Synthesis and adrenergic activity of benzimidazole bioisosteres of norepinephrine and isoproterenol

Abstract

The concept of bioisosterism between benzimidazole and catechol was applied to the design and synthesis of benzimidazole analogues of norepinephrine, (R,S)-1-[5(6)-benzimidazolyl]-2-aminoethanol (2), and of isoproterenol, (R,S)-1-[5(6)-benzimidazolyl]-2-isopropylaminoethanol (4). Compound 2 was shown to be a partial bioisostere of norepinephrine, with direct agonist activity at the alpha-adrenergic receptor. The ED50 for 2 in contracting the guinea pig isolated aortic strip was determined to be 8.0 x 10(-6) M. Compound 4 was shown to be a partial bioisostere of isoproterenol, with direct activity as a beta-adrenergic agonist. The ED50 values for positive chronotropic and inotropic effects of 4 on the isolated guinea pig atrial preparation were determined to be 6.2 x 10(-6) and 3.8 x 10(-6) M, respectively. The ED50 for 4 on the isolated guinea pig tracheal preparation was determined to be 1.6 x 10(-6) M. These results indicate that 4 shows greater selectively for the beta-2 adrenergic receptor than does isoproterenol. The chemical stability of benzimidazole, compared with that of catechol, suggests that benzimidazole bioisosteres of catecholamines may be of value as adrenergic drugs.

QseC MediatesSalmonella entericaSerovar Typhimurium VirulenceIn VitroandIn Vivo

“…Contradictory data concerning NE/Epi enhancement of motility were reported by Merighi et al (60), suggesting that Epi did not play a role in enhancement of motility in WT Salmonella serovar Typhimurium. However, it is worth noting that in vitro NE and Epi are photosensitive and labile compounds that quickly decompose in solution (4). The labile nature of these compounds could be responsible for the variation described in the previous motility studies.…”

Synthetic Utility of Catalytic Fe(III)/Fe(II) Redox Cycling Towards Fused Heterocycles: A Facile Access to Substituted Benzimidazole, Bisbenzimidazole and Imidazopyridine Derivatives

“…Prepared from 4-acetamido-3-nitrobenzaldehyde 25 and 4-(4-methyl-1-piperazinyl)-1,2-benzenediamine using Method B (84% yield); >300 °C.…”

“…Literature methods were followed for the preparation of 4-(4-methyl-1-piperazinyl)-1,2-benzenediamine (1), 12b-e 3,4-diaminobenzyl alcohol, 19 2-imidazolecarboxaldehyde, 18 1-methyl-4-nitro-2-pyrrolecarboxaldehyde, 24 and 4-acetamido-3-nitrobenzaldehyde. 25 Anhydrous CH 3 CN and DMF were distilled from BaO prior to use according to standard practices. The 1 H-and 13 C NMR spectra were obtained with a Bruker AMX-300 or AVANCE-500 spectrometers.…”

The Recognition of Unrelated Ligands by Identical Proteins

“…11,53,54 Meanwhile, medicinal chemists have long used bioisosteres to exchange topologically unrelated functional groups. Well-known examples include the replacement of carboxylates with tetrazoles, hydroxamic acids, and isoxazoles, 55 the replacement of benzene with thiophene, 19 the replacement of catechols with benzimidazoles, 56 and the replacement of phosphates with salicylates or isothiazolidinones. 20 Of the 76 pairs of protein−ligand complexes studied (152 total complexes), 32 reflected such bioisosteric swaps.…”