Rational Design and Synthesis of 3-Morpholine Linked Aromatic-Imino-1H-Indoles as Novel Kv1.5 Channel Inhibitors Sharing Vasodilation Effects

Figures

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  FIGURE 1. Design strategy of novel Kv1.5 inhibitors based on morpholine, 1H-indole, and the active linker (-N(CH2)nO-).

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  FIGURE 2. Simulated 3D structure of the transmembrane region of the Kv1.5 channel. (A) A single subunit of the transmembrane region of Kv1.5 viewed from the side. (B) Four subunits of the transmembrane region of Kv1.5 viewed from the side. (C) Four subunits of the transmembrane region of Kv1.5 viewed from the extracellular side of the pore. The subunits are represented as ribbons and colored individually.

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  FIGURE 3. Simulated 3D complex structure of compound T11 with its target Kv1.5 channel using Surflex Docking. (A) Kv1.5 channel was shown as a tetramer colored in cyan, and the binding site in the center was shown in the surface colored in yellow. (B) Binding site of the Kv1.5 channel was shown in the rainbow cartoon. Compound T11 was shown in the green and white stick situated in the center of the channel site. (C) Kv1.5 channel was shown in the rainbow cartoon. Compound T11 in the center of the Kv1.5 channel site was shown in the magenta mesh.

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  FIGURE 4. Simulated 3D complex structure of compound T10 with its target Kv1.5 channel using Surflex Docking. (A) T10 was shown in the surface while Kv1.5 was shown in the cyan cartoon. (B) Binding site around compound T10 (shown in mesh) was shown in the cyan cartoon. (C) Hydrogen bond (blue line) was formed between 1H of indole and O of the carbonyl group on the backbone of Thr479 amino acid residue.

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  FIGURE 5. Synthesis route of the target compounds.

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  FIGURE 6. Vasodilation effects of target compounds on superior mesenteric artery rings in vitro pre-contracted by KCl (60 mM) or by phenylephrine hydrochloride (PE, 10 μM). (A) KCl. (B) PE.

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  FIGURE 7. Vasodilation effects of compounds T4 and T16 on superior mesenteric artery rings in vitro pre-contracted by KCl (60 mM) or by phenylephrine hydrochloride (PE, 10 μM). (A) KCl. (B) PE. ***p < 0.05 versus a DMSO control (n = 3) indicates a significant difference compared with the control (DMSO).

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  FIGURE 8. Simulated 3D complex structure of compound T16 with its target Kv1.5 channel using Surflex Docking. (A) Kv1.5 channel was shown according to its secondary structure, in which the α-helixes were shown in cyan, and β-sheets were shown in magenta. Compound T16 situated in the center of the channel was shown in mesh. (B) Binding site was shown in the rainbow cartoon. Compound T16 situated in the center of the channel was shown in mesh. Kv1.5 channel was shown in ribbon, the color of which was shown according to the secondary structure. (C) Binding site of the Kv1.5 channel was shown in the rainbow cartoon. Compound T16 in the center of the binding site was shown in the ball and stick model, which was surrounded with electronic mesh.

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  FIGURE 9. Contrasting simulated molecular interaction models of compounds T16, T11, T10 and their target Kv1.5 channel. The binding site of Kv1.5 channel is composed of the following amino acid residues: T479, T480, A501, I502, I508, V512, and V516 in the S6 domain and selectivity filter of a single subunit of the channel. The binding model of compounds T11 and T10 is similar, which is different from compound T16. (A) compound T16 (C: gray, H: gray, O: red, N: blue); (B) compound T11 (C: green, H: gray, O: red, N: blue); (C) compound T10 (C: orange, H: gray, O: red, N: blue). A chain was shown in blue, B chain was shown in green, C chain was shown in yellow, and D chain was shown in red.