Design, synthesis, and structural investigations of novel (S)-amide derivatives as promising ACE inhibitors
Aisha Saddiqa, Cenk A. Andac, Osman Serdal Cakmak, Iqtrab Babar, Faiza Akhtar · Kuwait Journal of Science · 2024
Novel derivatives of potential angiotensin converting enzyme (ACE-I) inhibitors (compounds 5a-e ) were synthesized by reacting homophthalic anhydride with methyl esters of L-amino acids (L-isoleucine, L-phenylalanine, L-tyrosine, L-methionine, and L-serine). This reaction resulted in yields of 85% for compound 5a , 83% for compound 5b , 84% for compound 5c , 80% for compound 5d , and 85% for compound 5e . All the synthesized compounds were characterized by 1D and 2D NMR methods. In silico ADME properties of compounds 5a-e conform to Lipinski's drug rules. The in silico toxicological determination of the synthesized compounds suggest that compound 5a exhibits significant potential for adverse effects, such as causing hormonal imbalances. In comparison, the remaining compounds 5b-c demonstrate a lower risk profile. In silico biological activities of compounds 5a-e in the active site of ACE-I were determined by docking, which were then compared to the FDA approved antihypertensive drugs enalalapril and lisinopril. Docking studies revealed that compound 5b (ΔG comp = −8.851 kcal/mol) possesses the greatest binding affinity in the Zn 2+ binding site of ACE-I compared to those of lisinoprilat (ΔG comp = −8.066 kcal/mol) and enalapril (ΔG comp = −7.187 kcal/mol), strongly suggesting a great potential to be a lead candidate for novel antihypertensive drug development. • The methyl esters of (S)-amino acids 4a–e were synthesized. • Homophthallic acid 1 is converted into its respective anhydride 2. • The reaction between esters 4a–e and anhydride 2 created new derivatives 5a-e that could block ACE. • The molecular docking studies of the chiral derivatives 5a-e showed their ACE inhibitory potential.