ABSTRACT
A series of phosphonate analogues related to perindopril and ramipril were prepared and tested to estimate their ability to inhibit angiotensin converting enzyme. These new synthesized compounds were active ACE inhibitors with a promising activity.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/chemistry , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Organophosphonates/chemistry , Perindopril/analogs & derivatives , Perindopril/pharmacology , Ramipril/analogs & derivatives , Ramipril/pharmacology , Angiotensin-Converting Enzyme Inhibitors/chemical synthesis , Angiotensin-Converting Enzyme Inhibitors/metabolism , Binding Sites , Catalytic Domain , Enzyme Activation/drug effects , Humans , Molecular Docking Simulation , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism , Perindopril/chemical synthesis , Perindopril/metabolism , Protein Binding , Ramipril/chemical synthesis , Ramipril/metabolism , StereoisomerismABSTRACT
Tris(hydroxymethyl) aminomethane (tris) salt of API ramipril was synthesized, and characterized by FTIR, TG-DSC and ab initio X-ray powder structure analysis. The compound, ramipril-tris (II), crystallizes in the monoclinic space group P2(1) with a=24.3341(15), b=6.4645(5), c=9.5357(7) Å, ß=96.917(3)° and V=1489.1(3) Å(3). The crystal structure has been determined from laboratory X-ray powder diffraction data using direct space global optimization strategy (simulated annealing) followed by the Rietveld refinement. A network of intermolecular OH O, CH N and CH O hydrogen bonds between the ramipril-ramipril, tris-tris and ramipril-tris components in the compound generates a two-dimensional molecular assembly in (110) plane. A comparative study of solid-state stabilities of ramipril-tris (II) with that of ramipril (I) and ramipril-erbumine (III) indicates that ramipril-tris (II) is the most stable one among the three, and the conversion to impurity D after 72 h at 80 °C is only 1.5%. The solution phase analysis at different pH values also reveals a greater stability of ramipril-tris (II) over ramipril (I).
