As part of our program toward designing potassium channel openers, the synthesis of a novel series of substituted benzanilides and their vasodilating activity are presented. The facile synthetic pathway generally involves coupling between the appropriate benzoyl chloride and commercial available anilines, followed by the selective or non-selective cleavage of methyl ether substituent(s), affording the corresponding phenol or bisphenol derivatives. The pharmacological evaluation of these structurally novel potential BK-openers on vascular contractile activity was studied in vitro, using isolated rat aortic rings pre-contracted with KCl 20 mM. Some derivatives were found to be potent smooth muscle relaxants and the vasodilation effects of these compounds were inhibited by tetraethylammonium (TEA) and iberiotoxin (IbTX), suggesting that the opening of BK channels is prevalent in the mechanism of action of these compounds. The best compound of the series was N-(2-hydroxy-5-phenyl)-(2-methoxy-5-chloro)-benzamide (16b) showing a full vasorelaxant efficacy and almost nanomolar potency index.