Novel approach for synthesis of potent antimicrobial hybrid molecules containing pyrimidine-based imidazole scaffolds

Article abstract of DOI:10.1007/s00044-014-1005-1

This report describes the novel approach for the synthesis and exploration of hybrid molecules containing pyrimidine-based imidazole scaffolds as potent antimicrobial agents. The targeted compounds N-(4-arylidene-2-mercapto-5-oxo-4,5-dihydro-1H -imidazol-

Full text of DOI:10.1007/s00044-014-1005-1

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-014-1005-1
ORIGINAL RESEARCH
Novel approach for synthesis of potent antimicrobial hybrid
molecules containing pyrimidine-based imidazole scaffolds
•
N. C. Desai H. V. Vaghani K. M. Rajpara
•
•
•
V. V. Joshi H. M. Satodiya
Received: 11 November 2013 / Accepted: 5 April 2014
Ó Springer Science+Business Media New York 2014
Abstract This report describes the novel approach for the
synthesis and exploration of hybrid molecules containing
pyrimidine-based imidazole scaffolds as potent antimicro-
bial agents. The targeted compounds N-(4-arylidene-2-
mercapto-5-oxo-4,5-dihydro-1H-imidazol-1-yl)-6-methyl-
2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamides
(5a–l) were achieved by the Knoevenagel condensation of a
key precursor (4) with different aldehydes in good yields
having moderate to excellent antimicrobial activity. The
structural identification of final products was carried out by
much attention has been given to the design and synthesis of
new types of pharmacologically diverse structural hybrid
molecules (Vladimir and Alicia, 2009). One shining example
is vilazodone, which combined serotonin reuptake inhibitor
(SSRI) and 5-HT1A receptor which was a partial agonist and
was marketed under the tread name Viibryd (Ding et al.,
2013). Therefore, in this endeavor of our research group, we
have focused on a very unique and efficient synthesis and
exploration of antimicrobial activity of hybrid molecules
containing pyrimidine with imidazole pharmacophores.
Several pyrimidine derivatives have been developed as
versatile chemotherapeutic agents and have found wide
clinical applications such as antitumor (Diaa and Amira,
2010), antioxidant (Kumar et al., 2011), vasodilative (Singh
et al., 2009; Cho et al., 1989), antihypertensive (Alam et al.,
2010; Atwal et al., 1991; Rovnyak et al., 1992; Grover et al.,
1995), and adrenoceptor-selective antagonism (Barrow
et al., 2000). Also, different pyrimidine derivatives have
remarkable pharmaceutical importance because of their
biological activity as antitubercular (Virsodia et al., 2008),
antibacterial (Rostamizadeh et al., 2013), and anti-HIV
compounds (Wallis et al., 1999). Moreover, pyrimidines are
important analgesic and anti-inflammatory agents (Sondhia
et al., 2009).
1
known classical spectral techniques like IR, H NMR, 13C
NMR, and mass spectra. The obtained data indicated that the
majority of the tested compounds exhibited good antibacterial
activity over antifungal activity, particularly compounds 5j
and 5b (having MIC values 12.5 lg/mL) showed a compara-
ble effect to a standard antibacterial and antifungal agents.
Keywords Pyrimidine ꢀ Imidazole ꢀ
Antimicrobial activity ꢀ MIC ꢀ Hybrid molecules
Introduction
The epidemic of resistant pathogens has spurred renewed
concern in finding novel antimicrobials. In this pursuit,
molecular hybridization serves as an important tool for dis-
covery of new chemical entities. In the past several decades
Imidazole and its derivatives are reported to be physio-
logically and pharmacologically active and find applications
in the treatment of several diseases. The imidazolinones are
associated with a wide range of therapeutic activities such as
anticancer (Baviskar et al., 2011), 20HETE (20-hydroxy-
5,8,11,14-eicosatetraenoic acid) synthase inhibitors (Na-
kamura et al., 2004), carboxypeptidase inhibitors (Pozhar-
skii et al., 1997), antiaging agents (Congiu et al., 2008),
anticoagulants (Venkatesan et al., 2008), antiviral (Bab-
izhayev, 2006), antitubercular (Nantermet et al., 2004), and
antimicrobial (Desai et al., 2013a). This group presents in
N. C. Desai (&) ꢀ H. V. Vaghani ꢀ K. M. Rajpara ꢀ
V. V. Joshi ꢀ H. M. Satodiya
Division of Medicinal Chemistry, Department of Chemistry
(UGC NON-SAP & DST-FIST Sponsored), Maharaja
Krishnakumarsinhji Bhavnagar University, Mahatma Gandhi
Campus, Bhavnagar 364 002, India
e-mail: dnisheeth@rediffmail.com
123

Med Chem Res
Fig. 1 Structural similarity
between marketed drugs and
targeted compounds
O
Cl
N
Cl
H
N
N
H
N
N
O
R
N
N
N
N
N
N
HN
H
O
H
H
SH
Cl
O
N
H
Moxonidine
Antihypertensive
Clonidine
Antihypertensive
Targeted compounds 5a-l
azoles antifungal which inhibit the accumulation of meth-
ylated sterols destroy the composition of the lipid bilayer of
membranes. Motivated by the above findings and our pre-
vious work (Desai et al., 2013b, c), it was thought worth-
while to synthesize new pyrimidine bearing imidazole
derivatives (5a–l) that contain the aforementioned moieties
in a single molecular framework in order to investigate their
in vitro antibacterial and antifungal activity. The assumed
compounds were characterized on the basis of IR, 1H NMR,
13C NMR, and mass spectral data. These compounds were
evaluated for their antimicrobial screening on different
strains of bacteria and fungi (Fig. 1).
(5a–l) were afforded by the Knoevenagel condensation
reaction of compound (4) with different aldehydes in the
presence of sodium ethoxide in ethanol. Formation of final
products (5a–l) was explained based on the literature pre-
cedence, and the isomeric ratio of products was presumed to
be mainly Z in all cases. It was reported that the thermody-
namically stable Z-isomer predominated with a ratio of
Z:E isomers 10:1 after recrystallization for all arylidene (5a–
l). The ratio of the two geometrical stereoisomers was
1
readily quantified by H NMR as reported in the literature
(Ohishi et al., 1990).The purity of compounds was checked
by TLC as well as by column chromatography. The structure
of all the synthesized compounds was established by IR, 1H,
13C NMR, and mass spectral analysis. The result of ele-
mental analysis of the synthesized compounds was in
agreement with theoretical values. The outcome of antimi-
crobial studies of newly synthesized compounds revealed
that these compounds have significant antibacterial and
antifungal activities.
Results and discussion
Chemistry
The synthesis of titled compounds (5a–l) is outlined in
Scheme 1. In a typical experimental procedure, a mixture of
benzaldehyde, urea, and ethyl acetoacetate in 1,4-dioxane was
heated under reflux in the presence of concentrated HCl to give
ethyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-
5-carboxylate (1), followed by reaction with hydrazine hydrate
in 1,4-dioxane in the presence of H2SO4 to give 6-methyl-2-
oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carbohydrazide
(2) (Raval and Akhaja, 2011). The treatment of compound
(2) with KSCN in acidic medium afforded 2-(6-methyl-2-
oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carbonyl)hydra-
zinecarbothioamide (3) (Samshuddin et al., 2012). The key
precursor N-(2-mercapto-5-oxo-4,5-dihydro-1H-imidazol-1-
yl)-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-
carboxamide (4) was obtained by the reaction of compound (3)
with ClCH2COOH in the presence of anhydrous sodium acetate
in glacial acetic acid in reflux conditions. The lone pair of
electron on amido group of pyrimidine hydrazinecarbothioa-
mide (3) attacks on positively charged methyleneic C atom of
the chloroacetic acid to form an intermediate having a new C–N
bond with the elimination of HCl molecule. This intermediate
undergoes cyclization on loosing H2O molecule to form an
imidazole ring structure (4). These conversions are depicted in
Scheme 2. Finally, the title compounds N-(4-arylidene-2-
mercapto-5-oxo-4,5-dihydro-1H-imidazol-1-yl)-6-methyl-2-
oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide
Antimicrobial screening
From antimicrobial activity data (Table 1), key precursor,
imidazole (4) showed poor antibacterial activity at
MIC [ n with aromatic aldehydes. Collectively, compounds
(5a–l) could be considered as significant to potent active
broad-spectrum antimicrobials. Preliminary microbiological
screening results showed that compounds 5b (-2-F-C6H4)
and 5d (-2-OH-C6H4) exhibited good activity against
Escherichia coli, while compounds 5f (-4-Cl-C6H4) and 5j
(-2,6-(Cl)2-C6H3) demonstrated very good activity against
E. coli. Compounds 5b (-2-F-C6H4) and 5f (-4-Cl-C6H4)
showed good activity against Staphylococcus aureus. On
installation of -2,6-(Cl)2-C6H3 substituent in the compound
5j, the increment in activity was observed enormously and it
exhibited excellent activity against S. aureus.
In case of antifungal activity, compound 5j (-2,6-(Cl)2-
C6H3) exhibited good activity against Aspergillus niger,
while compound 5b (2-F-C6H4) demonstrated excellent
activity against Aspergillus clavatus. In a nutshell, these
preliminary screening showed that the series of these novel
compounds exhibited significant antibacterial activity in
comparison to antifungal activity.
123

Med Chem Res
Scheme 1 Reaction scheme.
Reagents and conditions:
(a) NH2NH2H2O, Con.H2SO4 ,
1,4-dioxane, reflux, 4 h;
(b) KSCN, HCl reflux, 4 h;
(c) ClCH2COOH, CH3COONa,
CH3COOH, reflux, 8 h;
(d) C2H5ONa, EtOH, reflux,
6–7 h
O
CONHNH2
COOEt
(b)
(a)
HN
HN
NHNHCSNH2
HN
N
H
2
N
H
O
N
H
O
O
1
3
(c)
CHO
O
R
O
O
N
N
N
O
N
H
HN
(d)
R
N
SH
N
HN
N
O
H
H
SH
N
O
4
H
5
Where, R = -H, -2-F, -4-F, -2-OH, -4-OH, -4-Cl, -2-NO2, -3-NO2,
-4-NO2, -2,6(Cl)2, -2-OCH3, -4-OCH3
Scheme 2 Plausible reaction
mechanism
O
O
H+
H
KS
N
NH2
N
NH
+
C
Ar
N
Ar
N
H
H
SH
O
O
H
H
N
N
S
NH2
Ar
N
Ar
N
H
H
NH2
S
OH
-HCl
O
Cl
O
O
S
NH
S
NH
N
Ar
HN
HO
Ar
NH
NH
-H2O
O
O
O
SH
NH
N
Ar
N
O
123

Med Chem Res
Structure activity relationship (SAR)
test organisms. The tubes were then incubated at 37 °C for
24 h for bacteria. Ten lg/mL suspensions were further
inoculated on appropriate media, and growth was noted after
24 and 48 h. The lowest concentration, which showed no
growth after spot subculture, was considered as MIC for each
drug. The highest dilution (lowest concentration) preventing
appearance of turbidity was taken as MIC i.e., the amount of
growth from the control tube before incubation (which rep-
resents the original inoculum) was compared. The test
mixture should contain 106 CFU/mL organisms. 2 %
DMSO and sterilized distilled water was used as negative
control, while ampicillin antibiotic (1 U strength) was used
as positive control. A set of tubes containing only seeded
broth and solvent controls were maintained under identical
conditions so as to make sure that the solvent had no influ-
ence on strain growth. The result of this was significantly
affected by the size of inoculum. The standard drug used in
the present study was ‘‘Ciprofloxacin’’ for evaluating anti-
bacterial activity which showed 25, 25, 50, and 50 lg/mL
MIC against E. coli, P. aeruginosa, S. aureus, and S. pyog-
enes, respectively. For bacterial growth, in the present pro-
tocol, we have used Mueller Hinton broth at 37 °C in aerobic
condition for 24 to 48 h.
Results of antimicrobial activity of final compounds and the
precursor (4) clearly suggested that the Knoevenagel adduct
of imidazolinone was found to be critical for broad spectrum
of antimicrobial activity. The substitution pattern was care-
fully altered to acquire a comprehensible design between the
electronic environment and response toward the pathogens.
Electron-releasing groups on aromatic ring, such as methyl,
methoxy, hydroxy, and electron withdrawing groups from
aromatic ring, such as nitro and halogen, are chosen as
substituents on the chemical structure of the target com-
pounds. Compounds 5j and 5b with electron withdrawing
groups (2,6-(Cl)2-C6H3 and 2-F-C6H4, respectively) repre-
sented much lower MIC values than reference drugs against
S. aureus and A. clavatus, respectively. From the data of
biological activity, we can presume that, to get most potent
antimicrobial agents, compounds must contain electron
withdrawing group as substitution. Therefore, the electron
withdrawing groups induced a positive effect on the bio-
logical activity. Thus, we have discussed and compared
antibacterial and antifungal activities based on standard
drugs ciprofloxacin and griseofulvin, respectively.
Antifungal assay
Biological evaluation
The same compounds were tested for antifungal activity as
primary screening in six sets against Candida albicans, A.
niger, and A. clavatus at various concentrations of 1,000,
500, 200, and 100 lg/mL as shown in Table 1. Results were
recorded in the form of primary and secondary screening.
Synthesized compounds were diluted to 1,000 lg/mL con-
centration, as a stock solution. Those synthesized com-
pounds which were found to be active in this primary
screening were further tested in a second set of dilution
against all microorganisms. Griseofulvin was used as a
standard drug for antifungal activity, which showed 500,
100, and 100 lg/mL MIC against C. albicans, A. niger, and
A. clavatus, respectively. Two percentage DMSO and ster-
ilized distilled water was used as negative control, while
griseofulvin (1 U strength) was used as positive control.
Results of antimicrobial evaluation of derivatives 5a–l are
shown in Table 1. For fungal growth, in the present protocol,
we have used Sabourauds dextrose broth at 28 °C in aerobic
condition for 48 h.
Antibacterial assay
The newly synthesized compounds were screened for their
antibacterial activity against Gram-positive bacteria [S.
aureus (MTCC-96), Streptococcus pyogenes (MTCC-442)]
and Gram-negative [E. coli (MTCC-443), Pseudomonas
aeruginosa (MTCC-1688)]. Antibacterial activity was
measured as per National Committee for Clinical Laboratory
Standards (NCCLS) protocol by Mueller Hinton broth
(Becton–Dickinson, USA) (Desai et al., 2013b). Standard
strains were procured by the Institute of Microbial Tech-
nology, Chandigarh. Compounds were primarily screened
for their antibacterial activity in six sets against E. coli, S.
aureus, P. aeruginosa, and S. pyogenes at different con-
centrations of 1,000, 500, and 250 lg/mL as shown in
Table 1. The drugs found to be active in primary screening
were similarly diluted to obtain 200, 125, 100, 62.5, 50, 25,
and 12.5 lg/mL concentrations for secondary screening to
test in a second set of dilution against all microorganisms.
Inoculum size for test strain was adjusted to 106 CFU/mL
(Colony Forming Unit per milliliter) by comparing the tur-
bidity (turbidimetric method). Synthesized compounds were
diluted to 1,000 lg/mL concentration, as a stock solution. A
control tube containing no antibiotic was immediately sub-
cultured (before inoculation) by spreading a loopful evenly
over a quarter of plate of medium suitable for the growth of
Materials and methods
General
All reactions except those in aqueous media were carried
out by standard techniques with the exclusion of moisture.
Melting points were determined on an electrothermal
123

Med Chem Res
hydrate (99 %) (0.01 mol) was added followed by the addi-
tion of a catalytic amount of conc. H2SO4 and allowed to stir
for 3 h at 100 °C. After completion of reaction, crude mass
was allowed to cool and poured on crushed ice. Product
obtained as yellowish precipitate was filtered and dried.
Purification was done by crystallization using ethanol (95 %).
Table 1 Antimicrobial activity of N-(4-arylidene-2-mercapto-5-oxo-
4,5-dihydro-1H-imidazol-1-yl)-6-methyl-2-oxo-4-phenyl-1,2,3,4-tet-
rahydropyrimidine-5-carboxamides
S. no. -R
Minimum inhibitory
concentration (MIC) for
bacteria (lg/mL)
Minimum inhibitory
concentration (MIC)
for fungi (lg/mL)
E.c. P.a. S.a.
S.p. C.a. A.n. A.c.
Physical constants and characterization of 6-methyl-2-oxo-
4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carbohydrazide
(2) Light yellow solid, yield: 69 %; m.p.: 195–198 °C;
IR (KBr) mmax/cm-1: 3452, 3342 (NH), 3071 (C–H, aro-
matic), 1513 (C=C), 1685 (C=O); 1H NMR (400 MHz,
DMSO-d6, d, ppm): 1.97 (s, 2H, NH2, D2O exch.), 2.35 (s,
3H, –CH3), 5.60 (s, 1H, –CH), 5.87 (s, 1H, –NHNH2), 6.05
(s, 1H, –NHCPh), 6.18 (s, 1H, –NHCCH3), 6.94 (d, 2H,
Ar–H), 7.23 (d, 2H, Ar–H); 13C NMR (100 MHz, DMSO-
d6, d, ppm): 16.2 (–CH3), 52.9 (–CH), 101.2 ([C\), 114.
6–132.4 (C-aromatic), 150.8 (C–CH3), 155.9 (–NHCONH–),
162.5 (–CONHNH2); LCMS (m/z): 246 (M)?; Anal. calcd.
for C12H14N4O2: C-58.53, H-5.73, N-22.75; Found: C-58.
92, H-5.55, N-22.12 %.
4
–
250 250
500 250
50 500
500 200
50 100
100 100
25 250
250
1000 1000 1000 1000
500 500 1,000 1,000
5a
5b
5c
5d
5e
5f
5g
5h
5i
-H
250
50
-2-F
100 100
500 1,000
500 200
200
200
500
12.5
200
500
-4-F
250
250
250
50
-2-OH
-4-OH
-4-Cl
-2-NO2
-3-NO2
-4-NO2
500 200 1,000 1,000
100 1,000
100
200
500 500 1,000 1,000 500 1,000
500
500 500 1,000 1,000 1,000 1,000 1,000
100 100 250 500 500 1,000 1,000
12.5 500 100 50 100
250 500 1,000 1,000
5j
5k
5l
-2,6-(Cl)2 25 100
-2-OCH3 250 200
-4-OCH3 250 250
250
250
50
500 1,000
50 –
500
500
Ciprofloxacin
Griseofulvin
25 25
–
–
–
–
–
–
500
100
100
General procedure for the preparation of 2-(6-methyl-2-
oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carbonyl)hydra-
zinecarbothioamide (3) (Samshuddin et al., 2012) A mixture
of 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-
carbohydrazide (2) (0.01 mol), potassium thiocyanate(0.
015 mol), and hydrochloric acid (5 mL) in water (25 mL)
was refluxed for 4 h with stirring. After completion of
reaction, the resulting solid thus separated was washed with
hot water and recrystallized from ethanol (95 %).
Bold values indicate the most active compounds
E.c. Escherichia coli (MTCC-443), P.a. Pseudomonas aeruginosa
(MTCC-1668), S.a. Staphylococcus aureus (MTCC-96), S.p. Strep-
tococcus pyogenes (MTCC-442), C.a. Candida albicans (MTCC-
227), A.n. Aspergillusniger (MTCC-282), A.c. Aspergillusclavatus
(MTCC-1,323)
melting point apparatus and are reported uncorrected. TLC
on silica gel plates (Merck, 60, F254) was used for purity
checking and reaction monitoring. Column chromatography
on silica gel (Merck, 70–230 and 230–400 mesh ASTH for
flash chromatography)was applied when necessary to isolate
and purify the reaction products. Elemental analysis (% C, H,
and N) was carried out using a Perkin-Elmer 2400 CHN
analyzer. IR spectra of all compounds have been recorded on
a Perkin-Elmer FT-IR spectrophotometer in KBr. 1H NMR
spectra were recorded on Bruker Avance II 400 MHz and
13C NMR spectra on Varian Mercury-400 100 MHz in
DMSO-d6 as a solvent and tetramethylsilane (TMS) as an
internal standard. Mass spectra were recorded on a Shimadzu
LCMS 2010 spectrometer. Anhydrous reactions were car-
ried out in ovendried glassware in nitrogen atmosphere.
Compound ethyl 4-(4-hydroxyphenyl)-6-methyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (1) was pre-
pared according to literature (Gupta et al., 2005) method.
Physical constants and characterization of 2-(6-methyl-2-
oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carbonyl)hy-
drazinecarbothioamide (3)
Light brown solid, yield
83 %; m.p.: 200–202 °C; IR (KBr) mmax/cm-1: 3433, 3367
(NH), 2987 (C–H, aromatic), 1578 (C=C), 1734 (C=O); 1H
NMR (400 MHz, DMSO-d6, d, ppm): 2.28 (s, 3H, –CH3),
5.40 (s, 1H, pyrimidine –CH), 6.02 (s, 1H, –NHCPh), 6.24
(s, 1H, –NHCCH3), 6.56 (s, 2H, –NH2), 6.67 (s, 1H,
–CONH), 7.34–7.45 (m, 5H, Ar–H), 8.32 (s, 1H,
–NHCSNH2); 13C NMR (100 MHz, DMSO-d6, d, ppm):
16.5 (–CH3), 52.9 (–CH of pyrimidine), 101.2 ([C\), 126.
6–140.8 (C-aromatic), 152.4 (–CCH3), 155.9 (–NHCONH–),
161.5 (–CONHNH), 182.5 (–CS); LCMS (m/z): 305(M)?;
Anal. calcd. for C13H15N5O2S: C-51.13, H-4.95, N-22.94;
Found: C-51.72, H-4.77, N-22.06.
General procedure for the preparation of N-(2-mercapto-5-
oxo-4,5-dihydro-1H-imidazol-1-yl)-6-methyl-2-oxo-4-phenyl-
1,2,3,4-tetrahydropyrimidine-5-carboxamide (4) A mixture
of 2-(6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-
5-carbonyl)hydrazinecarbothioamide (3) (0.001 mol),
General procedure for the preparation of 6-methyl-2-oxo-4-
phenyl-1,2,3,4-tetrahydropyrimidine-5-carbohydrazide (2)
(Raval and Akhaja, 2011) Compound (1) (0.01 mol) was
dissolved in 1,4-dioxane (20 mL), and to this hydrazine
123

Med Chem Res
monochloroacetic acid (0.001 mol), and anhydrous sodium
acetate (0.002 mol) in glacial acetic acid (30 mL) was
refluxed for 8 h. After completion of reaction, the reaction
mixture was poured on crushed ice. The resulting solid thus
separated was washed with hot water and recrystallized
from ethanol.
([C=CH–), 127.7–140.7 (Ar–C), 153.4 (–CCH3), 155.6
(–NHCONH–), 157.6 (–CONH), 165.0 (–CO of imidazole),
182.9 (–C–SH); LCMS (m/z): 433 (M)?; Anal. calcd. for
C22H19N5O3S: C-60.96, H-4.42, N-16.16; Found: C-60.26,
H-4.83, N-16.65 %.
N-(4-(2-fluorobenzylidene)-2-mercapto-5-oxo-4,5-dihydro-
1H-imidazol-1-yl)-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetra-
hydropyrimidine-5-carboxamide (5b) Light yellow solid,
yield 72 %; m.p.: 268–270 °C; IR (KBr) mmax/cm-1: 3467,
3389 (NH), 3034 (C–H, aromatic), 1578 (–C=N), 1556
(C=C), 1738 (C=O), 1245 (C–F); 1H NMR (400 MHz,
DMSO-d6, d, ppm): 2.19 (s, 1H, –SH), 2.34 (s, 3H, –CH3),
5.37 (s, 1H, –CH of pyrimidine), 6.10 (s, 1H, –CH=), 6.27
(s, 1H, –NHCPh), 7.21–7.45 (m, 9H, Ar–H), 7.67 (s, 1H,
–NHCCH3), 7.78 (s, 1H, –CONH); 13C NMR (100 MHz,
DMSO-d6, d, ppm): 16.4 (–CH3), 53.8 (–CH of pyrimi-
dine), 102.4 ([C\), 115.7 (2) ([C–C–F), 125.4 (–CH=),
126.5 ([C=CH–), 128.6–141.9 (Ar–C), 153.5 (–CCH3),
155.7 (–NHCONH–), 158.8 (–CONH), 163.5 (–C–F), 165.7
(–CO of imidazole), 181.9 (–C–SH); LCMS (m/z):
451(M)?; Anal. calcd. for C22H18FN5O3S: C-58.53,
H-4.02, N-15.51; Found: C-58.14, H-4.70, N-15.56 %.
Physical constants and characterization of N-(2-mercapto-
5-oxo-4,5-dihydro-1H-imidazol-1-yl)-6-methyl-2-oxo-4-phe-
nyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (4) Light
orange solid, yield 65 %; m.p.: 262–264 °C; IR (KBr)
m
max/cm-1: 3445, 3368 (NH), 3045 (C–H, aromatic), 1545
1
(C=C), 1734 (C=O); H NMR (400 MHz, DMSO-d6, d,
ppm): 2.04 (s, 1H, –SH), 2.40 (s, 3H, –CH3), 4.76 (s, 2H,
–CH2), 5.29 (s, 1H, –CH of pyrimidine), 6.19 (–NHCPh),
6.38 (s, 1H, –NHCCH3), 7.19 (s, 1H, –CONH), 7.29–7.38
(m, 5H, Ar–H); 13C NMR (100 MHz, DMSO-d6, d, ppm):
16.8 (–CH3), 48.9 (–CH2 of imidazole), 53.5 (–CH of
pyrimidine), 102.7 ([C\), 128.3–142.4 (Ar–C), 153.6
(–CCH3), 155.7 (–NHCONH–), 157.5 (–CONH), 173.5
(–CS), 178.5 (–CO of imidazole); LCMS (m/z): 345 (M)?;
Anal. calcd. for C15H15N5O3S: C-52.16, H-4.38, N-20.28;
Found: C-52.07, H-4.73, N-20.55 %.
General procedure for the preparation of N-(4-benzyli-
dene-2-mercapto-5-oxo-4,5-dihydro-1H-imidazol-1-yl)-6-
methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-car-
boxamide (5a–l) A solution of N-(2-mercapto-5-oxo-4,5-
dihydro-1H-imidazol-1-yl)-6-methyl-2-oxo-4-phenyl-1,2,3,
4-tetrahydropyrimidine-5-carboxamide (4) (0.01 mol) in
ethanol (25 mL) was taken in a flask equipped with a Dean-
Stark apparatus fitted with calcium guard tube. Benzalde-
hyde (0.01 mol) was slowly added to it with constant stir-
ring, and catalytic amount of sodium ethoxide (0.01 mol)
was added along with it. The reaction mixture was refluxed
for 6–7 h; after the completion of the reaction, the final
product (5) was obtained by cooling reaction mass on room
temperature, and excess amount of solvent was distilled out.
The crude product was filtered off and washed with meth-
anol, dried and recrystallized from ethanol (95 %).
N-(4-(4-fluorobenzylidene)-2-mercapto-5-oxo-4,5-dihydro-
1H-imidazol-1-yl)-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetra-
hydropyrimidine-5-carboxamide (5c) Light yellow solid,
yield 58 %; m.p.: 280–282 °C; IR (KBr) mmax/cm-1: 3456,
3378 (NH), 3023 (C–H, aromatic), 1598 (–C=N), 1545
(C=C), 1745 (C=O), 1222 (C–F); 1H NMR (400 MHz,
DMSO-d6, d, ppm): 2.24 (s, 1H, –SH), 2.29 (s, 3H, –CH3),
5.30 (s, 1H, –CH of pyrimidine), 5.98 (s, 1H, –CH=), 6.23
(s, 1H, –NHCPh), 7.15–7.38 (m, 9H, Ar–H), 7.52 (s, 1H,
–NHCCH3), 7.60 (s, 1H, –CONH); 13C NMR (100 MHz,
DMSO-d6, d, ppm): 16.7 (–CH3), 53.5 (–CH of pyrimi-
dine), 102.8 ([C\), 115.4 (2) ([C–C–F), 125.6 (–CH=),
125.9 ([C=CH–), 128.3–141.5 (Ar–C), 153.2 (–CCH3),
154.9 (–NHCONH–), 158.4 (–CONH), 162.6 (–C–F), 165.
4 (–CO of imidazole), 182.4 (–C–SH); LCMS (m/z):
451(M)?; Anal. calcd. forC22H18FN5O3S: C-58.53, H-4.02,
N-15.51; Found: C-58.17, H-4.27, N-15.68 %.
Physical constants and characterization of compounds
(5a–l) N-(4-benzylidene-2-mercapto-5-oxo-4,5-dihydro-1H-
imidazol-1-yl)-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydro-
pyrimidine-5-carboxamide (5a) Light brown solid, yield
68 %; m.p.: 272–274 °C; IR (KBr) mmax/cm-1: 3445, 3368
(NH), 3045 (C–H, aromatic), 1545 (C=C), 1734 (C=O); 1H
NMR (400 MHz, DMSO-d6, d, ppm): 2.08 (s, 1H, –SH),
2.34 (s, 3H, –CH3), 5.36 (s, 1H, –CH of pyrimidine), 6.04
(s, 1H, –NHCPh), 6.19 (s, 1H, –CH=), 7.24–7.48 (m, 10H,
N-(4-(2-hydroxybenzylidene)-2-mercapto-5-oxo-4,5-dihydro-
1H-imidazol-1-yl)-6-methyl-2-oxo-4-phenyl-1,2,3,4-tet-
rahydropyrimidine-5-carboxamide (5d)
Light gray
solid, yield 65 %; m.p.: 239–241 °C; IR (KBr) mmax/cm-1
3423(OH), 3459, 3379 (NH), 3022 (C–H, aromatic), 1563
:
1
(–C=N), 1538 (C=C), 1743 (C=O); H NMR (400 MHz,
DMSO-d6, d, ppm): 2.23 (s, 1H, –SH), 2.43 (s, 3H, –CH3),
5.28 (s, 1H,OH), 5.43 (s, 1H, –CH of pyrimidine), 6.14 (s,
1H, –CH =), 6.34 (s, 1H, –NHCPh), 7.28–7.53 (m, 9H, Ar–
H), 7.72 (s, 1H, –NHCCH3), 7.82 (s, 1H, –CONH); 13C
NMR (100 MHz, DMSO-d6, d, ppm): 18.4 (–CH3), 54.5
Ar–H), 7.40 (s, 1H, –CONH), 7.48 (s, 1H, –NHCCH3); 13
C
NMR (100 MHz, DMSO-d6, d, ppm): 16.3 (–CH3), 53.2
(–CH of pyrimidine), 102.4 ([C\), 125.4 (–CH=), 125.8
123

Med Chem Res
(–CH of pyrimidine), 104.4 ([C\), 124.8 (–CH =), 127.4
([C=CH–), 129.7–143.5 (Ar–C), 154.5 (–CCH3), 156.5
(–NHCONH–), 158.4 ([C–OH), 159.9 (–CONH), 167.9
(–CO of imidazole), 182.4 (–C–SH); LCMS (m/z):
449(M)?; Anal. calcd. for C22H19N5O4S: C-58.79, H-4.26,
N-15.58; Found: C-58.48, H-4.51, N-15.19 %.
DMSO-d6, d, ppm): 16.8 (–CH3), 53.6 (–CH of pyrimi-
dine), 102.5 ([C\), 123.9 (2) ([CH–C–NO2), 125.4
([C=CH), 126.3 ([C=CH–), 128.4–145.6 (Ar–C), 153.3
(–CCH3), 155.3 (–NHCONH–), 157.7 (–CONH), 165.3
(–CO of imidazole), 183.7 (–C–SH); LCMS (m/z): 478
(M)?; Anal. calcd. for C22H18N6O5S: C-55.22, H-3.79,
N-17.56; Found: C-55.37, H-4.23, N-17.91 %.
N-(4-(4-hydroxybenzylidene)-2-mercapto-5-oxo-4,5-dihy-
dro-1H-imidazol-1-yl)-6-methyl-2-oxo-4-phenyl-1,2,3,4-
tetrahydropyrimidine-5-carboxamide (5e) Orange yellow
N-(2-mercapto-4-(3-nitrobenzylidene)-5-oxo-4,5-dihydro-
1H-imidazol-1-yl)-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetra-
solid, yield 69 %; m.p.: 258-260 °C; IR (KBr) mmax/cm-1
:
hydropyrimidine-5-carboxamide (5h)
Light yellow
3434(OH), 3453, 3368 (NH), 3037 (C–H, aromatic), 1557
1
(–C=N), 1532 (C=C), 1756 (C=O); H NMR (400 MHz,
solid, yield 58 %; m.p.: 255–257 °C; IR (KBr) mmax/cm-1
3468, 3349 (NH), 2994 (C–H, aromatic), 1552 (–C=N),
:
1
1537 (C=C), 1478, 1349 (NO2), 1753 (C=O); H NMR
DMSO-d6, d, ppm): 2.32 (s, 1H, –SH), 2.48 (s, 3H, –CH3),
5.34 (s, 1H, OH), 5.48 (s, 1H, –CH of pyrimidine), 6.22 (s,
1H, –CH=), 6.37 (s, 1H, –NHCPh), 7.24–7.49 (m, 9H, Ar–
H), 7.67 (s, 1H, –NHCCH3), 7.75 (s, 1H, –CONH); 13C
NMR (100 MHz, DMSO-d6, d, ppm): 18.2 (–CH3), 54.7
(–CH of pyrimidine), 103.6 ([C\), 124.7 (–CH=), 127.7
([C=CH-), 130.4–144.7 (Ar–C), 153.6 (–CCH3), 155.7
(–NHCONH–), 157.6 ([C–OH), 160.4 (CONH), 166.4
(–CO of imidazole), 181.2 (–C–SH); LCMS (m/z):
449(M)?; Anal. calcd. for C22H19N5O4S: C-58.79, H-4.26,
N-15.58; Found: C-58.48, H-4.51, N-15.19 %.
(400 MHz, DMSO-d6, d, ppm): 2.23 (s, 1H, –SH), 2.47 (s,
3H, –CH3), 5.43 (s, 1H, –CH of pyrimidine), 6.29 (s, 1H,
–NHCPh), 6.48 (s, 1H, –CH=), 7.33–8.23 (m, 9H, Ar–H),
7.37 (s, 1H, –CONH), 7.72 (s, 1H, –NHCCH3); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 16.7 (–CH3), 53.3 (–CH of
pyrimidine), 102.9 ([C\), 123.3 (2) ([CH–C–NO2), 125.3
([C=CH), 126.6 ([C=CH–), 128.8–145.8 (Ar–C), 153.2
(–CCH3), 155.5 (–NHCONH–), 157.4 (–CONH), 165.7
(–CO of imidazole), 182.4 (–C–SH); LCMS (m/z): 478
(M)?; Anal. calcd. for C22H18N6O5S: C-55.22, H-3.79,
N-17.56; Found: C-55.69, H-4.68, N-17.89 %.
N-(4-(4-chlorobenzylidene)-2-mercapto-5-oxo-4,5-dihy-
dro-1H-imidazol-1-yl)-6-methyl-2-oxo-4-phenyl-1,2,3,4-
N-(2-mercapto-4-(4-nitrobenzylidene)-5-oxo-4,5-dihydro-1H-
imidazol-1-yl)-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahy-
dropyrimidine-5-carboxamide (5i) Dark yellow solid,
yield 64 %; m.p.: 268–270 °C; IR (KBr) mmax/cm-1: 3467,
3356 (NH), 2978 (C–H, aromatic), 1559 (–C=N), 1530
(C=C), 1458, 1353 (NO2), 1734 (C=O); 1H NMR (400 MHz,
DMSO-d6, d, ppm): 2.14 (s, 1H, –SH), 2.46 (s, 3H, –CH3),
5.35 (s, 1H, –CH of pyrimidine), 6.26 (s, 1H, –NHCPh),
6.34 (s, 1H, –CH =), 7.28–8.04 (m, 9H, Ar–H), 7.39 (s, 1H,
–CONH), 7.59 (s, 1H, –NHCCH3); 13C NMR (100 MHz,
DMSO-d6, d, ppm): 16.5 (–CH3), 53.3 (–CH of pyrimi-
dine), 102.7 ([C\), 124.8 (2) ([CH–C–NO2), 125.7
([C=CH), 125.9 ([C=CH–), 128.7–146.9 (Ar–C), 153.5
(–CCH3), 155.7 (–NHCONH–), 157.2 (–CONH), 165.4
(–CO of imidazole), 183.4 (–C–SH); LCMS (m/z): 478
(M)?; Anal. calcd. for C22H18N6O5S: C-55.22, H-3.79,
N-17.56; Found: C-55.70, H-3.77, N-17.60 %.
tetrahydropyrimidine-5-carboxamide (5f) Light red-
dish brown solid, yield 80 %; m.p.: 265–267 °C; IR (KBr)
m
max/cm-1: 3442, 3353 (NH), 2978 (C–H, aromatic), 1547
1
(–C=N), 1525 (C=C), 1720 (C=O), 730 (C–Cl); H NMR
(400 MHz, DMSO-d6, d, ppm): 2.19 (s, 1H, –SH), 2.34 (s,
3H, –CH3), 5.32 (s, 1H, –CH of pyrimidine), 6.34 (s, 1H,
–CH =), 6.20 (s, 1H, –NHCPh), 7.18–7.37 (m, 9H, Ar–H),
7.56 (s, 1H, –NHCCH3), 7.69 (s, 1H, –CONH); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 16.9 (–CH3), 54.4 (–CH of
pyrimidine), 102.5 ([C\), 124.4 (–CH=), 127.4 ([C=CH–),
129.2–143.8 (Ar–C), 132.5 (C–Cl), 152.8 (–CCH3), 155.3
(–NHCONH–), 161.2 (–CONH), 166.8 (–CO of imidaz-
ole), 181.8 (–C–SH); LCMS (m/z): 467(M)?; Anal. calcd.
for C22H18ClN5O3S: C-56.47, H-3.88, N-14.97; Found:
C-56.31, H-3.57, N-14.76 %.
N-(2-mercapto-4-(2-nitrobenzylidene)-5-oxo-4,5-dihydro-1H-
imidazol-1-yl)-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyr-
imidine-5-carboxamide (5g) Orange yellow solid, yield
77 %; m.p.: 139–141 °C; IR (KBr) mmax/cm-1: 3470, 3360
(NH), 2984 (C–H, aromatic), 1545 (–C=N), 1530 (C=C),
1443, 1363 (NO2), 1745 (C=O); 1H NMR (400 MHz,
DMSO-d6, d, ppm): 2.18 (s, 1H, –SH), 2.39 (s, 3H, –CH3),
5.40 (s, 1H, –CH of pyrimidine), 6.18 (s, 1H, –NHCPh),
6.43 (s, 1H, –CH =), 7.30-8.15 (m, 9H, Ar–H), 7.45 (s, 1H,
–CONH), 7.63 (s, 1H, –NHCCH3); 13C NMR (100 MHz,
N-(4-(2,6-dichlorobenzylidene)-2-mercapto-5-oxo-4,5-dihy-
dro-1H-imidazol-1-yl)-6-methyl-2-oxo-4-phenyl-1,2,3,4-tet-
rahydropyrimidine-5-carboxamide (5j)
Light brown
solid, yield 63 %; m.p.: 189–191 °C; IR (KBr) mmax/cm-1
:
3439, 3346 (NH), 3067 (C–H, aromatic), 1532 (–C=N),
1534 (C=C), 1735 (C=O), 734 (C–Cl); 1H NMR
(400 MHz, DMSO-d6, d, ppm): 2.04 (s, 1H, –SH), 2.28 (s,
3H, –CH3), 5.58 (s, 1H, –CH of pyrimidine), 6.11 (s, 1H,
–NHCPh), 6.24 (s, 1H, –CH =),6.89 (s, 1H, –CONH),
123

Med Chem Res
7.09–7.28 (m, 8H, Ar–H), 7.38 (s, 1H, –NHCCH3); 13C
NMR (100 MHz, DMSO-d6, d, ppm): 17.3 (–CH3), 53.2
(–CH of pyrimidine), 102.7 ([C\), 120.3 (–CH=),
128.2–140.4 (Ar–C), 132.5 (C–Cl), 142.5 ([C=CH–),
153.5 (–CCH3), 155.7 (–NHCONH–), 158.7 (–CONH),
165.5 (–CO of imidazole), 183.4 (–C–SH); LCMS (m/z):
501 (M)?; Anal. calcd. forC22H17Cl2N5O3S: C-52.60, H-3.
41, N-13.94; Found: C-52.71, H-3.79, N-13.01 %.
showed potent antibacterial activity as compared to anti-
fungal activity. Structure activity correlation of the obtained
results showed that the Knoevenagel adduct installation on
imidazolinone ring system with electron withdrawing fluoro
and dichloro groups as a substituent increases antibacterial as
well as antifungal activities. Efforts are currently being taken
up to optimize the lead structure and results of which will be
the basis of our future research endeavor. The major
advantages of this method are simple experimental and
work-up procedures, small amount of catalyst, short reaction
time, and high yields. Hence, this study has widened the
scope of developing easy method to synthesize functional-
ized pyrimidine-based imidazole derivatives as promising
antimicrobial agents.
N-(2-mercapto-4-(2-methoxybenzylidene)-5-oxo-4,5-dihydro-
1H-imidazol-1-yl)-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetra-
hydropyrimidine-5-carboxamide (5k)
Light gray solid,
yield 67 %; m.p.: 223–225 °C; IR (KBr) mmax/cm-1: 3473,
3345 (NH), 2882, 3017 (C–H, aromatic, OCH3), 1543
1
(–C=N), 1544 (C=C), 1734 (C=O); H NMR (400 MHz,
Acknowledgments We express our sincere gratitude to the
Department of Chemistry (UGC Non-SAP & DST-FIST Sponsored),
Mahatma Gandhi Campus, Maharaja Krishnakumarsinhji Bhavnagar
University, Bhavnagar for providing research and library facilities.
DMSO-d6, d, ppm): 2.49 (s, 3H, –CH3), 2.37 (s, 1H, –SH),
3.74 (s, 3H, –OCH3), 5.39 (s, 1H, –CH of pyrimidine), 6.19
(s, 1H, –NHCPh), 6.28 (s, 1H, –CH =), 6.97–7.49 (m, 9H,
Ar–H), 7.55 (s, 1H, –NHCCH3), 7.65 (s, 1H, –CONH); 13
C
NMR (100 MHz, DMSO-d6, d, ppm): 16.8 (–CH3), 53.7
(–CH of pyrimidine), 57.4 (–OCH3), 103.4 ([C\),
115.7–142.9 (Ar–C), 125.3 ([C=CH), 125.8 ([C=CH–), 153.9
(–CCH3), 155.4 (–NHCONH–), 157.9 (–CONH), 160.4
([C–OCH3), 165.9 (–CO of imidazole), 182.3 (–C–SH);
LCMS (m/z): 463 (M)?; Anal. calcd. for C23H21N5O4S: C-59.
60, H-4.57, N-15.11; Found: C-59.67, H-4.53, N-15.03 %.
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Table 1, we can presume that the targeted compounds
123

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