Synthesis and in vitro antimicrobial studies of thiodihydropyrimidine derivatives

Article abstract of DOI:10.1002/jccs.201900197

In the present study, a series of thiodihydropyrimidine derivatives were synthesized from different substituted aromatic aldehydes, ethyl acetoacetate, and urea/thiourea using a bimetallic TUD-1 catalyst. The structures of all the synthesized compounds we

Full text of DOI:10.1002/jccs.201900197

Received: 18 May 2019
Revised: 6 November 2019
Accepted: 12 November 2019
DOI: 10.1002/jccs.201900197
A R T I C L E
Synthesis and in vitro antimicrobial studies of
thiodihydropyrimidine derivatives
Mani Pasupathi1 | Namasivayam Santhi1 | Kasi Venkatesan2
1PG & Research, Department of
Abstract
Chemistry, Government Arts College,
C. Mutlur, Chidambaram, Tamil Nadu,
India
2Department of Humanities and Sciences,
CVR College of Engineering, Vastunagar,
Telangana, India
In the present study, a series of thiodihydropyrimidine derivatives were syn-
thesized from different substituted aromatic aldehydes, ethyl acetoacetate, and
urea/thiourea using a bimetallic TUD-1 catalyst. The structures of all the syn-
thesized compounds were characterized by melting point determination, thin
1
layer chromatography (TLC), infrared (IR), HNMR, and 13C-NMR values. All
Correspondence
the synthesized compounds were screened for their antimicrobial activities
against two gram positive bacteria, two-gram negative bacteria, and two fungal
strains.
Kasi Venkatesn, Department of
Humanities and Sciences, CVR College of
Engineering, Vastunagar, Telangana,
India.
Email: venkippk@gmail.com
K E Y W O R D S
antibacterial, antifungal, thiodihydropyrimidine
Namasivayam Santhi, PG & Research,
Department of Chemistry, Government
Arts College, C. Mutlur, Chidambaram,
Tamil Nadu, India.
Email: nsanthi@gmail.com
1 | INTRODUCTION
is related with different organic activities.[1] Pyrimidine deriva-
tives are found to exhibit exceedingly potent biological
The survival of pathogens against the accessible medications
is quickly turning into a noteworthy issue in the field of medic-
inal chemistry. Presently, most of the infections, organisms,
and microbes display the multiple drug resistant, and this phe-
nomenon is progressively dominant among human, creature,
and plant pathogens. Diseases caused by bacterial biofilms
cause high health costs and in addition economic loss in farm-
ing. Death from intense respiratory problems, diarrheal ill-
nesses, measles, AIDS, malaria, and tuberculosis, causes
excess of the mortality due to the infections by pathogens
around the world. The resistance toward the firstline drugs of
majority of the pathogens causing these infections is very dras-
tically increased from zero to almost 100%. Henceforth, the
need to plan new drugs to manage this obstruction has turned
out to be a standout among the most critical zones of research
today. Pyrimidine and their derivatives assumed to have the
dynamic role in the field of drug discovery and agriculture.
Pyrimidine could be a fundamental core in DNA and RNA; it
activity. Pyrimidine derivatives have been found to show
cytostatic,[2–4] immunomodulating,[5,6] and antibacterial
properties.[7–13] Pyrimidines and related fused heterocycles are
vital classes of heterocyclic compounds that display a wide
range of biological activities, for example, anticancerous,[14–16]
antiviral,[17,18] antibacterial,[19] antioxidant,[20] and anti-
inflammatory.[21] The partly hydrogenated pyrimidine deriva-
tives, for example, dihydropyrimidones and thiodihydro-
pyrimidones, have been utilized as key substrates to create
compounds as new drugs or powerful lead compounds in the
field of medicinal chemistry.[22]
The synthesis of substituted Pyrimidine and many more
review have been reported.[23,24] “Pyrimidine” and their
derivatives are predominant in inorganic synthetic chemis-
try. Pyrimidine does not exist in nature anyway with as its
various derivatives, they are broadly distributed. Pyrimidine
compounds are of high attraction because of their pharma-
cological properties such as anticancer,[25] analgesic,[26]
© 2019 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J Chin Chem Soc. 2019;1–7.
http://www.jccs.wiley-vch.de
1

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PASUPATHI ET AL.
antagonist,[27,28] antifolate,[29] antimicrobial,[30] anti-HIV,[31]
antiproliferative,[32] antiplatelet,[33] antithrombotic,[34] anti-
filarial[35] activities, and so on. Motivated by these percep-
tions, we synthesized a series of pyrimidine derivatives by
fusing the diketoester, aldehyde, and urea/thiourea with
the expectation of getting better antimicrobial action. All
these synthesized compounds have been screened for their
antimicrobial activities.
2.1.2 | Ethyl-1,2,3,4-tetrahydro-6-methyl-
4-(3-trifluorophenyl)-2-thioxopyrimidine-
5-carboxylate (4b)
IR (KBr, cm−1): 3,296 and 3,180 (N–H str.), 1,653 (C=O
str.), 1,448 (C–N str.), 1,373 (C–N–C str, sym.), 2,982 (C–H
aliphatic), and 3,102 (C–H phenyl ring); 1H NMR
(500 MHz, DMSO-d6) δ: 1.064–1.092 (t, 3H, J = 7.0 Hz,
OCH2CH3), 2.307 (s, 3H, CH3), 4.023–4.044 (q, 2H,
J = 3.5 Hz, CH2), 5.283–5.289 (d, 1H, J = 3.0 Hz, CH),
7.60–7.666 (m, 4H, Ar-H), and 9.721 and 10.458 (s, 1H, NH)
ppm; 13C NMR (125 MHz, DMSO-d6) δ: 14.3, 17.6, 54.2,
60.1, 100.5, 123.6, 124.9, 145.3, 146.2, 165.4, and 174.9 ppm.
2 | EXPERIMENTAL
All the chemicals were purchased from Sigma Aldrich.
M.p.s is uncorrected and was determined by open capil-
lary method. IR spectra recorded on KBr, cm−1 was
1
recorded on an FT IR/5300 spectrometer. H NMR spec-
2.1.3 | Ethyl-1,2,3,4-tetrahydro-6-methyl-
4-(2,4-dimethoxyphenyl)-
2-thioxopyrimidine-5-carboxylate (4c)
tra (ppm) were taken on Bruker AVIII (500 MHz) spec-
trometer and 13C NMR spectra were taken in the
200 MHz range.
IR (KBr, cm−1): 3,301 and 3,172 (N–H str.), 1,701 (C=O
str.), 1,446 (C–N str.), 1,384 (C–N–C str, sym.), 2,934 (C–H
aliphatic), and 3,098 (C–H phenyl ring); 1H NMR
(500 MHz, DMSO-d6) δ: 1.042–1.070 (t, 3H, J = 7 Hz,
OCH2CH3), 2.282 (s, 3H, CH3), 3.733 (s, 3H, OCH3), 3.774
(s, 3H, OCH3), 3.929–3.952 (q, 2H, J = 3.8 Hz, CH2),
5.409–5.414 (d, 1H, J = 2.5 Hz, CH), 6.452–6.540 (m, 3H,
Ar-H), and 9.180 and 10.181 (s, 1H, NH) ppm; 13C NMR
(125 MHz, DMSO-d6) δ: 14.4, 17.5, 49.5, 55.7, 56.0, 98.0,
100.1, 105.0, 158.1, 160.7, 165.7, and 174.4 ppm.
2.1 | General procedure
In typical reaction condition, the solution of benzaldehyde
(2 mmol), ethyl acetoacetic ester (2 mmol), and urea/thio-
urea (3 mmol) were transferred into 50 ml round base
flask, which contains pre-dried AlTiTUD-1 (100 mg) cata-
lyst and acetonitrile (5 ml) as solvent. The solution was
mixed well and warmed at 80ꢀC under reflux condition for
6 hr. The progress of the reaction was checked by thin
layer chromatography (TLC). After completion of the reac-
tion, the mixture was poured into crushed ice with con-
stant stirring. The crude compound obtained was filtered
and washed with 95% hot ethanol. At last, the catalyst was
separated and the obtained product was recrystallized
with hot ethanol to give pure dihydropyrimidines
(DHPMs). Spectral data of products are given in the
following.
2.1.4 | Ethyl-1,2,3,4-tetrahydro-6-methyl-
4-(2,4-dichlorophenyl)-2-thioxopyrimidine-
5-carboxylate (4d)
IR (KBr, cm−1): 3,400 and 3,177 (N–H str.), 1,707 (C=O str.),
1,461 (C–N str.), 1,380 (C–N–C str, sym.), 2,977 (C–H ali-
phatic), and 3,095 (C–H phenyl ring); 1H NMR (500 MHz,
DMSO-d6) δ: 1.000–1.029 (t, 3H, J = 7.25 Hz, OCH2CH3),
2.290 (s, 3H, CH3), 3.897–3.939 (q, 2H, J = 7.0 Hz, CH2),
5.600–5.606 (d, 1H, J = 3.0 Hz, CH), 7.533–7.630 (m, 3H, Ar-
H), and 9.628 and 10.407 (s, 1H, NH) ppm; 13C NMR
(125 MHz, DMSO-d6) δ: 14.3, 17.5, 51.2, 60.0, 99.8, 128.5,
133.6, 140.29, 146.3, 165.1, and 175.3 ppm.
2.1.1 | Ethyl-1,2,3,4-tetrahydro-6-methyl-
4-phenyl-2-thioxopyrimidine-
5-carboxylate (4a)
IR (KBr, cm−1): 3,321 and 3,167 (N–H str.), 1,662 (C=O
str.), 1,456 (C–N str.), 1,324 (C–N–C str, sym.), 2,918 (C–
H aliphatic), and 3,099 (C–H phenyl ring); 1H NMR
(500 MHz, DMSO-d6) δ: 1.093–1.119 (t, 3H, J = 6.5 Hz,
OCH2CH3), 2.307 (s, 3H, CH3), 3.985–4.030 (q, 2H,
J = 7.5 Hz, CH2), 5.191 (s, 1H, CH), 7.234–7.365 (m, 5H,
Ar-H), and 9.668 and 10.347 (s, 1H, NH) ppm; 13C NMR
(125 MHz, DMSO-d6) δ: 14.2, 17.6, 54.5, 60.1, 101.2,
126.9, 128.1, 129.0, 155.0, 165.6, and 174.7 ppm.
2.1.5 | Ethyl-1,2,3,4-tetrahydro-6-methyl-
4-(2,6-dichlorophenyl)-2-thioxopyrimidine-
5-carboxylate (4e)
IR (KBr, cm−1): 3,282 and 3,179 (N–H str.), 1,691 (C=O
str.), 1,466 (C–N str.), 1,371 (C–N–C str, sym.), 2,924 (C–
H aliphatic), and 2,980 (C–H phenyl ring); 1H NMR

PASUPATHI ET AL.
3
(500 MHz, DMSO-d6) δ: 0.889–0.917 (t, 3H, J = 7.0 Hz,
OCH2CH3), 2.172 (s, 3H, CH3), 3.818–3.864 (q, 2H,
J = 7.6 Hz, CH2), 6.145 (s, 1H, CH), 7.291–7.609 (m, 3H,
Ar-H), and 9.440 and 10.272 (s, 1H, NH) ppm; 13C NMR
(125 MHz, DMSO-d6) δ: 14.1, 17.6, 52.6, 59.6, 96.7, 128.5,
130.3, 146.5, 165.2, 174.2, and 184.3 ppm.
d6) δ: 14.3, 17.6, 50.4, 60.0, 99.2, 106.2, 108.4, 117.5, 146.7,
152.9, 155.5, 162.6, and 164.1 ppm.
3 | ANTIMICROBIAL ACTIVITY
3.1 | Test microorganisms
2.1.6 | Ethyl-1,2,3,4-tetrahydro-6-methyl-
4-(2,3-dimethoxyphenyl)-
2-thioxopyrimidine-5-carboxylate (4f)
Totally four bacterial strains and two fungal strains were
used for antimicrobial studies. All the bacterial and fungal
cultures were obtained from Microbial Type Culture Collec-
tion (MTCC), Institute of Microbial Technology, and Chan-
digarh, India. The bacterial strains such as Escherichia coli
(MTCC 1302), Bacillus subtillis (MTCC 1305), Enterococcus
IR (KBr, cm−1): 3,339 and 3,212 (N–H str.), 1,703 (C=O
str.), 1,459 (C–N str.), 1,385 (C–N–C str, sym.), 2,976 (C–
H aliphatic), and 3,106 (C–H phenyl ring); 1H NMR
(500 MHz, DMSO-d6) δ: 1.064 (t, 3H, J = 7 Hz,
OCH2CH3), 2.289 (s, 3H, CH3), 3.774 (s, 3H, OCH3),
3.808 (s, 3H. OCH3), 3.915–3.950 (q, 2H, J = 6 Hz, CH2),
5.455–5.461 (d, 1H, J = 2.5 Hz, CH), 6.690–7.017 (m, 3H,
Ar-H), and 9.307 and 10.236 (s, 1H, NH) ppm; 13C NMR
(125 MHz, DMSO-d6) δ: 14.4, 17.6, 50.4, 56.2, 56.5, 59.9,
100.4, 113.0, 146.7, 152.9, 165.6, and 174.4 ppm.
TABLE 1 Different groups substituted benzaldehyde with its
product and percentage yields
Various
Compound benzaldehydes
Yield
(%)
Melting
point (ꢀC)
4a
4b
80
183–185
2.1.7 | Ethyl4-(4-fluorophenyl)-
1,2,3,4-tetrahydro-6-methyl-
70
201–203
2-oxopyrimidine-5-carboxylate (4g)
IR (KBr, cm−1): 3,382 and 3,220 (N–H str.), 1,701 (C=O
str.), 1,453 (C–N str.), 1,397 (C–N–C str, sym.), 2,973 (C–
H aliphatic), and 3,088 (C–H phenyl ring); 1H NMR
(500 MHz, DMSO-d6) δ: 1.237–1.265 (t, 3H, J = 7 Hz,
OCH2CH3), 2.322 (s, 3H, CH3), 4.316–4.346 (q, 2H,
J = 4 Hz, CH2), 5.370 (s, 1H, CH), 6.180–7.017 (m, 2H,
Ar-H), 6.080–6.097 (m, 2H, Ar-H), and 7.307 and 8.541 (s,
1H, NH) ppm; 13C NMR (125 MHz, DMSO-d6) δ: 14.1,
18.5, 55.0, 60.1, 101.3, 115.4, 128.2, 128.4, 139.7, 146.4,
153.6, 163.3, and 165.5 ppm.
4c
4d
72
69
186–188
210–212
4e
4f
75
71
223–225
181–183
2.1.8 | Ethyl4-(2,4-dihydroxyphenyl)-
1,2,3,4-tetrahydro-6-methyl-
2-oxopyrimidine-5-carboxylate (4h)
IR (KBr, cm−1): 3,381 and 3,222 (N–H str.), 1,700 (C=O
str. of ester), 1,650 (C=O str. of pyrimidine ring), 1,453
(C–N str.), 1,397 (C–N–C str, sym.), 2,975 (C–H ali-
phatic), and 3,091 (C–H phenyl ring); 1H NMR
(500 MHz, DMSO-d6) δ: 1.266–1.302 (t, 3H, J = 7.2 Hz,
OCH2CH3), 2.366 (s, 3H, CH3), 4.316–4.346 (q, 2H,
J = 4 Hz, CH2), 5.234 (s, 1H, OH), 5.437 (s, 1H. OH),
5.710 (s, 1H, CH), 6.909–7.105 (m, 3H, Ar-H), and 7.658
and 7.698 (s, 1H, NH) ppm; 13C NMR (125 MHz, DMSO-
4g
72
68
177–179
204–206
4h

4
PASUPATHI ET AL.
O
faecalis (MTCC 439), and Serratia marcescens (MTCC 2645)
were used for antibacterial activity. The fungal strains used
were Aspergillus terreus (MTCC 1782) and Candida albicans
(MTCC 183). The young bacterial broth cultures were pre-
pared before the screening procedure.
O
O
Al-Ti-TUD-1
O
NH
O
NH2
X
+
H2N
+
N
X
-O
H
benzaldehyde
Thiourea/Urea
X= O, S
Ethylacetoacetate
SCHEME 1 Preparation of thio/oxodihydropyrimidine
3.2 | Antimicrobial assay
3.2.1 | Preparation of inoculums
Stock cultures were maintained at 4ꢀC on slopes of nutri-
ent agar. Active cultures of experiment were prepared by
transferring a loopful of cells from the stock cultures to
test tube of Muller–Hinton broth (MHB) for bacteria that
were incubated without agitation for 24 hr at 37ꢀC. The
cultures were diluted with fresh MHB to achieve optical
densities corresponding to 2.0 × 106 colony forming units
(CFU/ml) for bacteria.
3.3 | Antibacterial assay
The well diffusion method was used to screen the antimi-
crobial activity. in vitro antimicrobial activity was screened
by using Muller–Hinton Agar (MHA) obtained from
Himedia (Mumbai). The MHA plates were prepared by
pouring 15 ml of molten media into sterile petriplates. The
plates were allowed to solidify for 5 min and 0.1% inocu-
lums suspension was swabbed uniformly and the inocu-
lums were allowed to dry for 5 min. Wells were cut and
different concentrations of test drug were added. The plates
were then incubated at 37ꢀC for 24 hr. The antibacterial
activity was assayed by measuring the diameter of the inhi-
bition zone formed around the well (NCCLS, 1993). Chlor-
amphenicol disc was used as a positive control.
SCHEME 2 Mechanism of AlTiTUD-1-catalyzed Biginelli
reaction
into each 15 cm Petri dish. C. albicans and A. terreus were
grown in Sabouraud Dextrose Broth at 27ꢀC for 48 hr.
Growth was adjusted to OD (600 nm) of 0.1 by dilution
with Sabouraud Dextrose Broth. Then, Wells were cut and
different concentrations of test drug were placed on agar
to load 50 and 100 μL of each sample (1 mg/mL). Hundred
units of Fluconazole, obtained from a local pharmacy,
were used as a positive control. Zone of inhibition was
measured after incubation at 27ꢀC for 48 hr.
3.4 | Antifungal assay
Totally two fungal strains were used throughout investi-
gation. All the fungal cultures were obtained from
MTCC, Institute of Microbial Technology, Chandigarh,
India.
4 | RESULTS AND DISCUSSION
3.5 | Antifungal activity
The mesoporous AlTiTUD-1 catalyst is used for the Big-
inelli reactions of aromatic aldehydes with acetoacetate
ester and urea/thiourea (Scheme 1). The reaction condi-
tions, for example, catalytic quantity, time, and solubility
were streamlined by screening. The reaction was con-
ducted in 80ꢀC refluxing conditions and acetonitrile as sol-
vent. The various groups substituted benzaldehydes with
Antifungal activity was measured using methods of well
diffusion plates on agar. In order to test the antifungal
activity, the fractions of different concentrations of the
synthesized compounds were dissolved in 70% ethanol.
Twenty milliliters of Sabouraud Dextrose Agar was poured

PASUPATHI ET AL.
5
its product percentage yields are recorded in Table 1. Pre-
viously, the progress of the reaction is checked with the
assistance of TLC. As the reaction continues, white to yel-
low precipitate appears, because of the formation of
DHPMs. After the reaction is finished, catalyst is isolated
by filtration and recrystallization and the filtrate contained
the pure DHPM compounds. The separated and purified
catalyst was reused for the further reaction cycle. Amaz-
ingly, 65–86% of product yields are gotten by utilizing the
acidic catalyst for various substituted aldehydes. While
without catalyst, there is no transformation of reactant is
observed. This perception simply shows the significance of
catalyst for the progress of the reaction.
The mostly acknowledged mechanism of Biginelli
reaction was proposed by numerous researchers.[36–38]
By following the mechanism reported by Kumar et al.,
AlTiTUD-1-catalyzed reaction mechanism is proposed
in Scheme 2.[38] It incorporates the Bronsted acid site-
catalyzed development of an iminium intermediate (1),
from the parent aldehyde and thiourea, and on the assis-
tance of its nucleophilic attack by coordinated
acetoacetic ester to yield the dihydropyrimidinones
(3). Another plausible mechanism involves the
AlTiTUD-1 acidic-catalyzed development of acyl imine
intermediate formed by reaction of the aldehyde with
thiourea. Furthermore, the interference of iminium
intermediate by diketoester enolate produces an open
chain uride, which, in this manner, cyclizes to
dihydropyrimidinones. Remarkably, for the condensa-
tion steps, B/L acidic sites are required in the reaction.
The B/L acidic site-established homogeneous and het-
erogeneous catalysts have been used for the Biginelli
reaction.
In the AlTiTUD-1 catalyst, the presence of Bronsted
and Lewis sites is in charge of the formation of the prod-
uct. The interaction between B and L acidic sites in the
AlTiTUD-1 is hard to discover for the Biginelli reaction.
In the AlZrTUD-1 catalyst, B and L acidity impacts are
clearly discussed on the Prins cyclisation and meerwein–
ponndorf–verley reduction individually.[37] However, the
impacts of nature of acidity (B/L), strength of acidity, and
multicomponent reaction mechanism are still under
examination.
The various Bronstead and Lewis acid active sites of
the AlTiTUD-1 catalyst[39] are given in Figure 1
4.1 | Screening of antibacterial activity
The synthesized different substituted DHPM derivatives
4a–h were screened for in vitro antibacterial activity
using the standard procedure given in the Section 2. The
synthesized compound 4b exhibited highest activity
against E. coli, B. subtillis, and S. marcescens and moder-
ate activity against E. faecalis, while compounds 4e and
4g exhibited maximum activity against E. faecalis and
moderate activity against other bacterial strains. The
compounds 4f and 4h exhibited maximum activity
against E. coli and moderate activity against other organ-
isms. Compound 4c exhibited highest activity against
Bronsted site
O
O
Si
O
O
Si
O
O
Lewis site
H+
O
Ti
H+
O
Al
O
O
O
O
TUD-1
FIGURE 1 : Possible acid sites and incorporations developed
in the AlTiTUD-1 catalyst
TABLE 2 Antibacterial activities of the synthesized compounds 4a–h
Zone of inhibition (mm)
B. subtilis
Enterococcus faecalis
Escherichia coli
Serratia marcescens
Compound
50 μg/ml
100 μg/ml
50 μg/ml
100 μg/ml
50 μg/ml
100 μg/ml
50 μg/ml
100 μg/ml
4a
12
13
13
12
11
10
12
10
26
16
18
18
19
16
14
16
17
11
10
12
11
13
12
14
12
27
15
16
17
16
19
16
19
18
11
14
14
13
14
14
11
13
25
17
19
17
15
17
18
15
18
12
13
13
12
12
11
13
11
27
16
18
19
17
16
15
17
16
4b
4c
4d
4e
4f
4g
4h
Chloramphenicol

6
PASUPATHI ET AL.
TABLE 3 Antifungal activities of the synthesized compounds 4a–h
Zone of inhibition (mm)
Aspergillus terreus
Candida albicans
Compound
50 μg/ml
100 μg/ml
50 μg/ml
100 μg/ml
4a
12
10
11
10
08
09
08
09
22
16
14
16
15
14
12
12
14
13
12
10
09
10
11
10
08
25
18
17
14
13
15
14
16
14
4b
4c
4d
4e
4f
4g
4h
Fluconazole
ORCID
S. marcescens and the compound 4g exhibited highest
activity against E. faecalis. The antibacterial activity data
of the synthesized compounds were given in Table 2.
Kasi Venkatesan https://orcid.org/0000-0001-8010-0009
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4.2 | Screening of antifungal activity
All the synthesized DHPM derivatives 4a–h were
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5 | CONCLUSIONS
A simple and efficient method for the preparation of
thiodihydropyrimidine derivatives via one-pot synthesis
of various aldehydes, thiourea, and ethyl acetoacetate
using mesoporous AlTiTUD-1 catalyst has been pres-
ented. The synthesized compounds 4a–h were
screened for their in vitro antimicrobial activity. The
compound 4b exhibited highest antibacterial activity
against E. coli, B. subtillis, and S. marcescens and mod-
erate activity against E. faecalis. Compound 4a
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How to cite this article: Pasupathi M, Santhi N,
Venkatesan K. Synthesis and in vitro antimicrobial
studies of thiodihydropyrimidine derivatives.
J Chin Chem Soc. 2019;1–7. https://doi.org/10.
1002/jccs.201900197