Three leflunomide metabolite analogs.
The title compounds, 1-cyano-2-hydroxy-N-[4-(methylsulfonyl)phenyl]but-2-enamide, C(12)H(12)N(2)O(4)S, PHI492, 1-cyano-2-hydroxy-N-[3-(methylsulfonyl)phenyl]but-2-enamide, C(12)H(12)N(2)O(4)S, PHI493, and N-[3-bromo-4-(trifluoromethoxy)phenyl]-1-cyano-2-hydroxybut-2-e namide , C(12)H(8)BrF(3)N(2)O(3), PHI495, are potent inhibitors of Bruton's tyrosine kinase (BTK). The molecular structures of these compounds are similar and they display similar hydrogen-bonding networks and crystal packing. Examination of the crystal-packing interaction in the three compounds reveals an alternating direction of adjacent molecules in the crystalline lattice due to intermolecular cyano-amide hydrogen bonding. PHI492, a positional isomer of PHI493, does not form intermolecular O-H.O hydrogen bonds between molecules and crystallizes in a space group different from that of PHI493 and PHI495. The aromatic ring and the amide group of each molecule form a conjugated pi-system which ensures planarity, with further stabilization gained from intramolecular O-H.O hydrogen bonds.
Ghosh
S
S
Department of Structural Biology (Drug Discovery Program), Parker Hughes Institute, 2665 Long Lake Road, Suite 330, St Paul, MN 55113, USA. sghosh@ih.org.
Jennissen
J D
JD
Zheng
Y
Y
Uckun
F M
FM
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D007555:Isoxazoles / Q000737:chemistry* / Q000378:metabolism; D000077339:Leflunomide; D008958:Models, Molecular; D008968:Molecular Conformation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D011505:Protein-Tyrosine Kinases; D000077339:Leflunomide