eng URI http://hdl.handle.net/10795/3345 φυσικές επιστήμες χημεία ιατρικές επιστήμες ασθένεια του νευρικού συστήματος προσομοίωση φαρμακευτική 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. 19 pp. LOMv1.0 creator LOMv1.0 publisher LOMv1.0 Scientific Coordinator LOMv1.0 Project Executing Organisation 2013-01-02 Digital Library of the Operational Programme "Education and Lifelong Learning" abstract types Text AT1 receptor blockers N,N′-Bis-alkylated butylimidazole analogs Synthesis Wittig reaction Hydroxymethylation Structure elucidation Docking studies Molecular dynamics Biological evaluation 1983417 application/pdf http://repository.edulll.gr/edulll/bitstream/10795/3345/2/3345_1.153_%ce%94%ce%97%ce%9c_2_1_13.pdf URI http://hdl.handle.net/10795/3345 LOMv1.0creator 2016-05-23T11:49:11Z LOMv1.0validator 2016-05-23T11:49:11Z LOMv1.0 gre no no Copyright EYD-EPEDBM (Operational Programme "Education and Lifelong Learning")