N-substituted [phenyl-pyrazolo]-oxazin-2-thiones as COX-LOX inhibitors: influence of the replacement of the oxo -group with thioxo- group on the COX inhibition activity of N-substituted pyrazolo-oxazin-2-ones

2010 ARKIVOC  
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
more » ... he 4-Br-phenyl derivative exhibiting the best COX-2 inhibitory action combined with good COX-1 and LOX inhibitory capacity. ARKAT-USA, Inc. Scheme 2. Mechanism of synthetic root. Evaluation of biological activity Evaluation of COX-1 inhibitory action. All tested thioxo analogues exhibited COX-1 inhibitory activity, with the exception of the ethyl-derivative 4a and n-propyl-derivative 4b with IC50>200 M (Table 2) . Insertion of the bulky hydrophobic phenyl group in compounds 4c-4g strongly improved inhibitory action (IC50: 6.3 -25.0 M). The p-methoxy-phenyl-derivative 4f showed the best inhibitory activity (IC50=6.3 M). 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). Interestingly, the p-Br-phenyl derivative, 4g, exhibited better inhibitory activity (IC50=11.2 M) than the phenyl derivative, 4d (IC50=17.8 M). Six of the seven tested compounds present better inhibitory action than naproxen (IC50=125.8 M). Comparison of the results with that previously obtained for the 1,3-oxazin-2-one analogues showed a four to over thirty fold improvement of the inhibitory activity in the 1,3-oxazin-2-thione derivatives 4c-4g. Evaluation of COX-2 inhibitory action. Most compounds exhibit no COX-2 inhibitory action (IC50>200 M) (Table 2) . However, both thioxo-and oxo-4-Br-phenyl-derivatives, 4g, exhibited COX-2 inhibitory action with IC50 values 62 and 78 M respectively. Thioxo derivative 4g was slightly more active than the oxo-analogue, 4g(O), in this case, as well.
doi:10.3998/ark.5550190.0012.206 fatcat:ynxqkgigmrfbdfhz56suuvvgu4