Docking Studies and Biological Activity of Fosinopril Analogs

The purpose of the present study was to determine the angiotensin-I converting enzyme inhibitory activity of few novel Fosinopril derivatives which were predicted to possess better ACE inhibitory activity and lesser side effects than the existing drug molecule. In vitro study was carried out to determine ACE inhibitory activity of six different Fosinopril analogs by spectrophotometric assay procedure. Analog A2 showed the highest activity compared to other analogs and as well as Fosinopril itself. Docking studies of the compounds were done with the help of VLife MDS 3.0 software using GRIP batch docking method to find out which derivative had a better docking with ACE. The compounds which showed the highest negative score in docking have also exhibited good ACE inhibitory activity. 1. Introduction Angiotensin converting enzyme (ACE, EC 3.4.15.1) inhibitors work by inhibiting the action of angiotensin converting enzymes, thus preventing the conversion of angiotensin to angiotensin-II. ACE inhibitors are widely used in the treatment of hypertension as well as heart failure [1, 2]. Fosinopril is the first and only phosphonate containing ACE inhibitor. The search for ACE inhibitors that lacked the sulfhydryl group leads to the investigation of phosphorus containing compounds. The phosphinic acid is capable of binding to ACE in a manner similar to enalapril. The interaction of the zinc atom with the phosphinic acid is similar to that seen with sulfhydryl groups [3, 4]. Additionally, this compound is capable of forming the ionic, hydrogen, and hydrophobic bonds. A feature unique to this compound is the ability of the phosphinic acid to more truly mimic the ionized, tetrahedral intermediate of peptide hydrolysis. Structural modifications to investigate more hydrophobic, C-terminal ring systems, lead to a 4-cyclohexylproline analog of the original phosphinic acid. This compound, Fosinoprilat, was more potent than captopril but less potent than enalaprilat. Fosinoprilat proved to have the same problem as enalaprilat and other carboxylate-containing ACE inhibitors like poor bioavailability. The solution fortunately was very similar—the addition of a hydrophobic side chain to modulate the ionization characteristics of the molecule—thus Fosinopril was developed. Fosinopril is administered as a prodrug and is converted in vivo to the active form Fosinoprilat (Scheme 1). Scheme 1: Interaction of Fosinopril with ACE [ 4]. 2. Results and Discussion 2.1. Chemistry Fosinopril containing analogs of trans-4-phenyl-L-proline (A1), 1,2,3,4-tetrahydro