Novel heterocyclic inhibitors of matrix metalloproteinases: three 6H-1,3,4-thiadiazines.
The title compounds, (2S)-N-[5-(4-chlorophenyl)-2,3-dihydro-6H-1,3,4-thiadiazin-2-ylidene]-2-[(phenylsulfonyl)amino]propanamide, C18H17ClN4O3S2, (I), (2R)-N-[5-(4-fluorophenyl)-6H-1,3,4-thiadiazin-2-yl]-2-[(phenylsulfonyl)amino]propanamide, C18H17FN4O3S2, (II), and (2S)-N-[5-(5-chloro-2-thienyl)-6H-1,3,4-thiadiazin-2-yl]-2-[(phenylsulfonyl)amino]propanamide, C16H15ClN4O3S3, (III), are potent inhibitors of matrix metalloproteinases. In all three compounds, the thiadiazine ring adopts a screw-boat conformation. The molecules of compound (I) show a short intramolecular N(Ala)-H...N(exo) hydrogen bond [N...N 2.661 (3) A] and are linked into a chain along the c axis by N(endo)-H...S(endo) and N(endo)-H...O(Ala) hydrogen bonds [N...S 3.236 (3) and N...O 3.375 (3) A] between neighbouring molecules. In compound (II), the molecules are connected antiparallel into a chain along the a axis by N(exo)-H...O(Ala) and N(Ala)-H...N(endo) hydrogen bonds [N...O 2.907 (6) and N...N 2.911 (6) A]. The molecules of compound (III) are dimerized antiparallel through N(exo)-H...N(endo) hydrogen bonds [N...N 2.956 (7) and 2.983 (7) A]. The different hydrogen-bonding patterns can be explained by an amido-imino tautomerism (prototropic shift) shown by different bond lengths within the 6H-1,3,4-thiadiazine moiety.
Schröder
J
J
Universität Bielefeld, Fakultät für Chemie, Abteilung Biochemie I, 33615 Bielefeld, Germany.
Wenzel
H
H
Stammler
H G
HG
Stammler
A
A
Neumann
B
B
Tschesche
H
H
D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006860:Hydrogen Bonding; D061965:Matrix Metalloproteinase Inhibitors; D015394:Molecular Structure; D013829:Thiadiazines / Q000737:chemistry* / Q000494:pharmacology
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D013829:Thiadiazines