Fig. 1

Design concept for rivastigmine and NAP analogues as well as chemical structures and synthesis of phenols. a Hydrolysis of rivastigmine and designed rivastigmine analogues by cholinesterases (ChEs). We hypothesised that rivastigmine analogues containing one or two additional hydroxy groups on the aromatic ring would react with the ChE active-site serine, releasing polyphenolic analogues of NAP, which possesses the anti-Aβ fibrillation property of polyphenols such as epigallocatechin gallate (EGCG). The carbamylated serine is identical to that formed by rivastigmine; hence, we hypothesised that the rivastigmine analogues would also cause pseudo-irreversible inhibition of ChEs. b Chemical structures of racemic NAP (1) and NAP analogues (2–7). Red indicates hydroxy group/s added to the NAP structure. NAP 226–90 is the (S)-enantiomer of compound 1. (c) Synthesis of racemic NAP (1) using a previously unreported synthetic route. Reagents and conditions: (i) NH₂OH·HCl, triethylamine, MeOH, reflux; (ii) 10 wt % Pd/C, H₂, MeOH, rt; (iii) 10 wt% Pd/C, H₂, HCHO (40 vol % aq. solution), MeOH, rt; (iv) 32 wt% aq. HCl, MeOH, rt. d Synthesis of NAP analogues 2–7. Reagents and conditions: (i) BF₃-etherate/NaI, MeCN, rt; (ii) BBr₃, CH₂Cl₂, −5 °C; (iii) TBDMS-Cl, DMAP, imidazole, CH₂Cl₂, 0 °C to rt; (iv) NH₂OH·HCl, triethylamine, MeOH, reflux; (v) 10 wt% Pd/C, H₂, MeOH, rt; (vi) 10 wt% Pd/C, H₂, HCHO (40 vol % aq. solution), MeOH, rt; (vii) 32 wt% aq. HCl. MeOH, rt. Yields and substituents are described in Table 1