Synthesis and Angiotensin Converting Enzyme (ACE) inhibition activity of chalcone derivatives
Marco Bonesi, MR Loizzo, Rosa Tundis, Filomena Conforti, Francesco Menichini, Mariangela Marrelli, Giancarlo Antonio Statti, Sylvie Michel, Francesco Menichini · Planta Medica · 2007
Hypertension is a common and often progressive disorder that poses a major risk for cardiovascular and renal disease [1,2]. It is well recognized that the Renin-Angiotensin System (RAS) has an important role in cardiovascular physiology, water-electrolyte balance, and cell function. Excessive activation of this system has been considered to be a main cause of hypertension. Angiotensin Converting Enzyme (ACE) is the most important regulatory site of RAS [3]. Aldolic condensations of 3,4,5-trimethoxy-acetophenone with appropriately substituted benzaldehydes were carried for synthesize a set of chalcone derivatives with a series of substituents on the B-ring, using commercially available compounds. The in vitro ACE inhibitory activity was measured trough the cleavage of the chromophore-fluorophore labelled substrate dansyltriglycine by Angiotensin I-Converting Enzyme preparation from rabbit lung (EC 3.4.15.1) into dansylglycine, which is quantitatively measured by HPLC [4]. The most active compound was 7 (IC 50 0.219 mM), it was substituted with amino group in position R 1 and a methoxylic group in position R 2 . The high activity was conserved when the amino group was substituted with an hydroxylic group as in 4 (IC 50 0.225 mM). Chalcone 5 showed an IC 50 0.246 mM on ACE, this compound was characterized by an hydroxylic group in position R 2 and a methoxylic group in position R 1 . The absence of hydroxylic group in position R 1 as in 3 cause a reduction of ACE inhibition activity (IC 50 0.574 mM) when you compared with 4 . We believe that the current finding would be important start point for design of ACE inhibitor as new therapeutic agent. References: [1] Chalmers, J. (1999) Blood Press 8: 9. [2] Odama, U. et al. (2000) J. Clin. Hypertens. 2: 312. [3] Schricker, K. et al. (1994) Hypertension, 24: 157. [4] Elbl, G. & Wagner, H. (1991) Planta Med. 57: 137.