Design, synthesis and evaluation of 3,4-dihydroxybenzoic acid derivatives as antioxidants, bio-metal chelating agents and acetylcholinesterase inhibitors

Figures & data

Scheme 1. Reagents and conditions: (a): 6 M HCl, benzene, Dean-Stark distillation; (b): R₂NCOCl, CH₃CN, reflux, 12 h; (c): N,N′-bis(4-methylphenyl)carbodiimide, CH₃CN, 40 °C, 12 h; (d): 4–7, CH₃CN, 40 °C, 24–72 h.

Table 1. Antioxidant EC₅₀ values of compounds 8--11 obtained with DPPH method.

Compound	EC50^a
8	0.093
9	0.110
10	0.112
11	0.118
Trolox	0.150

^aEC₅₀: efficient concentration, moles of antioxidant per mole of DPPH needed to reduce to 50% the initial DPPH.

Figure 1. (a) UV-Vis spectral changes obtained for Fe³⁺ in presence of increasing amounts of carbamate 11; (b) Job’s plot of ΔA observed at 269 and 309 nm versus the molar ratio of the carbamate.

Table 2. Complexation of Fe⁺³, Fe⁺², Cu⁺² and Zn⁺²with carbamates 8--11.

	Fe^+3			Fe^+2			Cu^+2			Zn^+2
Compound	ΔAmax^a	X^b	n^c	ΔAmax^a	X^b	n^c	ΔAmax^a	X^b	n^c	ΔAmax^a	X^b	n^c
8	1.48	0.75	3	0.63	0.75	3	0.62	0.7	2	^d
9	1.63	0.75	3	0.88	0.8	4	0.55	0.3	0.5	0.2	0.7	2
10	1.02^e	0.75	3	0.38^e	0.75	3	0.26^e	0.75	3	0.2	0.7	2
11	1.22	0.75	3	0.41	0.75	3	0.61	0.75	3	^d

^aMaximum absorbance changes at absorption maxima.

^bMolar ratio of ligand needed to obtain ΔA_max.

^cLigand stoichiometry – molecules of ligand per metal cation.

^dNo changes observed.

^eTurbidity was observed, probably due to the formation of insoluble complexes.

Table 3. Anticholinesterase activity of carbamates 8–11.

	AChE			BChE
Compd	Ki, μM	SD, μM	r2	% inh	Conc, μM
8	5.8^a	0.4	0.945	13	100
9	6.6^b	2.4	0.983	41	100
10	18.9^b	17.0	0.986	0	100
11	1.5^b	1.1	0.958	23	100

^aNon-competitive inhibition.

^bMixed inhibition.

Figure 2. Docking conformations of carbamates 8 (yellow), 9 (blue), 10 (red) and 11 (green) in the active site of TcAChE (1EVE). The selected aminoacids are dark cyan colored.

Kozlowski H, Luczkowski M, Remelli M, Valensin D. Copper, zinc and iron in neurodegenerative diseases (Alzheimer's, Parkinson's and prion diseases). Coordin Chem Rev 2012;256:2129–41

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