Design, synthesis, and structural investigations of novel (S)-amide derivatives as promising ACE inhibitors

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 Zn²⁺ 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.