Design, synthesis and biological evaluation of edaravone derivatives bearing the N-benzyl pyridinium moiety as multifunctional anti-Alzheimer’s agents

Figures & data

Figure 1. The two moieties combined to synthesise the novel MTDLs in this study. (a) Edaravone. (b) R-substituted N-benzyl pyridinium.

Figure 2. Edaravone-N-benzyl pyridinium hybrid compounds designed and evaluated in this study. R = H, Br, F, Cl, or CH₃.

Figure 3. The active site cavity of AChE exhibiting the binding and interactions of representative compound 5f (Scheme 1). (a) Two-dimensional (2D) representation of the docked compound 5f. The close proximity of the Arg 289 residue to edaravone’s pyrazoline ring can be observed. (b) Three-dimensional (3D) representation of the docked compound 5f, showing the orientation and positing of 5f within the AChE active site cavity.

Figure 4. The active site cavity of AChE exhibiting the binding and interactions of representative compound 5c (Scheme 1). (a) 2 D representation of the docked compound 5c. Interactions with Trp 279 (PAS) and Trp 84 (CAS) can be observed. (b) 3D representation of the docked compound 5c, showing the orientation and positing of 5c within the AChE active site cavity.

Scheme 1. Synthesis pathway of the edaravone-N-benzyl pyridinium derivatives 5a–5l. Reagents and conditions: (i) HATU, DMF, DIPEA, 2 h, stirring under reflux. (ii) DMF, stirring under reflux, 4–6 h at 40–50 °C. (1) Edaravone-COOH, (2) 4-(aminomethyl) pyridine, (4) R-benzyl bromide derivatives.

Figure 5. Two major tautomeric forms of the edaravone-N-benzyl pyridinium hybrid compounds and their respective ¹H NMR chemical tautomeric shifts in deuterated solvents.

Figure 6. Overlaid ¹H NMR spectra of compound 5g in methanol-d4 (blue) and DMSO-d6 (red). (a) Singlet that represents the CH-group of the amine tautomer.

Table 1. In silico BBB predictions and IC₅₀ values (µM) of the test compounds and controls for eeAChE, eqBuChE, and DPPH⁺.

Compound	R….	AChE	BuChE	SI AChE^a	DPPH^+	BBB prediction^b
3	–	>100	>1000	n.d.	12.5	0.108
5a	H	30	>1000	>33	22.9	0.081
5b	2-F	1.2	>1000	>83	28.8	0.068
5c	3-F	4.6	926	201	25	0.064
5d	4-F	3.6	>1000	>278	11.5	0.064
5e	2-Cl	1.9	890	468	13.8	0.060
5f	3-Cl	3.3	891	270	13.1	0.055
5g	2-Br	3.5	160	46	19	0.055
5h	3-Br	>100 µM	>1000	n.d.	13.3	0.062
5i	4-Br	11.5	>1000	>87	18.1	0.056
5j	2-CH3	19.9	630	32	9.5	0.056
5k	3-CH3	69.1	>1000	>15	27.5	0.080
5l	4-CH3	95.5	>1000	>11	14.5	0.077
1	–	n.d.	n.d.	n.d.	45.7	–
Donepezil^c	–	0.006	7.14	1252	–	–
Trolox	–	n.d.	n.d.	n.d.	13.1	–
Edaravone^d	–	–	–	–	–	–

^aAChE selectivity index = IC₅₀(eqBuChE)/IC₅₀(eeAChE).

^bA value higher than 0.02 is predicted to cross the BBB using AlzPlatform’s intergrade cloud computing server^49,63.

^cIC₅₀ values of donepezil reported by reference [64].

^dIC₅₀ values of edaravone reported by reference [65].

n.d.: not determined.

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