Abstract
Targeting to the synthesis of potent dual acting COX/LOX inhibitors as future anti-inflammatory drugs, we attempted a modification of the compounds based on docking analysis results. A substitution of the oxygen of the oxo-group of the oxazin-2-one ring by sulphur resulted in a four to over ten fold improvement of COX and LOX inhibitory action. N-phenyl derivatives exhibited the best biological properties with the 4-methoxy-phenyl derivative showing the best COX-1 and LOX inhibitory action and the 4-Br-phenyl derivative exhibiting the best COX-2 inhibitory action combined with good COX-1 and LOX inhibitory capacity.
Highlights
We reported previously the synthesis and biological activity evaluation of a new series of Nsubstituted pyrazolo-oxazin-2-one compounds on the basis of PASS prediction results
Positive COX-1 inhibition activity predicted by PASS was confirmed by experimental evaluation[22] the compounds exhibited only mild inhibitory action
Docking results Docking of the oxo- and thioxo- derivatives of compound 4f into the COX-1 active site are presented as an example of the influence of the oxygen to sulfur replacement in complex stabilization
Summary
Positive COX-1 inhibition activity predicted by PASS was confirmed by experimental evaluation[22] the compounds exhibited only mild inhibitory action. All novel compounds and their oxo- analogues[22] were tested for COX-1 as well as COX-2 and LOX inhibitory action. The absence of the p-methoxy-group in the phenyl-derivative, 4d, resulted in diminished activity (IC50=17.8 M) while the presence of a pmethyl- substituent as well as a methylene-bridge between the phenyl and the oxazinone rings in compounds 4e and 4c further reduced inhibitory action (IC50 : 21.4 M and 25.0 M respectively).
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