N-Benzylated benzimidazol-2-one derivatives: activators of large-conductance Ca2+-dependent K+ channels

4,5-Diphenyltriazol-3-ones: Openers of Large-Conductance Ca2+-Activated Potassium (Maxi-K) Channels

“…Thus far, SAR described above parallels that reported for the N-benzylated analogue 4. 19 On the basis of the observation that the methylene unit was well-tolerated, the activity observed for the N-benzylated series suggests that some flexibility exists in the binding region of the channel. 19 However, this observation does not transfer to the deannulated series as seen in compound 8 (maxi-K ) 109%) with the corresponding pattern of "methylene" insertion.…”

“…19 On the basis of the observation that the methylene unit was well-tolerated, the activity observed for the N-benzylated series suggests that some flexibility exists in the binding region of the channel. 19 However, this observation does not transfer to the deannulated series as seen in compound 8 (maxi-K ) 109%) with the corresponding pattern of "methylene" insertion. Similarly, neither its regioisomeric counterpart 9 (maxi-K ) 84%) nor two other methylene-inserted analogues, imidazole 19 and oxadiazolone 21, were found to possess channel-opening ability (although the nature of the heterocycle may be influencing the loss of channel-opening activity for the latter compounds).…”

“…20,21 Elucidation of structureactivity relationships (SAR) indicated that electron deficient substituents on the aromatic ring fused to the heterocycle were important to the pharmacophore and revealed that the inserted methylene unit was welltolerated. 19 Similarly, electron deficient 3-hydroxyoxindoles have also demonstrated significant increases in maxi-K current expressed in ooyctes, 22 and the development of a pharmacophore model has led to identification of flavanoids as maxi-K openers. 23 In an effort to further explore and develop maxi-K opener chemotypes, we sought to deannulate the benzimidazolone ring system (Figure 1) to the 4,5-diphenyl heterocyclic system 5 (n ) 0), and homologue (n ) 1), and examine this area of the pharmacophore by systematic variation of the heterocyclic nucleus.…”

Potassium Channel Openers: The Case of BK Channel Activators

“…This effort provided a set of BKopeners with comparable pharmacological properties (1) (Fig. (1) [49] [50] and demonstrated some possible flexibility in the binding region of the receptor. A further optimisation has been attempted by using the molecular complication strategy, as shown by the potent bioisosteric oxindole eutomer 2 [51] and analogues [52] (Fig.…”

Potassium Hydroxide/Dimethyl Sulfoxide Promoted Intramolecular Cyclization for the Synthesis of Benzimidazol-2-ones

“…They can exhibit a wide range of biological activities including, for example, inhibitions of the respiratory syncytial virus (RSV) fusion and the non-nucleoside reverse transcriptase (NNRT) . Furthermore, benzimidazol-2-one derivatives play important roles as progesterone receptor antagonists, in the selective inhibition of farnesyltransferase (FTase), and the activation of K + channels . Challenged by the demand, various synthetic approaches toward those interesting compounds have been developed, most of them using benzene-1,2-diamines as key intermediates.…”