The discovery of new potent non-peptide Angiotensin II AT1 receptor blockers: a concise synthesis, molecular docking studies and biological evaluation of N-substituted 5-butylimidazole derivatives
| Autor: | George Agelis, Jiřina Slaninová, Tereza Tůmová, Panagiotis Giannopoulos, Thomas Mavromoustakos, Amalia Resvani, Serdar Durdagi, Katerina Spyridaki, Demetrios Vlahakos, George Liapakis, John Matsoukas |
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| Rok vydání: | 2012 |
| Předmět: |
Stereochemistry
Protein Conformation Chemistry Techniques Synthetic In Vitro Techniques Receptor Angiotensin Type 1 chemistry.chemical_compound Inhibitory Concentration 50 Uterine Contraction Drug Discovery medicine Imidazole Moiety Animals Humans Hydroxymethyl Rats Wistar Pharmacology Angiotensin II receptor type 1 Organic Chemistry Uterus Imidazoles General Medicine Ligand (biochemistry) Angiotensin II Rats Molecular Docking Simulation Losartan HEK293 Cells chemistry Docking (molecular) Female Angiotensin II Type 1 Receptor Blockers medicine.drug |
| Zdroj: | European journal of medicinal chemistry. 55 |
| ISSN: | 1768-3254 |
| Popis: | A convenient and facile synthesis, in silico docking studies and in vitro biological evaluation of N-substituted 5-butylimidazole derivatives as potent Angiotensin II (ANG II) receptor type 1 (AT1) blockers (ARBs) has been reported in the current study. Our efforts have been directed towards the development of an efficient synthetic route allowing the facile introduction of substituents on the imidazole ring. In particular, a series of imidazole based compounds bearing the biphenyl moiety at the N − 1 position, a halogen atom at the C-4 and polar substituents such as hydroxymethyl, aldo or carboxy group at the C-2 position were designed and synthesized. These compounds were evaluated for binding to human AT1 receptor and for ANG II antagonism in vitro on isolated rat uterus. Among them, 5-butyl-1-[[2′-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-2-carboxylic acid (30) exhibited higher binding affinity compared to the other analogues tested (−log IC50 = 8.46). The latter analogue was also found to be the most active in the rat uterotonic test (pA2 = 7.83). Importantly, the binding affinity was higher to that of losartan (−log IC50 = 8.25) indicating the importance of carboxy group at the C-2 position. Experimental findings are in good agreement with docking studies, which were undertaken in order to investigate ligand/AT1 receptor interactions. |
| Databáze: | OpenAIRE |
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