Synthesis Of4-alkyl-7-substituted Acetamido-2H-benzo[B][1,4]Oxazin-3(4H)-one Derivatives And Their Platelet Aggregation Inhibition Activity

The4-ethyl-7-(2-(4-phenylpiperazin-1-yl)acetamido)-2H-benzo[b][1,4]oxazin-3(4H)-one (6a),4-ethyl-7-(2-(4-(2-fluorophenyl)piperazin-1-yl)acetamido)-2H-benzo[b]1,4]oxazin-3(4H)-one (6b),4-ethyl-7-(2-(4-(4-fluorophenyl)piperazin-1-yl)acetamido)-2H-benzo[b][1,4]oxazin-3(4H)-one (6c),4-ethyl-7-(2-(4-benzylpiperazin-1-yl)acetami-do)-2H-benzo[b][1,4]oxazin-3(4H)-one(6d),4-ethyl-7-(2-(morpholin-4-yl)acetamido)-2H-benzo[b][1,4]oxazin-3(4H)-one (6e),4-ethyl-7-(2-(4-methylpiperazin-1-yl)aceta-mido)-2H-benzo[b][1,4]oxazin-3(4H)-one (6f),4-propyl-7-(2-(4-phenylpiperazin-1-yl) acetamido)-2H-benzo[b][1,4]oxazin-3(4H)-one(6g),4-propyl-7-(2-(4-(2-fluorophenyl) piperazin-1-yl)acetamido)-2H-benzo[b][1,4]oxazin-3(4H)-one(6h),4-propyl-7-(2-(4-(4-fluorophenyl)piperazin-1-yl)acetamido)-2H-benzo[b][1,4]oxazin-3(4H)-one(6i),4-propyl-7-(2-(4-benzylpiperazin-1-yl)acetamido)-2H-benzo[b][1,4]oxazin-3(4H)-one (6j),4-propyl-7-(2-(morpholin-4-yl)acetamido)-2H-benzo[b][1,4]oxazin-3(4H)-one (6k),4-propyl-7-(2-(4-methylpiperazin-1-yl)acetamido)-2H-benzo[b][1,4]oxazin-3(4H)-one (61),4-isopropyl-7-(2-(4-phenylpiperazin-1-yl)acetamido)-2H-benzo[b][1,4]oxazin-3(4H)-one (6m),4-isopropyl-7-(2-(4-(2-fluorophenyl)piperazin-1-yl)acetamido)-2H-benz-o[b][1,4]oxazin-3(4H)-one(6n),4-isopropyl-7-(2-(4-(4-fluorophenyl)piperazin-1-yl)a-cetamido)-2H-benzo[b][1,4]oxazin-3(4H)-one (6o),4-isopropyl-7-(2-(4-benzylpiperaz-in-1-yl)acetamido)-2H-benzo[b][1,4]oxazin-3(4H)-one(6p),4-isopropyl-7-(2-(morph-olin-4-yl)acetamido)-2H-benzo[b][1,4]oxazin-3(4H)-one (6q),4-isopropyl-7-(2-(4-me-thylpiperazin-1-yl)acetamido)-2H-benzo[b][1,4]oxazin-3(4H)-one (6r),4-butyl-7-(2-(4-phenylpiperazin-1-yl)acetamido)-2H-benzo[b][1,4]oxazin-3(4H)-one (6s),4-butyl-7-(2-(4-(2-fluorophenyl)piperazin-1-yl)acetamido)-2H-benzo[b][1,4]oxazin-3(4H)-one (6 t),4-butyl-7-(2-(4-(4-fluorophenyl)piperazin-1-yl)acetamido)-2H-benzo[b][1,4]oxazin-3(4H)-one (6u),4-butyl-7-(2-(4-benzylpiperazin-1-yl)acetamido)-2H-benzo[b][1,4]o-xazin-3(4H)-one(6v),4-butyl-7-(2-(morpholin-4-yl)acetamido)-2H-benzo[b][1,4]oxa-zin-3(4H)-one (6w),4-butyl-7-(2-(4-methylpiperazin-1-yl)acetamido)-2H-benzo[b][1,4]oxazin-3(4H)-one (6x), were synthesized by introducing condensation, reduction and Smiles rearrangement. All the desired compounds were easily prepared from commercial materials in moderate to good yields, and they were purified by melting point determination, TCL identification,1H NMR,13C NMR and HRMS.All the synthesized compounds were assayed on the platelet aggregation inhibition effect, compared with controlled drug, and were investigated on the SAR. The results showed that all the compounds had good anti-platelet aggregation activity induced by ADP, and the inhibition effect was positively correlated with concentration. The compound6f and6u showed the strongest inhibition effect in all the new synthetic compounds, and their IC50values were8.93μmol·L-1and8.67μmol·L-1, respectively, closed to aspirin, the positive control. The n-octanol/water partition coefficient of all the compounds was measured by a shake-flask method, and the results indicated that the relevance of partition coefficient and the inhibitory effect. The experiment initially concluded that n-octanol/water partition coefficient was a key factor affecting drug absorption, as well as they provided important information for the reasonable design of drugs in the future.In addition, we tried to find the interactions of compound6f and6u with GPIIb/IIIa receptor through molecular docking studies, to propose their plausible bind mode against the active site of GPIIb/IIIa receptor. The research demonstrated that these set of compounds could be the GPIIb/IIIa antagonist for that they could be situated in the binding site of GPIIb/IIIa receptor quite well. Compounds6f and6u, which have the most potent antiaggregatory activity, can serve as lead compounds for the next generation of platelet inhibition agents, making use of established binding modes and SAR.