| Title : Identification of aplysinopsin as a blood-brain barrier permeable scaffold for anti-cholinesterase and anti-BACE-1 activity - Nuthakki_2020_Bioorg.Chem_107_104568 |
| Author(s) : Nuthakki VK , Yadav Bheemanaboina RR , Bharate SB |
| Ref : Bioorg Chem , 107 :104568 , 2020 |
| Abstract : Aplysinopsins are a group of marine-derived indole alkaloids that display diverse array of pharmacological effects. However, their effect on anti-Alzheimer targets has not been reported. Herein, we report the synthesis of aplysinopsin (1) and its effect on cholinesterases and beta-site amyloid-precursor protein cleaving enzyme 1 (BACE-1). It inhibits electric eel acetylcholinesterase (AChE), equine serum butyrylcholinesterase (BChE), and human BACE-1 with IC(50) values of 33.9, 30.3, and 33.7 microM, respectively, and excellent BBB permeability (P(e) 8.92 x 10(-6) cm/s). To optimize its sub-micromolar activity, the first-generation analogs were prepared and screened. Two most active analogs 5b and (Z)-8g were found to effectively permeate the BBB (P(e) > 5 x 10(-6) cm/s). The N-sulphonamide derivative 5b display better cholinesterase inhibition, whereas the other analog (Z)-8g strongly inhibits BACE-1 (IC(50) 0.78 microM) activity. The analog 5b interacts primarily with PAS of AChE, and thus exhibit a mixed-type of inhibition. In addition, aplysinopsin along with new analogs inhibited the self-induced Abeta(1-42) aggregation. The data presented herein indicate that the aplysinopsin-scaffold holds a potential for further investigation as a multi-targeted anti-Alzheimer agent. |
| ESTHER : Nuthakki_2020_Bioorg.Chem_107_104568 |
| PubMedSearch : Nuthakki_2020_Bioorg.Chem_107_104568 |
| PubMedID: 33418314 |
Nuthakki VK, Yadav Bheemanaboina RR, Bharate SB (2020)
Identification of aplysinopsin as a blood-brain barrier permeable scaffold for anti-cholinesterase and anti-BACE-1 activity
Bioorg Chem
107 :104568
Nuthakki VK, Yadav Bheemanaboina RR, Bharate SB (2020)
Bioorg Chem
107 :104568