Y. Gautam et al.
Bioorganic & Medicinal Chemistry 42 (2021) 116252
4.2.6. General procedure for the synthesis of alkyloxy alkane and alkyloxy
ester derivatives
Table 3
Details about docking studies of indole derivatives with estrogen receptor alpha
and beta sub-types.
4.2.6.1. Synthesis of 1-(4-methoxybenzyl)-5-methoxy-2-(3,4,5-trimethox-
yphenyl)-1H-indole (10). 5-Methoxy-2-(3,4,5-trimethoxyphenyl)-1(4-
hydroxy benzyl)-indole (8) was taken in 10 mL of dry acetone and
anhydrous potassium carbonate (1 g, 7.24 mmol) was added to it. To this
refluxing mixture dimethylsulphate was added (0.15 mL, 1.35 mmol)
and further refluxed for an hour. After completion, reaction mixture was
filtered, washed with acetone and evaporated to dryness under reduced
pressure. The residue was taken in ethyl acetate, washed with water and
organic layer was dried over anhydrous sodium sulphate. It was evap-
orated to dryness to get crude compound which was purified through
column chromatography over silica gel (100–200 mesh) eluting with
ethyl acetate- hexane to get 10 in 84% yield (amorphous solid). Simi-
larly, compounds 11, 17 and 18 were also synthesized by this procedure.
Compd
code
Estrogen receptor-alpha (PDB
entry 2OCF)
Estrogen receptor-beta (PDB
entry 5TOA)
Binding
affinity
(Kcal/
mol)
Binding pocket
amino acids
Binding
affinity
(kcal/
mol)
Binding pocket
amino acids
Compound
ꢀ 6.5
LEU320,
ꢀ 6.0
GLY352, ASP363,
ARG364,
19
GLU323, ILE326,
GLU353,
GLU375,
GLY390,
ASP378,
TRP393,
MET379,
ARG394,
LEU381,
HIS398, LEU403,
PRO406,
ALA382,
THR383,
GLY442,
SER385,
GLU443
ARG388, HIS464
PRO351,
Compound
ꢀ 6.1
LEU320,
ꢀ 5.5
4.2.6.2. Synthesis of 1-(4-(2-(N,N’-dimethylamine-1-yl)-ethoxy)-benzyl)-
20
GLU323,
GLY352,
5-methoxy-2-(3,4,5-trimethoxyphenyl)-1H-indole (12). Compound
8
PRO325, ILE326,
LEU327,
ARG364,
(419 mg, 1 mmol) was taken in dry acetone (10 mL) and potassium
carbonate (1 g, 7.24 mmol) was added to it. To this refluxing mixture, N,
N’-dimethylethyl chloride hydrochloride was added (181 mg, 1.2 mmol)
and further refluxed for 2–3 h. After completion, the reaction mixture
was filtered, washed with acetone and solvent was evaporated to dry-
ness under reduced pressure. The residue was taken in ethyl acetate,
washed with water, organic layer was dried over anhydrous sodium
sulphate. It was evaporated to dryness to get crude mass which was
purified through column chromatography by using 100–200 mesh silica
gel, eluting with methanol-chloroform solvent to get pure compound as
amorphous solid in 85% yield. Similarly compounds 13–16 and 19–23
were also synthesized by this procedure.
ASP378,
GLU353,
MET379,
GLY390,
LEU381,
TRP393,
ALA382,
ARG394,
THR383,
MET396,
GLU397,
SER385,
ARG386, HIS464
GLY442,
PHE445, LYS449
LEU320,
Compound
ꢀ 6.9
ꢀ 6.6
ꢀ 10.9
ꢀ 8.0
ꢀ 6.9
ꢀ 11.0
LEU273,
22
GLU323,
GLU276,
PRO324, ILE326,
GLU353,
PRO277,
PRO278, HIS279,
GLU305,
TRP393,
ARG394,
MET309,
MET396,
GLU397,
VAL338,
4.2.6.3. 1,3-Bis[4-(2-(N,N’-dimethylamine-1-yl)ethoxy)benzyl]-5-
methoxy-2-(3,4,5-trimethoxyphenyl)-1H-indole (19). Yield: 86%, yellow
gummy; ESI-MS (MeOH) for C40H49N3O6: 668 [M+H]+; ESI-HRMS
LEU339,
GLN441,
TRP345,
GLY442,
ARG346, ILE348,
ASP349, ILE355,
PRO358, HIS394,
TYR397,
46H57N3O6 for [M+H]+, cald, 668.3699, found
GLU443
(MeOH) for
C
668.3645. 1H NMR (CDCl3,300 MHz): δ2.39 (s, 12H, 4 × N-CH3 of
chain), 2.79 (t, 4H, 2 × N-CH2 of chain), 3.50 (s, 6H, 2 × OCH3), 3.72 (s,
3H, OCH3), 3.73 (s, 3H, OCH3), 4.05 (bt, 4H, 2 × OCH2 & 3-CH2), 5.18
(s, 2H, N-CH2), 6.40 (s, 2H, 2xCH, aromatic), 6.77 (bd, 4H, 4xCH, aro-
matic), 6.83 (d, 1H, CH, aromatic), 6.90 (bs, 1H, CH, aromatic), 6.93 (d,
2H, 2xCH, aromatic, J = 8.4 Hz), 7.08 (bd, 3H, 3xCH, aromatic); 13C
NMR (CDCl3,75 MHz): δ30.0, 30.2, 45.6, 45.6, 45.6, 45.7., 47.7, 54.9,
56.1, 56.1, 56.1 ,56.2, 58.1, 61.2, 65.9, 101.8, 107.7, 107.7, 111.2,
112.0, 112.3, 114.8, 114.8, 114.8, 115.14, 115.1, 115.1, 127.3, 127.4,
129.1, 129.4, 129.4, 131.5, 132.8, 135.0, 139.7, 153.2, 153.27,
154.6,157.0,158.0.
LEU398, LYS401
LEU273,
Compound
GLU330,
TYR331,
ASP332,
23
GLU276,
PRO277,
ARG335,
PHE337,
SER338,
PRO278, HIS279,
GLU305,
VAL338,
ALA340,
SER341,
GLY342,
TRP345,
GLY344,
LEU345,
ASN348,
VAL534,
PRO535,
SER537
ARG346, ILE355,
PRO358,
TYR397, HIS394,
LEU398, LYS401
4.2.6.4. 1,3-Bis[4-(2-(N,N’-diethylamine-1-yl)ethoxy)benzyl]-5-methoxy-
2-(3,4,5-trimethoxyphenyl)-1H-indole (20). Yield: 83%, yellow viscous;
ESI-MS (MeOH) for C44H57N3O6: 724 [M+H]+; HRMS for C44H57N3O6,
[M+H]+, calcd, 724.4306, obsvd 724.4306; 1H NMR (CDCl3, 300 MHz):
δ 1.15 (m, 12H, 4 × CH3 of chain), 2.80 (bs, 8H, (CH2)4), 3.02 (bs, 4H, N-
(CH2)2), 3.51 (s, 6H, 2 × OCH3), 3.80 (s, 6H, 2 × OCH3), 4.04 (bd, 6H, 3
× CH2), 5.19 (s, 2H, 1-N-CH2), 6.41 (s, 2H, 2xCH, aromatic), 6.79 (bs,
5H, 5xCH, aromatic), 6.92 (bd, 3H, 3xCH, aromatic), 7.10 (s, 3H, 3xCH,
aromatic); 13C NMR (CDCl3, 75 MHz): δ10.6, 10.6, 10.8, 10.8, 32.0,
32.0, 32.0, 32.0, 34.2, 47.8, 47.8, 51.7, 56.1, 56.2 ,56.2, 61.2, 65.6,
65.9, 101.8, 107.7, 107.7, 111.9, 112.3, 114.4, 114.7, 115.0, 115.0,
116.2, 116.2, 127.5, 127.5, 129.1, 129.1,129.1, 129.4, 131.6, 132.8,
138.1, 139.7, 153.2, 153.2, 154.6, 156.8, 157.9.
β-estradiol
GLU353,
LEU384,
LEU387,
MET388,
LEU391,
ARG394,
PHE404,
MET421,
ILE424, LEU428,
GLY521,
HIS524, LEU525
LEU298,
LEU301,
GLU305,
MET336,
LEU339,
MET340,
LEU343,
ARG346,
PHE356, ILE373,
ILE376, LEU380,
GLY472, HIS475,
LEU476
(CDCl3,75 MHz): δ47.3, 55.4, 55.6, 55.6, 60.1, 101.6, 108.2, 108.2,
111.3, 111.8, 112.3, 115.3, 115.3, 115.3, 127.5, 127.7, 127.7, 127.7,
129.4, 129.4, 129.4, 129.4, 129.4, 130.1, 132.8, 133.3, 139.6, 153.6,
154.6, 155.7, 156.8.
4.2.6.5. 1,3-Bis[4-(2-(piperidin-1-yl)ethoxy)benzyl]-5-methoxy-2-(3,4,5-
trimethoxyphenyl)-1H-indole (22). Yield: 82%, yellow solid; m.p.:
170–173 ◦C; ESI-MS (MeOH) for C46H57N3O6: 748 [M+H]+, HRMS for
11