SAR of Benzodiazepines | Medicinal chemistry - Learn Pharmeasy

  Benzodiazepines are nervous system depressants. Used in the treatment of anxiety. Commonly used benzodiazepines: Alprazolam and Diazepam.

Origin of Structure

Azepine: 7 member ring with one nitrogen (azo group)
Diazepine: 7 member ring with two nitrogen (azo group)
Benzodiazepine: Benzene + Diazepine; Fused ring molecule

General Structure

• It is an three ring structure, named as A, B and C. B (diazepine) ring fused with A (Benzene) ring. C (another benzene) attached to the B ring. (AB + C).
• R - Alkyl Group; X - Electron Withdrawing group.


Ring A

• Aromatic or Heteroaromatic ring A is required for the activity.
• An electronegative substituent (like chlorine) at position 7 is required for the activity, and the more electronegative it is, the higher the activity. (eg - Diazepam)
• Positions 6, 8 and 9 should not be substitutes.


Ring B

• Position 1 - Aminoa alkyl (N-R) group is optimal for activity.
• Position 2 - Ketone group (C=O) is important for activity. 1 ans 2 position fused trazole or imidazole increases activity. eg: Midazolam.
• Position 3 - Without substitution is Optimal for activity. On 3-OH substitution, drug become polar, easily metabolized. Thus, decreased duration of action (DOA). Eg: Oxazepam
• Saturation of the 4,5-double bond or shift of it to the 3,4-position decreases activity.
• Position 5 - Phenyl ring (C ring), promotes activity.

Ring C

• Substitution of electron withdrawing in 2' (ortho) or 2',6'(diortho) leads to increases in activity. Eg: Triazolam
• But, Para (4') substitution decreases activity.