Design, Synthesis, Antitubercular and Antibacterial Activities of 1,3,5-Triazinyl Carboxamide Derivatives and In Silico Docking Studies

Article abstract of DOI:10.1134/S1070363220070208

Abstract: A series of novel N-{2-fluoro-6-[(4,6-dimethoxy-1,3,5-triazin-2-yl)methyl]phenyl} carboxamide derivatives has been synthesized, and their molecular structures are confirmed by ¹H and ¹³C NMR, and mass spectra. Screening of the products for their antitubercular and antibacterial activities indicates the difluoro-4-chlorophenyl and 6-chloropyridine-3-yl derivatives as more potent agents than the reference drugs Pyrazinamide and Streptomycin. All compounds have been docked into MTB enoyl reductase (PDB code: 4U0J) to explore their binding interactions at the active sites.

Full text of DOI:10.1134/S1070363220070208

ISSN 1070-3632, Russian Journal of General Chemistry, 2020, Vol. 90, No. 7, pp. 1322–1330. © Pleiades Publishing, Ltd., 2020.
Design, Synthesis, Antitubercular and Antibacterial Activities
of 1,3,5-Triazinyl Carboxamide Derivatives
and In Silico Docking Studies
a
b
a
a
a
S. Bodige , P. Ravula , K. Ch. Gulipalli , S. Endoori , P. Koteswara Rao Cherukumalli ,
c
a,
J. N. Narendra Sharath Chandra , and N. Seelam *
a
Department of Chemistry, Koneru Lakshmaiah Education Foundation, Green Fields, Vaddeswaram, Guntur, 522502 India
b
Department of Pharmaceutical Chemistry, Gurunanak Institutions Technical Campus, School of Pharmacy,
Hyderabad, 501506 India
c
Department of Pharmaceutical Chemistry, Gurukrupa Institute of Pharmacy, Maharashtra, 431129 India
*
e-mail: nareshvarma.klu@gmail.com
Received April 27, 2020; revised June 6, 2020; accepted June 10, 2020
Abstract—A series of novel N-{2-fluoro-6-[(4,6-dimethoxy-1,3,5-triazin-2-yl)methyl]phenyl} carboxamide
1
13
derivatives has been synthesized, and their molecular structures are confirmed by H and C NMR, and mass
spectra. Screening of the products for their antitubercular and antibacterial activities indicates the difluoro-4-chlo-
rophenyl and 6-chloropyridine-3-yl derivatives as more potent agents than the reference drugs Pyrazinamide and
Streptomycin. All compounds have been docked into MTB enoyl reductase (PDB code: 4U0J) to explore their
binding interactions at the active sites.
Keywords: 1,3,5-triazine, synthesis, docking studies, antitubercular activity
DOI: 10.1134/S1070363220070208
INTRODUCTION
tuberculosis using the microplate alamar blue assay
(MABA) method.
Triazine derivatives are well known for their anti-
Molecular docking study was performed for
microbial [1], antibacterial [2], anti-HIVand anticancer [3]
activities. 2,4,6-Trisubstituted-1,3,5-triazine derivatives
and their analogues are potent anti-BT agents [4–7]
the structures of the synthesized compounds with
Mycobacterium tuberculosis enoyl acyl carrier protein
reductase (MTB enoyl reductase) to explore their binding
interactions at the active sites.
(Fig. 1).
In continuation of our study of 1,3,5-triazines, some
RESULTS AND DISCUSSION
novel N-{2-fluoro-6-[(4,6-dimethoxy-1,3,5-triazin-2-
yl)methyl]phenyl}carboxamide derivatives were
synthesized (Scheme 1), their structures were confirmed
Synthesis of the designed N-{2-fluoro-6-[(4, 6-dime-
thoxy-1,3,5-triazin-2-yl)methyl]phenyl}carboxamide
derivatives 7a–7r (Scheme 1) started with treatment
1
13
by H and C NMR, and mass spectral analysis.Anti-TB
activity of the products was tested against Mycobacterium
of sodium dicyanamide (1) by ZnCl and formation
2
Fig. 1. 2,4,6-Trisubstituted-1,3,5-triazines characterized by anti-tubercular activity: (a) R = 1,2,3,4-tetrahydroquinoline,
1
1
1
,2,3,4-tetrahydroisoquinoline, R = variousamines; (b) R = 1,2,3,4-tetrahydroquinoline, piperidine, R = variousamines; (c) R =
2
1
2
1
,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, piperidine, aniline, R = variousamines.
2
1
322

DESIGN, SYNTHESIS, ANTITUBERCULAR AND ANTIBACTERIAL ACTIVITIES
1323
Scheme 1. Synthesis of the title compounds.
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1324
BODIGE et al.
Table 1. Antitubercular activity of synthesized compounds 7a–7r
Compound
MIC, μg/mL
50.00
Compound
MIC, μg/mL
25.00
6.25
Compound
MIC, μg/mL
12.5
7
a
7g
7h
7i
7j
7k
7l
7n
7o
7p
7q
7r
7
b
25.00
6.25
3.12
12.50
25.0
50.0
25.0
50.0
3.12
6.25
7
c
12.5
7
d
25.00
25.00
12.50
3.12
7
e
7
f
12.50
Pyrazinamide
Streptomycin
7m
of zinc salt 2, which on cyclization with chloroacetyl
chloride led to 2-(chloromethyl)-4,6-dimethoxy-1,3,5-
triazine (3) in good yield. The intermediate 3 was reacted
with sodium thiomethoxide yielding compound 4, the
reaction of which with 2-fluoroaniline in the presence
of t-BuOCl and sodium methoxide afforded 2-fluoro-
Molecular structures of the products were confirmed by
H and C NMR, and mass spectral analysis. Initially
the amide coupling was tried with EDCI·HCl and HOBT
in DCM, or HATU and DIPEA, and it did not bring
the process to completion. On the contrary, the amide
1
13
coupling progressed smoothly with T P /DIPEA at room
3
temperature within 2 h.
6
-[(4,6-dimethoxy-1,3,5-triazin-2-yl)(methylthio)-
Antitubercular activity. Anti-TB activity of the
synthesized compounds 7a–7r was evaluated against
Mycobacterium tuberculosis using the MABA method
methyl]benzenamine (5). The following desulfonation of
compound 5 with NiCl ·H O in the presence of NaBH
gave the intermediate 6. Its reaction with different
2
2
4
(
Table 1). The accumulated data revealed that the
substituted acids upon T P/DIPEA action afforded the
3
compounds 7d and 7m exhibited comparatively more
potent activity than the reference drugs Pyrazinamide
and Streptomycin. The compounds 7c and 7h also
demonstrated the appreciable inhibitory activity.Activity
of the other products was relatively lower.
corresponding targeted compounds 7a–7r in good yields.
Antibacterial activity. The synthesized compounds
were tested for their antibacterial activity using the Agar
well diffusion method against Escherichia coli (gram-
negative) and Staphylococcus aureus (gram-positive)
strains. The accumulated data (Table 2) indicated the
compounds 7b and 7c bearing 3-methoxyphenyl and
2
,4-dichlorophenyl moieties as antibacterially active in
comparison with the standard drug Chloramphenicol.
Molecular docking. Docking interactions between
the synthesized compounds and MTB enoyl reductase
(PDB code: 4U0J) were considered on Windows 2007,
version MOE 2008.10, and revealed that the synthesized
compounds 7a–7r interacted with amino acid residues
GLY 96, VAL 65, PHE 41, LYS 118, and ILE 16, that
also could interact with MTB enoyl reductase inhibitors
[
10–13]. Compound 7d showed effective H-bond
interaction with GLY 96 of 38.2% binding at a distance
of 1.85 Å, and 1,3,5-triazine moiety showed stacking
interaction with PHE 41 (Fig. 2). The compound was
surrounded also by ILE 16, ILE 95, ILE 122, PHE 97,
andALA198. Such interactions emphasized its significant
inhibitory capacity against MTB enoyl reductase.
Fig. 2. (a) Two-dimensional presentation of the interacting
mode of 7d with MTB enoyl reductase. (b) Three-dimensional
structural model of compound 7d docked into MTB enoyl
reductase.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 7 2020

DESIGN, SYNTHESIS, ANTITUBERCULAR AND ANTIBACTERIAL ACTIVITIES
Table 2. Antibacterial activity of synthesized compounds 7a–7r
1325
Zone of inhibition (mm)
Escherichia coli (gram-negative) Staphylococcus aureus (gram-positive)
Compound
concentration, ꢀg/mL
1
00
200
15
27
28
24
21
19
20
19
19
18
17
20
19
15
19
17
19
16
30
100
14
22
24
18
16
17
15
16
17
14
13
16
14
13
14
15
17
12
25
200
19
27
28
23
20
19
18
19
19
18
17
21
18
16
20
19
19
16
29
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
13
23
26
19
18
16
17
14
17
16
13
19
16
12
13
14
17
13
27
Chloramphenicol
Similarly, compound 7m exhibited one H-bond
interaction with GLY 96 of 36.5% binding at a distance
of 1.63 Å. Further, 1,3,5-triazine moiety of the compound
demonstrateded stacking interactions with PHE 41.
The compound was surrounded by ILE 16, ILE 95,
ILE 122, and PHE 97. Docking interactions have been
observed also for the other compounds making those to
be considered as promising inhibitors for tuberculosis.
was refluxed gently for 18 h. After completion of the
process, the reaction mixture was cooled down to room
temperature and filtered. The residue was suspended
in dichloromethane (200 mL), the insoluble material
was filtered off, and the filtrate was concentrated under
reduced pressure to afford compound 2 as a white solid.
1
Yield 55%, mp 85–87°C. H NMR spectrum, δ, ppm:
3.73 s (12H, 4OCH ), 5.05 br. s (4H, 4C=NH).
3
Synthesis of 2-(chloromethyl)-4,6-dimethoxy-1,3,5-
triazine (3). A stirred solution of compound 2 (20.0 g,
EXPERIMENTAL
All chemicals were purchased from Sigma–Aldrich,
Merck and Combi blocks, and were used without further
purification. Melting points were determined in open end
capillary tubes on a Guna Digital Melting Point apparatus.
Elemental analysis was carried out on a Perkin-Elmer 240
6
1.5 mmol) in dichloromethane (100 mL) was mixed
with chloroacetylchloride (10.6 mL, 135 mmol in 100 mL
dichloromethane) drop wise over 20 min at a temperature
below –40°C. Then the reaction mixture was stirred for
3
0 min at –50°C, warmed up to room temperature and
1
13
CHN elemental analyzer. H and C NMR spectra were
measured on a Bruker AMX 300 spectrometer operating
stirred for 3 h more. The reaction mixture was filtered
and washed with dichloromethane (150 mL). The filtrate
was washed with water (2×150 mL) and saturated sodium
bicarbonate (150 mL), dried over anhydrous Na SO ,
and concentrated under reduced pressure. The residue
obtained was purified by column chromatography (SiO2,
100–200 mesh) using 12% EtOAc in n-hexane as an
eluent to afford compound 3 as a white solid. Yield 52%,
1
13
at 400 MHz for H and 100 MHz for C NMR using
TMS as an internal standard and CDCl or DMSO-d as
3
6
2
4
the solvent. Mass spectra were measured on an Agilent
technologies mass spectrometer.
Synthesis of zinc complex 2. A suspension of
sodium dicyanamide (20.0 g, 22.4 mmol) in methanol
1
(
150 mL) was mixed with ZnCl (15.2 g, 11.2 mmol) at
mp 57–59°C. H NMR spectrum, δ, ppm: 4.08 s (6H,
2OCH ), 4.48 s (2H, CH Cl). C NMR spectrum, δ ,
2
1
3
room temperature in one go, and the reaction mixture
3 2 C
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 7 2020

1326
BODIGE et al.
ppm: 42.11, 55.62, 172.8, 181.1. Found, %: C 38.11; H
2OCH ), 4.55 s (2H, NH ), 5.07 s (1H, CHS), 6.65–6.70 m
3 2
4
4
.14; N 22.28. C H ClN O . Calculated, %: C 38.01; H
.25; N 22.16. MS (MM): m/z: 190.2 [М + Н] .
(1H, H ), 6.94 t (1H, J = 9.2, H ), 7.24 d (1H, J = 10.8,
6
8
3
2
Ar
13
Ar
+
H ). C NMR spectrum, δ , ppm: 14.20, 43.42, 56.93,
Ar
C
1
15.5, 115.7, 119.5, 119.6, 125.7, 181.4, 125.8, 127.9,
28.0, 135.9, 136.0, 152.7, 155.1, 174.2. Found, %: C
0.21; H 4.76; N 18.16. C H FN O S. Calculated, %: C
Synthesis of 2,4-dimethoxy-6-[(methylthio)methyl]-
,3,5-triazine (4). A stirred solution of compound 3
1
5
5
1
(
12.0 g, 63.4 mmol) in DMF (60.0 mL) was mixed with
NaSMe (5.34 g, 76.1 mmol) portion wise over 10 min at
°C. The reaction mixture was stirred at 0–5°C for 3 h
and then partitioned between 100 mL ethyl acetate and
00 mLwater. The layers were separated, and the aqueous
13 15
4
2
+
0.31; H 4.87; N 18.05. MS (MM): m/z: 311.3 [М + Н] .
0
Synthesis of 2-fluoro-6-[(4,6-dimethoxy-1,3,5-
triazin-2-yl)methyl]benzenamine (6). Astirred solution
of compound 5 (5.00 g, 16.1 mmol) in methanol (50.0 mL)
was mixed at 0°C with NiCl ·6H O (7.64 g, 32.2 mmol)
2
layer was extracted with ethyacetate (2×100 mL). The
combined organic layers were washed with water (2×
2
2
and NaBH (2.43 g, 64.5 mmol) portion wise over 20 min
4
1
00 mL), dried over anhydrous Na SO , and concentrated
while keeping the temperature below 10°C. The process
of addition was exothermic and accompanied by an
instant change from brown solution to black suspension.
External cooling was removed, the reaction mixture was
warmed up to room temperature and then stirred for
2.5 h. Then the mixture was filtered through a small plug
of celite and washed with methanol (100 mL); the filtrate
was concentrated under reduced pressure. The residue
was portioned between 200 mL aqueous ammonia (2 M)
and 100 mL of ethyl acetate. The layers were separated
and the aqueous layer was extracted with ethyl acetate
2
4
under reduced pressure. The crude residue was purified
by column chromatography (SiO , 100–200 mesh) using
2
15% EtOAc in n-hexane as an eluent to afford compound
1
4
as a yellow solid. Yield 60%, mp 52–54°C. H NMR
spectrum, δ, ppm: 2.24 s (3H, CH S), 3.61 s (2H, CH S),
3
2
13
4.05 s (6H, 2OCH ). C NMR spectrum, δ , ppm: 14.16,
3 C
4
1.38, 54.89, 172.1, 181.4. Found, %: C 41.88; H 5.62;
N 20.77. C H N O S. Calculated, %: C 41.78; H 5.51;
N 20.88. MS (MM): m/z: 202.1 [М + Н] .
7
11
3
2
+
Synthesis of 2-fluoro-6-[(4,6-dimethoxy-1,3,5-
triazin-2-yl) (methylthio)methyl]benzenamine (5). A
stirred solution of 2-fluoroaniline (3.60 mL, 37.3 mmol)
in dichloromethane (40.0 mL) under the atmosphere of
nitrogen was cooled down to –70°C and charged with
t-BuOCl (4.19 mL, 37.3 mmol in 40 mLdichloromethane)
drop wise over 10 min. The reaction mixture was stirred
for 10 min at –70°C, and triazine 4 (7.50 g, 37.3 mmol,
in 20 mL dichloromethane) was added drop wise over
(2×200 mL). The combined organic layers were washed
with water (2×200 mL), dried over anhydrous Na SO ,
2
4
and concentrated under reduced pressure. The crude
residue was purified by column chromatography (SiO2,
1
00–200 mesh) using 12% EtOAc in n-hexane as an
eluent to afford compound 6 as a pale brown solid. Yield
1
7
3%, mp 75–77°C. H NMR spectrum, δ, ppm: 3.94 s
(
(
8H, CH , 2OCH ), 5.07 br. s (2H, NH ), 6.50–6.55 m
2
3
2
1H, H ), 6.84 d (1H, J = 7.6, H ), 6.94 d. d (1H,
1
5 min while keeping the temperature below –60°C. The
Ar
Ar
1
3
J = 10.4, J = 8.4, H ). C NMR spectrum, δ , ppm:
mixture was stirred at –70°C for 75 min, and sodium
methoxide (3.62 g, 67.1 mmol, 30% solution in methanol)
was added drop wise over 15 min. The external cooling
was removed, and the reaction mixture was warmed up
to room temperature. Stirring of the mixture at room
temperature for 10 min made it turn quickly from yellow
to dark red solution. Water (150 mL) was added to the
mixture. The layers were separated, and the aqueous layer
was extracted with dichloromethane (2×200 mL). The
combined organic layers were washed with water (2×
1
2
Ar
C
40.36, 40.39, 54.96, 113.3, 113.4, 115.8, 115.9, 123.24,
123.24, 123.28, 126.05, 126.07, 134.7, 134.8, 149.9,
152.2, 172.0, 180.4. Found, %: C 54.44; H 4.85; N 21.29.
C H FN O . Calculated, %: C 54.54; H 4.96; N 21.20.
12 13
4
2
+
MS (MM): m/z: 265.1 [М + Н] .
General procedure for the synthesis of compounds
7a–7r. To a solution of compound 6 (0.50 mmol) in THF
(10.0 mL) were added Et N (1.00 mmol), a solution of
3
T3P (0.60 mmol) 50% in EtOAc and an appropriate acid
(0.50 mmol). The mixture was stirred at room temperature
200 mL), dried over anhydrous Na SO , and concentrated
2 4
under reduced pressure. The crude residue was purified
for 2 h, then quenched with saturated NaHCO solution
3
by column chromatography (SiO , 100–200 mesh)
(10.0 mL) and extracted with EtOAc (2×10.0 mL).
2
using 15% EtOAc in n-hexane as an eluent to afford
compound 5 as an orange gum with the yield 44%. H
The combined organic layers were washed with H O
2
1
(5.00 mL), brine solution (5.00 mL), dried over Na SO ,
2
4
NMR spectrum, δ, ppm: 2.07 s (3H, CH S), 4.04 s (6H,
and concentrated. The crude product was purified by
3
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DESIGN, SYNTHESIS, ANTITUBERCULAR AND ANTIBACTERIAL ACTIVITIES
1327
column chromatography (EtOAc/n-hexanes) to afford
the corresponding title compounds 7a–7r.
131.6, 131.8, 136.0, 136.5, 156.3, 158.8, 161.8, 161.4,
162.1, 171.8, 179.8. Found, %: C 53.16; H 3.46; N 12.70.
C H ClF N O . Calculated, %: C 53.05; H 3.56; N
N-{2-Fluoro-6-[(4,6-dimethoxy-1,3,5-triazin-2-yl)-
methyl]phenyl}cyclopropanecarboxamide (7a). Off
white solid, yield 77%, mp 95–99°C. H NMR spectrum,
20 16
3
4
3
+
1
2.59. MS (MM): m/z: 453.1 [М + Н] .
1
2-Chloro-4-fluoro-N-{2-fluoro-6-[(4,6-dimethoxy-
δ, ppm: 0.69–0.73 m (4H, 2CH ), 1.67–1.71 m (1H,
1,3,5-triazin-2-yl)methyl]phenyl} benzamide (7e).
Light yellow solid, yield 76%, mp 102–106°C. H NMR
2
1
CHC=O), 3.91 s (6H, 2OCH ), 4.02 s (2H, ArCH ),
3
2
7
(
.14–7.18 m (2H, H ), 7.24–7.28 m (1H, H ), 9.51 s
spectrum, δ, ppm: 3.85 s (6H, 2OCH ), 4.12 s (2H, CH ),
Ar
Ar
3
2
1H, NH). 13C NMR spectrum, δ , ppm: 6.80, 13.44,
7.18–7.23 m (2H, H ), 7.29–7.35 m (2H, HAr), 7.54 d. d
C
Ar
4
1
0.64, 54.83, 114.1, 114.3, 124.4, 124.6, 126.3, 127.3,
27.4, 136.9, 156.5, 158.9, 171.6, 171.9, 180.5. Found,
(1H, J = 8.8, J = 2.4, HAr), 7.60 d. d (1H, J = 8.8, J =
1
2
1
2
13
6.4, HAr), 9.93 s (1H, NH). C NMR spectrum, δ , ppm:
C
%
%
: C 57.73; H 5.05; N 16.75. C H FN O . Calculated,
40.44, 54.87, 114.2, 114.3, 114.4, 114.5, 117.0, 117.3,
123.7, 123.8, 126.64, 126.66, 128.0, 128.1, 130.7, 130.8,
131.3, 131.5, 132.83, 132.86, 136.8, 156.5, 158.9, 161.0,
1
6
17
4
3
: C 57.83; H 5.16; N 16.86. MS (MM): m/z: 333.2
+
[
М + Н] .
N-{2-Fluoro-6-[(4,6-dimethoxy-1,3,5-triazin-2-
yl)methyl]phenyl}-2-(3-methoxyphenyl) acetamide
1
63.5, 164.3, 172.0, 180.3. Found, %: C 54.34; H 3.70;
N 13.21. C H ClF N O . Calculated, %: C 54.23; H
19 15
2
4
3
+
1
3.59; N 13.31. MS (MM): m/z: 421.1 [М + Н] .
(7b). Off white solid, yield 82%, mp 81–83°C. H NMR
spectrum, δ, ppm: 3.56 s (2H, CH C=O), 3.71 s (3H,
4-Bromo-2-chloro-N-{2-fluoro-6-[(4,6-dimethoxy-
2
ArOCH ), 3.87 s (6H, 2OCH triazine), 3.97 s (2H,
1,3,5-triazin-2-yl)methyl]phenyl} benzamide (7f).
Yellow solid, yield 77%, mp 101–105°C. H NMR
3
3
1
ArCH ), 6.76 d. d (1H, J = 8.4, J = 2.4, H ), 6.84–6.88 m
2
1
2
Ar
(
2H, H ), 7.11–7.19 m (3H, H ), 7.22–7.28 m (1H, H ),
spectrum, δ, ppm: 3.87 s (6H, 2OCH ), 4.13 s (2H, CH ),
Ar
Ar
Ar
3
2
1
3
9
4
1
1
6
6
.37 s (1H, NH). C NMR spectrum, δ , ppm: 40.28,
7.21–7.25 m (2H, H ), 7.31–7.35 m (1H, H ), 7.50 d
C
Ar Ar
2.13, 54.83, 111.9, 114.2, 114.4, 114.5, 121.1, 124.3,
24.4, 126.2, 126.3, 127.5, 127.6, 129.1, 136.4, 137.1,
56.4, 158.8, 159.1, 169.0, 171.8, 180.1. Found, %: C
1.26; H 5.24; N 13.08. C H FN O . Calculated, %: C
(1H, J = 8.4, H ), 7.67–7.70 m (1H, H ), 7.86 d (1H,
Ar Ar
1
3
J = 2.0, H ), 9.99 s (1H, NH). C NMR spectrum, δ ,
Ar
C
ppm: 40.43, 54.88, 114.4, 114.6, 123.2, 123.5, 123.6,
126.65, 126.68, 128.1, 128.2, 130.2, 180.3, 130.4, 130.4,
131.3, 131.9, 135.4, 136.7, 156.5, 158.9, 164.3, 172.0.
2
1
21
4
4
+
1.16; H, 5.13; N, 13.59. MS (MM): m/z: 413.2 [М + Н] .
Found, %: C 47.27; H 3.25; N 11.73. C H BrClFN O .
2
-(2,6-Dichlorophenyl)-N-{2-fluoro-6-[(4,6-
19 15
4
3
Calculated, %: C 47.37; H 3.14; N 11.63. MS (MM): m/z:
dimethoxy-1,3,5-triazin-2-yl)methyl]phenyl}-
acetamide (7c). Orange solid, yield 85%, mp 121–123°C.
H NMR spectrum, δ, ppm: 3.90 s (6H, 2OCH ), 3.96 s
+
4
81.0 [М + Н] .
1
2-Fluoro-N-{2-fluoro-6-[(4,6-dimethoxy-1,3,5-
3
(
7
2H, CH C=O), 9.55 s (1H, NH), 4.05 s (2H, CH Ar),
triazin-2-yl)methyl]phenyl}-5-iodobenzamide (7g).
Yellow solid, yield 81%, mp 103–106°C. H NMR
2
2
1
.13–7.18 m (2H, H ), 7.46 s (1H, H ), 7.24–7.33 m
Ar
Ar
13
(2H, H ), 7.44 s (1H, H ). C NMR spectrum, δ , ppm:
spectrum, δ, ppm: 3.86 s (6H, 2OCH ), 4.10 s (2H, CH ),
Ar
Ar
C
3
2
3
1
1
3
7.39, 40.33, 54.88, 114.2, 114.4, 124.2, 180.4, 124.3,
26.35, 126.38, 127.6, 127.7, 128.1, 129.4, 132.0, 135.5,
36.5, 156.4, 158.9, 166.5, 171.9. Found, %: C 53.32; H
.70; N 12.31. C H Cl FN O . Calculated, %: C 53.23;
7.16–7.25 m (3H, H ), 7.32–7.37 m (1H, H ), 7.83 d. d
Ar Ar
(1H, J = 6.4, J = 2.0, H ), 7.88–7.92 m (1H, H ),
1
2
Ar
Ar
1
3
9.91 s (1H, NH). C NMR spectrum, δ , ppm: 40.72,
C
54.87, 88.10, 88.13, 114.4, 114.6, 118.7, 118.9, 123.7,
123.8, 125.7, 125.9, 126.72, 126.75, 128.1, 128.2, 136.9,
20
17
2
4
3
+
H 3.80; N 12.42. MS (MM): m/z: 451.1 [М + Н] .
-(4-Chlorophenyl)-2,2-difluoro-N-{2-fluoro-6-
(4,6-dimethoxy-1,3,5-triazin-2-yl)methyl]phenyl}-
acetamide (7d). Light yellow solid, yield 88%, mp
1
1
37.9, 141.1, 141.2, 156.4, 157.8, 158.9, 160.3, 161.2,
71.9, 180.3. Found, %: C 44.65; H 2.85; N 10.83.
2
[
C H F IN O . Calculated, %: C 44.55; H 2.95; N 10.94.
19 15
2
4
3
+
1
MS (MM): m/z: 513.0 [М + Н] .
7
2
7
0–74°C. H NMR spectrum, δ, ppm: 3.87 s (6H,
OCH ), 4.03 s (2H, CH ), 7.20–7.25 m (2H, H ),
3-Bromo-5-chloro-N-{2-fluoro-6-[(4,6-dimethoxy-
3
2
Ar
.33–7.38 m (1H, H ), 7.58–7.65 m (4H, H ), 10.5 s
1,3,5-triazin-2-yl)methyl]phenyl} benzamide (7h).
Ar
Ar
1H, NH). 13C NMR spectrum, δ , ppm: 40.17, 54.81,
Off white solid, yield 79%, mp 112–116°C, H NMR
1
(
C
111.9, 114.4, 114.5, 114.7, 116.9, 122.4, 122.5, 126.84,
spectrum, δ, ppm: 3.81 s (6H, 2OCH ), 10.0 s (1H, NH),
3
127.00, 127.06, 127.1, 128.6, 126.82, 128.7, 128.9, 131.3,
4.06 s (2H, CH ), 7.22–7.28 m (2H, H ), 7.33–7.39 m
2
Ar
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 7 2020

1328
BODIGE et al.
1
(
1H, H ), 7.84 d (1H, J = 1.2, H ), 7.93 br. s (1H, H ),
105°C. H NMR spectrum, δ, ppm: 3.77 s (6H, 2OCH ),
Ar
Ar
Ar
3
1
3
7
4
1
1
.99 t (1H, J = 2.0, H ). C NMR spectrum, δ , ppm:
4.10 s (2H, CH ), 7.25–7.30 m (2H, H ), 7.36–7.42 m
Ar
C
2
Ar
1.05, 54.77, 114.4, 114.6, 122.4, 123.7, 123.9, 126.7,
26.83, 126.86, 128.30, 128.39, 129.1, 133.7, 134.4,
36.9, 137.3, 156.6, 159.1, 162.5, 171.9, 180.3. Found, %:
(1H, H ), 8.12 d (1H, J = 8.4, H ), 8.48 d. d (1H, J =
Ar Ar 1
8.4, J = 1.6, H ), 9.14 s (1H, H ), 10.2 s (1H, NH).
C NMR spectrum, δ , ppm: 40.94, 54.69, 114.4, 114.6,
2
Ar
Ar
1
3
C
C 47.27; H 3.25; N 11.73. C H BrClFN O . Calculated,
119.9, 120.6, 120.7, 122.6, 123.5, 123.6, 125.3, 126.84,
126.87, 128.4, 128.5, 132.1, 136.7, 137.4, 137.7, 148.2,
148.9, 149.0, 156.6, 159.1, 162.5, 171.9, 148.5, 180.3.
19
15
4
3
%
: C 47.37; H 3.14; N 11.63. MS (MM): m/z: 481.0
+
[
М + Н] .
-Chloro-N-{2-fluoro-6-[(4,6-dimethoxy-1,3,5-
triazin-2-yl)methyl]phenyl}pyridine-2-carboxamide
Found, %: C 52.28; H 3.55; N 16.11. C H F N O .
5
19 15
4
5
3
Calculated, %: C 52.18; H 3.46; N 16.01. MS (MM):
+
1
m/z: 438.1 [М + Н] .
(7i). Off white solid, yield 83%, mp 105–109°C. H NMR
spectrum, δ, ppm: 3.83 s (6H, 2OCH ), 4.09 s (2H, CH ),
6-Chloro-N-{2-fluoro-6-[(4,6-dimethoxy-1,3,5-
3
2
7
.21–7.25 m (2H, H ), 7.30–7.36 m (1H, H ), 8.06 d
triazin-2-yl)methyl]phenyl}pyridine-3-carboxamide
(7m). Yellow solid, yield 88%, mp 106–110°C. H
Ar
Ar
1
(1H, J = 8.4, H ), 8.17 d. d (1H, J = 8.4, J = 2.4, H ),
Ar
1
2
Ar
1
3
8
.73 d (1H, J = 2.4, H ), 10.4 s (1H, NH). C NMR
NMR spectrum, δ, ppm: 3.79 s (6H, 2OCH ), 3.79 s
Ar
3
spectrum, δ , ppm: 40.83. 54.82, 114.5, 114.7, 123.7,
(6H, 2OCH ), 4.09 s (2H, CH ), 7.23–7.29 m (2H, H ),
C
3
2
Ar
1
1
24.0, 124.1, 126.34, 126.37, 127.9, 128.0, 134.3, 136.6,
37.6, 147.1, 147.6, 156.6, 159.1, 161.8, 171.8, 180.2.
7.35–7.40 m (1H, H ), 7.71 d (1H, J = 8.0, H ), 8.25 d. d
Ar Ar
(1H, J = 8.4, J = 2.4, H ), 8.85 d (1H, J = 2.0, H ),
1
2
Ar
Ar
1
3
Found, %: C 53.44; H 3.64; N 17.45. C H ClFN O .
10.1 s (1H, NH). C NMR spectrum, δ , ppm: 40.93,
1
8
15
5
3
C
Calculated, %: C 53.54; H 3.74; N 17.34. MS (MM):
m/z: 404.1 [М + Н] .
54.72, 114.4, 114.6, 123.6, 123.8, 124.1, 124.4, 126.7,
126.8, 128.3, 128.41, 128.49, 137.4, 138.8, 140.3, 149.1,
+
153.0, 156.6, 159.1, 150.7, 162.6, 171.9,180.3. Found, %:
N-{2-Fluoro-6-[(4,6-dimethoxy-1,3,5-triazin-2-
C 53.44; H 3.85; N 17.23. C H ClFN O . Calculated,
yl)methyl]phenyl}-4-nitropyridine-2-carboxamide
18 15
5
3
1
(7j). Brown solid, yield 83%, mp 105–109°C. H NMR
%: C 53.54; H 3.74; N 17.34. MS (MM): m/z: 404.1
+
spectrum, δ, ppm: 3.82 s (6H, 2OCH ), 4.10 s (2H, CH ),
[М + Н] .
3
2
7
.23–7.28 m (2H, H ), 7.33–7.38 m (1H, H ), 8.40 d. d
6-Fluoro-N-{2-fluoro-6-[(4,6-dimethoxy-1,3,5-
Ar
Ar
(
9
1H, J = 5.2, J = 2.0, H ), 8.53 d (1H, J = 2.0, H ),
.07 d (1H, J = 5.2, H ), 10.6 s (1H, NH). C NMR
Ar
1 2 Ar Ar
triazin-2-yl)methyl]phenyl}pyridine-3-carboxamide
(7n). Orange solid, yield 88%, mp 106–110°C. H NMR
1
3
1
spectrum, δ , ppm: 40.82, 54.85, 119.4, 123.8, 123.9,
C
spectrum, δ, ppm: 3.79 s (6H, 2OCH ), 4.09 s (2H, CH ),
3
2
1
1
3
3
26.45, 126.48, 128.1, 128.2, 136.7, 151.5, 152.0, 154.9,
59.0, 156.6, 161.2, 171.9, 180.1. Found, %: C 52.28; H
7
.23–7.29 m (2H, H ), 7.34–7.40 m (2H, H ), 8.39 td
Ar Ar
(1H, J = 8.0, J = 2.0, H ), 8.70 d (1H, J = 2.0, H ),
1 2 Ar Ar
13
.54; N 20.18. C H FN O . Calculated, %: C 52.18; H
1
8
15
6
5
10.0 s (1H, NH). C NMR spectrum, δ , ppm: 40.9, 54.7,
1
C
+
.65; N 20.28. MS (MM): m/z: 415.1 [М + Н] .
09.3, 109.7, 114.4, 114.6, 123.7, 123.8, 126.7, 126.8,
N-{2-Fluoro-6-[(4,6-dimethoxy-1,3,5-triazin-2-yl)
127.8, 127.9, 128.4, 128.3, 137.5, 141.6, 141.7, 147.5,
147.7, 156.7, 159.1, 162.5, 163.2, 165.6, 171.9, 180.3.
Found, %: C 55.91; H 3.78; N 18.17. C18H15F2N5O3.
Calculated, %: C 55.81; H 3.90; N 18.08. MS (MM):
methyl]phenyl}-5-nitropyridine-2-carboxamide (7k).
1
Brown solid, yield 88%, mp 73–77°C. H NMR spectrum,
δ, ppm: 3.82 s (6H, 2OCH ), 4.10 s (2H, CH ), 7.23–7.27 m
3
2
+
(
2H, H ), 7.32–7.38 m (1H, H ), 8.29 d (1H, J = 8.8,
m/z: 388.1 [М + Н] .
Ar
Ar
H ), 8.80–8.82 m (1H, H ), 9.41 d (1H, J = 2.4, H ),
Ar
Ar
Ar
2-Ethoxy-N-{2-fluoro-6-[(4,6-dimethoxy-1,3,5-
1
3
1
5
1
1
0.6 s (1H, NH). C NMR spectrum, δ , ppm: 40.79,
C
triazin-2-yl)methyl]phenyl}pyridine-3-carboxamide
4.87, 114.5, 114.8, 123.2, 123.8, 123.9, 126.4, 128.1,
28.2, 133.5, 136.6, 143.8, 145.8, 153.2, 156.6, 159.0,
61.1, 171.9, 180.1. Found, %: C 52.29; H 3.55; N 20.17.
1
(
7o). Yellow solid, yield 88%, mp 106–110°C. H NMR
spectrum, δ, ppm: 1.28 t (3H, J = 7.2, OCH CH ), 3.83 s
2
3
(
6H, 2OCH triazine), 4.12 s (2H, ArCH ), 4.43 q (2H,
3
2
C H FN O . Calculated, %: C 52.18; H 3.65; N 20.28.
1
8
15
6
5
J = 6.8, OCH ), 7.13–7.16 m (1H, H ), 7.20–7.25 m
2 Ar
+
MS (MM): m/z: 415.1 [М + Н] .
(
2H, H ), 7.30–7.35 m (1H, H ), 8.14 d. d (1H, J = 7.6,
Ar Ar 1
N-{2-Fluoro-6-[(4,6-dimethoxy-1,3,5-triazin-2-
yl)methyl]phenyl}-6-(trifluoromethyl)pyridine-3-
carboxamide (7l). Off white solid, yield 87%, mp 102–
J = 2.0, H ), 8.34 d. d (1H, J = 4.8, J = 2.0, H ), 9.61 s
2
Ar
1
1
2
Ar
3
(1H, NH). C NMR spectrum, δ , ppm: 14.16, 40.53,
C
54.83, 62.22, 114.3, 114.5, 116.7, 117.2, 124.1, 124.3,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 7 2020

DESIGN, SYNTHESIS, ANTITUBERCULAR AND ANTIBACTERIAL ACTIVITIES
1329
1
1
4
4
26.23, 126.26, 127.9, 128.0, 136.5, 140.3, 149.6, 156.5,
59.0, 159.8, 162.6, 171.9, 180.3. Found, %: C 55.21; H
.77; N 16.85. C H F N O . Calculated, %: C 55.11; H
100 ꢀL of the Middlebrook 7H9 broth and serial dilution
of compounds were made directly on plate. The final
drug concentrations tested were 100 to 0.2 ꢀg/mL. Plates
were covered and sealed with parafilm and incubated at
20
20
2
5
4
+
.88; N 16.94. MS (MM): m/z: 414.2 [М + Н] .
-Bromo-N-{2-fluoro-6-[(4,6-dimethoxy-
,3,5-triazin-2-yl)methyl]phenyl}pyrimidine-2-
37°C for 5 days.After this time, 25ꢀLof freshly prepared
5
1
: 1 mixture of Almar Blue reagent and 10% tween 80
1
was added to the plate and incubated for 24 h. Blue color
in the well was interpreted as no bacterial growth, and
pink color was scored as growth [12].
carboxamide (7p). Off white solid, yield 72%, mp 93–
1
9
6°C. H NMR spectrum, δ, ppm: 3.84 s (6H, 2OCH ),
3
4
.10 s (2H, CH ), 7.22–7.26 m (2H, H ), 7.31–7.36 m
2
Ar
1
3
(1H, H ), 9.21 s (2H, H ), 10.5 s (1H, NH). C NMR
Antibacterial activity. Antibacterial activity of all
the synthesized compounds was screened by the Agar
well diffusion method, as recommended by the National
Committee for clinical laboratory standards against
gram-positive bacteria such as Staphylococcus aureus
Ar
Ar
spectrum, δ , ppm: 40.73, 54.88, 114.5, 114.7, 122.4,
C
1
1
4
23.9, 124.0, 126.35, 126.38, 128.0, 128.1, 136.5, 155.5,
56.5, 158.3, 159.0, 160.2, 171.9, 180.2,. Found, %: C
5.35; H 3.24; N 17.68. C H BrFN O . Calculated, %:
1
7
14
6
3
+
C 45.45; H 3.14; N 17.79. MS (MM): m/z: 449.0 [М + Н] .
-Chloro-N-{2-fluoro-6-[(4,6-dimethoxy-1,3,5-
triazin-2-yl)methyl]phenyl}pyrazine-2-carboxamide
(NCIM 2079) and gram-negative bacteria Escherichia
5
coli (NCIM 2068) at concentrations 100 and 200 ꢀg/mL.
The obtained results were compared with standard drug
Chloramphenicol. The fresh culture of bacteria was
obtained by inoculating bacteria into nutrient broth media
and incubated at 37°C for 24 h. This culture mixed with
nutrient agar media was poured into petri dishes under
aseptic conditions. After solidification of media, bores
were made by using sterile cork borer (8 mm diameter).
Into these cups, the standard and synthesized drugs were
introduced; the plates were stored in a refrigerator at
100°C for proper diffusion of drugs into the media. After
2 h, the petri plates were transferred to an incubator and
maintained at 37±2°C for 24 h. Upon the incubation
period completion, the petri plates were observed for
the zone of inhibition. The results were evaluated by
comparing the zone of inhibition demonstrated by the
synthesized compounds with that of the standard drug
1
(7q). Yellow solid, yield 77%, mp 92–97°C. H NMR
spectrum, δ, ppm: 3.83 s (6H, 2OCH ), 4.09 (2H, CH ),
3
2
7
.22–7.27 m (2H, H ), 7.32–7.36 m (1H, H ), 8.93 d
Ar Ar
(
1H, J = 1.2, H ), 9.03 d (1H, J = 1.2, H ), 10.5 s (1H,
Ar Ar
13
NH). C NMR spectrum, δ , ppm: 40.77, 54.84, 114.5,
C
114.7, 123.6, 123.7, 126.43, 126.46, 128.20, 128.28,
1
1
36.7, 142.8, 143.1, 143.6, 151.1, 156.6, 159.0, 161.0,
71.9, 180.2. Found, %: C 50.33; H 3.59; N 20.67.
C H ClFN O . Calculated, %: C 50.44; H 3.49; N
1
7
14
6
3
+
2
0.76. MS (MM): m/z: 405.1 [М + Н] .
N-{2-Fluoro-6-[(4,6-dimethoxy-1,3,5-triazin-2-yl)
methyl]phenyl}-5-methylpyrazine-2-carboxamide
(
7r). Yellow solid, yield 77%, mp 92–97°C. Brown solid,
1
H NMR spectrum, δ, ppm: 2.63 s (3H, ArCH ), 3.81 s
3
(
(
6H, 2OCH triazine), 4.09 s (2H, CH ), 7.24–7.25 m
3
2
[13, 14].
2H, H ), 7.33 br. s (1H, H ), 8.66 s (1H, H ), 9.05 s
Ar
Ar
3
Ar
1
(1H, H ), 10.4 s (1H, NH). C NMR spectrum, δ , ppm:
Docking studies. Docking was performed on
Ar
C
2
1
1
4
4
1.38, 40.86, 54.82, 114.5, 114.7, 123.9, 124.0, 126.40,
26.42, 128.01, 128.09, 180.2, 136.7, 141.4, 142.7, 142.9,
56.6, 157.3, 159.1, 161.9, 171.9. Found, %: C 56.35; H
Windows 2007 using MOE 2008.10 version. MTB enoyl
reductase was imported from the protein data bank (PDB
ID: 4U0J) and the receptor was visualized using sequence
option and non interacting water molecules were deleted
along with the previously bound ligand. The partial
charge of protein was adjusted, using the force field
method AMBER 99. Later, the protein was subjected to
3D protonation at cut off 12.0, and further hydrogen was
added according to standard geometry and the enzyme
was energy minimized using force field MMFF94x
at 0.01 kJ/mol gradients. The ligand preparation was
done by drawing the structure of ligands by using a
builder module, and adjusting the partial charges using
Hamilton MMFF94 force field method and subsequently
.35; N 21.98. C H FN O . Calculated, %: C 56.25; H
1
8
17
6
3
+
.46; N 21.86. MS (MM): m/z: 385.1 [М + Н] .
Antitubercular activity. Antitubercular activity
of compounds was assessed against Mycobacterium
tuberculosis using the MABAmethod. This methodology
is non-toxic, uses a thermally stable reagent and shows
good correlation with proportional and BACTEC
radiometric method. Briefly, 200ꢀL of sterile deionzed
water was added to all outer perimeter wells of sterile 96
wells plate to minimized evaporation of medium in the
test wells during incubation. The 96 wells plate received
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 7 2020

1330
BODIGE et al.
3
D protonation and hydrogen addition was performed
5. Gerum, A.B., Ulmer, J.E., Jacobus, D.P., Jensen, N.P.,
Sherman, D.R., and Sibley, C.H., Antimicrob. Agents
Chemother., 2002, vol. 46, p. 3362.
according to standard geometry. Ligands were energy
minimized at cut off 12 using MMFF94x force field at
0
.01KJ mole gradient. Docking was performed using the
https://doi.org/10.1128/AAC.46.11.3362-3369.2002
. Naresh, S., Leena, G., Vinita, C., Richa, D.,
Sudhir, S., and Prem, M.S.C., Eur. J. Med. Chem.,
6
option simulation followed by docking on selected active
site amino acids. After obtaining docking results out of
the 10 best posed resulted for each chemical structure,
the best pose was retained. The resultant best pose score
values in the series were used for analysis of docking
and interactions [15–17].
2
010, vol. 45, p. 3335.
https://doi.org/10.1016/j.ejmech.2010.04.017
. Izumizono, Y., Arevalo, S., Koseki, Y., Kuroki, M.,
and Aoki, S., Eur. J. Med. Chem., 2011, vol. 1, p. 1849.
https://doi.org/10.1016/j.ejmech.2011.02.047
. Dessen, A., Quemard, A., Blanchard, J.S., Jacobs, W.R.,
and Sacchettini, J.C., Science, 1995, vol. 17, p. 1638.
https://doi.org/10.1126/science.7886450
. Joshi, S.D., Dixit, S.R., Kulkarni, V.H., Lherbet, C.,
Nadagouda, M.N., and Aminabhavi, T.M., Eur. J.
Med. Chem., 2017, vol. 27, p. 286.
7
8
9
CONCLUSIONS
Aseries of some novel N-{2-fluoro-6-[(4,6-dimethoxy-
,3,5-triazin-2-yl)methyl]phenyl} carboxamide
1
derivatives has been synthesized and the structures
1
13
confirmed by H and C NMR, and Mass spectra. The
compounds have been screened for their antitubercular
and antibacterial activities. Compounds 7d (difluoro-
https://doi.org/10.1016/j.ejmech.2016.11.032
0. Kouassi, A., Kone, M., Keita, M., Esmel, A., Megnassan, E.,
1
4
-chlorophenyl) and 7m (6-chloropyridine-3-yl) are
N’Guessan, Y., Frecer, V., and Miertus, S., Int. J. Mol. Sci.,
characterized by comparatively more potent antitubercular
activity than the reference drugs Pyrazinamide and
Streptomycin. Compounds, 7b and 7c demonstrate
significant antibacterial activity against Escherichia
coli and Staphylococcus aureus strains. Docking studies
support the initial pharmacophoric hypothesis and suggest
a mode of interaction at the binding site of MTB enoyl
reductase demonstrating that the target compounds are
potential anti-TB agents.
2
015, vol. 16, p. 29744.
https://doi.org/10.3390/ijms161226196
1. Achutha, L., Parameshwar, R., Reddy, B.M., and
1
Babu, V.H., J. Chem., 2013, p. 1.
https://doi.org/10.1155/2013/578438
1
1
2. Gulipalli, K.C., Bodige, S., Ravula, P., Bolla, R.S.,
Endoori, S., Cherukumalli, P.K.R., and Seelam, N.V.,
Asian J. Chem., 2018, vol. 30, p. 2495.
https://doi.org/10.14233/ajchem.2018.21491
3. Srinu, B., Parameshwar, R., Kali Charan, G., Srinivas, E.,
Koteswara Rao, Ch.P., Narendra Sharath Chandra, J.N.,
and Naresh Varma, S., Russ. J. Gen. Chem., 2019, vol. 89,
p. 836.
https://doi.org/10.1134/S1070363219040327
4. Bodige, S., Ravula, P., Gulipalli, K.C., Endoori, S.,
Narendra Sharath Chandra, J.N., Cherukumalli, P.K.R.,
Vanaja, G.R., and Seelam, N.V., Anticancer Agents Med.
Chem., 2018, vol, 18, p. 891.
ACKNOWLEDGMENTS
The authors would like to thank the management of AMRI
Hyderabad research centre for giving an opportunity to carry
out this research. The authors are also thankful to Sai Innotech
Labs Pvt.Ltd. for providing synthesis facility.
1
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
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