 1 =Me, R 2 =R 3 =H (0.9 M)

b . R 1 = R 3 =H, R 2 =Me (1.63

µ

N

N

O µ M)

O

c . R 1 = R 2 =R 3 =H (9.82

M)
d . R 1 =NH 2 , R 2 =R 3 =H (8.14

µ R 2

NH 2

NH 2

µ M)

(racemic)- 26

e . R 1 = R 3 =H, R 2 =NH 2 , (467

µ M) (racemic)- 28

f . R 1 =H, R 2 +R 2 =CH 2

Figure 4-2. Racemic HA analogs (part IC 50 values in parentheses).