title: Rational design, efficient syntheses and biological evaluation of N,N'-symmetrically bis-substituted butylimidazole analogs as a new class of potent Angiotensin II receptor blockers.
abstract: A series of symmetrically bis-substituted imidazole analogs bearing at the N-1 and N-3 two biphenyl moieties ortho substituted either with tetrazole or carboxylate functional groups was designed based on docking studies and utilizing for the first time an extra hydrophobic binding cleft of AT1 receptor. The synthesized analogs were evaluated for their in vitro antagonistic activities (pA2 values) and binding affinities (-logIC50 values) to the Angiotensin II AT1 receptor. Among them, the potassium (-logIC50 = 9.04) and the sodium (-logIC50 = 8.54) salts of 4-butyl-N,N'-bis{[2'-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl}imidazolium bromide (12a and 12b, respectively) as well as its free acid 11 (-logIC50 = 9.46) and the 4-butyl-2-hydroxymethyl-N,N'-bis{[2'-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl}imidazolium bromide (14) (-logIC50 = 8.37, pA2 = 8.58) showed high binding affinity to the AT1 receptor and high antagonistic activity (potency). The potency was similar or even superior to that of Losartan (-logIC50 = 8.25, pA2 = 8.25). On the contrary, 2-butyl-N,N'-bis{[2'-[2H-tetrazol-5-yl)]biphenyl-4-yl]methyl}imidazolium bromide (27) (-logIC50 = 5.77) and 2-butyl-4-chloro-5-hydroxymethyl-N,N'-bis{[2'-[2H-tetrazol-5-yl)]biphenyl-4-yl]methyl}imidazolium bromide (30) (-logIC50 = 6.38) displayed very low binding affinity indicating that the orientation of the n-butyl group is of primary importance. Docking studies of the representative highly active 12b clearly showed that this molecule has an extra hydrophobic binding feature compared to prototype drug Losartan and it fits to the extra hydrophobic cavity. These results may contribute to the discovery and development of a new class of biologically active molecules through bis-alkylation of the imidazole ring by a convenient and cost effective synthetic strategy.
authors: Department of Chemistry, University of Patras, 26500 Patras, Greece. aggelisgeorge@hotmail.com
authors: George
authors: G
authors: Agelis
authors: Amalia
authors: A
authors: Resvani
authors: Catherine
authors: C
authors: Koukoulitsa
authors: Tereza
authors: T
authors: Tůmová
authors: Jiřina
authors: J
authors: Slaninová
authors: Dimitra
authors: D
authors: Kalavrizioti
authors: Katerina
authors: K
authors: Spyridaki
authors: Antreas
authors: A
authors: Afantitis
authors: Georgia
authors: G
authors: Melagraki
authors: Athanasia
authors: A
authors: Siafaka
authors: Eleni
authors: E
authors: Gkini
authors: Grigorios
authors: G
authors: Megariotis
authors: Simona Golic
authors: SG
authors: Grdadolnik
authors: Manthos G
authors: MG
authors: Papadopoulos
authors: Demetrios
authors: D
authors: Vlahakos
authors: Michael
authors: M
authors: Maragoudakis
authors: George
authors: G
authors: Liapakis
authors: Thomas
authors: T
authors: Mavromoustakos
authors: John
authors: J
authors: Matsoukas
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011789:Quantum Theory; D013329:Structure-Activity Relationship
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles