Background: Discovery of novel agents with anticoagulant and antioxidant activity is
very important to treat cerebrovascular disease. Lead compound LR3d discovered in our laboratory
exhibited stronger anticoagulant ability and good antioxidant activity, compared with scutellarein
(2), which is the major in vivo active metabolite of the natural product scutellarin (1).
Objective: Design and synthesis novel scutellarein derivatives with improved anticoagulant and
Methods: By utilizing a scaffold hopping strategy on LR3d, we describe the design and synthesis
of a series of novel hexacyclic scutellarein derivatives 4 with a 1,3-oxazine ring fused at positions
7 and 8 in A ring. The thrombin inhibitory activities of all these new compounds were studied by
the analysis of thrombin time (TT), activated partial thromboplastin time (APTT), prothrombin
time (PT) and fibrinogen (FIB). The antioxidant abilities of these analogs were evaluated by using
3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) method through 1,1-
diphenyl-2-picrylhydrazyl radical 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl (DPPH) assay.
Results: Nine new hexacyclic scutellarein derivatives with a 1,3-oxazine ring fused at A-ring were
synthesized, the results of the biological activity evaluation showed that compound 4e exhibited
stronger anticoagulant and antioxidant ability compared to LR3d.
Conclusion: 4e could be used for further development to treat ischemic cerebrovascular disease.