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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.
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.
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.
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
activity.
H OK
N C l Chlorazepate
N
OH COOK Cl
Cl
Lorazepam
Cl
Long-acting tranquilizers
4.Position 4 :
8
R1
9 1
A
6
5
O
3
R7
N4
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
An electron withdrawing (Fluorine or chlorine) group in ortho or di ortho position increase the activity. (Eg. Lorazepam, Flurazepam).