Three-Component Access to Functionalized Spiropyrrolidine Heterocyclic Scaffolds and Their Cholinesterase Inhibitory Activity

Abstract

A novel one-pot [3+2]-cycloaddition reaction of (E)-3-arylidene-1-phenyl-succinimides, cyclic 1,2-diketones (isatin, 5-chloro-isatin and acenaphtenequinone), and diverse α-aminoacids such as 2-phenylglycine or sarcosine is reported. The reaction provides succinimide-substituted dispiropyrrolidine derivatives with high regio- and diastereoselectivities under mild reaction conditions. The stereochemistry of these N-heterocycles has been confirmed by four X-ray diffraction studies. Several synthetized compounds show higher inhibition on acetylcholinesterase (AChE) than butyrylcholinesterase (BChE). Of the 17 synthesized compounds tested, five exhibit good AChE inhibition with IC₅₀ of 11.42 to 22.21 µM. A molecular docking study has also been undertaken for compound 4n possessing the most potent AChE inhibitory activity, disclosing its binding to the peripheral anionic site of AChE enzymes.

Keywords: [3+2]-cycloaddition reaction; azomethine ylides; dispiropyrrolidine derivatives; succinimide.

Figure 1

Clinical and biologically important spiropyrrolidines bearing acenaphthylene-1,2-dione or oxindole moieties.

Figure 2

Examples of bioactive molecules containing succinimide unit.

Figure 3

Design of novel succinimide-substituted dispiropyrrolidine derivatives.

Scheme 1

1,3-Dipolar cycloaddition reaction for the synthesis of dispiropyrrolidine 4a.

Scheme 2

Reaction of (E)-3-arylidene-1-phenylpyrrolidine-2,5-dione 1a–g with 2-phenylglycine 2 and cyclic 1,2-diketones 3.

Scheme 3

Reaction of (E)-3-arylidene-1-phenylpyrrolidine-2,5-diones 1a-f with sarcosine 6 and cyclic 1,2-diketones 3.

Figure 4

Selected ¹H and ¹³C-NMR (red) chemical shifts of 4b.

Figure 5

Selected ¹H and ¹³C-NMR (red) chemical shifts of 5b.

Figure 6

Selected ¹H and ¹³C-NMR (red) chemical shifts of 7f.

Figure 7

(B) Ball and Sticks presentation of the molecular structure of 4b in the crystal. For clarity, only stereochemically significant hydrogen atoms are shown. Only one of the two independent molecules in the unit cell is presented. Selected bond lengths (Å) and angles (°): C1–N1 1.4144(17), N1–C8 1.3437(19), C8–O1 1.2329(17), C8–C7 1.5556(18), C6–C7 1.5126(19), C7–N2 1.4488(18), N2–C27 1.4669(19), C11–O2 1.2060(17), C11–N3 1.36965(18), C10–N3 1.3959(17); C7–C9–C19103.62(10), C9–C19–C27105.21(11), C9–C19–C27105.21(11), C19–C27–N2102.89(11), C27–N2–C7108.10(11), N2–C7–C8114.02(11), N2–C7–C8114.02(11), C7–C8–N1108.41(11), C8–N1–C1111.33(11), N1–C1–C6109.24(11), C6–C7–C9115.09(11), C9–C10–N3109.24(11), C10–N3–C11112.56(11). (A) Pairwise association of two molecules in the packing through intermolecular N-H····O hydrogen bonding. d(N-H····O 2.00(2) Å.

Figure 8

Ball and Sticks presentation of the molecular structure of 4m in the crystal. For clarity, only stereochemically significant hydrogen atoms are shown. Selected bond lengths (Å) and angles (°):C6–N2 1.395(2), N2–C9 1.397(2), C6–O2 1.2093(18), C9–O3 1.2074(18), C13–O1 1.52152(18),C24–N1 1.461(2), N1–C18 1.4787(18); C8–C10–C6105.67(12), C10–C6–N2107.92(13), C6–N2–C9113.11(13), N2–C9–C8108.11(13), C9–C8–C24115.07(12), N1–C24–C8103.31(12), C24–N1–C18110.43(12), C7–C18–N1105.11(12), C18–C7–C8101.90(12), C7–C8–C10114.28(12).

Figure 9

(B) Ball and Sticks presentation of the molecular structure of 5m in the crystal. For clarity, only stereochemically significant hydrogen atoms are shown. Selected bond lengths (Å) and angles (°): C12–N1 1.462(3), N1–C30 1.469(3), C1–O1 1.217(3), C22–O2 1.212(3), C23–O3 1.204(3), C22–N2 1.394(3), N2–C23 1.4787(18); C20–C13–C12 104.46(17), C12–N1–C30 106.91(17), N1–C30–C20 112.96(18), C20–C21–C22 104.86(18), N2–C22–C21 107.52(18), C22–N2–C23 112.24(19), N2–C23–C20 107.98(19), N2–C23–O3 124.4(6). (A) Association of two molecules in the packing through intermolecular N-H····O hydrogen bonding.

Figure 10

Ball and Sticks presentation of the molecular structure of 7f in the crystal. For clarity, only stereochemically significant hydrogen atoms are shown. Selected bond lengths (Å) and angles (°):C24–N1 1.461(2), N1–C18 1.4784(18), C24–C8 1.587(2), C8–C9 1.525(2), C9–O3 1.2074(18), C9–N2 1.397(2), C6–N2 1.395(2), C6–O2 1.2093(18), C13–O1 1.2152(18); C7–C8–C24 99.71(12), C7–C8–C24 99.71(12), C24–C13–O1 123.67(14), C24–C8–C9 115.07(12), C8–C9–O3 127.87(14), C8–C9–N2 108.11(13), C9–N2–C6 113.11(13), N2–C6–O2 124.19(15).

Scheme 4

Proposed mechanism for the 1,3-dipolar cycloaddition of azomethine ylides d_3,4 with (E)-3-arylidene-1-phenylpyrrolidine-2,5-dione.

Figure 11

Binding interactions of 4n with the acetylcholinesterase domain.