Discovery of N-(1-(3-fluorobenzoyl)-1H-indol-5-yl)pyrazine-2-carboxamide: a novel, selective, and competitive indole-based lead inhibitor for human monoamine oxidase B

Figures & data

Figure 1. Chemical structures of well-known MAO-B inhibitors.

Figure 2. Rational design of the newly synthesized analogues (series A and B).

Scheme 1. Reagents and conditions: (a) appropriate halide derivative, NaH (60% in oil), DMF, 0–100 °C, 24 h; (b) dimethyl carbonate, K₂CO₃, DMF, reflux, 3 h; (c) NH₄Cl, Fe, EtOH/H₂O, reflux, 1 h; (d) appropriate heteroaryl carboxylic acid, DIPEA, HATU, DMF, MW, 116 °C, 45 min.

Table 1. Inhibitory effects of the synthesized compounds against MAO-B.

^a Inhibition percent of MAO-B at single dose of 10 µM of the prepared compound.

Figure 3. Dose dependent assay of compounds 4b and 4e over MAO-B.

Table 2. Inhibitory effects of the compounds 4b and 4e against MAO-A.

Compound	MAO-A % inhibition^a	MAO-A (IC50, µM)	SI^b
4b	12.95 ± 1.09	>100	>60
4e	4.76 ± 0.59	>100	>120

^a Inhibition percent of MAO-A at single dose of 100 µM of the prepared compound.

^b SI = selectivity index, the selectivity for the MAO-B isoform and is given as the ratio of IC₅₀ (MAO-A)/IC₅₀ (MAO-B).

Figure 4. Type of inhibition of MAO-B by compound 4e. The catalytic rates were measured at different concentrations of benzylamine (0.065, 0.125, 0.25, 0.5, 1, 2, and 4 mM) in the absence and in the presence of different concentrations (10, 30, and 100 nM) of compound 4e. The V_max, K_m, and K_i values were calculated using SigmaPlot^®.

Figure 5. The docked model of the most active compounds 4b (A) and 4e (B) into MAO-B binding pocket.

Figure 6. Two-dimensional (2D) interaction model for 4b (A) and 4e (B) with MAO-B.

Figure 7. Binding orientation of ligand 4b and 4e inside the MAO-A protein structure. Ligand 4b (A) and 4e (B) shown in orange and blue colour stick format. FAD molecule shown in yellow stick format. Hydrophobic surface area shown around the ligand.

Figure 8. 2D interactions of ligands 4b and 4e inside MAO-A binding pocket. 4b (A) and 4e (B) ligands shown in orange and blue colour, respectively.