Benzo[b]tiophen-3-ol derivatives as effective inhibitors of human monoamine oxidase: design, synthesis, and biological activity

Figures & data

Figure 1. (a) Molecular properties of the pharmacophore for the inhibition of the hMAOs. The part of the structure shown in red corresponds to the chalcone moiety (adapted from reference13); (b) Structure of aurone (I) and indanone (II) derivatives; (c) Benzo[b]thiophen-3-ol scaffold: similarities and differences with previously reported compounds.

Scheme 1. Synthesis of compounds PM1-PM20.

Scheme 2. Proposed mechanism of reaction.

Table 1. Inhibitory activity (IC₅₀) and selectivity index (SI) of compounds PM1-PM20 towards hMAO-A and hMAO-B.

^a Values are the mean ± SD of triplicate determinations. ^bSelectivity index for the MAO-B isoform, given as the ratio: (IC₅₀ hMAO-A)/(IC₅₀ hMAO-B).

Figure 2. Effect of the PM series of inhibitors on DOPAC/DA ratio in rat cortex synaptosomes. ANOVA: p<.0001; post-hoc: ***p<.001 vs. vehicle group. All the compounds and deprenyl were tested at the same concentrations: 20 nM, 0.1 μM, and 1 μM.

Figure 3. Effect of the PM series of inhibitors on DOPAC/DA ratio in rat cortex synaptosomes challenged with LPS. ANOVA: p<.0001; post-hoc: *p<.05, ***p<.001 vs. LPS group. All the compounds and deprenyl were tested at the same concentrations: 20 nM, 0.1 μM and 1 μM.

Figure 4. Effect of the PM series of inhibitors on LDH activity in rat cortex synaptosomes. ANOVA: p<.0001; post-hoc: *p<.05, **p<.01, ***p<.001 vs. vehicle group. All the compounds and deprenyl were tested at the same concentrations: 20 nM, 0.1 μM, and 1 μM.

Figure 5. Effect of the PM series of inhibitors on LDH activity in rat cortex synaptosomes challenged with LPS. ANOVA: p<.0001; post-hoc: *p<.05, **p<.01, ***p<.001 vs. LPS group. All the compounds and deprenyl were tested at the same concentrations: 20 nM, 0.1 μM, and 1 μM.

Table 2. IC₅₀ values in the antioxidant assays (mM).

Samples	DPPH	ABTS	FRAP	CUPRAC	Chelating ability	Phosphomolybdenum assay
PM4	1.13 ± 0.01	>5	3.04 ± 0.03	1.88 ± 0.08	2.63 ± 0.42	4.40 ± 0.07
PM5	1.20 ± 0.02	>5	3.27 ± 0.08	1.14 ± 0.04	1.74 ± 0.19	4.40 ± 0.70
PM6	1.13 ± 0.01	3.18 ± 0.40	3.11 ± 0.11	1.62 ± 0.10	1.89 ± 0.08	>5
PM9	1.31 ± 0.04	2.49 ± 0.30	>5	3.57 ± 0.11	1.97 ± 0.09	>5
PM10	1.10 ± 0.01	3.28 ± 0.44	3.50 ± 0.07	1.41 ± 0.12	2.35 ± 0.13	>5
PM12	1.11 ± 0.01	3.42 ± 0.66	3.95 ± 0.16	1.13 ± 0.06	1.55 ± 0.28	>5
PM13	1.11 ± 0.01	2.68 ± 0.75	2.74 ± 0.10	1.43 ± 0.11	4.71 ± 1.04	>5
Trolox	0.09 ± 0.01	0.15 ± 0.01	0.20 ± 0.01	0.38 ± 0.01	2.63 ± 0.42	2.17 ± 0.10
EDTA	–	–	–	–	0.05 ± 0.01	–

Figure 6. 2 D structures of the conformers/tautomers investigated by quantum-mechanics approach for each compound reported in Table 1.

Table 3. Theoretical interaction energy and its van der Waals (vdW) and Coulomb (Coul) components are reported (in kcal/mol) for each ligand-target complex.

Compounds	hMAO-A			hMAO-B
	Interaction Energy			Interaction Energy
	VdW	Coul	Total	VdW	Coul	Total
PM1	−26.91	−0.81	−27.72	−39.51	0.51	−39.00
PM2	−30.73	−0.24	−30.97	−37.60	−0.79	−38.39
PM3	−15.49	−5.59	−21.08	−45.05	−0.47	−45.52
PM4	−15.12	−4.88	−20.00	−40.88	0.02	−40.87
PM5	−33.95	−1.00	−34.94	−44.92	−0.69	−45.61
PM6	−36.02	−1.23	−37.25	−43.11	0.27	−42.84
PM7	−31.50	−1.77	−33.27	−42.08	0.72	−41.36
PM8	−16.59	−2.93	−19.51	−35.20	−1.44	−36.64
PM9	−16.87	−5.11	−21.97	−46.49	−0.80	−47.28
PM10	−18.41	−3.10	−21.50	−43.35	−0.22	−43.57
PM11	−33.83	−1.49	−35.32	−33.39	−0.40	−33.79
PM12	−19.74	−3.46	−23.20	−47.43	−0.86	−48.29
PM13	−36.96	−2.20	−39.16	−44.01	−0.27	−44.28
PM14	−20.86	−2.78	−23.63	−41.96	−4.55	−46.51
PM15	−37.63	−2.86	−40.49	−43.49	−1.47	−44.96
PM16	−35.75	−1.91	−37.66	−42.30	−0.84	−43.14
PM17	−27.60	−3.00	−30.60	−36.93	−1.22	−38.15
PM18	−38.05	−0.61	−38.66	−41.52	−1.08	−42.59
PM19	−11.88	−0.54	−12.42	−24.22	−0.48	−24.70
PM20	−26.78	−0.69	−27.47	−37.34	−1.16	−38.50

Figure 7. The most stable binding modes of PM12 in the (a) hMAO-A and (b) hMAO-B active sites, represented in grey and lilac colouring, respectively. The ligand is depicted in polytube with the carbons coloured green, the FAD cofactor is displayed in space fill and the most relevant ligand interacting amino acids are shown as thin tubes. Yellow, light blue, and orange dotted lines represent inter-molecular hydrogen bonds, π–π interactions and unfavourable contacts, respectively.

Wouters J. Structural aspects of monoamine oxidase and its reversible inhibition. Curr Med Chem 1998;5:137–62.

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