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摘要
The synthesis, toxicity, neuroprotection, and human acetylcholinesterase (hAChE) / human butyrylcholinesterase (hBuChE) inhibition properties of beta-naphthotacrines 1-14 as new drugs for Alzheimer%26apos;s disease (AD) potential treatment, are reported. beta-Naphthotacrines 1-14 showed lower toxicity than tacrine; moreover, at the highest concentration assayed (300 mu M) compounds 7, 10 and 11 displayed 2.25-2.01-fold higher cell viability than tacrine in HepG2 cells. A neuroprotective effect was observed for compounds 10 and 11 in a neuronal cortical culture exposed to a combination of oligomycin A/rotenone. An efficient and selective inhibition of hAChE, was only observed for the beta-naphthotacrines bearing electron-donating substituents at the aromatic ring, beta-naphthotacrine 10 being the most potent (hAChE: IC50 = 0.083 +/- 0.024 mu M). Kinetic inhibition analysis clearly demonstrated that beta-naphthotacrine 10 behaves as a mixed-type inhibitor (K-i2 = 0.72 +/- 0.06 mu M) at high substrate concentrations (0.5-10 mu M), while at low concentrations (0.01-0.1 mu M) it behaves as a hAChE competitive inhibitor (K-i1 = 0.007 +/- 0.001 mu M). These findings identified beta-naphthotacrine 10 as a potent and selective hAChE inhibitor in a nanomolar range, with toxicity lower than that of tacrine both in human hepatocytes and rat cortical neurons, with a potent neuroprotective activity and, consequently, an attractive multipotent active molecule of potential application in AD treatment.
- 出版日期2013-6
