Design, Synthesis, and Antimicrobial Activity of Novel 6-Oxopyrimidin-1(6H)-yl Benzamide Derivatives

Article abstract of DOI:10.1134/S1070363219040236

A series of novel 1-(benzamide)-N-cyclopropyl-2-(amino substituted)-6-oxo-1,6-dihydropyrimidine-5-carboxamide derivatives is synthesised and characterized by IR, ¹H and ¹³C NMR, and mass spectra. The synthesized compounds 6a-6j and 8a-8j are screened for their in vitro antimicrobial activity against two Grampositive (Staphylococcus aureus, Bacillus subtilis) and two Gram-negative bacteria (Escherichia coli, Klebesiella aerogenes), and two pathogenic fungi (Aspergillus flavus, Fusarium oxysporum). Most of the compounds demonstrate good to excellent antimicrobial activity in comparison with the standard drugs ciproflaxin and hymexazole. Among the screened compounds morpholine substituted dihydropyrimidone carboxamide 8j is determined to be the most potent anti-bacterial agent.

Full text of DOI:10.1134/S1070363219040236

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 4, pp. 780–788. © Pleiades Publishing, Ltd., 2019.
Design, Synthesis, and Antimicrobial Activity
of Novel 6-Oxopyrimidin-1(6H)-yl Benzamide Derivatives
K. Devarasettya, J. Vantikommub, J. Sh. Anireddyb, and P. Srinivasa*
a Chemistry Services Unit, GVK Biosciences Pvt. Ltd, IDA Nacharam, Hyderabad, AP, India
*e-mail: srinivas.pusuluri18@gmail.com
b Centre for Chemical Sciences and Technology, Institute of Science and Technology, JNT University Hyderabad, India
Received August 6, 2018; revised April 12, 2019; accepted April 15, 2019
Abstract—A series of novel 1-(benzamide)-N-cyclopropyl-2-(amino substituted)-6-oxo-1,6-dihydropyrimidine-5-
1
carboxamide derivatives is synthesised and characterized by IR, H and 13C NMR, and mass spectra. The
synthesized compounds 6a–6j and 8a–8j are screened for their in vitro antimicrobial activity against two Gram-
positive (Staphylococcus aureus, Bacillus subtilis) and two Gram-negative bacteria (Escherichia coli,
Klebesiella aerogenes), and two pathogenic fungi (Aspergillus flavus, Fusarium oxysporum). Most of the
compounds demonstrate good to excellent antimicrobial activity in comparison with the standard drugs
ciproflaxin and hymexazole. Among the screened compounds morpholine substituted dihydropyrimidone
carboxamide 8j is determined to be the most potent anti-bacterial agent.
Keywords: Pyrimidones, oxadiazolo[3,2-a]pyrimidin-5-ol, oxadiazolo[3,2-a]pyrimidin-5-one, antibacterial
activity, antifungal activity
DOI: 10.1134/S1070363219040236
INTRODUCTION
diester 2 in 88% yield. Heating of compound 2 at 260–
270°C led to pyrimidone oxadiazole 3 (yield 92%),
which was subjected to ring opening [13] by using
various amines 4a–4j in the presence of K2CO3 to
afford the corresponding amino pyrimidone carbo-
xylates 5a–5j in high yields (71–85%). Upon
hydrolysis of compounds 5a–5j the corresponding
acids 6a–6j were accumulated and characterized by IR,
NMR, and mass spectra. The newly synthesized
dihydropyrimidine-5-carboxylic acids (6a–6j) were
coupled with cyclopropyl amine following the
traditional procedure, which led to the title compounds
8a–8j (Scheme 1). The structures of 8a–8j were
Synthesis, reactions and biological activities of
pyrimidine containing molecules constitute an important
area heterocyclic chemistry research, and these make
the structural blocks of a large number of pharma-
ceutical agents and natural products [1, 2]. Pyrimidines
demonstrate a broad range of biological properties
including antiviral [3], antitumor [4], antibacterial [5],
anti-inflammatory [6], and many more.
Likewise, pyrimidone derivatives demonstrate a
broad spectrum of biological activities. Among these
Uramustine [7], Tegafur [8], Fluorouracil (Antineo-
plastic) [9, 10], Flucytosine (Antifungal) [11], and
Idoxuridine (Antiviral) [12] are known as marketed
drugs (Fig. 1).
1
elucidated from IR, H, and 13C NMR, and mass
1
spectral data. H NMR spectrum of the representative
compound 8e demonstrated a singlet at 11.16 ppm of
the amide NH proton. The tertiary proton of
cyclopropyl group displayed a doublet of triplet at
2.90 ppm and with coupling constants of 3.7 and
7.2 Hz.
In continuation to our prior studies [13] of synthesis
of 6-oxopyrimidin-1(6H)-yl benzamide derivatives, we
constructed new hydrophilic 6-oxopyrimidones
containing amino carboxylates. Their antimicrobial
activity is tested.
Antimicrobial activity. The synthesised com-
pounds 6a–6j and 8a–8j were screened in vitro for
their antibacterial activity against two Gram-positive
Staphylococcus aureus (ATCC-6538), Bacillus subtilis
(ATCC-6633), two Gram-negative bacteria Escherichia
coli (ATCC-25922), and Klebsiella pneumonia (ATCC-
RESULTS AND DISCUSSION
The recently synthesised oxadiazole 1 [13] upon
reaction with diethylethoxy methylene malonate gave
780

DESIGN, SYNTHESIS, AND ANTIMICROBIAL ACTIVITY
781
(a)
(b)
(c)
NH2
O
OH
O
N
N
H
F
N
N
NH
N
O
F
O
H2N
N
O
O
N
H
O
N
S
N
OH
(d)
(e)
(f)
O
I
NH
H
N
F
O
O
N
O
HO
O
N
O
NH
O
F
NH
O
OH
Fig. 1. Biologically active pyrimidone based drugs: (a) Raltegravir, (b) Flucytosine, (c) Lamivudine, (d) Fluorouracil,
(e) Idoxuridine, and (f) Tegafur.
13883) by the disc diffusion method at concentrations
20 and 40 μg/mL. Nutrient agar medium was used for
the antibacterial screening. The zone of inhibition (in
mm) was compared with that of the standard drug
Ciprofloxacin.
against Fusarium oxysporum and Aspergillus flavus.
Potato dextrose agar (PDA) medium was used for the
antifungal screening, and Hymexazole was used as the
standard (Table 1). However all acids and amides were
determined to be ineffective against the tested fungal
strains up to concentration of 500 μg /mL.
The accumulated antibacterial activity data (Table 1)
revealed that the terminal amides derivatives 8a–8j
demonstrated higher activity than the intermediate
acids 6a–6j. Compounds 8e, 8g, and 8j exhibited
excellent growth inhibition of Bacillus subtilis in
comparison with Ciprofloxacin at concentrations 20
and 40 μg/mL. Compounds 8d, 8e, and 8j (>27 mm)
were found to be potent against Staphylococcus
aureus. Compounds 8d, 8e, 8g, and 8j demonstrated
good activity against both Gram-positive bacterial strains.
MIC of the compounds 8e, 8g and 8j. The
compounds of the highest antibacterial activity, 8e, 8g,
and 8i, were further assayed for minimum inhibitory
concentration (MIC) (Table 2). The compounds 8e and
8j displayed MIC values lower than compound 8g. The
MIC values of compounds 8e and 8j against Bacillus
subtilis were equal to the standard drug ciprofloxacin
and the MBC value is 2·MIC. The compound 8j
displayed lower MIC values on Staphylococcus aureus
and Escherichia coli than compounds 8e and 8g and
equal to the standard (MBC value 4·MIC). According
to the accumulated data, compounds 8e and 8j are
potential antibacterial agents against Bacillus subtilis,
Staphylococcus aureus, and Escherichia coli.
According to antibacterial activity evaluation
against Gram-negative bacteria Klebsiella pneumonia
the tested compounds, except 8h, demonstrated
moderate to excellent activity vs the standard drug
Ciprofloxacin. The products 8g and 8j were
significantly more active than the standard drug.
Overall, among the target molecules, the compounds
6a–6j, 8b, and 8h did not affect any bacterial strains,
whereas compounds 8c–8j demonstrated excellent
activity against all bacterial strains.
The structure–activity relationship analysis indicated
that, as a trend, the presence of cyclic moieties like
cyclo propyl, furan, pyran, pyrrolidine, piperidine, and
morpholine on the pyrimidine ring of the products
resulted in larger zones of inhibition than the
compounds with acyclic groups like ethanolamine,
2-methyl amine, propyl amine, and isobutyl amine.
All the synthesized compounds 6a–6j and 8a–8j
were screened in vitro for their antifungal activity
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 4 2019

782
Br
DEVARASETTY et al.
Scheme 1. Synthesis pattern for dihydropyrimidine-5-carboxamide derivatives (8a–8j).
Br
Br
O
N
O
Diethylethoxymethylene
malonate
N
Diphenyl ether
NH
O
N
N
N
N
130−140°C, 2 h
260−270°C, 1 h
NH2
Br
EtO2C
N
O
CO2Et
CO2Et
2
1
3
Br
H
R1
H
R1
N
N
N
R−NH (4a−4j), K2CO3,
N
N
N
NaOH, EtOH
DMF
O
O
O
RT, 2 h
RT, 2−16 h
O
CO2H
CO2Et
5a−5j
6a−6j
Br
R1
H
N
N
N
.
EDC HCl, HOAt
O
DMF, RT, 2−16 h
O
O
NH2
N
H
8a−8j
7
R1 = NHCH2CH2OH (5a, 6a, 8a), NHCH2CH2OCH3 (5b, 6b, 8b), NHCH2CH2CH3 (5c, 6c, 8c), NHCH=CH(CH3)2 (5d, 6d, 8d),
N
HN
HN
(5h, 6h, 8h),
(5g, 6g, 8g),
(5e, 6e, 8e),
(5f, 6f, 8f),
HN
O
O
N
N
(5i, 6i, 8i),
(5j, 6j, 8j).
O
EXPERIMENTAL
Synthesis of compounds 5a–5j (general
procedure). To a solution of compound 4 (1.0 mmol)
in DMF (5 mL) was added K2CO3 (3.0 mmol) and a
substituted amine (1.0 mmol) at room temperature.
The reaction mixture was stirred for 2–16 h, until the
reaction was complete as indicated by TLC. After
completion of the process, the reaction mixture was
poured into ice cold water (20 mL), the precipitate
formed was filtered off, washed with water and then
purified by flash column chromatography using hexane
and ethyl acetate to afford the corresponding pure
compounds 5a–5j as off-white solid.
Melting points were measured in open capillary
tubes on a Stuart SMP3 melting-point apparatus and
are uncorrected. All the reactions were monitored by
TLC on Merck precoated 60 F254 (mesh) silica gel
plates. Spots were visualized with iodine vapour and
under UV light. Merck silica gel (60–120 mesh) was
used for the column chromatography. IR spectra (KBr
pellets) were recorded on a Shimadzu FT-IR 8400 S
1
spectrophotometer. H and 13C NMR spectra were
measured on a Bruker AVANCE-400 spectrometer
using DMSO-d6 as a solvent and TMS as an internal
standard. Mass spectra were measured on a Shimadzu
GCMS-QP 1000 spectrometer.
Ethyl-1-(4-bromobenzamido)-2-[(2-hydroxyethyl)-
amino]-6-oxo-1,6-dihydropyrimidine-5-carboxylate
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DESIGN, SYNTHESIS, AND ANTIMICROBIAL ACTIVITY
783
Table 1. Antimicrobial activity of compounds 6a–6j and 8a–8j
Gram positive bacteria
B. Subtilis S. Aeureus
Gram negative bacteria
K. Pneumoniae E. Coli
Concentration, µg/well
Fungi strains
E. Oxysporum A. Flavus
Compound
20
40
20
40
20
40
20
40
500
6a
8.5
6.6
17.5
11.1
10.4
24.1
19.5
17.5
22.5
5.5
8.6
10.3
5.3
16.5
16.7
11.2
16.5
15.4
16.5
19.5
6.0
8.8
14.5
20.6
14.5
20.5
20.6
24.5
22.3
15.0
14.2
28.5
35.4
31.5
33.2
35.4
34.7
30.2
41.5
15.4
31.6
41.5
38.5
–
7.5
3.5
12.0
8.8
2.2
6.5
11.0
3.7
6b
17.5
12.5
13.5
15.6
17.6
12.5
11.0
10.6
20.7
19.4
15.7
15.8
19.7
18.4
19.8
25.4
10.4
18.7
22.3
24.5
–
6c
7.9
12.5
12.5
15.4
18.0
9.5
10.4
19.0
12.5
26.0
18.0
12.0
–
6.2
4.7
6d
10.5
10.5
8.6
11.5
12.5
8.5
7.6
6.6
6e
8.2
6.5
6f
11.4
6.5
10.5
4.5
6g
10.4
3.5
13.5
2.5
6h
6.5
5.4
2.7
6i
8.7
15.6
26.7
29.2
10.6
29.6
30.3
34.0
30.2
35.6
27.2
25.6
34.6
34.2
–
8.5
16.8
21.3
18.6
15.6
19.7
20.6
22.5
18.6
19.0
21.6
20.1
22.8
20.4
–
15.6
20.5
14.1
12.5
15.4
22.6
18.9
14.9
18.7
12.4
16.6
21.2
19.5
–
6.3
4.2
6j
11.5
14.5
8.5
15.5
12.5
11.5
12.7
15.5
14.6
11.5
11.2
12.6
12.5
14.5
13.6
–
34.2
27.2
28.4
30.2
29.8
36.9
30.2
37.9
30.2
36.0
37.5
36.6
–
14.3
12.6
6.5
18.2
14.6
7.5
8a
8b
8c
12.4
13.8
15.7
15.5
15.1
11.5
11.5
14.6
15.6
–
9.3
10.9
15.6
11.5
4.5
8d
14.5
17.5
8.2
8e
8f
8g
15.6
5.4
14.2
3.5
8h
8i
11.6
15.6
–
8.5
8j
21.5
–
Ciprofloxacin
Hymexazole
18.2
22.8
Table 2. MBC and MIC values for compounds 8e, 8g, and 8j
Minimum inhibitory concentration MBC (MIC), µg/well
Compound
B. Subtilis
10 (40)
20 (40)
10 (20)
10 (20)
S. aeureus
20 (80)
K. pneumoniae
40 (>160)
E. Coli
40 (160)
40 (160)
10 (40)
10 (20)
8e
8g
40 (160)
10 (40)
80 (>160)
8j
80 (>160)
Ciprofloxacin
10 (20)
20 (>160)
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DEVARASETTY et al.
(5a). Yield 53.4%, mp 231.4°C. IR spectrum, ν, cm–1:
3295, 1751, 1662. H NMR spectrum, δ, ppm: 1.22 t
7.0 Hz, 3H), 2.90 m (1H), 4.16–4.24 q (J = 7.0 Hz,
2H), 7.78–7.80 m (2H), 7.85–7.97 m (2H), 8.36–8.45 s
(1H), 8.45 s (1H), 11.01 br.s (1H). 13C NMR spectrum,
δ, ppm: 5.8, 6.2, 14.2, 24.5, 59.5, 103.9, 125.4, 126.1,
126.3, 130.2, 130.7, 131.4, 155.6, 157.9, 160.8, 163.8,
165.5. HRMS. Calculated for C17H18BrN4O4: 421.0511.
Found: 421.0518.
1
(3H, J = 7.1 Hz), 3.34–3.42 m (1H), 3.51 br.d (J =
2.4 Hz, 3H), 4.15 q (J = 7.3 Hz, 2H), 4.77 t (1H, J =
5.1 Hz), 7.82 d (J = 8.3 Hz, 2H), 7.94 d (J = 8.3 Hz,
2H), 8.40–8.49 m (2H), 11.11 s (1H). 13C NMR
spectrum, δ, ppm: 14.2, 43.5, 59.0, 59.4, 103.3, 126.4,
130.2, 130.6, 131.4, 155.7, 156.8, 160.8, 163.8, 165.5.
HRMS. Calculated for C16H18BrN4O5: 425.0461.
Found: 425.0454.
Ethyl 1-(4-bromobenzamido)-6-oxo-2-{[(tetra-
hydrofuran-3-yl)methyl]amino}-1,6-dihydropyrimidine-
5-carboxylate (5f). Yield 54.9 %, mp 228.2°C. IR
1
Ethyl 1-(4-bromobenzamido)-2-[(2-methoxyethyl)-
amino]-6-oxo-1,6-dihydropyrimidine-5-carboxylate
(5b). Yield 50%, mp 182.6°C. IR spectrum, ν, cm–1:
3289, 1736, 1651. 1H NMR spectrum, δ, ppm: 1.22 br.t
(J = 6.8 Hz, 3H), 3.24 s (3H), 3.46 br.s (3H), 3.56–
3.68 m (1H), 4.16 q (J = 6.7 Hz, 2H), 7.82 br.d (J =
8.3 Hz, 2H), 7.94 br.d (J = 7.9 Hz, 2H), 8.44 s (1H),
8.51 br.s (1H), 11.11 br.s (1H). 13C NMR spectrum, δ,
ppm: 14.2, 40.6, 57.9, 59.4, 69.9, 103.5, 126.4, 129.3,
130.2, 130.6, 131.4, 155.7, 156.7, 160.7, 163.7, 165.5.
HRMS. Calculated for C17H20BrN4O5: 439.0617.
Found: 439.0612.
spectrum, ν, cm–1: 3348, 1739, 1681. H NMR spec-
trum, δ, ppm: 1.22 br.t (J = 7.0 Hz, 3H), 1.55–1.60 m
(1H), 1.95 m (1H), 2.55-2.60 m (1H), 3.20–3.45 m
(3H), 3.6 m (2H), 3.70–3.75 m (H), 4.09–4.17 q (J =
7.5 Hz 2H), 7.76–7.97 m (5H), 8.36–8.45 m (1H), 8.45–
8.58 m (1H), 11.01 br.s (1H). 13C NMR spectrum, δ,
ppm: 14.2, 29.0, 38.3, 43.3, 59.5, 66.6, 70.0, 103.5,
126.4, 130.2, 130.7, 131.5, 155.8, 156.7, 160.7, 163.8,
165.5. HRMS. Calculated for C19H22BrN4O5:
465.0774. Found: 465.0782.
Ethyl 1-(4-bromobenzamido)-6-oxo-2-{[(tetra-
hydro-2H-pyran-4-yl)methyl]amino}-1,6-dihydro-
pyrimidine-5-carboxylate (5g). Yield 91.4 %, mp
Ethyl 1-(4-bromobenzamido)-6-oxo-2-(propyl-
amino)-1,6-dihydropyrimidine-5-carboxylate (5c).
Yield 49.5%, mp 211.3°C. IR spectrum, ν, cm–1: 3279,
1
210.5°C. IR spectrum, ν, cm–1: 3291, 1743, 1642. H
NMR spectrum, δ, ppm: 1.03–1.29 m (5H), 1.52 br.d
(J = 12.1 Hz, 2H), 1.95 m (1H), 3.15–3.28 m (4H),
3.82 br.d (J = 8.8 Hz, 2H), 4.15 q (2H, J = 7.0 Hz),
7.77–7.85 m (2H), 7.88–7.99 m (2H), 8.39–8.55 m
(2H), 10.99 br.s (1H). 13C NMR spectrum, δ, ppm: 14.2,
29.7, 30.4, 34.6, 47.4, 60.1, 67.4, 103.4, 127.7, 129.6,
131.6, 156.4, 158.9, 161.8, 163.9, 165.9. HRMS.
Calculated for C20H24BrN4O5: 479.0930. Found: 479.0925.
1
1745, 1671. H NMR spectrum, δ, ppm: 0.84 t (J =
7.3 Hz, 3H), 1.22 t (J = 7.1 Hz, 3H), 1.53 m (2H), 3.32
–3.39 m (2H), 4.10–4.19 m (2H), 7.82 d (J = 8.8 Hz,
2H), 7.94 d (J = 8.8 Hz, 2H), 8.39–8.51 m (2H), 11.10
s (1H). 13C NMR spectrum, δ, ppm: 11.0, 14.2, 22.0,
42.5, 59.4, 103.1, 126.4, 130.2, 130.7, 131.5, 155.8,
156.6, 160.9, 163.8, 165.5. HRMS. Calculated for
C17H20BrN4O4: 423.0668. Found: 423.0675.
Ethyl 1-(4-bromobenzamido)-6-oxo-2-(pyrrol-
idin-1-yl)-1,6-dihydropyrimidine-5-carboxylate (5h).
Yield 50.4%, mp 184.6°C. IR spectrum, ν, cm–1: 3279,
1756, 1665. 1H NMR spectrum, δ, ppm: 1.22 t (3H, J =
8.8 Hz), 1.85–1.95 m (4H), 3.50–3.58 br.d (2H), 3.75
br.d (J = 8.8 Hz, 2H), 4.15 q (2H, J = 7.0 Hz), 7.77–
7.85 m (2H), 7.88–7.99 m (2H), 8.4 s (1H), 11.4 br.s
(1H). 13C NMR spectrum, δ, ppm: 14.2, 24.7, 50.5,
59.4, 103.0, 126.7, 129.8, 130.0, 131.9, 155.8, 157.0, 160.0,
163.7, 165.2. HRMS. Calculated for C18H20BrN4O4:
435.0668. Found: 435.0674.
Ethyl 1-(4-bromobenzamido)-2-(isobutylamino)-
6-oxo-1,6-dihydropyrimidine-5-carboxylate
(5d).
Yield 67.2 %, mp 199.2°C. IR spectrum, ν, cm–1:
1
3310, 1748, 1678. H NMR spectrum, δ, ppm: 0.82 t
(J = 7.3 Hz, 3H), 1.49 qd (J = 7.3, 14.7 Hz, 2H), 3.18
br.s (2H), 4.12 q (2H), 7.51 br.d (J = 7.8 Hz, 2H), 7.96
d (J = 8.8 Hz, 2H), 8.35 s (1H), 11.09 s (1H). 13C
NMR spectrum, δ, ppm: 14.2, 19.7, 27.7, 48.0, 59.3,
103.1, 126.3, 129.7, 130.2, 130.7, 131.4, 155.8, 156.7,
160.8, 163.8, 165.5. HRMS. Calculated for C18H22BrN4O4:
437.0824. Found: 437.00819.
Ethyl 1-(4-bromobenzamido)-6-oxo-2-(piperidin-
1-yl)-1,6-dihydropyrimidine-5-carboxylate (5i). Yield
52%, mp 177°C. IR spectrum, ν, cm–1: 3316, 1734,
Ethyl 1-(4-bromobenzamido)-2-(cyclopropylamino)-
6-oxo-1,6-dihydropyrimidine-5-carboxylate
(5e).
1
Yield 46.1%, mp 210.6°C. IR spectrum, ν, cm–1: 3324,
1761, 1641. 1H NMR spectrum, δ, ppm: 0.60 br.d (J =
10.1 Hz, 2H), 0.75 br.d (J = 7.5 Hz, 2H), 1.22 br.t (J =
1649. H NMR spectrum, δ, ppm: 1.20 t (3H, J =
7.0 Hz), 1.34–1.67 m (6H), 3.40–3.79 m (4H), 4.17 q
(2H, J = 7.0 Hz), 7.75–7.80 m (4H), 8.4 s (1H), 11.6
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DESIGN, SYNTHESIS, AND ANTIMICROBIAL ACTIVITY
785
br.s (1H). 13C NMR spectrum, δ, ppm: 14.2, 23.4, 25.4,
49.1, 59.5, 104.8, 126.6, 129.6, 130.2, 131.9, 158.1,
158.9, 159.3, 163.5, 164.2. HRMS. Calculated for
C19H22BrN4O4: 449.0824. Found: 449.0816.
1715, 1046. 1H NMR spectrum, δ, ppm: 0.82 t (3H, J =
7.3 Hz), 1.49 (qd, J = 7.3, 14.7 Hz, 2H), 3.28 br.s
(2H), 6.8 br.m (1H), 7.51 br.d (J = 7.8 Hz, 2H), 7.96 d
(J = 8.8 Hz, 2H), 8.35 s (1H), 14.-14.2 (br.m, 1H). 13C
NMR spectrum, δ, ppm: 11.2, 24.6, 43.2, 105.1, 126.9,
129.8, 130.4, 132.3, 155.2, 159.5, 163.0, 165.1, 166.1.
HRMS. Calculated for C15H16BrN4O4: 395.0355.
Found: 413.0349.
Ethyl 1-(4-bromobenzamido)-2-morpholino-6-
oxo-1,6-dihydropyrimidine-5-carboxylate (5j). Yield
58.5%, mp 256°C. IR spectrum, ν, cm–1: 3248, 1751,
1
1646. H NMR spectrum, δ, ppm: 1.17–1.29 m (3H),
3.49–3.69 m (6H), 3.72–3.84 m (2H), 4.18 q (2H, J =
6.8 Hz), 7.76–7.84 m (2H), 7.84–7.91 m (2H), 8.44 s
(1H), 11.61 s (1H). 13C NMR spectrum, δ, ppm: 14.2,
48.5, 59.7, 65.7, 105.7, 126.7, 129.7, 130.1, 131.9,
157.8, 158.9, 159.1, 163.4, 164.5. HRMS. Calculated
for C18H20BrN4O5: 451.0617. Found: 451.0611.
1-(4-Bromobenzamido)-2-(isobutylamino)-6-oxo-
1,6-dihydropyrimidine-5-carboxylic acid (6d). Yield
85.4%, mp 243.5°C. IR spectrum, ν, cm–1: 3355, 2448,
1
1716, 1612, 1089. H NMR spectrum, δ, ppm: 0.82 m
(6H), 1.95 m (1H), 3.28 br.s (2H), 7.82 d (J = 7.8 Hz,
2H), 7.96 d (J = 8.8 Hz, 2H), 8.52 s (1H), 8.78 br.m
(1H), 11.4 br.s (1H), 12.3 br.s (1H). 13C NMR
spectrum, δ, ppm: 19.8, 27.7, 48.2, 101.8, 126.5,
130.2, 130.5, 131.5, 156.4, 160.4, 161.3, 164.5, 165.3.
HRMS. Calculated for C16H18BrN4O4: 409.0511.
Found: 413.0518.
Synthesis of compounds 6a–6j (general proce-
dure). Mixture of a solution of an ester 5 (1.0 mmol) in
THF-H2O (5 mL) with LiOH (3.0 mmol) was stirred at
ambient temperature for 2 h. The reaction was
monitored by TLC. After completion of the process,
the solvent was evaporated under reduced pressure, the
residue was treated with ice cold water (20 mL) and
acidified with 1 N HCl. The precipitated product was
filtered off, washed with water, then 50% pet ether and
EtOAc to afford the corresponding pure compounds
6a–6j as off-white solid.
1-(4-Bromobenzamido)-2-(cyclopropylamino)-6-
oxo-1,6-dihydropyrimidine-5-carboxylic acid (6e).
Yield 85.7%, mp 260.7°C. IR spectrum, ν, cm–1: 3354,
1
2470, 1711, 1655, 1132. H NMR spectrum, δ, ppm:
0.57–0.68 m (1H), 0.72–0.84 m (2H), 2.94 q.t (1H, J =
3.8, 7.3 Hz), 7.81 d (J = 8.8 Hz, 2H), 7.93 d (J =
8.3 Hz, 2H), 8.57 s (1H), 8.68 d (J = 3.5 Hz, 1H),
11.27 s (1H), 12.18 br.s (1H). 13C NMR spectrum, δ,
ppm: 5.9, 6.2, 24.7, 102.7, 126.6, 130.3, 131.5, 157.7,
159.9, 161.4, 164.4, 165.4. HRMS. Calculated for
C15H14BrN4O4: 393.0198. Found: 393.0203.
1-(4-Bromobenzamido)-2-[(2-hydroxyethyl)amino]-
6-oxo-1,6-dihydropyrimidine-5-carboxylic acid (6a).
Yield 81.3%, mp 214.5°C. IR spectrum, ν, cm–1: 3350,
1
2450, 1705, 1652, 1041. H NMR spectrum, δ, ppm:
3.36–3.46 m (1H), 3.48–3.63 m (3H), 4.82 br.s (1H),
7.82–7.84 d (J = 8.3 Hz, 2H), 7.95 d (J = 8.8 Hz, 2H),
8.53 s (1H), 8.68–8.81 m (1H), 11.40 s (1H), 12.20
br.s (1H). 13C NMR spectrum, δ, ppm: 43.5, 59.4,
103.3, 126.4, 130.2, 130.6, 131.4, 155.7, 156.8, 160.8,
163.8, 165.5. HRMS. Calculated for C14H14BrN4O5:
397.0148. Found: 397.0156.
1-(4-Bromobenzamido)-6-oxo-2-{[(tetrahydro-
furan-3-yl)methyl]amino}-1,6-dihydropyrimidine-5-
carboxylic acid (6f). Yield 75.1%, mp 178.2°C. IR
1
spectrum, ν, cm–1: 3331, 2465, 1721, 1653, 1092. H
NMR spectrum, δ, ppm: 1.51–1.66 m (1H), 1.82–1.97
m (1H), 3.34–3.66 m (5H), 3.66–3.77 m (1H), 7.83
br.d (J = 8.8 Hz, 2H), 7.95 br.d (J = 8.3 Hz, 2H), 8.53
s (1H), 8.81 br.s (2H), 11.39 s (1H), 12.17 br.s (1H).
13C NMR spectrum, δ, ppm: 33.8, 38.2, 40.1, 68.9,
76.4, 106.2, 126.5, 129.7, 130.2, 131.7, 156.7, 160.8,
163.6, 165.9, 166.1. HRMS. Calculated for C17H18BrN4O5:
437.0461. Found: 437.0457.
1-(4-Bromobenzamido)-2-[(2-methoxyethyl)amino]-
6-oxo-1,6-dihydropyrimidine-5-carboxylic acid (6b).
Yield 85.4%, mp 217.4°C. IR spectrum, ν, cm–1: 3345,
1
2465, 1703, 1648, 1141. H NMR spectrum, δ, ppm:
3.24 s (3H), 3.48 s (3H), 3.58–3.74 m (1H), 7.77–7.87
m (2H), 7.90-8.00 m (2H), 8.53 s (1H), 8.82 br.s (1H),
11.39 s (1H), 12.19 s (1H). 13C NMR spectrum, δ,
ppm: 40.9, 58.0, 69.8, 102.2, 126.6, 130.3, 130.4,
131.6, 156.5, 160.0, 161.4, 164.5, 165.3. HRMS.
Calculated for C15H15BrN4O5: 411.0304. Found: 411.0296.
1-(4-Bromobenzamido)-6-oxo-2-{[(tetrahydro-2H-
pyran-4-yl)methyl]amino}-1,6-dihydropyrimidine-5-
carboxylic acid (6g). Yield 88.7%, mp 256.9°C. IR
1
spectrum, ν, cm–1: 3365, 2454, 1754, 1711, 1052. H
1-(4-Bromobenzamido)-6-oxo-2-(propylamino)-
1,6-dihydropyrimidine-5-carboxylic acid (6c). Yield
86.5%, mp 299.1°C. IR spectrum, ν, cm–1: 3365, 2478,
NMR spectrum, δ, ppm: 1.09–1.26 m (2H), 1.52 br.s
(2H), 1.8–1.93 m (1H), 3.14–3.30 m (4H), 3.78–3.90
m (2H), 7.78–7.88 m (2H), 7.89–8.01 m (2H), 8.52 s
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DEVARASETTY et al.
(1H), 8.77 br.t (1H, J = 5.9 Hz), 11.8 br.s (1H), 12.8 s
(1H). 13C NMR spectrum, δ, ppm: 29.6, 33.2, 42.2,
68.9, 104.2, 126.6, 129.8, 131.2, 131.7, 154.5, 159.1, 162.3,
165.5, 165.9. HRMS. Calculated for C18H20BrN4O5:
451.0617. Found: 451.0611.
MeOH as an eluent to afford the corresponding pure
compounds 8a–8j as off-white solid.
1-(4-Bromobenzamido)-N-cyclopropyl-2-[(2-hyd-
roxyethyl)amino]-6-oxo-1,6-dihydropyrimidine-5-
carboxamide (8a). Yield 78%, mp 186.2°C. IR spec-
trum, ν, cm–1: 3300, 1665, 1539. 1H NMR spectrum, δ,
ppm: 3.56–3.68 m (6H), 3.74–3.89 m (2H), 7.77–7.84
m (2H), 7.85–7.94 m (2H), 8.50 s (1H), 8.54 br.s (1H),
11.83 s (1H), 12.33 br.s (1H). 13C NMR spectrum, δ,
ppm: 6.0, 6.1, 27.8, 40.2, 61.3, 126.4, 129.1, 129.4,
131.0, 131.4, 154.1, 156.5, 159.9, 163.2, 164.9.
HRMS. Calculated for C17H19BrN5O4: 436.0620.
Found: 436.0632.
1-(4-Bromobenzamido)-6-oxo-2-(pyrrolidin-1-yl)-
1,6-dihydropyrimidine-5-carboxylic acid (6h). Yield
81.2%, mp 219.6°C. IR spectrum, ν, cm–1: 3355, 2477,
1
1741, 1625. H NMR spectrum, δ, ppm: 1.78–1.80
br.m (2H), 1.82–1.93 br.m (2H), 3.5–3.6 m (2H), 3.75–
3.85 m (2H), 7.78–7.88 m (2H), 7.90–7.95 m (2H),
8.52 s (1H), 11.22 s (1H), 11.65 s (1H). 13C NMR
spectrum, δ, ppm: 24.7, 50.9, 101.9, 126.5, 129.6,
129.9, 131.9, 155.4, 160.5, 161.5, 164.5, 165.0. HRMS.
Calculated for C16H16BrN4O4: 407.0355. Found:
413.0349.
1-(4-Bromobenzamido)-N-cyclopropyl-2-[(2-meth-
oxyethyl)amino]-6-oxo-1,6-dihydropyrimidine-5-
carboxamide (8b). Yield 51%, mp 192.6°C. IR
1
1-(4-Bromobenzamido)-6-oxo-2-(piperidin-1-yl)-
1,6-dihydropyrimidine-5-carboxylic acid (6i). Yield
85.3%, mp 170.1°C. IR spectrum, ν, cm–1: 3365, 2478,
spectrum, ν, cm–1: 3288, 1672, 1555. H NMR spec-
trum, δ, ppm: 0.45 br.s (2H), 0.68 br.d (J = 4.4 Hz,
2H), 2.78 br.s (1H), 3.13–3.27 m (1H), 3.24 s (3H),
3.46 br.s (3H), 3.62 br.s (1H), 7.82 br.d (J = 7.8 Hz,
2H), 7.94 br.d (J = 7.8 Hz, 2H), 8.50 br.s (3H), 11.27
br.s (1H). 13C NMR spectrum, δ, ppm: 6.0, 6.3, 22.1,
40.7, 58.0, 69.8, 104.8, 126.5, 130.2, 130.4, 131.5,
155.9, 158.9, 159.5, 164.0, 165.3. HRMS. Calculated
for C18H21BrN5O4: 450.0777. Found: 450.0782.
1
1723, 1664, 1145. H NMR spectrum, δ, ppm: 1.40–
1.62 br.m (6H), 3.85–3.88 m (4H), 3.75–3.90 m (2H),
7.78–7.88 m (2H), 7.85–7.95 m (2H), 8.5 s (1H), 11.95
s (1H), 12.24 br.s (1H). 13C NMR spectrum, δ, ppm:
23.3, 25.4, 49.3, 103.8, 126.8, 129.7, 130.0, 131.9,
158.5, 159.6, 162.1, 164.1, 164.4. HRMS. Calculated
for C17H18BrN4O4: 421.0511. Found: 421.0517.
1-(4-Bromobenzamido)-N-cyclopropyl-6-oxo-2-
(propylamino)-1,6-dihydropyrimidine-5-carboxamide
(8c). Yield 78%, mp 240–242°C. IR spectrum, ν, cm–1:
1-(4-Bromobenzamido)-2-morpholino-6-oxo-1,6-
dihydropyrimidine-5-carboxylic acid (6j). Yield
85.3%, mp 184.6°C. IR spectrum, ν, cm–1: 3335, 2452,
1
3292, 1654, 1538. H NMR spectrum, δ, ppm: 0.45
1
1701, 1632, 1123. H NMR spectrum, δ, ppm: 3.58–
br.s (2H), 0.68 br.d (J = 4.4 Hz, 2H), 2.78 br.s (1H),
3.13 –3.27 m (1H), 3.24 s (3H), 3.46 br.s (3H), 3.62
br.s (1H), 7.82 br.d (J = 7.8 Hz, 2H), 7.94 br.d (J =
7.8 Hz, 2H), 8.50 br.s (3H), 11.27 br.s (1H). 13C NMR
spectrum, δ, ppm: 6.0, 6.2, 12.2, 24.4, 28.9, 44.1,
126.1, 129.6, 129.5, 131.9, 132.0, 153.2, 156.2, 159.1,
163.2, 164.6. HRMS. Calculated for C18H21BrN5O3:
434.0828. Found: 434.0840.
3.68 m (6H), 3.80–3.82 m (2H), 7.77–7.84 m (2H),
7.85–7.94 m (2H), 8.50 s (1H), 11.83 s (1H), 12.33
br.s (1H). 13C NMR spectrum, δ, ppm: 48.6, 65.7,
104.9, 126.9, 130.0, 131.9, 158.6, 159.5, 161.2, 164.3,
164.4. HRMS. Calculated for C16H16BrN4O5:
423.0304. Found: 423.0292.
Synthesis of compounds 8a–8j (general proce-
dure). To a solution of a compound 6a–6j (1.0 mmol)
in DMF (5 mL) were added EDC.HCl (2.0 mmol),
HOAt (2.0 mmol) and DIPEA (4.0 mmol), followed by
addition of cyclopropylamine (1.0 mmol). The mixture
was stirred at room temperature for 16 h. The progress
of the reaction was monitored by TLC. After
completion of the reaction, the mixture was poured
into ice cold water (10 mL) and extracted with EtOAc
(3×10 mL). The combined organic layers were washed
with ice water (2×5 mL), brine, dried over anhydrous
Na2SO4, filtered, and concentrated. The residue was
subjected to column chromatography using DCM:
1-(4-Bromobenzamido)-N-cyclopropyl-2-(isobutyl-
amino)-6-oxo-1,6-dihydropyrimidine-5-carboxamide
(8d). Yield 76%, mp 240–242°C. IR spectrum, ν, cm–1:
1
3295, 1672, 1539, 1124. H NMR spectrum, δ, ppm:
0.39 m (2H), 0.66 m (2H), 0.91 d (J = 4.4 Hz, 6H),
1.67 m (1H), 2.67 d (J = 4.4 Hz, 1H), 2.77 m (1H),
7.80 br.d (J = 7.8 Hz, 2H), 7.92 br.d (J = 7.8 Hz, 2H),
8.95 br.s (1H), 11.17 br.s (1H). 13C NMR spectrum, δ,
ppm: 6.0, 6.4, 21.3, 26.4, 29.0. 43.1, 126.9, 129.0,
129.9, 131.0, 131.7, 153.2, 155.3, 159.4, 163.2, 164.7.
HRMS. Calculated for C19H23BrN5O3: 448.0984.
Found: 448.0997.
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DESIGN, SYNTHESIS, AND ANTIMICROBIAL ACTIVITY
787
1-(4-Bromobenzamido)-N-cyclopropyl-2-(cyclo-
propylamino)-6-oxo-1,6-dihydropyrimidine-5-car-
boxamide (8e). Yield 56%, mp 243.5°C. IR spectrum,
ν, cm–1: 3301, 1654, 1523. 1H NMR spectrum, δ, ppm:
0.37–0.50 m (2H), 0.52–0.83 m (6H), 2.69–2.83 m
(1H), 2.90 dt (1H, J = 3.7, 7.2 Hz), 7.70–7.84 m (2H),
7.85–7.98 m (2H), 8.45 br.d (J = 3.7 Hz, 1H), 8.48–
8.58 m (2H), 11.16 s (1H). 13C NMR spectrum, δ,
ppm: 5.9, 6.1, 6.2, 6.4, 22.1, 24.5, 105.2, 126.5, 130.2,
130.5, 131.5, 157.1, 158.9, 159.4, 164.0, 165.4.
HRMS. Calculated for C18H19BrN5O3: 432.0671.
Found: 432.0662.
δ, ppm: 6.0, 6.4, 22.1, 24.8, 50.6, 104.5, 126.9, 129.8,
132.0, 155.0, 158.4, 160.9, 164.1, 165.1. HRMS. Cal-
culated for C19H21BrN5O3: 446.0828. Found: 446.0814.
1-(4-Bromobenzamido)-N-cyclopropyl-6-oxo-2-
(piperidin-1-yl)-1,6-dihydropyrimidine-5-carboxamide
(8i). Yield 67.1%, mp 257.3°C. IR spectrum, ν, cm–1:
1
3299, 1660, 1548. H NMR spectrum, δ, ppm: 0.29–
0.53 m (2H), 0.60–0.85 m (2H), 1.35–1.71 m (6H),
2.66–2.91 m (1H), 3.43–3.78 m (4H), 7.78–7.80 m
(2H), 7.82–7.86 m (2H), 8.50–8.58 m (2H), 11.75 s
(1H). 13C NMR spectrum, δ, ppm: 6.0, 6.4, 22.1, 23.4,
25.4, 49.3, 106.6, 126.8, 129.7, 129.9, 132.0, 157.6,
158.2, 161.8, 163.8, 164.1. HRMS. Calculated for
C20H23BrN5O3: 460.0984. Found: 460.0988.
1-(4-Bromobenzamido)-N-cyclopropyl-6-oxo-2-
{[(tetrahydrofuran-3-yl)methyl]amino}-1,6-dihydro-
pyrimidine-5-carboxamide (8f). Yield 45.8%, mp
1-(4-Bromobenzamido)-N-cyclopropyl-2-morpholino-
6-oxo-1,6-dihydropyrimidine-5-carboxamide (8j).
Yield 68%, mp 229.6°C. IR spectrum, ν, cm–1: 3301,
1685, 1541. 1H NMR spectrum, δ, ppm: 0.47 br.d (J =
3.9 Hz, 2H), 0.66–0.73 m (2H), 2.79 tdd (1H, J = 3.9,
7.5, 11.1 Hz), 3.53–3.68 m (6H), 3.70–3.84 m (2H),
7.76–7.84 m (2H), 7.86–7.93 m (2H), 8.52 s (2H),
11.73 s (1H). 13C NMR spectrum, δ, ppm: 6.0, 6.4,
22.2, 48.6, 65.7, 107.4, 126.9, 129.7, 129.9, 131.9,
157.4, 158.1, 161.6, 163.6, 164.3. HRMS. Calculated
for C19H21BrN5O4: 462.0777. Found: 462.0785.
1
162.6°C. IR spectrum, ν, cm–1: 3285, 1657, 1565. H
NMR spectrum, δ, ppm: 0.45 br.d (2H, J = 3.4 Hz),
0.61–0.71 m (2H), 1.20–1.30 m (1H), 1.57 td (1H, J =
6.1, 12.2 Hz), 1.83–1.94 m (1H), 2.84 m (1H), 2.50–
2.60 m (1H), 3.36–3.52 m (2H), 3.59 br.d (2H, J =
2.9 Hz), 3.73 dt (1H, J = 5.9, 8.1 Hz), 7.83 d (2H, J =
8.3 Hz), 7.94 d (2H, J = 8.3 Hz), 8.44–8.63 m (3H),
11.27 s (1H). 13C NMR spectrum, δ, ppm: 6.0, 6.3,
22.1, 29.0, 38.3, 43.3, 66.6, 69.9, 104.7, 126.5, 130.2,
130.4, 131.6, 155.9, 158.9, 159.6, 164.0, 165.3.
HRMS. Calculated for C20H23BrN5O4: 476.0933.
Found: 476.0916.
All the synthesized compounds were tested against
gram +ve and –ve bacterial and fungal cultures.
1-(4-Bromobenzamido)-N-cyclopropyl-6-oxo-2-
{[(tetrahydro-2H-pyran-4-yl)methyl]amino}-1,6-di-
hydropyrimidine-5-carboxamide (8g). Yield 54.5%,
mp 234.6°C. IR spectrum, ν, cm–1: 3278, 1645, 1511,
Antibacterial activity. The bacterial cultures used
for the tests were Staphylococcus aureus (ATCC-
6538) and Bacillus subtilis (ATCC-6633) (Gram-
positive), and Escherichia coli (ATCC-25922) and
Klebsiella (ATCC-13883) (Gram-negative) by disc
diffusion method. The cultures were grown in nutrient
agar media and subcultured for log phasic cultures in a
liquid nutrient broth medium for minimum inhibitory
concentration studies and further subcultured onto
media in petri plates for the experimental purposes.
1
1244. H NMR spectrum, δ, ppm: 0.45 br.d (J =
3.7 Hz, 2H), 0.60–0.73 m (2H), 1.07–1.20 m (2H),
1.52 br.d ( J = 12.1 Hz, 2H), 1.76–1.91 m (1H), 2.77
d.d.d (J = 4.0, 7.7), 3.15–3.30 m (4H), 3.82 br.d (J =
9.2 Hz, 2H), 7.76–7.86 m (2H), 7.87–7.99 m (2H),
8.42–8.56 m (3H), 11.22 br.s (1H), 11.4 Hz, 1H). 13C
NMR spectrum, δ, ppm: 6.0, 6.5, 25.2, 29.2, 32.5,
42.8, 68.7, 126.5, 129.0, 129.7, 131.4, 131.7, 153.4,
155.1, 159.1, 163.0, 164.8. HRMS. Calculated for
C21H25BrN5O4: 490.1090. Found: 490.1103.
The broth cultures were diluted with sterilized
saline to bring the final size of inoculum ap-
proximately to 105–106 CFU/mL. The compounds
were diluted in DMSO for biological assays. The
bacterial cultures were placed on the media and
incubated at 37°C for 24 h. The zones of bacterial
growth were measured in mm.
1-(4-Bromobenzamido)-N-cyclopropyl-6-oxo-2-
(pyrrolidin-1-yl)-1,6-dihydropyrimidine-5-carboxamide
(8h). Yield 52.1%, mp 286.4°C. IR spectrum, ν, cm–1:
1
3298, 1689, 1545. H NMR spectrum, δ, ppm: 0.46
Antifungal activity. The antifungal activity of the
synthesized compounds were tested against two
pathogenic fungi Fusarium Oxysporum and Aspergilus
Flavus by the poison plate technique. Test compounds
br.d (J = 2.9 Hz, 2H), 0.60–0.73 m (2H), 1.69–1.98 m
(4H), 2.78 br.d (J = 4.0 Hz, 1H), 3.44–3.62 m (2H),
3.72–3.78 br.d (J = 5.5 Hz, 2H), 7.75–7.96 m (2H),
8.48–8.58 m (2H), 11.54 s (1H). 13C NMR spectrum,
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DEVARASETTY et al.
were dissolved in DMSO (10 mL) before mixing with
Potato Dextrose Agar medium (PDA, 90 mL). The
final concentration of compounds in the medium was
maintained at 500 µg/mL. The above mentioned types
of fungi were incubated in PDA at 25±1°C for 48 h to
get long mycelium for antifungal assay. The mycelia
disks of approximately 0.45 cm diameter were cut
from the PDA medium with a sterilized inoculation
needle and inoculated in the center of PDA plates. The
inoculated plates were incubated at 27±1°C for 3 days.
DMSO in sterilized distilled water was used as a
control, Hymexazole was used as a positive control for
all treatments. Growth of the fungal colonies was
measured on the third day and the data were
statistically analyzed.
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CONCLUSIONS
In the present study, a synthetic route for a series of
novel dihydropyrimidone derivatives (6a–6j and 8a–
8j) is developed. The compounds 6a–6j and 8a–8j
exhibit very good anti-bacterial activity against both
Gram positive and Gram negative bacteria in
comparison to ciprofloxacin a first line antibiotic drug.
The structure and biological activity relationship of
title compounds indicates that the presence of
biologically active pyrimidone nuclei and amino
guanidine skeleton, as well as cyclic moieties like
cyclopropyl, pyran and morpholine groups attached to
the pyrimidone ring are responsible for good
antibacterial activity.
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ACKNOWLEDGMENTS
The authors K. Devarasetty and P. Srinivas are
grateful to the management of GVK Biosciences
Private Limited, India and JNTUH, Hyderabad, India
for providing facilities, financial and academic support
for this program. Author J. Vantikommu thanks the
DST, Govt of India for financial support through DST
Women Scientist-A program.
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CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 4 2019