In vitro and in vivo biological evaluation of newly synthesized multi-target 20(R)-panaxadiol derivatives for treating Alzheimer's disease

An extensive study was performed to discover a series of novel 20( R )-panaxadiol derivatives with various substituents at the 3-OH position as nontoxic, brain-permeable, multi-target leads for treating Alzheimer's disease. In vitro analysis revealed that a compound bearing benzyl-substituted carbamate, which we denoted compound 14a , exhibited the most potent neuroprotective activity, with an EC 50 of 13.17 μM. The neuroprotective effect of compound 14a was slightly more potent than that of donepezil and much more potent than that of 20( R )-panaxadiol. Compound 14a at 7.5–120 μM exhibited low toxicity in various cell lines. In addition, compound 14a exhibited a wide range of biological activities, including inhibiting apoptosis; inducing tau hyperphosphorylation; affecting beta-amyloid (Aβ), β-secretase, reactive oxygen species, tumor necrosis factor-α, cyclooxygenase-2, and interleukin-1β production; and promoting Aβ 25-35 disaggregation. The effective permeability of compound 14a across the blood-brain barrier was 26.13 × 10 −6 cm/s, indicating that it can provide adequate exposure in the central nervous system. Further, compound 14a improved learning, memory, and novel object recognition in mice, and in vivo toxicity experiments confirmed a good therapeutic safety range. Thus, compound 14a is a promising multifunctional lead for treating Alzheimer's disease and offers new avenues for natural product-derived anti-Alzheimer's disease drugs. • Novel 20( R )-panaxadiol derivatives have been designed, synthesized, and initially evaluated neuroprotective activity. • Compound 14a exhibits multi-target profile and low-toxic brain permeability in vitro. • Compound 14a effectively alleviate pathologies caused by amyloid and tau protein. • Compound 14a exhibits disease-modifying and cognitive-enhancing effects in in vivo biological studies.