Synthesis and L-type calcium channel blocking activity of new chiral oxadiazolothiazinones

• We identified new oxadiazolothiazinones active as L-type calcium channel blockers.
• They are negative inotropic agents and relax nonvascular smooth muscle.
• Compound 3b showed the highest negative inotropic potency (EC50 = 0.006 μM).
• Compound 3a was the most active on ileum and highly stereoselective.
• They hold the same absolute configuration-optical rotation relationship, (S)-(+)/(R)-(−).

Oxadiazolo[3,4-c][1,4]thiazin-3-ones are cardiovascular agents that block L-type calcium channels. Previous data of cardiac and vasorelaxant activity on guinea-pig for several derivatives indicated the two positions ortho to the thiazine's sulphur as crucial for modulating the activity; but these positions are likely susceptible to metabolic biotransformations, as indicated by in silico predictions. We designed new derivatives, and obtained three negative inotropic agents with EC50 in the low nanomolar range, more potent than all the precursors published so far. In particular, benzocondensation at the thiazine ring led to 3a (EC50 = 0.013 μM) and 3b (EC50 = 0.006 μM). Besides negative inotropy, we also observed relaxant activity on nonvascular muscle in the micromolar range. We resolved the new derivatives by chiral chromatography, and determined their absolute configuration by comparing experimental and calculated chiroptical properties (VCD, ECD and ORD): they hold the same absolute configuration-optical rotation relationship, (S)-(+)/(R)-(−). Both cardiac and nonvascular activity are majorly or mostly retained in the R-form for all the compounds, but for the nonvascular activity we observed a strong stereoselectivity for 3a, with the R-form in the nanomolar range (IC50 = 0.020 μM) and 259-fold more potent than the S-one.

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