Nantenine as an acetylcholinesterase inhibitor: SAR, enzyme kinetics and molecular modeling investigations

Figures & data

Figure 1.  Clinically available AChE inhibitors.

Figure 2.  Structures of known aporphinoid AChE inhibitors (5, 6 and 7) and nantenine (8).

Scheme 1.  Synthesis of target analogs 15a-15b. Reagents and conditions: (a) Pd(PPh₃)₄, DME, K₂CO₃, reflux, 24h; (b) CH₃NO₂, NH₄OAc, reflux, 4h; (c) LiBH₄, TMSCI, THF, reflux; (d) HCOOEt, Et₃N, DCM for 14a; (e) acetyl chloride, Et₃N, DCM for 14b; (f) POCl₃, MeCN, 50°C, 12h; (g) NaBH₄, MeOH, 0°C, 4h; (h) HCNO, NaBH(OAc)₃, DCM, rt, 24h.

Figure 3.  Other seco-ring C nantenine analogs.

Table 1.  AChE inhibitory activity of analogues.

Compound	IC50 AChE (μM)^a
Nantenine (8)	1.09 ± 0.17
15a	2.63 ± 0.38
15b	2.38 ± 0.21
16	18.06 ± 1.92
17	> 100^b
Galanthamine^c	0.53 ± 0.11

^aResults are the mean of three replications (± SEM of three experiments).

^bConsidered inactive

^cReference compound.

Figure 4.  Lineweaver-Burk steady-state inhibition plot showing mixed inhibition for nantenine.

Figure 5.  Dixon plot. (Intercept on the x- axis is -K_i).

Table 2.  ICM docking scores for nantenine (8) and galanthamine (1) in AChE.

Pose number^a	ICM docking scores	Binding site
1	−59.2	Catalytic
2	−55.09	Catalytic
3	−53.9	Catalytic
4	−53.75	PAS
5	−53.56	Catalytic
6	−53.4	Catalytic
7	−52.61	PAS
8	−52.56	PAS
9	−52.31	PAS
10	−51.43	Catalytic
Galanthamine	−59.52^b	Catalytic

^aranked in order of increasing energy

^btop score which corresponds to the lowest energy in ICM

Figure 6.  A is an ICM model of nantenine in the catalytic site of AChE. Pose shown is for lowest energy conformation (pose number 1 in Table 2) and B the LigPlot model of nantenine in the catalytic site of AChE.

Figure 7.  A is an ICM model of nantenine in the PAS of AChE. Pose shown is for the lowest energy conformation in the PAS (pose number 4 in Table 2) and B is the LigPlot model of Nantenine in the PAS.

Table 3.  ICM predicted binding sites for 15a, 16 and 17.

Compound	Pose number	ICM scores	Binding site^a
15a^b	1	−60.84	Catalytic
	2	−57.93	Catalytic
	3	−56.9	Catalytic
16^c	1	−69.7	PAS
	2	−68.14	Catalytic
	3	−67.75	PAS/Catalytic
17	1	−85.27	–
	2	−84.49	–
	3	−84.34	−

^aCatalytic site or PAS

^bTop nine binding poses were in catalytic site, tenth in PAS

^cBinding poses four to ten are in PAS