Table 1 Effect of catalyst on synthesized compound 3a
Entry
|
Catalyst
|
Solvent
|
Temperature (oC)
|
Time (min)
|
Yield (%)
|
1
|
H2O2: HCl
|
EtOH: H2O
|
Reflux
|
10
|
96
|
2
|
CuO NPs
|
-
|
RT
|
10
|
93[15]
|
3
|
PVP-Ni NPs
|
Ethylene glycol
|
Reflux
|
10
|
87[16]
|
4
|
Fe3O4 NPs
|
EtOH
|
Reflux
|
30
|
70[17]
|
5
|
L-tyrosine
|
H2O
|
RT
|
16
|
93[18]
|
6
|
NH2SO3H
|
-
|
Grinding
|
120
|
96[19]
|
7
|
EAN
|
Ionic liquids
|
RT
|
10
|
96[20]
|
8
|
Bi(NO3)3.5H2O
|
EtOH
|
Reflux
|
20
|
95[21]
|
9
|
-
|
EtOH
|
Reflux
|
120
|
89[22]
|
Table 2 Effect of temperature on synthesized compound 3a
Entry
|
Temperature (oC)
|
Time (min)
|
Yield (%)
|
1
|
RT
|
60
|
96
|
2
|
50
|
20
|
96
|
3
|
80
|
10
|
96
|
Table 3 Physical and analytical data of synthesized compound (3a-d)
Entry
|
Comp.
|
X
|
R
|
Product
|
Yield (%)
|
MP (oC)
|
Observed
|
Reported
|
1
|
3a
|
O
|
H
|
|
98
|
278-280
|
271
|
2
|
3b
|
O
|
CH3
|
|
95
|
302-306
|
-
|
3
|
3c
|
S
|
H
|
|
94
|
320-322
|
>300
|
4
|
3d
|
S
|
CH3
|
|
96
|
310-312
|
-
|
Table 4 Antibacterial activity results of synthesized compounds (3a-d)
Compd.
|
Zone of inhibition in mm
|
Escherichia coli
|
Staphylococcus aureus
|
Concentration in µg/mL
|
20
|
40
|
20
|
40
|
3a
|
3.5
|
7.8
|
3.0
|
7.5
|
3b
|
3.8
|
7.8
|
3.1
|
7.6
|
3c
|
3.3
|
7.2
|
3.5
|
7.4
|
3d
|
3.4
|
7.1
|
3.7
|
7.9
|
Ciproflaxin
|
4
|
8
|
4.2
|
8.4
|
Table 5 Percentage of cell viability against MCF-7 cell line of the synthesized compounds (3a-d)
Concentration
in µg/mL
|
Mean cell Viability of MCF-7
|
3a
|
3b
|
3c
|
3d
|
6.25
|
44.16±0.76
|
50.93±0.42
|
66.82±0.41
|
53.12±0.34
|
12.5
|
38.11±0.82
|
48.68±0.31
|
58.1±0.13
|
46.88±0.52
|
25
|
34.09±1.2
|
43.72±0.52
|
48.6±0.23
|
43.93±0.42
|
50
|
32.37±0.82
|
40.23±0.61
|
40.03±0.82
|
40.03±0.62
|
100
|
30.06±0.62
|
36.8±0.20
|
37.38±0.61
|
37.85±0.34
|
200
|
23.68±0.41
|
29±0.16
|
31.31±0.42
|
26.95±0.52
|
Values are Mean ±SE, N=3, *P<0.01 vs. Control
Table 6 DNA binding results of synthesized compounds (3a-d)
Compd.
|
λ max (nm)
|
Δλ max (nm)
|
% H
|
Kb (M-1)
|
ΔG (kJ/mol)
|
Free
|
Bound
|
3a
|
240
|
239
|
1
|
6.1879x10-4
|
1.1216X107
|
-40.205
|
3b
|
236
|
236
|
0
|
6.0157x10-4
|
1.4072X107
|
-40.767
|
3c
|
239
|
239
|
0
|
1.1560x10-3
|
1.0634X107
|
-40.073
|
3d
|
236
|
236
|
0
|
1.2388x10-3
|
3.4872X107
|
-43.015
|
Table 7 Bioavailability, druglikeness and in-silico pharmacokinetic assessment of synthesized compounds (3a-d)
Comp.
|
Bioavailability and Druglikeness
|
In-silico Pharmacokinetics
|
Total Molecular
weight
|
cLogP
|
H-Acceptors
|
H-Donors
|
Rotatable Bonds
|
Polar Surface Area
|
Druglikeness
|
Human intestinal absorption
|
Caco-2 permeability
|
Blood brain barrier
|
CYP450 2D6 substrate
|
3a
|
222.224
|
0.2739
|
5
|
2
|
1
|
103.51
|
5.2698
|
+0.982
|
-0.779
|
+0.982
|
-0.873
|
3b
|
236.251
|
0.6178
|
5
|
2
|
1
|
103.51
|
4.9763
|
+0.728
|
-0.753
|
+0.980
|
-0.889
|
3c
|
238.291
|
0.6344
|
4
|
2
|
1
|
118.53
|
4.2229
|
+0.979
|
-0.698
|
+0.977
|
-0.871
|
3d
|
252.318
|
0.9783
|
4
|
2
|
1
|
118.53
|
3.9143
|
+0.987
|
-0.673
|
+0.976
|
-0.886
|
Table 8: In-silico pharmacodynamics and bioactivity assessment of synthesized compounds (3a-d)
Comp.
|
In-silico Pharmacodynamics
|
Bioactivity score
|
Mutagenic
|
Tumorigenic
|
Reproductive Effective
|
Irritant
|
Aerobic biodegradability
|
Ames toxicity
|
Hepatotoxicity
|
GPCR ligand
|
Ion channel modulator
|
Kinase
inhibitor
|
Nuclear receptor
ligand
|
Protease inhibitor
|
Enzyme inhibitor
|
3a
|
NONE
|
NONE
|
HIGH
|
NONE
|
-0.590
|
-0.706
|
+0.925
|
-1.12
|
-1.58
|
-0.86
|
-1.26
|
-1.30
|
-0.69
|
3b
|
NONE
|
NONE
|
HIGH
|
NONE
|
-0.562
|
-0.694
|
+0.950
|
-1.07
|
-1.44
|
-0.90
|
-0.91
|
-1.32
|
-0.73
|
3c
|
HIGH
|
NONE
|
HIGH
|
NONE
|
-0.859
|
-0.731
|
+0.900
|
-1.43
|
-1.77
|
-1.41
|
-1.73
|
-1.32
|
-1.00
|
3d
|
HIGH
|
NONE
|
HIGH
|
NONE
|
-0.843
|
-0.711
|
+0.850
|
-1.35
|
-1.62
|
-1.42
|
-1.35
|
-1.34
|
-1.03
|
Table 9 Binding energies of synthesized compounds (3a-d) with GlcN-6-P and P38 MAPk targets
Antibacterial activity
|
Anticancer activity
|
Compd.
|
Binding energy in kcal/mol
|
Compd.
|
Binding energy in kcal/mol
|
Ciprofloxacin
|
-7.7
|
5-Fluorouracil
|
-4.7
|
3a
|
-7.6
|
3a
|
-6.4
|
3b
|
-7.9
|
3b
|
-6.4
|
3c
|
-7.4
|
3c
|
-6.0
|
3d
|
-7.4
|
3d
|
-6.2
|