posted on 2005-12-29, 00:00authored byMarkus Pietsch, Michael Gütschow
A series of thieno[1,3]oxazin-4-ones and thieno[1,3]thiazin-4-ones were synthesized and
investigated as inhibitors of the α/β hydrolases cholesterol esterase (CEase) and acetylcholinesterase (AChE). The introduction of a cycloaliphatic five- or six-membered ring fused at
the thiophene was favorable for CEase inhibition. Such compounds were analyzed as true
alternate substrate inhibitors. 6,7-Dihydro-2-(dimethylamino)-4H,5H-cyclopenta[4,5]thieno[2,3-d][1,3]oxazin-4-one (33) exhibited a Ki value of 630 nM and excelled in its low susceptibility
to CEase-catalyzed degradation. Compound 33 and its analogues did not inhibit AChE. The
introduction of a tetrahydropyrido ring with bulky hydrophobic substituents at the basic
nitrogen provided inhibitors of AChE which were completely inactive toward CEase. 7-Benzyl-5,6,7,8-tetrahydro-2-(N-3,4-dimethoxybenzyl-N-methylamino)-4H-pyrido[4‘,3‘:4,5]thieno[2,3-d][1,3]oxazin-4-one (21) had the IC50 value of 330 nM for AChE inhibition. A residual enzymatic
activity at an infinite inhibitor concentration and thus a catalytically active ternary enzyme−substrate−inhibitor complex was concluded. To specify kinetic parameters of inhibition, a new
method was derived to characterize selected thieno[1,3]oxazin-4-ones as hyperbolic mixed-type
inhibitors of AChE.