4-Isoxazolyl-1,4-dihydropyridines: biological, theoretical, and structural studies.
Biological activity was determined for a series of seven isoxazolyldihydropyridines (IDHPs). The highest biological activity was observed for 5-alkyl-3-phenyl-IDHP (1), for which the O-endo conformation at the ring juncture between the heterocyclic rings is known in the solid state. The 3,5-dialkyl-IDHPs were intermediate in overall activity. A theoretical study of rotation about this ring juncture was performed to estimate the relative energy and barrier to rotation for the different conformers as a function of both the ring juncture between the heterocyclic rings and the esters in the 3- and 5-position of the dihydropyridine. Molecular mechanics predicts the minimum energy conformer to be O-exo-ap,ap, while quantum mechanical calculations predict O-exo-sp,sp as the minimum-energy conformer. Both methods indicate that the barrier to rotation about the heterocyclic ring juncture should be relative low, but both methods appear to overestimate the difficulty of ester rotation. A single-crystal X-ray diffractometry study of the (3,5-dimethylisoxazolyl)dihydropyridine 2 was carried out, and shows the O-endo ring juncture and sp,sp ester conformation. 2D NOESY NMR spectroscopy indicates the presence of both conformations about the ring juncture, at room temperature, as evidenced by correlations for both alkyl groups on the isoxazole with the C-2 methyl on the DHP moiety. The ap ester conformer was also evidenced by NOESY, indicating that ester interconversion must take place.
Natale
N R
NR
School of Pharmacy, State University of New York, Cooke-Hochstetter Complex, Buffalo 14260.
Triggle
D J
DJ
Palmer
R B
RB
Lefler
B J
BJ
Edwards
W D
WD
D000818:Animals; D001667:Binding, Competitive; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003460:Crystallization; D004095:Dihydropyridines / Q000378:metabolism / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000378:metabolism; D007555:Isoxazoles / Q000378:metabolism / Q000494:pharmacology*; D017275:Isradipine; D008968:Molecular Conformation; D015394:Molecular Structure; D009206:Myocardium / Q000378:metabolism; D010069:Oxadiazoles / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D007555:Isoxazoles; D010069:Oxadiazoles; D010080:Oxazoles; D017275:Isradipine