Captopril and its dimer captopril disulfide: comparative structural and conformational studies.
The crystal structures of captopril {systematic name: (2S)-1-[(2S)-2-methyl-3-sulfanylpropanoyl]pyrrolidine-2-carboxylic acid}, C(9)H(15)NO(3)S, (1), and its dimer disulfide metabolite, 1,1'-{disulfanediylbis[(2S)-2-methyl-1-oxopropane-3,1-diyl]}bis-L-proline, C(18)H(28)N(2)O(6)S(2), (2), were determined by single-crystal X-ray diffraction analysis. Compound (1) crystallizes in the orthorhombic space group P2(1)2(1)2(1), while compound (2) crystallizes in the monoclinic space group P2(1), both with one molecule per asymmetric unit. The molecular geometries of (1) and (2) are quite similar, but certain differences appear in the conformations of the five-membered proline rings and the side chains containing the sulfhydryl group. The proline ring adopts an envelope conformation in (1), while in (2) it exists in envelope and slightly deformed half-chair conformations. The conformation adopted by the side chain is extended in (1) and folded in (2). A minimum-energy conformational search using Monte Carlo methods in the aqueous phase reveals that the optimized conformations of the title compounds differ from those determined crystallographically, which depend on their immediate environment. Intermolecular O-H...O and relatively weak C-H...O interactions seem to be effective in both structures and, together with S-H...O and C-H...S contacts, they create three-dimensional networks.
Institute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Łódź, Poland.
Joanna
J
Bojarska
Institute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Łódź, Poland.
Waldemar
W
Maniukiewicz
Institute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Łódź, Poland.
Andrzej
A
Fruziński
Institute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Łódź, Poland.
Lesław
L
Sieroń
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University Bratislava, Odbojarov 10, SK-832 32 Bratislava, Slovakia.
Milan
M
Remko
D002216:Captopril / Q000031:analogs & derivatives* / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D008968:Molecular Conformation
D002216:Captopril; C035974:captopril disulfide
angiotensin-converting enzyme (ACE) inhibitors; captopril; captopril disulfide; conformational search; crystal structure; hydrogen-bond motifs; theoretical calculations