Dibenzothiazepinones as potential calcium channel antagonists. I

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Structural Chemistry

Background:

• Dibenzo[a,d]cycloheptenes and dibenzo[b,e]thiepins are known potent calcium channel antagonists.
• Antagonist potency correlates with a decreased angle between aromatic ring planes, as predicted by computational studies.

Purpose of the Study:

• To synthesize and evaluate novel dibenzo[b,f]-1,4-thiazepinones as potential bioisosteres of known calcium channel antagonists.
• To investigate the relationship between the flexure angle of these new compounds and their calcium channel antagonistic activity.

Main Methods:

• Synthesis of a series of 10-[omega-[4-(4-fluorophenyl)piperazin-1-yl]alkyl]dibenzo[b,f]-1,4-thiazepin-11(10H)-ones (compounds 10-14).
• X-ray diffraction analysis to determine the crystal structure and flexure angle of the parent dibenzo[b,f]-1,4-thiazepinone (compound 4).
• Evaluation of synthesized compounds for calcium channel antagonistic activity using hamster aorta assays.

Main Results:

• The parent dibenzo[b,f]-1,4-thiazepinone (4) exhibits a flexure angle of 108.4 degrees, with a planar amide moiety due to electron delocalization.
• The synthesized dibenzo[b,f]-1,4-thiazepinones (10-14) were evaluated for their calcium channel antagonistic effects.
• Results of the bioactivity assays on hamster aorta are presented for compounds 10-14.

Conclusions:

• Dibenzo[b,f]-1,4-thiazepinones represent a promising class of compounds for developing new calcium channel antagonists.
• The structural modifications, including the flexure angle, are key factors influencing the calcium channel antagonistic activity.
• These findings support the potential of dibenzo[b,f]-1,4-thiazepinones as bioisosteres in drug design for cardiovascular therapies.