SAR OF BENZODIAZEPINE

By

Somnath Mondal

M.Pharm (Pharmacology) Pharmacovigilance Associate Calcutta School of Tropical Medicine Kolkata, India

R1
1

O
2 3

A
R7
7 6 5

C
The term benzodiazepine derived from Chlordiazepoxide consists of composed of a seven-membered 1,4 diazepine ring (B) And an aryl substituent ring (C) `
Hence the term, the term aryl-1,4-benzodiazepines.

6 membered a benzene ring (A) fused to

The Benzodiazepine activity (Sedative, &hypnotic, anticonvulsant & anxiolytic ) may be affected by the following: I. Modification in Ring A
8 7

CH2
9 1

A
6

O
II. Modification of Ring B
3

B
5

N 4

C
III. Modification of Ring C

I.Modification in Ring A
Position 7 (R7) of ring A has the most influence on the structure 8 activity relationship of the compound.
At this position

electron withdrawing substitution i.e heavier halogen, CF3, NO2, CN etc.) increased the activity.

R7

A
6

N
5

2 3

N 4

- stacking van der waals of C7 electronegative group most probably is responsible for increasing activity.
CH3
N O
CH2

CF3

N
N Cl

O N Cl

CH2

Cl

Halazepam

Diazepam

Prazepam

Electron withdrawing substitution ( preferably chlorine in most of the compounds) evidencing the fact.

Electron donating group [-CH3, -CH2CH3,-CH(CH3)2] at position 7 decreased the activity.

Substitution at position 6, 8 & 9 both by electron withdrawing or electron donation group decreased the activity.

II. Modification in Ring B

1. Position 1 (R1) :
Substituents at this position tolerant of substituents hence does not affect the activity in great extent. If the substituents is methyl (CH3) there is evidence of increase in activity. If it is larger than CH3 there are evidence of variable of their effect in terms of duration of action.
8

R1
9 1

A
6

O
3

R7

B
5

N4

CH3

Methyl group
O

Cyclopropyl methyl

Trifluoro-1-ethyl
CF3

N
Cl

CH2

CH2

N
Cl
Diazepam Prazepam

N
N

O
Cl

N
N

Halazepam

Longer-lasting action.

Shorter lasting action.

The pharmacological properties of this drug are basically the same.

2. Position 2 :
Carbonyl group at this position is responsible for the potency of the compound as because replacement of this carbonyl group with two hydrogen decreased the potency of the compound. R7
8 7

R1
9 1

A
6
5

O
3

N4

3. Position 3 :
Modification of this position is having diversified impact on activity.
a) Introduction 0f (OH) group at this position , changes the pattern of activity.

H N

O
N
OH

b) Introduction of carbonyl group in this position increases duration of

activity.

H OK

N C l Chlorazepate
N

OH COOK Cl

Cl
Lorazepam

Cl

Exhibits shorter-lasting action

Long-acting tranquilizers

c) Alkyl substitution at 3rd position decrease the activity.

4.Position 4 :
8

R1
9 1

A
6
5

O
3

R7

N4

The N(4) usually substituted with a low electron density group.

4,5 double bond is saturated or shift to 3,4th position decrease the activity

5.Position 5 :
A phenyl substitution at position 5
its activity. Hetroatomic or cycloalkyl (cyclo hexenyl) groups .,generally reduced the activity is more satisfactory for

III. Modification of Ring C

A phenyl group at 5th position promotes the activity.
Not required for in vitro binding but is for in vivo efficacy 4 very sensitive to substitution.

An electron withdrawing (Fluorine or chlorine) group in ortho or di ortho position increase the activity. (Eg. Lorazepam, Flurazepam).