A. Elkamhawy, et al.
BioorganicChemistry92(2019)103261
3.1.1. Synthesis
of
3-(4-(4-(4-methylpiperazin-1-yl)butoxy)phenyl)
132.01, 132.13, 132.77, 138.03, 143.22, 153.27, 159.46, 165.80,
167.38. HRMS (ES+): m/z calculated for C27H30N6O3S: 519.2178 [M
+H]+. Found 519.2172.
thiazolidine-2,4-dione (6)
1-Methylpiperazine (0.15 mL, 1.34 mmol) was added to a solution
of intermediate 5 (262.1 mg, 0.67 mmol) and potassium carbonate
(180 mg, 1.34 mmol) in acetonitrile (3 mL). The reaction mixture was
stirred at room temperature for 9 h. The mixture was quenched by
addition of water and extracted with dichloromethane. The organic
layer was dried over anhydrous MgSO4, filtered and evaporated under
reduced pressure. The residue was purified by column chromatography
(SiO2, DCM/MeOH 15:1 v/v including 1% of ammonium hydroxide) to
yield the desired product 6. White solid, yield: 57%, 1H NMR (400 MHz,
DMSO‑d6) δ 1.64–1.70 (m, 2H), 1.78–1.83 (m, 2H), 2.29 (s, 3H),
2.38–2.50 (m, 10H), 3.99 (t, J = 6.3 Hz, 2H), 4.09 (s, 2H), 6.97 (d,
J = 8.9 Hz, 2H), 7.14 (d, J = 8.9 Hz, 2H). HRMS (ES+): m/z calculated
for C18H25N3O3S: 364.1695 [M+H]+. Found 364.1687.
3.1.2.5. (Z)-5-(3-Chloro-4-(1H-pyrazol-1-yl)benzylidene)-3-(4-(4-(4-
methylpiperazin-1-yl)butoxy)phenyl)thiazolidine-2,4-dione
(7e). White
solid, yield: 67%, HPLC purity: 8.40 min, 100%, 1H NMR (400 MHz,
DMSO‑d6) δ 1.54–1.61 (m, 2H), 1.71–1.78 (m, 2H), 2.14 (s, 3H),
2.30–2.33 (m, 10H), 4.04 (t, J = 6.4 Hz, 2H), 6.59 (t, J = 2.0 Hz, 1H),
7.07 (d, J = 9.0 Hz, 2H), 7.35 (d, J = 9.0 Hz, 2H), 7.75–7.83 (m, 3H),
8.03 (d, J = 1.8 Hz, 1H), 8.05 (s, 1H), 8.27 (d, J = 2.5 Hz, 1H). 13C
NMR (100 MHz, CDCl3) δ 23.42, 27.18, 46.03, 53.16, 55.14, 58.13,
68.07, 107.41, 115.31, 123.58, 124.76, 127.92, 128.07, 128.38,
128.96, 131.23, 131.29, 132.33, 133.67, 139.08, 141.65, 159.65,
165.49, 166.66. HRMS (ES+): m/z calculated for C28H30ClN5O3S:
552.1836 [M+H]+. Found 552.1833.
3.1.2. General procedure of target compounds (7a–r)
NaOAc anhydrous (17.6 mg, 0.21 mmol), the appropriate aldehyde
derivative (0.14 mmol), and intermediate 6 (25.4 mg, 0.07 mmol) were
dissolved in AcOH (3 mL) and stirred at 110 °C for 16 h. After cooling,
the mixture was neutralized to pH 8 by addition of NH4OH and ex-
tracted with DCM. The organic layer was dried over anhydrous MgSO4,
filtered and concentrated under reduced pressure. The residue was
purified by column chromatography (SiO2, DCM/MeOH 15/1 v/v in-
cluding 1% of NH4OH) to produce the final target compounds.
3.1.2.6. (Z)-5-(3-Chloro-4-(1H-imidazol-1-yl)benzylidene)-3-(4-(4-(4-
methylpiperazin-1-yl)butoxy)phenyl)thiazolidine-2,4-dione (7f). Yellow
solid, yield: 58%, 1H NMR (400 MHz, DMSO‑d6) δ 1.60–1.64 (m, 2H),
1.71–1.78 (m, 2H), 2.4 (s, 3H), 2.66–2.77 (m, 10H), 4.06 (t, J = 6.2 Hz,
2H), 7.09 (d, J = 8.9 Hz, 2H), 7.16 (s, 1H), 7.37 (d, J = 8.9 Hz, 2H),
7.55 (s, 1H), 7.76–7.77 (m, 2H), 8.02 (s, 1H), 8.05–8.06 (m, 2H). 13C
NMR (100 MHz, CDCl3) δ 22.75, 26.75, 44.73, 51.64, 53.95, 57.05,
68.01, 115.05, 115.37, 121.30, 124.79, 125.74, 129.19, 129.32,
129.52, 129.63, 129.71, 130.58, 132.80, 135.13, 136.14, 138.21,
159.48, 165.61, 167.08. HRMS (ES+): m/z calculated for
3.1.2.1. (Z)-5-((2,3-Dihydrobenzofuran-5-yl)methylene)-3-(4-(4-(4-
methylpipera zin-1-yl)butoxy)phenyl)thiazolidine-2,4-dione (7a). Light
brown solid, yield: 14%, HPLC purity: 4.48 min, 98.86%, 1H NMR
(400 MHz, CDCl3) δ 1.65–1.70 (m, 2H), 1.79–1.84 (m, 2H), 2.31 (s,
3H), 2.38–2.59 (m, 10H), 3.29 (t, J = 8.7 Hz, 2H), 4.01 (t, J = 6.2 Hz,
2H), 4.67 (t, J = 8.7 Hz, 2H), 6.89 (d, J = 8.2 Hz, 1H), 7.00 (d,
J = 8.9 Hz, 2H), 7.22 (d, J = 9.0 Hz, 2H), 7.35 (d, J = 8.4 Hz, 1H),
7.40 (s, 1H), 7.93 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 14.10, 23.36,
27.17, 29.69, 45.89, 52.98, 55.00, 58.06, 68.00, 72.14, 110.32, 115.21,
117.20, 125.21, 126.08, 127.04, 128.49, 128.73, 132.32, 134.73,
159.44, 162.60, 166.21, 167.71. HRMS (ES+): m/z calculated for
C
28H30ClN5O3S: 552.1836 [M+H]+. Found 552.1846.
3.1.2.7. (Z)-5-(3-(1H-Imidazol-1-yl)benzylidene)-3-(4-(4-(4-
methylpiperazin-1-yl)butoxy)phenyl)thiazolidine-2,4-dione
(7g). Yellowish white solid, yield: 35%, HPLC purity: 3.33 min, 100%,
1H NMR (400 MHz, DMSO‑d6) δ 1.57–1.60 (m, 2H), 1.74–1.77 (m, 2H),
2.18 (s, 3H), 2.32–2.37 (m, 10H), 4.05 (t, J = 5.9 Hz, 2H), 7.08 (d,
J = 8.6 Hz, 2H), 7.17 (s, 1H), 7.36 (d, J = 8.6 Hz, 2H), 7.61 (d,
J = 7.7 Hz, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.82–7.84 (m, 2H), 8.04 (s,
2H), 8.36 (s, 1H). 13C NMR (100 MHz, DMSO‑d6) δ 23.13, 26.93, 46.04,
52.94, 55.10, 57.68, 68.12, 115.34, 118.38, 122.41, 123.15, 123.67,
125.74, 127.06, 129.70, 130.66, 131.46, 132.14, 135.24, 136.05,
138.09, 159.48, 165.77, 167.34. HRMS (ES+): m/z calculated for
C28H31N5O3S: 518.2226 [M+H]+. Found 518.2228.
C
27H31N3O4S: 494.2113 [M+H]+. Found 494.2112.
3.1.2.2. (Z)-3-(4-(4-(4-Methylpiperazin-1-yl)butoxy)phenyl)-5-((5-
phenylthiophen-2-yl)methylene)thiazolidine-2,4-dione (7b). Yellow solid,
yield: 13.6%, HPLC purity: 5.21 min, 98.28%, 1H NMR (400 MHz,
CDCl3) δ 1.67–1.72 (m, 2H), 1.79–1.86 (m, 4H), 2.36 (s, 3H), 2.44–2.58
(m, 8H), 4.01 (t, J = 6.2 Hz, 2H), 6.99 (d, J = 8.9 Hz, 2H), 7.23 (d,
J = 8.9 Hz, 2H), 7.37–7.46 (m, 5H), 7.67 (d, J = 8.6 Hz, 2H), 8.11 (s,
1H). HRMS (ES+): m/z calculated for C29H31N3O3S2: 534.1885 [M
+H]+. Found 534.1888.
3.1.2.8. (Z)-5-(3-Chloro-4-morpholinobenzylidene)-3-(4-(4-(4-
methylpiperazin-1-yl)butoxy)phenyl)thiazolidine-2,4-dione (7h). Yellow
solid, yield: 28%, HPLC purity: 8.45 min, 91.45%, 1H NMR (400 MHz,
CDCl3) δ 1.67–1.73 (m, 2H), 1.83–1.88 (m, 2H), 1.99 (bs, 2H), 2.36 (s,
3H), 2.45–2.57 (m, 8H), 3.2 (t, J = 4.5 Hz, 4H), 3.92 (t, J = 4.4 Hz,
4H), 4.04 (t, J = 6.2 Hz, 2H), 7.02 (d, J = 8.9 Hz, 2H), 7.13 (d,
J = 8.4 Hz, 1H), 7.25 (d, J = 8.9 Hz, 2H), 7.46 (dd, J = 2.1, 8.4 Hz,
1H), 7.58 (d, J = 2.1 Hz, 1H), 7.88 (s, 1H). 13C NMR (100 MHz, CDCl3)
δ 23.30, 27.13, 45.75, 51.20, 52.80, 54.85, 57.99, 66.90, 67.98,
115.25, 120.16, 120.40, 124.98, 128.44, 128.54, 128.78, 129.70,
132.58, 132.83, 150.81, 159.51, 165.84, 167.22. HRMS (ES+): m/z
calculated for C29H35ClN4O4S: 571.2146 [M+H]+. Found 571.2197.
3.1.2.3. (Z)-5-(4-(1H-Pyrazol-1-yl)benzylidene)-3-(4-(4-(4-
methylpiperazin-1-yl)butoxy)phenyl)thiazolidine-2,4-dione
(7c). Yellowish white solid, yield: 49%, 1H NMR (400 MHz, DMSO‑d6)
δ 1.29–1.38 (m, 2H), 1.60–1.62 (m, 2H), 1.74–1.78 (m, 2H), 2.24 (s,
3H), 2.38–2.44 (m, 8H), 4.06 (t, J = 6.5 Hz, 2H), 6.63 (s, 1H), 7.08 (d,
J = 8.8 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 7.81–7.84 (m, 3H), 8.05 (d,
J = 12.6 Hz, 2H), 8.08 (s, 1H), 8.64–8.65 (m, 1H). HRMS (ES+): m/z
calculated for C28H31N5O3S: 518.2226 [M+H]+. Found 518.2233.
3.1.2.9. (Z)-5-(2-Fluoro-4-(4-methylpiperazin-1-yl)benzylidene)-3-(4-(4-
(4-methylpiperazin-1-yl)butoxy)phenyl)thiazolidine-2,4-dione
3.1.2.4. (Z)-5-(4-(1H-1,2,4-triazol-1-yl)benzylidene)-3-(4-(4-(4-
methylpiperazin-1-yl)butoxy)phenyl)thiazolidine-2,4-dione
(7i). Brown solid, yield: 31%, HPLC purity: 3.40 min, 100%, 1H NMR
(400 MHz, CDCl3) δ 1.66–1.71 (m, 2H), 1.78–1.83 (m, 2H), 2.05 (bs,
4H), 2.32 (s, 3H), 2.35 (s, 3H), 2.43 (t, J = 7.5 Hz, 2H), 2.49–2.59 (m,
8H), 3.37 (t, J = 5.0 Hz, 4H), 4.00 (t, J = 6.1 Hz, 2H), 6.57–6.61 (dd,
J = 2.4, 14.0 Hz, 1H), 6.72–6.75 (dd, J = 2.24, 8.96 Hz, 1H), 6.98 (d,
J = 8.8 Hz, 2H), 7.22 (d, J = 8.9 Hz, 2H), 7.41 (t, J = 8.8 Hz, 1H), 8.12
(s, 1H). 13C NMR (100 MHz, CDCl3) δ 23.29, 27.13, 45.73, 46.06,
47.07, 52.77, 54.52, 54.84, 57.99, 67.99, 101.05, 110.27, 115.19,
125.28, 126.74, 128.51, 130.09, 159.38. HRMS (ES+): m/z calculated
(7d). Yellowish white solid, yield: 32%, HPLC purity: 8.00 min,
92.60%, 1H NMR (400 MHz, DMSO‑d6)
δ 1.57–1.60 (m, 2H),
1.74–1.77 (m, 2H), 2.18 (s, 3H), 2.26–2.47 (m, 10H), 4.05 (t,
J = 6.3 Hz, 2H), 7.08 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 8.7 Hz, 2H),
7.88 (d, J = 8.5 Hz, 2H), 8.04 (s, 1H), 8.08 (d, J = 8.5 Hz, 2H), 8.32 (s,
1H), 9.43 (s, 1H). 13C NMR (100 MHz, DMSO‑d6) δ 23.13, 26.93, 46.04,
52.94, 55.09, 57.69, 68.12, 115.33, 120.37, 122.63, 125.78, 129.70,
7