Abstract
A series of novel 2-butyl-4-chloro-1-methylimidazole derived peptidomimetics were designed, synthesized and evaluated for their Angiotensin Converting Enzyme (ACE) inhibitor activity. 2-Butyl-4-chloro-1-methylimidazole-5-carboxylic acid 2 obtained after oxidation of respective carboxaldehyde 1, was condensed with various amino acid methyl esters 3a-k to give imidazole-amino acid conjugates 4a-k in very good yields. Ester hydrolysis of 4a-k with aqueous LiOH gave the desired peptidomimetics 5a-k. Screening all the new compounds 4a-k and 5a-k using ACE inhibition assay, resulted five compounds 4i, 4k, 5e, 5h and 5i as potent ACE inhibitors with IC50 of 0.647, 0.531, 1.12, 0.657 and 0.100μM with minimal toxicity. Among them, 5i emerged as most active ACE inhibitor with greater potency than marketed drugs Lisinopril, Ramipril and relatively equipotent to Benazepril, Quinapril and Enalapril.
Keywords:
Amino acids; Angiotensin Converting Enzyme; Cytotoxicity; Imidazole; Inhibitors.
Copyright © 2015. Published by Elsevier Ltd.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiotensin-Converting Enzyme Inhibitors / chemical synthesis*
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Angiotensin-Converting Enzyme Inhibitors / pharmacology
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Antihypertensive Agents / chemical synthesis*
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Antihypertensive Agents / pharmacology
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Benzazepines / chemistry
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Benzazepines / pharmacology
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Catalytic Domain
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Cell Line, Tumor
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Cell Survival / drug effects
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Drug Design
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Enalapril / chemistry
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Enalapril / pharmacology
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Epithelial Cells
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HEK293 Cells
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Humans
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Imidazoles / chemical synthesis*
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Imidazoles / pharmacology
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Lisinopril / chemistry
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Lisinopril / pharmacology
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Molecular Docking Simulation
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Peptidomimetics / chemical synthesis*
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Peptidomimetics / pharmacology
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Peptidyl-Dipeptidase A / chemistry*
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Protein Binding
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Quinapril
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Ramipril / chemistry
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Ramipril / pharmacology
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Structure-Activity Relationship
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Tetrahydroisoquinolines / chemistry
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Tetrahydroisoquinolines / pharmacology
Substances
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Angiotensin-Converting Enzyme Inhibitors
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Antihypertensive Agents
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Benzazepines
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Imidazoles
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Peptidomimetics
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Tetrahydroisoquinolines
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Enalapril
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Lisinopril
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ACE protein, human
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Peptidyl-Dipeptidase A
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Ramipril
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Quinapril
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benazepril