Synthesis, vasorelaxant activity and antihypertensive effect of benzo[d]imidazole derivatives

A series of 1H-benzo[d]imidazole analogues of Pimobendan, substituted at position 5 with either –CF3 or –NO2, were synthesized using a short synthetic route. All the nitro derivatives were potent, and exhibited a concentration- and partial endothelium-dependent vasorelaxant effects, with EC50s <5 μM. 2-Methoxy-4-[5-nitro-1H-benzo[d]imidazol-2-yl]phenol (compound 13) was the most potent derivative of the series, showing an EC50 value of 1.81 μM and Emax of 91.7% for ex vivo relaxant response in intact aortic rings, resulting in a 2.5-fold higher activity compared to Pimobendan. The closely related 5-CF3 analogue (compound 8), was 19 times less potent than 13. The antihypertensive activity of compound 13 was evaluated at doses of 25, 50 and 100 mg kg−1, using spontaneously hypertensive rats (SHR), showing a statistically significant dose-dependent effect.

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