S1 Design, Synthesis, Biological Evaluation and Molecular modeling studies of Novel Quinoline Derivatives Against Mycobacterium tuberculosis Ram Shankar Upadhayaya, *,† V. Jaya Kishore, † V. Nageswar Rao, † Vivek Sharma, † , Shailesh S. Dixit † and Jyoti Chattopadhyaya *,‡ † Institute of Molecular Medicine, Pune 411 057, India and ‡ Department of Bioorganic Chemistry, Biomedical Centre, Uppsala University, Sweden
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S1
Design, Synthesis, Biological Evaluation and Molecular
modeling studies of Novel Quinoline Derivatives Against
Mycobacterium tuberculosis
Ram Shankar Upadhayaya,*,† V. Jaya Kishore, † V. Nageswar Rao, † Vivek Sharma, †,
Shailesh S. Dixit† and Jyoti Chattopadhyaya*,‡
†Institute of Molecular Medicine, Pune 411 057, India and
‡Department of Bioorganic Chemistry, Biomedical Centre, Uppsala University, Sweden
S2
Table T1: Sr. No. Contents Page No.
1 1H-NMR spectra of compound 2 S6
2 13C-NMR spectra of compound 2 S7
3 1H-NMR spectra of compound 3 S8
4 13C-NMR spectra of compound 3 S9
5 1H-NMR spectra of compound 4 S10
6 D2O-NMR spectra of compound 4 S11
7 13C-NMR spectra of compound 4 S12
8 1H-NMR spectra of compound 5 S13
9 D2O-NMR spectra of compound 5 S14
10 13C-NMR spectra of compound 5 S15
11 1H-NMR spectra of compound 6 S16
12 D2O-NMR spectra of compound 6 S17
13 13C-NMR spectra of compound 6 S18
14 DEPT-NMR spectra of compound 6 S19
15 1H-NMR spectra of compound 7 S20
16 D2O-NMR spectra of compound 7 S21
17 13C-NMR spectra of compound 7 S22
18 DEPT-NMR spectra of compound 7 S23
19 1H-NMR spectra of compound 8 S24
20 13C-NMR spectra of compound 8 S25
21 DEPT-NMR spectra of compound 8 S26
22 1H-NMR spectra of compound 9 S27
23 13C-NMR spectra of compound 9 S28
24 DEPT-NMR spectra of compound 9 S29
25 1H-NMR spectra of compound 10 S30
S3
26 13C-NMR spectra of compound 10 S31
27 DEPT-NMR spectra of compound 10 S32
28 1H-NMR spectra of compound 11 S33
29 13C-NMR spectra of compound 11 S34
30 1H-NMR spectra of compound 12 S35
31 13C-NMR spectra of compound 12 S36
32 DEPT-NMR spectra of compound 12 S37
33 1H-NMR spectra of compound 13 S38
34 13C-NMR spectra of compound 13 S39
35 DEPT-NMR spectra of compound 13 S40
36 1H-NMR spectra of compound 14 S41
37 D2O-NMR spectra of compound 14 S42
38 13C-NMR spectra of compound 14 S43
39 DEPT-NMR spectra of compound 14 S44
40 1H-NMR spectra of compound 15 S45
41 13C-NMR spectra of compound 15 S46
42 1H-NMR spectra of compound 16 S47
43 13C-NMR spectra of compound 16 S48
44 1H-NMR spectra of compound 17 S49
45 13C-NMR spectra of compound 17 S50
46 1H-NMR spectra of compound 18 S51
47 D2O-NMR spectra of compound 18 S52
48 13C-NMR spectra of compound 18 S53
49 1H-NMR spectra of compound 19 S54
50 13C-NMR spectra of compound 19 S55
51 DEPT-NMR spectra of compound 19 S56
52 1H-NMR spectra of compound 20 S57
S4
53 13C-NMR spectra of compound 20 S58
54 DEPT-NMR spectra of compound 20 S59
55 1H-NMR spectra of compound 21 S60
56 13C-NMR spectra of compound 21 S61
57 1H-NMR spectra of compound 22 S62
58 D2O-NMR spectra of compound 22 S63
59 13C-NMR spectra of compound 22 S64
60 1H-NMR spectra of compound 23 S65
61 13C-NMR spectra of compound 23 S66
62 DEPT-NMR spectra of compound 23 S67
63 1H-NMR spectra of compound 24 S68
64 13C-NMR spectra of compound 24 S69
65 1H-NMR spectra of compound 25 S70
66 13C-NMR spectra of compound 25 S71
67 DEPT-NMR spectra of compound 25 S72
68 1H-NMR spectra of compound 26 S73
69 13C-NMR spectra of compound 26 S74
70 DEPT-NMR spectra of compound 26 S75
71 1H-NMR spectra of compound 27 S76
72 13C-NMR spectra of compound 27 S77
73 DEPT-NMR spectra of compound 27 S78
74 1H-NMR spectra of compound 28 S79
75 13C-NMR spectra of compound 28 S80
76 DEPT-NMR spectra of compound 28 S81
77 1H-NMR spectra of compound 29 S82
78 13C-NMR spectra of compound 29 S83
79 1H-NMR spectra of compound 30 S84
S5
80 13C-NMR spectra of compound 30 S85
81 DEPT-NMR spectra of compound 30 S86
82 1H-NMR spectra of compound 31 S87
83 13C-NMR spectra of compound 31 S88
84 DEPT-NMR spectra of compound 31 S89
85 Table S1: Forcefield based refinement of DARQ-ATP synthase complex. S90
86 Table S2: Split of AutoDock docking energetics. S91
87 Table S3: Standard Deviation Table S93
S6
Br
NOMe Br
2
S7
Br
NOMe Br
2
S8
N
BrN
O
N
3
S9
N
BrN
O
N
3
S10
N
BrNH
O
N
4
S11
N
BrNH
O
N
4
S12
N
BrNH
O
N
4
S13
N
Br
NHO
N
5
S14
N
Br
NHO
N
5
S15
N
BrNH
O
N
5
S16
O
N
BrNH
O6
S17
O
N
Br
NHO
6
S18
O
N
Br
NHO
6
S19
O
N
BrNH
O6
S20
S
N
Br
NHO
7
S21
S
N
BrNH
O7
S22
S
N
Br
NHO
7
S23
S
N
BrNH
O7
S24
N
Br
N
ON
CF3
8
S25
N
BrN
ON
CF3
8
S26
N
BrN
ON
CF3
8
S27
N
BrN
O9
S28
N
BrN
O9
S29
N
BrN
O9
S30
N
BrN
OO
10
S31
N
BrN
OO
10
S32
N
BrN
OO
10
S33
N
Br
N
ONNN
11
S34
N
BrN
ONNN
11
S35
N
Br
N
O
OO
12
S36
N
BrN
O
OO
12
S37
N
Br
N
O
OO
12
S38
N
Br
N
OO
O
13
S39
N
BrN
OO
O
13
S40
N
Br
N
OO
O
13
S41
N
Br
NHO
N
14
S42
N
BrNH
ON
14
S43
N
BrNH
ON
14
S44
N
BrNH
ON
14
S45
N
Br
O
N
15
S46
N
Br
O
N
15
S47
N
Br
O
NNNO2
16
S48
N
Br
O
NNNO2
16
S49
N
Br
O
NN
17
S50
N
Br
O
NN
17
S51
N
Br
O
NH
OO
18
S52
N
Br
O
NH
OO
18
S53
N
Br
O
NH
OO
18
S54
N
Br
O
OO
19
S55
N
Br
O
OO
19
S56
N
Br
O
OO
19
S57
N
Br
O
OO
20
S58
N
Br
O
OO
20
S59
N
Br
O
OO
20
S60
Br
N
OMe
OOOMe
OMe
21
S61
Br
N
OMe
OOOMe
OMe
21
S62
N
Br
O
OO
OH
O22
S63
N
Br
O
OO
OH
O22
S64
N
Br
O
OO
OH
O22
S65
N
Br
O
OO
NO
O
23
S66
N
Br
O
OO
NO
O
23
S67
N
Br
O
OO
NO
O
23
S68
N
Br
O
OO
NO
O
24
S69
N
Br
O
OO
NO
O
24
S70
N
Br
O
OO
NO
25
S71
N
Br
O
OO
NO
25
S72
N
Br
O
OO
NO
25
S73
N
Br
O
OO
NO
26
S74
N
Br
O
OO
NO
26
S75
N
Br
O
OO
NO
26
S76
N
Br
O
OO
NO
27
S77
N
Br
O
OO
NO
27
S78
N
Br
O
OO
NO
27
S79
N
Br
O
OO
NO
O
28
S80
N
Br
O
OO
NO
O
28
S81
N
Br
O
OO
NO
O
28
S82
N
Br
O
OO
NO
N29
S83
N
Br
O
OO
NO
N29
S84
N
Br
O
OO
NO
N
CF3
30
S85
N
Br
O
OO
NO
N
CF3
30
S86
N
Br
O
OO
NO
N
CF3
30
S87
N
Br
O
OO
NO
N
CF3
31
S88
N
Br
O
OO
NO
N
CF3
31
S89
N
Br
O
OO
NO
N
CF3
31
S90
Table S1 Forcefield based refinem
ent of DA
RQ
-ATP synthase com
plex. D
AR
Q
Interaction Energy (kcal/m
ol) Potential Energy (kcal/m
ol) stereosiom
ers R
S
~ -73
~ -2289 SR
~ -66
~ -2260 SS
~ -72
~ -2260
RR
~ -70
~ -2280
S91
Table S2 Split of A
utoDock docking energetics.
Com
pounds
DA
RQ
3 8
17 18
23/24
------------------------------
RS
RR
SR
SS
I.E. 1
-10.53 -10.0
-10.01 -10.61 -9.1 -9.07
-9.36 -10.61 -12.15
Vdw
2
-9.52 -9.78
-8.95 -10.25 -9.1
-9.07 -9.36
-10.60 -12.15 Elec. 3
-1.01 -0.22
-1.07 -0.36
0 0
0 -0.02
0 1 I.E.: Interm
olecular Energy 2 V
dW: van der W
aals, hydrogen bond and desolvation energy 3 Elec.: Electrostatic Energy
S92
Antim
ycobacterial activity:
All the com
pounds were screened for antim
ycobacterial activity against mycobacterium
tuberculosis by BA
CTEC
460 radiometric m
ethods.
The broth based BA
CTEC
460 TB system
was used for the grow
th of Mycobacteria. In this grow
th system, M
ycobacterium Tuberculosis
H37R
V was grow
n in the C14 labelled substrate in 7H
12 medium
, substrate is utilized by growing m
ycobacteria and 14CO
2 is produced, which
is detected in the form of ‘G
rowth Index’ (G
I), which reflects the rate and am
ount of growth in the m
edium vial. If an antituberculosis drug
will be added to the m
edium vial, it w
ill suppress the growth of the bacteria w
hich is detected by the decrease of the GI values as com
pared to
the control vial. The positive controls taken in the experiment w
ere the standard therapeutic drugs presently used for the treatment of the
tuberculosis, Isoniazid and Rifam
pin.
The rate of increase in GI values or the change in G
I over the previous day GI is called delta (∆) G
I, is compared w
ith that of control values.
If ∆GI of the drug-containing vial is equal to or greater than (≥) than that in control vial the organism
s are considered resistant to the drug. On
the contrary if ∆GI of the drug-containing vial is less (<) than that in control vial the organism
s are considered susceptible.
On the basis of the values calculated for ∆G
, out of all screened compounds, four com
pounds i.e. 3, 8, 17 and 18 were found to act as active
antimycobacterial agents. B
elow given table depicts ∆G
of the compounds tested.
S93
Table S3: Standard Deviation Table
Day
s 1
2 3
4 5
6 7
∆∆∆ ∆ G
I 8
∆∆∆ ∆ G
I 9
∆∆∆ ∆ G
I %
Inhibition
12 22
25 28
34 33
35 02
35 0
56 21
94.4 16
27 32
40 51
49 57
08 47
10 57
10 94.3
G
I 14
24 30
39 48
48 53
05 55
2 61
6 94
N
N
OMe
Br
N
SD
2 2.51
3.6 6.6
9.1 9
11.7
10.1
2.6
0.20 1
1 0
0 0
0 0
0 0
0 0
0 100
1 0
0 0
0 0
0 0
0 0
0 0
100 G
I
1 1
0 0
0 0
0 0
0 0
0 0
100 N
N
OMe
Br
NCF3
SD
0
0.6 0
0 0
0 0
0
0
0
1 0
0 0
0 0
0 0
0 0
0 0
100 9
10 10
10 9
8 9
01 8
1 8
0 99.2
G
I 3
10 11
10 0
7 7
0 7
0 6
-1 99.4
N
N
OMe
Br
N
SD
4.1
5.8 6.1
5.8 5.2
4.3 4.7
4.3
4.2
0.41
23 40
52 67
81 81
95 14
98 3
106 08
89.4 15
27 37
45 52
48 53
05 53
0 55
-2 94.5
G
I 18
34 44
55 63
58 64
06 64
0 64
0 93.6
N
NHOMe
Br
OO
SD
4.0
6.5 7.5
11 14.6
16.9 21.7
23.5
27.2
2.7
12 12
10 9
8 7
5 0
5 -1
4 0
99.6 13
11 11
9 9
8 8
1 7
-2 8
0 99.2
G
I 14
14 12
4 10
8 9
1 9
-1 8
0 99.2
Isoniazid
SD
1 1.52
1 2.9
1 0.57
2.1
2
2.3
0.23 20
48 86
159 290
437 711
6 817
13 903
23
21 49
87 161
288 435
713 9
820 13
945 25
G
I
20 48
86 148
292 439
711 1
815 6
935 21
Control
SD
0.57 0.57
0.57 7
2 2
1.15
2.51
21.9
S94
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