A series of novel quinoline-
O
-carbamate derivatives was rationally designed for treating Alzheimer’s disease (AD) by multi-target-directed ligands (MTDLs) strategy. The target compounds were synthesised and evaluated by AChE/BuChE inhibition and anti-inflammatory property. The in vitro activities showed that compound
3f
was a reversible dual
ee
AChE/eqBuChE inhibitor with IC
50
values of 1.3 µM and 0.81 µM, respectively. Moreover, compound
3f
displayed good anti-inflammatory property by decreasing the production of IL-6, IL-1β and NO. In addition, compound
3f
presented significant neuroprotective effect on A
β
25-35
-induced PC12 cell injury. Furthermore, compound
3f
presented good stabilities in artificial gastrointestinal fluids, liver microsomes
in vitro
and plasma. Furthermore, compound
3f
could improve AlCl
3
-induced zebrafish AD model by increasing the level of ACh. Therefore, compound
3f
was a promising multifunctional agent for the treatment of AD.
Oleanolic acid derivative DKS26 has hypolipidemic, islet, and hepatoprotective effects. However, high lipophilicity and low water solubility led to DKS26 extremely low oral bioavailability. Herein, lipid-based nanocarriers, including lipid nanodiscs (sND/DKS26) and liposomes (sLip/DKS26), are prepared to improve DKS26 oral absorption. In comparison to free DKS26 (5.81%), the absolute oral bioavailabilities are significantly increased to 29.47% (sND/DKS26) and 37.25% (sLip/DKS26) without detectable toxicity or immunogenicity even after repeated administrations. Both sND/DKS26 and sLip/DKS26 significantly reduce the feeding glucose level and the AUC of OGTT in db/db diabetic mice. Aiding by the newly developed scFv-based nanocarrier separation methods, no intact nanocarriers are detected in blood circulation after oral administration, suggesting that both formulations are unable to penetrate the intestinal epithelium. They enhance DKS26 absorption mainly by improving intestinal cell uptake and rapid intracellular release of the payload. Since pre-existing anti-PEG is widely detected in humans, the present oral absorption pathway of both nanocarriers successfully avoids unfavorable immunological responses after interaction with anti-PEG antibodies. The application of lipid-based nanocarriers paves an efficient and safe avenue for the clinical translation and application of poorly soluble therapeutics derived from traditional Chinese medicine.
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