Synthesis and biological evaluation of N-alkyl-1,4-dihydroquinoline prodrugs of scutellarin methyl ester as neuroprotective agents
A series of N-alkyl-1,4-dihydroquinoline prodrugs of scutellarin methyl ester have been synthesized (4a–4f). Compared to the parent compound scutellarin, we demonstrated that these prepared compounds had higher water solubility, more appropriate logP and better stability. Importantly, compounds 4a–4e showed improved neuroprotective activity against the H2O2-induced cell death in PC12 cells, and higher cell permeability (Papp AP–BL) and lower efflux ratio were observed for compounds 4d and 4e. The optimized compound 4d was further evaluated by cerebral ischemia/reperfusion in the middle cerebral artery occlusion (MCAO) model and could decrease the neuronal cell damage in CA1 pyramidal neurons in rats, inhibit the activation of autophagy protein beclin 1 and downregulate the expression of apoptotic protein caspase-3.
Keywordsscutellarin 1,4-dihydroquinoline antioxidant activity hCMEC/D3 cell cerebral ischemia/reperfusion (I/R) injury
This work was supported by National Natural Science Foundation of China (Nos. 81260473 and 81460523), Natural Science Foundation of Guizhou Province (No. 2016-1127).
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Conflict of interest
The authors declare that they have no conflict of interest.
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