348
Chem. Pharm. Bull.
Vol. 67, No. 4 (2019)
was added by dropping funnel (3.72g, 20.0mmol), refluxed
for 10h. Monitored by TLC, and then filtered, concentrated by
vacuum. The crude compound was purified by column chro-
matography on silica gel to give the desired intermediate 4
2-(2-bromoethyl)isoindoline-1,3-dione (1.83g, 72.5% yield) as
a white solid.
General Procedures for the Synthesis of Compounds 5a–i
To a solution of compound 4 (2mmol) in N,N-dimeth-
ylformamide (DMF) (40.0mL), the intermediate 2 (0.44g,
2.5mmol) and KHCO3 (0.40g, 4.0mmol) were added. The
mixture was heated at 35–40°C for 10h. Monitored by TLC,
and then filtered, concentrated by vacuum. The crude com-
pound was purified by column chromatography on silica
gel (VEtOAc–VPet =2:3) to give compound 5. (Chart 1). The
1H-NMR data of compounds 5a–i were listed as follow.
2-(2-(3-Methyl-5-oxo-4-(2,2,2-trifluoroethyl)-4,5-dihydro-
1H-1,2,4-triazol-1-yl)ethyl)isoindoline-1,3-dione (5a)
1
White solid, yield 56.2%, mp 173–175°C. H-NMR (CDCl3,
300MHz) δ: 2.24 (3H, s), 3.95–4.01 (4H, m), 4.21–4.30 (2H,
m), 7.71–7.74 (2H, m), 7.82–7.85 (2H, m). Anal. Calcd for
C15H13F3N4O3: C, 50.85; H, 3.70, N, 15.81. Found: C, 50.78; H,
Fig. 4. Hypothetical Binding Mode between 5h and the DmAChE Ac-
tive Site (Only a Few Amino Acid Residues Are Shown for Clarity)
ibility than 5g, the flexibility caused to the higher bond energy 3.66, N, 15.85. HR-MS (Electron Spray Ionization (ESI)) m/z
between the small molecular and the binding active pocket, C15H14F3N4O3 (M+H) 355.1018. Found: 355.1029.
which made the unconducive to the stability of the complex.
2-(3-(3-Methyl-5-oxo-4-(2,2,2-trifluoroethyl)-4,5-dihydro-
Finally, it could conclude that compound 5g acts as a potent 1H-1,2,4-triazol-1-yl)propyl)isoindoline-1,3-dione (5b)
1
dual binding site inhibitor of AChE.
White solid, yield 44.7%, mp 158–160°C. H-NMR (CDCl3,
300MHz) δ: 2.08–2.16 (2H, m), 2.45 (3H, s), 3.69–3.79 (4H,
m), 4.25–4.33 (2H, m), 7.72–7.75 (2H, m), 7.84–7.86 (2H,
Conclusion
The present study described the synthesis and biological m). Anal. Calcd for C16H15F3N4O3: C, 52.18; H, 4.11, N,
evaluation of a novel series of 1,2,4-triazolin-3-one derivatives 15.21. Found: C, 52.07; H, 4.15, N, 15.27. HR-MS (ESI) m/z
with phthalimide moieties connected by the linker. The results C16H16F3N4O3 (M+H) 369.1175. Found: 369.1194.
showed that compound 5g exhibited very potent anti-AChE
2-(4-(3-Methyl-5-oxo-4-(2,2,2-trifluoroethyl)-4,5-dihydro-
activities, even better than CP. Meanwhile, the in vivo insec- 1H-1,2,4-triazol-1-yl)butyl)isoindoline-1,3-dione (5c)
1
ticidal activity study of compound 5g displayed the highest
White solid, yield 62.8%, mp 136–138°C. H-NMR (CDCl3,
mortality among all compounds to Tetranychus cinnabarinus 300MHz) δ: 1.71–1.83 (4H, m), 2.25 (3H, s), 3.68 (2H, t),
and Lipaphis erysimi. The docking study showed compound 3.74 (2H, t), 4.27–4.35 (2H, m), 7.71–7.76 (2H, m), 7.83–7.87
5g bound to the catalytic site and the peripheral site of the (2H, m). Anal. Calcd for C17H17F3N4O3: C, 53.40; H, 4.48, N,
DmAChE simultaneously. The results presented in this work 14.65. Found: C, 53.46; H, 4.52, N, 14.74. HR-MS (ESI) m/z
demonstrate that the “cluster effect” is a very powerful strat- C17H18F3N4O3 (M+H) 383.1331. Found: 383.1353.
egy and of high potential in the field of agrochemical.
2-(5-(3-Methyl-5-oxo-4-(2,2,2-trifluoroethyl)-4,5-dihydro-
1H-1,2,4-triazol-1-yl)pentyl)isoindoline-1,3-dione (5d)
1
White solid, yield 42.3%, mp 176–178°C. H-NMR (CDCl3,
Experimental
Chemistry
300MHz) δ: 1.26–1.41 (2H, m), 1.68–1.78 (4H, m), 2.25 (3H,
General Procedures for the Synthesis of Compound 1
s), 3.61 (2H, t), 3.70 (2H, t), 4.27–4.33 (2H, m), 7.71–7.75 (2H,
The solution of (2,2,2-trifluoroethyl)hydrazine (0.23g, m), 7.81–7.86 (2H, m). Anal. Calcd for C18H19F3N4O3: C, 54.54;
2.0mmol), acetaldehyde (0.24g, 6.0mmol), and NaOCN H, 4.83, N, 14.14. Found: C, 54.65; H, 4.79, N, 14.20. HR-MS
(0.26g, 4.0mmol) in Isopropyl Alcohol (IPA) (10.0mL) were (ESI) m/z C18H20F3N4O3 (M+H) 397.1488. Found: 397.1510.
stirred at 0–5°C for 12h. And then filtered, concentrated by
2-(6-(3-Methyl-5-oxo-4-(2,2,2-trifluoroethyl)-4,5-dihydro-
vacuum. The crude compound was obtained (0.18g, 50.2% 1H-1,2,4-triazol-1-yl)hexyl)isoindoline-1,3-dione (5e)
1
yield) as white solid.
White solid, yield 36.9%, mp 192–194°C. H-NMR (CDCl3,
General Procedures for the Synthesis of Compound 2
300MHz) δ: 1.36–1.41 (4H, m), 1.58–1.70 (4H, m), 2.23 (3H,
To a solution of intermediate 1 (0.35g, 2.0mmol) in tBuOH s), 3.61 (2H, t), 3.69 (2H, t), 4.29–4.35 (2H, m), 7.70–7.74 (2H,
(20.0mL), sodium hypochlorite (0.32g, 1.0mmol) was added m), 7.83–7.85 (2H, m). Anal. Calcd for C19H21F3N4O3: C, 55.61;
and the mixture was stirred at 0–5°C for 12h. Monitored by H, 5.16, N, 13.65. Found: C, 55.68; H, 5.09, N, 13.56 HR-MS
TLC, and then filtered, concentrated by vacuum. The crude (ESI) m/z C19H22F3N4O3: (M+H) 411.1644. Found: 411.1664.
compound was purified by column chromatography on silica
gel to give compounds 2 as a white solid.
General Procedures for the Synthesis of Compounds 4a–i
2-(7-(3-Methyl-5-oxo-4-(2,2,2-trifluoroethyl)-4,5-dihydro-
1H-1,2,4-triazol-1-yl)heptyl)isoindoline-1,3-dione (5f)
1
White solid, yield 31.1%, mp 221–223°C. H-NMR (CDCl3,
To a solution of potassium 1,3-dioxoisoindolin-2-ide (1.85g, 300MHz) δ: 1.32–1.40 (6H, m), 1.64–1.68 (4H, m), 2.24 (3H,
10.0mmol), potassium iodide (0.08g, 0.5mmol) in acetone s), 3.60 (2H, t), 3.68 (2H, t), 4.30–4.33 (2H, m), 7.70–7.73 (2H,
(25.0mL), 1,2-dibromoethane dissolved in acetone (5.0mL) m), 7.83–7.86 (2H, m). Anal. Calcd for C20H23F3N4O3: C, 56.60;