Bioorganic & Medicinal Chemistry 2010-06-01

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

Gabriel Navarrete-Vázquez, Sergio Hidalgo-Figueroa, Mariana Torres-Piedra, Jorge Vergara-Galicia, Julio Cesar Rivera-Leyva, Samuel Estrada-Soto, Ismael León-Rivera, Berenice Aguilar-Guardarrama, Yolanda Rios-Gómez, Rafael Villalobos-Molina, Maximiliano Ibarra-Barajas

Index: Bioorg. Med. Chem. 18 , 3985-91, (2010)

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Abstract

A series of 1H-benzo[d]imidazole analogues of Pimobendan, substituted at position 5 with either -CF(3) or -NO(2), were synthesized using a short synthetic route. All the nitro derivatives were potent, and exhibited a concentration- and partial endothelium-dependent vasorelaxant effects, with EC(50)s <5microM. 2-Methoxy-4-[5-nitro-1H-benzo[d]imidazol-2-yl]phenol (compound 13) was the most potent derivative of the series, showing an EC(50) value of 1.81microM and E(max) 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-CF(3) analogue (compound 8), was 19 times less potent than 13. The antihypertensive activity of compound 13 was evaluated at doses of 25, 50 and 100mgkg(-1), using spontaneously hypertensive rats (SHR), showing a statistically significant dose-dependent effect.