Design and synthesis of bis-pyrimidines linked with thiazolidin-4-one as new antibacterial agents

Article abstract of DOI:10.14233/ajchem.2019.22002

A series of novel 3-4-[2-hydroxy-5-(4-hydroxy-3-2-[2-(aryl)-4-oxo-1,3-thiazolan-3-yl]-6-phenyl-4-pyrimidinylbenzyl)phenyl]-6-phenyl-2-pyrimidinyl-2-(aryl)-1,3-thiazolan-4-ones 5(a-j) have been synthesized and assayed for their antibacterial activity again

Full text of DOI:10.14233/ajchem.2019.22002

Asian Journal of Chemistry; Vol. 31, No. 9 (2019), 1913-1918
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2019.22002
Design and Synthesis of Bis-pyrimidines Linked with Thiazolidin-4-one as NewAntibacterialAgents
1,*
2
1
1
CH. SANJEEVA REDDY , A. NAGARAJ , V. YAKUB and B. KALYANI
1Department of Chemistry, Kakatiya University, Warangal-506009, India
2Department of Chemistry, Telangana University, Nizamabad-503322, India
*Corresponding author: E-mail: chsrkuc@yahoo.co.in
Received: 15 February 2019;
Accepted: 9 April 2019;
Published online: 31 July 2019;
AJC-19476
A series of novel 3-4-[2-hydroxy-5-(4-hydroxy-3-2-[2-(aryl)-4-oxo-1,3-thiazolan-3-yl]-6-phenyl-4-pyrimidinylbenzyl)phenyl]-6-phenyl-
2-pyrimidinyl-2-(aryl)-1,3-thiazolan-4-ones 5(a-j) have been synthesized and assayed for their antibacterial activity against B. subtilis, B.
sphaericus, S. aureus, P. aeruginosa, K. Aerogenes and C. violaceum. The inhibition zones and minimal inhibitory concentrations were
measured and compared with the streptomycin. The antibacterial screening data reveal that the compounds containing 4-nitrophenyl (5c),
3-nitrophenyl (5d), 4-dimethylaminophenyl (5g) and 1,3-benzodioxole (5j) moiety at 2-position of the thiazolidin-4-one ring exhibited
potent inhibitory activity towards all the tested microorganism, which is higher than streptomycin. The other compounds also showed
moderate to good activity.
Keywords: Bis-heterocycles, Thiazolidin-4-one, Pyrimidine, Antibacterial activity.
and nematicidal [21]. Further, thiazolidinones have also been
used for the treatment of cardiac diseases [22], diabetic compli-
cations like cataracts, nephropathy and neuropathy [23] and
selective antiplatelet activating factor [24].
INTRODUCTION
The heterocyclic compounds participate in important
biochemical processes and are the constituents of main subs-
tances in living cells [1] and comprises the core of the active
moiety or pharmacophore.An especially more attention is given
to nitrogen and sulphur containing heterocyclic compounds,
as they possess a broad spectrum of biological activities and
are used in various fields of pharmacy [2]. Various natural pro-
ducts and biologically active synthetic compounds have five
member, nitrogen and sulphur containing heterocyclic ring in
their structures [3], such important class of compound is
thiazolidn-4-one [4], this nucleus appears in the structure of
thiamine [5], penicillin [6], antibiotics such as micrococcin
[7], compounds possessing cardiac and glycemic benefit such
as troglitazone [8] and many metabolic products of fungi and
primitive marine animals, including 2-(aminoalkyl)-thiazole-
4-carboxylic acids [9]. This moiety can also be found in various
well known drugs with the desired therapeutic uses [10] and
shows considerable physiological effects such as sedative [11],
antiinflammatory [12], antibacterial [13], antifungal [14],
antitubercular [15], analgesic and hypothermic [16], local [17]
and spinal [18] anesthetic, CNS stimulant [19], anti-HIV [20]
Similarly, pyrimidine and its derivatives have a unique place
and have contributed significantly to biological and medicinal
fields [25] such as antitubercular [26], calcium channel blockers
[27] and also many pyrimidines have displayed diverse pharma-
ceutical activities [28] depending upon the geometry and type
of substituents attached to the ring [29]. 3-Azido-3-deoxythy-
midine (AZT) [30] a pyrimidine derivative has been found to
be a potent antiviral agent against HIV type 1 in vitro and has
found to decrease mortality and opportunistic infections in
patients with AIDS.
Further, inspite of a large number of antibiotics and
chemotherapeutic agents available for medical use, but the
treatment of infectious diseases still challenging problem [31]
because of emerging infectious diseases [32] and the microbial
pathogens have turning out to be more resistant towards antibiotics/
chemotherapeutics [33], resulted a significant universal health
failure [34]. Therefore, the broad spectrum potency is preferred
for newly found antimicrobial agents. The recent efforts have
been made towards the investigation of more potential anti-
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1914 Reddy et al.
Asian J. Chem.
microbial agents [35]. Further, the synthesis of a variety of
bis-heterocyclic compounds has received great attention [36]
not only as main chain polymers but also because of many bio-
logically active natural [37] and synthetic products have mole-
cular symmetry [38]. Thus, bis-heterocyclic compounds may
avoid the microbial resistance. In the synthesis of bis-hetero-
cyclics, researchers have tried to extend various existing methods
by using a broad range of protocols to improve the scope and
limitations regarding their yield, purity and biological appli-
cations [39].
Owing to the immense importance and varied biological
activities exhibited by thiazolidin-4-one and pyrimidine and
in continuation of our ongoing research on biologically active
bis-heterocyclic compounds [39-41], it was considered to synthe-
size the bis-heterocyclic compounds containing thiazolidin-
4-one and pyrimidine moieties in one molecule for enhancing
biological activity (Fig. 1). In the present study, the synthesis
of novel 3-4-[2-hydroxy-5-(4-hydroxy-3-2-[2-(aryl)-4-oxo-
1,3-thiazolan-3-yl]-6-phenyl-4-pyrimidinylbenzyl)phenyl]-6-
phenyl-2-pyrimidinyl-2-(aryl)-1,3-thiazolan-4-ones 5(a-j)
with a view to explore their potential biological activity. The
antibacterial activity of the compounds has also been evaluated.
in a nitrogen atmosphere at a temperature of ≈ 90 °C. This
temperature was maintained for 24 h, while stirring solution.
The reaction mixture was then poured into ice-cold water and
allowed to stand overnight. The deposited solid was filtered
and extracted twice with ether and the solid obtained was
purified by crystallization in acetone to give pure compound
2 as white solid in 62 % yield, m.p.132-134. IR (KBr, νmax
,
1
cm–1): 3435, 2736, 1665, 843, 813; H NMR (CDCl3, 300
MHz): δ 3.99 (s, 2H, CH2), 7.32 (m, 4H,ArH), 7.40 (d, J = 8.1
Hz, 2H, ArH), 9.93 (s, 2H, CHO), 10.9 (s, 2H, OH); MS: m/z
256 (M+), 227, 181, 152, 135, 77.
Preparation of (E)-3-(2-hydroxy-5-4-hydroxy-3-[(E)-
3-oxo-3-phenyl-1-propenyl]benzylphenyl)-1-phenyl-2-
propen-1-one (3): A solution of compound 2 (0.01 mol) and
acetophenone (0.02 mol) in 20 mL of ethanol was treated with
20 mL of 60 % KOH solution at 5-10 °C. The reaction mixture
was stirred at room temperature for 5 h. It was then diluted
with water (50 mL) and extracted with diethyl ether (3 × 20
mL). The aqueous solution was acidified with dilute HCl. The
solid obtained was filtered, washed thoroughly with water,
dried the crude product and purified by crystallization from
benzene: MeOH (3:2) to give pure 3 in 70 % of yield, m.p.
108-109 °C. IR (KBr, νmax, cm–1): 3439, 3055, 1641, 1571, 1487,
1
1223; H NMR (DMSO-d6, 300 MHz): δ 3.84 (s, 2H, CH2),
antiinflammatory
antiasthamatic
antiinflammatory
hypothermic
nematicidal
bronchodilator
7.15 (d, J = 16.4 Hz, 2H, α-H), 7.65-7.85 (m, 16H,ArH), 8.04
(d, J = 16.4 Hz, 2H, b-H), 10.18 (s, 2H, OH); MS: m/z 460 (M+).
Preparation of 2-(2-amino-6-phenyl-4-pyrimidinyl)-4-
[3-(2-amino-6-phenyl-4-pyrimidinyl)-4-hydroxybenzyl]-
phenol (4): A solution of compound 3 (0.01 mol) and guanidine
hydrochloride (0.03 mol) in 20 mL ethanol was added 5 mL of
aqueous NaOH (0.02 mol). The reaction mixture was refluxed.
TLC (EtOAc:petroleum-ether, 2:1) showed that the reaction
was complete in 6 h. The reaction mixture was poured in 50
mL of 10 % cold HCl solution and the precipitate was filtered,
washed with water, until free from acid and on recrystallized
from benzene-ethanol to give pure compound 4 in 69 % of yield,
m.p. 211-213 °C. IR (KBr, νmax, cm–1): 3320, 3025, 2587, 1641,
R1
O
anesthetic
analgesic
anti-HIV
R4
N
R1
cardiotonic
antitumor
R2
antimalarial
N
N
R3
S
R2
sedative
antiallergic
R3
antimicrobial
CNS stimulant
antimicrobial
antitubercular
antitubercular
O
+2
Ca chanel blocker
S
Ph
Ar
N
N
OH
N
O
N
S
N
N
Ar
HO
Ph
Fig. 1. Title compounds containing thiazolidin-4-one and pyrimidine moieties
1
1487; H NMR (DMSO-d6, 300 MHz): δ 4.10 (s, 2H, CH2),
4.85 (bs, 2H, OH), 5.95 (bs, 4H, NH2), 6.98 (s, 2H,ArH), 7.00 (d,
J = 8.4 Hz, 2H, ArH), 7.30 (d, J = 8.4 Hz, 2H, ArH), 7.50-7.60
(m, 10H,ArH), 7.90 (d, J = 7.6 Hz, 2H,ArH); MS: m/z 538 (M+).
General procedure for the synthesis of 3-4-[2-hydroxy-
5-(4-hydroxy-3-2-[2-(aryl)-4-oxo-1,3-thiazolan-3-yl]-6-
phenyl-4-pyrimidinylbenzyl)phenyl]-6-phenyl-2-pyrimi-
dinyl-2-(aryl)-1,3-thiazolan-4-one 5(a-j): To a stirred mixture
of compound 4 (0.01 mol), aryl/heteryl aldehyde (0.02 mol)
and thioglycolic acid (0.02 mol) in dry toluene (20 mL), ZnCl2
(0.02 mol) was added and refluxed for 5 h at 110 °C. After
cooling, the filtrate was concentrated to dryness under reduced
pressure and the residue was taken-up in ethyl acetate. The
ethyl acetate layer was washed with brine, 5 % sodium bicarbo-
nate solution and finally with brine. The organic layer was
dried over Na2SO4 and evaporated to dryness at reduced pre-
ssure; the crude product thus obtained was purified by column
chromatography on silica gel with hexane-ethyl acetate as
eluent to get the pure compounds.
EXPERIMENTAL
All the chemicals and solvents were of commercial grade
and were used as supplied or were prepared according to proce-
dures described in literature. Reactions were monitored by
thin-layer chromatography (TLC) on pre-coated silica gel F254
plates from Merck and compounds visualized either by expo-
sure to UV light. Melting points were determined in open capi-
llary tube on a Fisher-Johns apparatus and are uncorrected. IR
spectra were recorded using KBr disk on a Perkin-Elmer FTIR
spectrometer. The NMR spectra were recorded on a Varian
Gemini spectrometer at 300 MHz for 1H and 75 MHz for 13C
NMR. Mass spectra were recorded on aVG micro mass 7070H
spectrometer. Structures of all the newly synthesized comp-
ounds were assigned on the basis of their spectral data.
Preparation of 5-(3-formyl-4-hydroxybenzyl)-2-hydro-
xybenzaldehyde (2): Trioxane (0.2 mol) was dissolved to the
solution of salicylaldehyde (1) (0.65 mol in 50 mL of glacial
acetic acid). To this a mixture of 0.5 mL of conc. sulfuric acid
and 2.5 mL of glacial acetic acid was added slowly with stirring
3-4-[2-Hydroxy-5-(4-hydroxy-3-2-[2-(4-methylphenyl)-
4-oxo-1,3-thiazolan-3-yl]-6-phenyl-4-pyrimidinylbenzyl)-

Vol. 31, No. 9 (2019)
Design and Synthesis of Bis-pyrimidines Linked with Thiazolidin-4-one as New Antibacterial Agents 1915
phenyl]-6-phenyl-2-pyrimidinyl-2-(4-methylphenyl)-1,3-
3-4-[2-Hydroxy-5-(4-hydroxy-3-2-[2-(2-hydroxyphenyl)-
4-oxo-1,3-thiazolan-3-yl]-6-phenyl-4-pyrimidinylbenzyl)-
phenyl]-6-phenyl-2-pyrimidinyl-2-(2-hydroxyphenyl)-1,3-
thiazolan-4-one (5f): Yield: 47 %, m.p. 180-182 °C; IR (KBr,
thiazolan-4-one (5a): Yield: 52 %, m.p. 149-151 °C; IR (KBr,
ν
max, cm–1): 3345, 3037, 2970, 1675, 1496, 783, 674; 1H NMR
(DMSO-d6, 300 MHz): δ 2.18 (s, 6H, CH3), 3.50-3.60 (m, 4H,
CH2-S), 3.98 (s, 2H, CH2), 5.20 (s, 2H, OH), 5.82 (s, 2H, N-CH-
S), 6.70 (s, 2H, ArH), 7.20-7.40 (m, 22H, ArH), 7.60 (s, 2H,
ArH); 13C NMR (DMSO-d6, 75 MHz): δ 31.0, 34.3, 42.1, 57.4,
110.8, 111.4, 118.1, 122.5, 123.1, 124.2, 128.1, 130.8, 131.0,
134.7, 141.9, 149.0, 152.7, 158.3, 162.7, 174.7; MS: m/z892 (M+).
2-(4-Chlorophenyl)-3-4-[5-(3-2-[2-(4-chlorophenyl)4-
oxo-1,3-thiazolan-3-yl]-6-phenyl-4-pyrimidinyl-4-hydroxy-
benzyl)-2-hydroxyphenyl]-6-phenyl-2-pyrimidinyl-1,3-
thiazolan-4-one (5b): Yield: 49 %, m.p. 160-162 °C; IR (KBr,
ν
max, cm–1): 3400-3300, 30427, 2922, 1696, 1600, 1592, 717,
1
685; H NMR (DMSO-d6, 300 MHz): δ 3.67-3.70 (m, 4H,
CH2-S), 4.12 (s, 2H, CH2), 5.20 (s, 2H, OH), 5.87 (s, 2H, OH),
5.96 (s, 2H, N-CH-S), 6.84-6.90 (m, 6H, ArH), 7.20-7.35 (m,
12H, ArH), 7.55-7.60 (m, 8H, ArH); 13C NMR (DMSO-d6, 75
MHz): δ 38.5, 42.1, 60.7, 110.4, 111.4, 117.2, 118.1, 121.2,
122.0, 125.8, 126.0, 126.7, 128.1, 130.8, 132.0, 138.7, 141.2,
152.8, 154.3, 157.3, 157.2, 161.2, 174.1; MS: m/z 896 (M+).
2-[4-(Dimethylamino)phenyl]-3-(4-5-[3-(2-2-[4-(di-
methylamino)phenyl]-4-oxo-1,3-thiazolan-3-yl-6-phenyl-4-
pyrimidinyl)4-hydroxybenzyl]2-hydroxyphenyl-6-phenyl-
2-pyrimidinyl)1,3-thiazolan-4-one (5g): Yield: 55 %, m.p.
196-198 °C; IR (KBr, νmax, cm–1): 3400-3300, 3042, 2965,
1698, 1599, 1592, 716, 686; 1H NMR (DMSO-d6, 300 MHz):
δ 2.91 (s, 12H, N-CH3), 3.67-3.70 (m, 4H, CH2-S), 4.10 (s,
2H, CH2), 5.18 (s, 2H, OH), 5.82 (s, 2H, N-CH-S), 6.70-6.80
(s, 6H, ArH), 7.20-7.35 (m, 12H, ArH), 7.55-7.60 (m, 8H,
ArH); 13C NMR (DMSO-d6, 75 MHz): δ 38.4, 42.1, 43.8, 67.4,
110.8, 111.4, 112.0, 117.8, 126.1, 127.8, 129.1, 130.8, 131.3,
132.0, 138.7, 142.3, 142.9, 153.8, 157.3, 158.3, 162.4, 174.5;
MS: m/z 950 (M+).
ν
max, cm–1): 3340-3300, 3032, 1698, 1603, 1597, 712, 687; 1H
NMR (DMSO-d6, 300 MHz): δ 3.67-3.70 (m, 4H, CH2-S),
4.12 (s, 2H, CH2), 5.20 (s, 2H, OH), 5.86 (s, 2H, N-CH-S),
6.84 (s, 2H, ArH), 7.20-7.35 (m, 16H, ArH), 7.55-7.60 (m,
8H, ArH); 13C NMR (DMSO-d6, 75 MHz): δ 38.3, 42.1, 67.5,
110.7, 111.6, 118.9, 126.3, 127.7, 128.1, 128.9, 130.5, 131.8,
132.0, 134.7, 138.4, 141.2, 154.3, 157.3, 158.3, 162.2, 173.6;
MS: m/z 932 (M+).
3-4-[2-Hydroxy-5-(4-hydroxy-3-2-[2-(4-nitrophenyl)-
4-oxo-1,3-thiazolan-3-yl]-6-phenyl-4-pyrimidinylbenzyl)-
phenyl]-6-phenyl-2-pyrimidinyl-2-(4-nitrophenyl)-1,3-
thiazolan-4-one (5c): Yield: 45 %, m.p. 195-197 °C; IR (KBr,
ν
max, cm–1): 3340-3300, 3035, 1699, 1603, 1596, 1520, 1370,
3-4-[2-Hydroxy-5-(4-hydroxy-3-2-[2-(4-hydroxy-3-
methoxyphenyl)-4-oxo-1,3-thiazolan-3-yl]-6-phenyl-4-
pyrimidinylbenzyl)phenyl]-6-phenyl-2-pyrimidinyl-2-(4-
hydroxy-3-methoxyphenyl)-1,3-thiazolan-4-one (5h): Yield:
58 %, m.p. 177-179 °C; IR (KBr, νmax, cm–1): 3350-3300, 2967,
1697, 1598, 1590, 1067, 716, 686; 1H NMR (DMSO-d6, 300
MHz): δ 3.67-3.70 (m, 4H, CH2-S), 3.82 (s, 6H, OCH3), 4.11
(s, 2H, CH2), 5.04 (s, 2H, OH), 5.19 (s, 2H, OH), 5.83 (s, 2H,
N-CH-S), 6.84-6.90 (m, 4H, ArH), 7.15-7.30 (m, 12H, ArH),
7.50-7.60 (m, 8H, ArH); 13C NMR (DMSO-d6, 75 MHz): δ
38.4, 42.1, 56.7, 70.1, 110.1, 111.8, 112.4, 118.1, 119.0, 120.3,
126.1, 127.1, 130.8, 131.7, 132.8, 137.5, 141.9, 146.3, 148.1,
154.3, 156.9, 158.3, 161.2, 173.9; MS: m/z 956 (M+).
2-(2-Furyl)-3-4-[5-(3-2-[2-(2-furyl)-4-oxo-1,3-thiazolan-
3-yl]-6-phenyl-4-pyrimidinyl-4-hydroxybenzyl)-2-hydroxy-
phenyl]-6-phenyl-2-pyrimidinyl-1,3-thiazolan-4-one (5i):
Yield: 60 %, m.p. 210-212 °C; IR (KBr, νmax, cm–1): 3400-
3300, 3039, 1694, 1600, 1594, 1592, 1030, 715, 682; 1H NMR
(DMSO-d6, 300 MHz): δ 3.67-3.70 (m, 4H, CH2-S), 4.10 (s,
2H, CH2), 5.18 (s, 2H, OH), 5.98 (s, 2H, N-CH-S), 6.20-6.30
(m, 4H, ArH), 6.84 (s, 2H, ArH), 7.20-7.35 (m, 8H, ArH),
7.55-7.60 (m, 10H, ArH); 13C NMR (DMSO-d6, 75 MHz): δ
38.4, 42.1, 61.3, 104.5, 110.8, 111.0, 112.0, 118.1, 126.1,
127.1, 130.8, 131.0, 136.9, 141.9, 144.7, 153.9, 157.3, 158.3,
160.4, 161.0, 174.0; MS: m/z 842 (M+).
1
710, 686; H NMR (DMSO-d6, 300 MHz): δ 3.67-3.70 (m,
4H, CH2-S), 4.12 (s, 2H, CH2), 5.09 (s, 2H, OH), 5.86 (s, 2H,
N-CH-S), 6.84 (s, 2H, ArH), 7.20-7.35 (m, 12H, ArH), 7.55-
7.60 (m, 12H, ArH); 13C NMR (DMSO-d6, 75 MHz): δ 38.4,
42.2, 67.5, 110.8, 111.5, 117.4, 122.3, 127.1, 127.9, 128.7,
130.8, 131.0, 137.5, 141.8, 142.0, 144.8, 154.3, 157.3, 158.3,
162.2, 174.1; MS: m/z 954 (M+).
3-4-[2-Hydroxy-5-(4-hydroxy-3-2-[2-(3-nitrophenyl)-
4-oxo-1,3-thiazolan-3-yl]-6-phenyl-4-pyrimidinylbenzyl)-
phenyl]-6-phenyl-2-pyrimidinyl-2-(3-nitrophenyl)-1,3-
thiazolan-4-one (5d): Yield: 54 %, m.p. 190-192 °C; IR (KBr,
ν
max, cm–1): 3342-3300, 3062, 2980, 1689, 1600, 1595, 1517,
1365, 714, 685; 1H NMR (DMSO-d6, 300 MHz): δ 3.67-3.70
(m, 4H, CH2-S), 4.10 (s, 2H, CH2), 5.11 (s, 2H, OH), 5.94 (s,
2H, N-CH-S), 6.84 (s, 2H, ArH), 7.20-7.35 (m, 10H, ArH),
7.55-7.60 (m, 10H, ArH), 8.00-8.05 (m, 4H, ArH); 13C NMR
(DMSO-d6, 75 MHz): δ 38.4, 42.1, 67.1, 110.8, 111.7, 118.1,
119.8, 122.4, 126.1, 127.1, 130.8, 131.0, 132.1, 132.9, 138.0,
139.0, 141.9, 147.2, 154.3, 157.3, 158.9, 161.2, 173.5; MS:
m/z 954 (M+).
3-4-[2-Hydroxy-5-(4-hydroxy-3-2-[2-(4-hydroxyphenyl)-
4-oxo-1,3-thiazolan-3-yl]-6-phenyl-4-pyrimidinylbenzyl)-
phenyl]-6-phenyl-2-pyrimidinyl-2-(4-hydroxyphenyl)-1,3-
thiazolan-4-one (5e): Yield: 42 %, m.p. 182-184 °C; IR (KBr,
ν
max, cm–1): 3400-3320, 3047, 2922, 1695, 1603, 1595, 715,
2-(1,3-Benzodioxol-5-yl)-3,4-[5-(3-2-[2-(1,3-benzodioxol-
5-yl)-4-oxo-1,3-thiazolan-3-yl]-6-phenyl-4-pyrimidinyl-4-
hydroxybenzyl)-2-hydroxyphenyl]-6-phenyl-2-pyrimidinyl-
1,3-thiazolan-4-one (5j): Yield: 57 %, m.p. 164-166 °C; IR
(KBr, νmax, cm–1): 3400-3300, 3042, 1695, 1603, 1592, 1120,
1
689; H NMR (DMSO-d6, 300 MHz): δ 3.67-3.70 (m, 4H,
CH2-S), 4.11 (s, 2H, CH2), 5.17 (s, 2H, OH), 5.27 (s, 2H, OH),
5.85 (s, 2H, N-CH-S), 6.84-6.90 (m, 6H, ArH), 7.20-7.35 (m,
12H, ArH), 7.55-7.60 (m, 8H, ArH); 13C NMR (DMSO-d6, 75
MHz): δ 38.4, 42.1, 67.0, 111.8, 112.4, 115.1, 118.1, 126.1,
127.7, 128.1, 129.9, 130.5, 131.0, 137.6, 141.9, 154.3, 157.3,
157.7, 158.3, 161.2, 173.4; MS: m/z 896 (M+).
1
717, 682; H NMR (DMSO-d6, 300 MHz): δ 3.67-3.70 (m,
4H, CH2-S), 4.11 (s, 2H, CH2), 5.65-5.70 (m, 4H, O-CH2-O),
5.85 (s, 2H, N-CH-S), 6.80-6.90 (m, 6H, ArH), 7.20-7.35 (m,

1916 Reddy et al.
Asian J. Chem.
10H, ArH), 7.50-7.60 (m, 8H, ArH); 13C NMR (DMSO-d6, 75
MHz): δ38.4, 42.1, 68.4, 100.6, 108.3, 110.8, 111.4, 113.1, 118.1,
121.1, 126.1, 128.1, 130.8, 131.0, 134.0, 138.7, 141.9, 145.6,
147.3, 154.3, 157.3, 158.3, 161.2, 174.7; MS: m/z 952 (M+).
The IR spectrum of compound 2 showed the absorption
band at 2736, 1665, 813 and a broad band in the 3435 cm-1
region. Its protons NMR spectrum showed resonances at δ
10.9 as singlet for two protons corresponding to hydroxyl
protons, at δ 9.93 as singlet for two protons of carboxyl group,
at δ 7.40 as doublet, 7.32 as multiplet corresponding to aromatic
protons and at δ 3.99 as singlet for two protons corresponding
to methylene protons. Its mass spectrum showed a signal at
m/z 256 corresponding to molecular ion, at m/z 227 correspon-
ding to the ion, which resulting by the loss of formyl radical,
at m/z 181 corresponding the ion resulted subsequent loss of
water and carbon monoxide from the molecular ion and the
other signals at m/z 152, 135 and 77 confirming its structure.
The IR spectrum of 3 exhibited a strong absorption band at 1641
cm-1 due the carbonyl group and at 3439 cm-1 due to hydroxyl
group. Its proton NMR spectrum showed a signal at δ 10.18
ppm, as a singlet integrating for two protons assigned to hydroxyl
protons, at δ 7.65-7.85 ppm, as a multiplet, for sixteen protons
of aromatic, at δ 8.04 ppm, as a doublet with J value 16.4 Hz is
assigned to β-H, at δ 7.15 ppm, as a doublet with J value 16.4
Hz, for two protons is assigned to α-H and at δ 3.84 ppm, as a
singlet for two methylene protons. The mass spectrum of
compound showed molecular ion peak at m/z 460 (77 %).
Further, the cyclocondensation of compound 3 with guani-
dine hydrochloride in ethanol in the presence of sodium hydro-
xide at reflux for 6 h, at the end of the reaction, the ethanolic
solution was concentrated to half of its volume under reduced
pressure and poured into cold 10 % HCl solution. The solid that
separated was filtered and on purification by recrystallization
from benzene-ethanol gave pure 2-(2-amino-6-phenyl-4-pyri-
midinyl)-4-[3-(2-amino-6-phenyl-4-pyrimidinyl)-4-hydro-
xybenyl]phenol (4) in 69 % of yield [44]. The one-pot cyclo-
condensation of compound 4 with aryl/heteryl aldehyde and
thioglycolic acid in the presence of ZnCl2 in toluene at reflux
for 5 h to gave 3-4-[2-hydroxy-5-(4-hydroxy-3-2-[2-(4-methyl-
phenyl)-4-oxo-1,3-thiazolan-3-yl]-6-phenyl-4-pyrimidiny-
lbenzyl)phenyl]-6-phenyl-2-pyrimidinyl-2-(4-methylphenyl)-
1,3-thiazolan-4-one 5(a-j) in good yields (Scheme-II). The
RESULTS AND DISCUSSION
The most general and widely employed synthetic route
to pyrimidine involves the combination of a reagent containing
the N-C-N skeleton with C-C-C unit. There are typical examples
of bis-nucleophile with bis-electrophile method of constructing
heterocycles. Both the nitrogens of the N-C-N reagent act as
nucleophiles and both the terminal carbon atoms of C-C-C
reagent are electrophiles. Urea and thiourea are the most com-
monly used N-C-N reagent and chalcones are typically C-C-C
substrates. Method which involves the reaction of guanidine
hydrochloride with chalcone has been adopted for the synthesis
of pyrimidine derivatives, because, the synthesis and purifi-
cation of the required starting materials i.e. chalcones is easy
and they are stable. Further, these pyrimidine derivatives are
cyclo-condensed with the thioglycolic acid and aldehydes to
get the title compounds.
Condensation of salicylaldehyde (1) with trioxane in the
presence of a mixture of conc. sulphuric acid and acetic acid at
95 °C with stirring for 24 h gave 5-(3-formyl-4-hydroxybenzyl)-
2-hydroxybenzaldehyde (2) in 62 % yield [42]. The conden-
sation of compound 2 with acetophenone in ethanol in the
presence of 60 % aqueous potassium hydroxide at room tempe-
rature for 5 h to give (E)-3-(2-hydroxy-5-4-hydroxy-3-[(E)-
3-oxo-3-phenyl-1-propenyl]benzylphenyl)-1-phenyl-2-propen-
1-one (3) in 70 % yield [43] (Scheme-I). The crude product
contaminated by some starting materials was purified by
extracting with ether. When aqueous layer was neutralized with
dilute hydrochloric acid, the crude product was separated out,
which was purified by crystallization from benzene: methanol
in 3:2 ratio. The products showed orange red colour with
concentrated sulfuric acid, which is a characteristic feature of
chalcones. Structures of compounds were confirmed by their
EI mass, IR, 1H NMR and 13C NMR spectral data.
Ph
O
OH
CHO
OH
trioxane
H2SO4
CHO
OH
HO
Ph-COCH3
O
HO
60% KOH/EtOH
r.t. 5 h
AcOH/95 0C
stirring, 24 h
CHO
3
Ph
1
2
Scheme-I
S
O
Ar
N
Ph
Ph
N
N
OH
Ar-CHO
OH
NH2
N
N
N
NH
H2N
N
HS-CH2-COOH
O
N
S
N
N
H2N
NH2
ZnCl2 / PhMe
reflux, 5 h
Ar
3
aq. NaOH/EtOH
reflux, 6 h
HO
HO
Ph
Ph
4
5(a-j)
5: Ar = a) 4-methylphenyl; b) 4-chlorophenyl; c) 4-nitrophenyl; d) 3-nitrophenyl; e) 4-hydroxyphenyl;
f) 2-hydroxyphenyl; g) 4-dimethylaminophenyl; h) 4-hydroxy-3-methoxyphenyl; i) 2-furyl; j) 1,3-benzoxole
Scheme-II

Vol. 31, No. 9 (2019)
Compounds
Design and Synthesis of Bis-pyrimidines Linked with Thiazolidin-4-one as New Antibacterial Agents 1917
TABLE-1
ANTIBACTERIAL ACTIVITY OF COMPOUNDS 5(a-j)
Minimum inhibitory concentration in µg/mL (zone of inhibition in mm)*
B. subtilis
26 (12)
30 (9)
14 (18)
13 (17)
18 (12)
25 (9)
15 (14)
27 (10)
30 (11)
13 (18)
15 (15)
B. sphaericus
25 (11)
27 (10)
18 (20)
19 (20)
20 (17)
30 (10)
18 (19)
26 (11)
21 (12)
15 (15)
19 (17)
S. aureus
26 (9)
P. aeruginosa
20 (17)
20 (16)
18 (20)
19 (19)
26 (12)
28 (10)
20 (22)
30 (11)
21 (15)
20 (22)
20 (18)
K. aerogenes
30 (9)
C. violaceum
20 (16)
20 (14)
17 (23)
18 (20)
25 (11)
28 (13)
18 (19)
27 (9)
5a
5b
5c
5d
5e
5f
5g
5h
30 (10)
17 (22)
18 (22)
30 (13)
28 (10)
17 (24)
28 (10)
20 (16)
16 (20)
18 (20)
26 (9)
20 (16)
19 (20)
25 (10)
30 (8)
20 (20)
28 (10)
28 (9)
5i
5j
26 (10)
16 (17)
18 (20)
20 (18)
20 (16)
Streptomycin
*The values in parentheses indicate the zone of inhibition.
structures of compounds were confirmed by its EI mass, IR,
1H NMR and 13C NMR spectral data.
measured and compared with the standard drug streptomycin
(Table-1).
The IR spectrum of compound 4 showed the absorption
band corresponding to the -OH and C=N groups at 3320 and
1641 cm-1 respectively. Its proton NMR spectrum showed a
signal at δ 7.50-7.80 ppm, as a multiplet integrating for ten
protons is assigned for aromtic protons, at δ 7.30 as a doublet
with J value 8.4 Hz, integrating for two protons is assigned for
aromatic protons. A singlet signal at δ 6.98 ppm, integrating
for two protons is assigned to the aromatic protons, at δ 7.00 as
a doublet with J value 8.4 Hz, integrating for two protons is
assigned for aromatic protons.A signal at δ 5.95 ppm, as a broad
singlet for four protons is assigned to -NH2 protons, at δ 4.85 as
a broad singlet for two protons is assigned to -OH group. A
singlet signal at δ 4.10 ppm, for two protons is assigned to
methylene group. The mass spectrum of compound showed
molecular ion peak at m/z 538.
The IR spectrum of compound 5a, disappearance of amine
(-NH2) absorption and the absroption band at 3345 and 1675
cm-1 which are charcteristic of -OH and amide C=O stretching
vibrations respectively. Its proton NMR spectrum showed
signals at δ 7.60, 7.20-7.40 and 6.70 ppm as a singlets, for a
total of twenty four aromatic protons, at δ 5.82 and 3.50-3.60
ppm as a singlet and a multiplet, integrating for two and four
protons respectively, are assigned to the N-CH-S and CH2-S
groups of thiazolidin-4-one ring. The three singlet signals at
δ 5.20, 3.98 and 2.18 ppm, integrating for two, two and six
protons, are assigened to the -OH, CH2 and CH3 groups respec-
tively. Its 13C NMR spectrum exhibited the prominent signals
corresponding to the carbons of thiazolidin-4-one ring observed
at δ 34.3, 57.4 and 174.7 ppm and for pyrimidine ring were
observed at δ 118.1, 152.7, 158.3 and 162.7 ppm respectively.
In summary, all the newly synthesized compounds exhibited
satisfactory elemental analyses consistent with the proposed
structures.
The antibacterial screening data reveal that the compounds
containing 4-nitrophenyl (5c), 3-nitrophenyl (5d), 4-dimethyl-
aminophenyl (5g) and 1,3-benzodioxole (5j) moiety at 2-posi-
tion of the thiazolidin-4-one ring exhibited potent inhibitory
activity towards all the tested microorganism, which is higher
than the standard drug streptomycin. Further, the compounds
containing 4-methylphenyl (5a)and 4-chlorophenyl (5b) moiety
showed good activity towards P. aeruginosa and C. violaceum.
The compound 5e containing 4-hydroxyphenyl moiety also
showed potent activity towards B. subtilis and B. sphaericus
and the compound 5i containing 2-furyl moiety, showed good
activity towards B. sphaericus, S. aureus and P. aeruginosa.
Conclusion
A series of 3-4-[2-hydroxy-5-(4-hydroxy-3-2-[2-(aryl)-
4-oxo-1,3-thiazolan-3-yl]-6-phenyl-4-pyrimidinylbenzyl)-
phenyl]-6-phenyl-2-pyrimidinyl-2-(aryl)-1,3-thiazolan-4-ones
5(a-j) has been synthesized and assayed for their antibacterial
activity against Gram-positive and Gram-negative bacteria. The
compounds 5c, 5d, 5g, 5i and 5j exhibited potent inhibitory
activity towards all the tested organisms, higher than that of
activity of the standard drug streptomycin, hence could be
used as lead compounds for further studies.
ACKNOWLEDGEMENTS
The authors are thankful to the Director, Indian Institute
of Chemical Technology, Hyderabad, India, for providing NMR
and mass spectral data. Financial assistance from the UGC,
New Delhi, India, in the form of UGC-BSR-FF (Ch. S. Reddy)
is gratefully acknowledged.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interests
regarding the publication of this article.
Antibacterial activity: All the compounds 5(a-j) were
assayed for their antibacterial activity against Gram-positive
bacteria viz. Bacillus subtilis, Bacillus sphaericus and Staphy-
lococcus aureus and Gram-negative bacteria viz. Pseudomonas
aeruginosa, Klobsinella aerogenes and Chromobacterium
violaceum by disc diffusion method [45]. The inhibition zones
and minimal inhibitory concentrations (MIC, µg/mL) were
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