Design, synthesis and evaluation of novel 2-butyl-4-chloroimidazole derived peptidomimetics as Angiotensin Converting Enzyme (ACE) inhibitors.
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.
Organic Chemistry Division-II, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
Anvesh
A
Jallapally
Organic Chemistry Division-II, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
Dinesh
D
Addla
Department of Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
Pankaj
P
Bagul
Centre for X-Ray Crystallography, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
Balasubramanian
B
Sridhar
Department of Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
Sanjay K
SK
Banerjee
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.
Srinivas
S
Kantevari
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001552:Benzazepines / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004656:Enalapril / Q000737:chemistry / Q000494:pharmacology; D004847:Epithelial Cells; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D017706:Lisinopril / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry*; D011485:Protein Binding; D000077583:Quinapril; D017257:Ramipril / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000737:chemistry / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001552:Benzazepines; D007093:Imidazoles; D057786:Peptidomimetics; D044005:Tetrahydroisoquinolines; D004656:Enalapril; D017706:Lisinopril; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A; D017257:Ramipril; D000077583:Quinapril; C044946:benazepril
Amino acids; Angiotensin Converting Enzyme; Cytotoxicity; Imidazole; Inhibitors