Design, synthesis and evaluation of novel 2-butyl-4-chloroimidazole derived peptidomimetics as Angiotensin Converting Enzyme (ACE) inhibitors

Anvesh Jallapally; Dinesh Addla; Pankaj Bagul; Balasubramanian Sridhar; Sanjay K Banerjee; Srinivas Kantevari

doi:10.1016/j.bmc.2015.04.024

Design, synthesis and evaluation of novel 2-butyl-4-chloroimidazole derived peptidomimetics as Angiotensin Converting Enzyme (ACE) inhibitors

Bioorg Med Chem. 2015 Jul 1;23(13):3526-33. doi: 10.1016/j.bmc.2015.04.024. Epub 2015 Apr 16.

Authors

Anvesh Jallapally¹, Dinesh Addla¹, Pankaj Bagul², Balasubramanian Sridhar³, Sanjay K Banerjee², Srinivas Kantevari⁴

Affiliations

¹ Organic Chemistry Division-II, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
² Department of Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
³ Centre for X-Ray Crystallography, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
⁴ Organic Chemistry Division-II, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India; Academy of Council and Scientific Research, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India. Electronic address: kantevari@yahoo.com.

PMID: 25922179
DOI: 10.1016/j.bmc.2015.04.024

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiotensin-Converting Enzyme Inhibitors / chemical synthesis*
Angiotensin-Converting Enzyme Inhibitors / pharmacology
Antihypertensive Agents / chemical synthesis*
Antihypertensive Agents / pharmacology
Benzazepines / chemistry
Benzazepines / pharmacology
Catalytic Domain
Cell Line, Tumor
Cell Survival / drug effects
Drug Design
Enalapril / chemistry
Enalapril / pharmacology
Epithelial Cells
HEK293 Cells
Humans
Imidazoles / chemical synthesis*
Imidazoles / pharmacology
Lisinopril / chemistry
Lisinopril / pharmacology
Molecular Docking Simulation
Peptidomimetics / chemical synthesis*
Peptidomimetics / pharmacology
Peptidyl-Dipeptidase A / chemistry*
Protein Binding
Quinapril
Ramipril / chemistry
Ramipril / pharmacology
Structure-Activity Relationship
Tetrahydroisoquinolines / chemistry
Tetrahydroisoquinolines / pharmacology

Substances

Angiotensin-Converting Enzyme Inhibitors
Antihypertensive Agents
Benzazepines
Imidazoles
Peptidomimetics
Tetrahydroisoquinolines
Enalapril
Lisinopril
ACE protein, human
Peptidyl-Dipeptidase A
Ramipril
Quinapril
benazepril