Synthesis of some new thiazolo[3,2-A]pyrimidine derivatives and screening of their in vitro antibacterial and antitubercular activities

Article abstract of DOI:10.1007/s00044-015-1481-y

The novel 5H-thiazolo[3,2-A]pyrimidin-5-ones were synthesized by thiophene ring closure. The first step is the synthesis of S-alkylated derivatives by the reaction of 6-substituted-2-thiouracils with the appropriate substituted phenacyl halides. Upon trea

Full text of DOI:10.1007/s00044-015-1481-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-015-1481-y
ORIGINAL RESEARCH
Synthesis of some new thiazolo[3,2-a]pyrimidine derivatives
and screening of their in vitro antibacterial and antitubercular
activities
Dong Cai1 Zhi-Hua Zhang2 Yu Chen3 Xin-Jia Yan4 Shi-Ti Zhang1
•
•
•
•
•
Liang-Jing Zou1 Li-Hong Meng1 Fang Li1 Bing-Jie Fu1
•
•
•
Received: 8 August 2015 / Accepted: 18 November 2015
Ó Springer Science+Business Media New York 2015
Abstract The novel 5H-thiazolo[3,2-a]pyrimidin-5-ones
were synthesized by thiophene ring closure. The first step is
the synthesis of S-alkylated derivatives by the reaction of
6-substituted-2-thiouracils with the appropriate substituted
phenacyl halides. Upon treatment of S-alkylated deriva-
tives at different temperatures, intramolecular cyclization
to 3-(substituted phenyl)-5H-thiazolo[3,2-a]pyrimidin-5-
ones or sulfonation of cyclized products to the corre-
sponding sulfonic acid derivatives occurred. Further, acy-
lation of the 7-NH2 group of 5H-thiazolo[3,2-a]pyrimidin-
5-ones afforded amide derivatives, and reduction of the
NO2 group of 5H-thiazolo[3,2-a]pyrimidin-5-ones gave
amino derivatives. All the new compounds were confirmed
Some compounds showed significant antibacterial and
antitubercular activities.
Keywords Thiazole Á Cyclization Á Thiazolopyrimidine Á
Antibacterial Á Antitubercular
Introduction
The remarkable ability of bacteria to develop resistance to
antimicrobial agents is a pressing concern for public health
(Boucher et al., 2009). Consequently, new antimicrobial
drugs to combat this problem are therefore in great
demand. Over the past 50 years, only two new structural
types of antimicrobial drugs, linezolid and daptomycin,
have been introduced into the clinic (Simmons et al.,
2010). The design of new scaffolds to deal with antimi-
crobial resistance has become one of the most important
areas of antimicrobial research today.
1
by H NMR, 13C NMR, IR and HRMS spectra, and their
antibacterial and antitubercular activities were screened.
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-015-1481-y) contains supplementary
material, which is available to authorized users.
Thiazolo[3,2-a]pyrimidines have been consistently
regarded as a structural analogs of biogenic purine bases
and can be considered as potential purine antagonists (El-
Bayouki and Basyouni, 2010; Nagarajaiah et al., 2012).
The synthesis of thiazolo[3,2-a]pyrimidines has received
considerable attention from both synthetic and medicinal
chemists because of their wide range of biological activi-
ties, including antiinflammatory (Tozkoparan et al., 1998,
1999), antihypertensive (Jeanneau-Nicolle et al., 1992),
antiviral (Mohamed et al., 2010), antioxidant (Maddila
et al., 2012), antitumor (Flefel et al., 2007; Al-Omary
et al., 2012), anti-HIV (Danel et al., 1998), calcium
channel blocking (Balkan et al., 1992), acetylcholine
esterase inhibitory (Liu et al., 2014), CDC25B phosphatase
inhibitory (Kolb et al., 2009), Bcl-2 family proteins inhi-
bitory (Kolb et al., 2009), glutamate receptor antagonistic
& Dong Cai
Caidong0804@163.com
Zhi-Hua Zhang
Bridge1026@163.com
Yu Chen
gzweishengwu@126.com
Xin-Jia Yan
yanxinjia@yeah.net
1
Liaoning Medical University, Jinzhou 121000, China
2
School of Chemical and Environmental Engineering,
Liaoning University of Technology, Jinzhou 121001, China
3
School of Life Science and Biopharmaceutics, Shenyang
Pharmaceutical University, Shenyang 110016, China
4
College of Pharmacy, Harbin University of Commerce
Harbin, Harbin 150076, China
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Med Chem Res
(Wichmann et al., 1999) and 5-HT2a receptor antagonistic
activities (Awadallah, 2008). These thiazolopyrimidines
have also been found to elicit antibacterial (Ghorab et al.,
2000), antifungal (Pan et al., 2011) and antitubercular
activities (Geist et al., 2010).
group appeared as a two-proton singlet at d 4.84 ppm. The
signal of the 5-H proton of pyrimidine is observed at d
6.04 ppm as a singlet. The signal of the N3-H proton
appeared at d 12.79 ppm as a broad singlet. Within the
aromatic region, a multiplet appeared at d 8.30–8.37 ppm
due to the substituted phenyl protons. In addition, the
compound 2b seems to exist partially in the cyclic form
(Danel et al., 1998), which had a pair of doublets centered
at d 3.74 and 3.65 ppm comprising an AB system
(J = 12.5 Hz), but an AB quartet did not fully account for
two methylene protons. Moreover, two singlets at d 2.25
and d 1.99 were all assigned to CH3. All these indicate that
the presence of an equilibrium mixture of open-chain and
cyclic forms is possible. Furthermore, the intermediate
S-alkylated thiouracil exists as enol tautomeric form (Lin
et al., 1979; Kaye et al., 1983; Meslin and Quiniou, 1974,
1975), and a one-proton singlet was present at d 6.02 ppm,
corresponding to the enol form of compound 2b in DMSO
(Matiichuk et al., 2008) (Scheme 2).
Compounds containing sulfonic acid groups have great
practical usefulness, primarily, due to a very wide spectrum
of biological activities. The phosphate functional group can
be replaced by sulfonic acid moieties via bioisosteric
replacement. These features are functionally interchange-
able due to their ability to adopt a negative charge at
biological pH (Cai, 2004). Numerous compounds con-
taining sulfonic acid group are well known as antibacterial
(Khan and Rastogi, 1991; Veretennikov and Pavlov, 2013;
Janietz et al., 1988; Doria et al., 1985), antifungal (Allen
et al., 1959; Dhapalapur et al., 1968; Raval et al., 2012;
Fujiwara and Inoi, 1992; Bondock et al., 2013) and anti-
tubercular activities (Parekh and Maheria, 2012). Addi-
tionally, these sulfonic acids are also used as dyes (Youssef
and Youssef, 2003), metal arenesulfonates complexes
(El-Emary and Abdel-Mohsen, 2006).
Compounds 3a–d can be synthesized from the S-alky-
lated thiouracils in concentrated H2SO4 at 80 °C by a one-
pot procedure via an intramolecular cyclization/sulfonation
sequence. The S-alkylated thiouracils undergo only
intramolecular cyclization in concentrated H2SO4 at room
temperature to give compounds 4a–h, which can be
reduced to give the corresponding amines 5a–d.
In the light of the above facts, we have synthesized some
5H-thiazolo[3,2-a]pyrimidin-5-one derivatives and related
compounds containing sulfonic acid active moieties with
the hope to possess better antibacterial and antitubercular
activities.
Theoretically, the intramolecular cyclization reactions
of intermediates 2a–j may afford the two possible isomeric
products: 5H-thiazolo[3,2-a]pyrimidin-5-ones and 7H-thi-
azolo[3,2-a]pyrimidin-7-ones. However, in practice
cyclization of compounds 2a–j was found to afford only
the corresponding 5H-thiazolo[3,2-a]pyrimidin-5-ones
3a–f and 4a–h. The regioselectivity of the intramolecular
cyclization step was assumed to be the difference in the
electron density at the N1 and N3 position of compounds
2a–j. The higher basicity of the N3 resulted in the exclu-
sive cyclization at this position (Bakavoli et al., 2008;
Dallinger et al., 2003). Moreover, the selective C2–N3
annulation has been proven by single-crystal X-ray crys-
tallographic studies (Quan et al., 2008). Additionally, it
seems that the steric hindrance at the position 6 in the
S-alkylated derivatives 2a–j exerts a directive influence
during this cyclization.
Results and discussion
Chemistry
The synthetic strategies adopted for the preparation of the
intermediates and target compounds are depicted in
Scheme 1.
6-Substituted anilino-2-thiouracils 1a–b were nearly
quantitatively S-alkylated with the appropriate substituted
phenacyl halides in the presence of anhydrous K2CO3 to
give compounds 2a–j. These intermediates 2a–j were of
sufficient purity (by TLC) to be used in subsequent reac-
tions without further purification. The S-alkylated
2-thiouracils are proved to exist in solution largely in the
lactam form as indicated by spectroscopic studies (Brown
et al., 1955; Andrew and Bradsher, 1967). The tautomeric
hydrogen was found to be in position 3 (Brown et al., 1955;
Andrew and Bradsher, 1967; Abdel-Mohsen et al., 2013;
Kwiatkowski and Pullman, 1975; Mizutani et al., 1985)
(Scheme 2).
For products 3a–d, all the sulfonic acid groups locate
the ortho-positions relative to R3 (electron-donating
groups, such as R2=CH3, CH3O). The best explanation of
this phenomenon is the influence of electronic and steric
factors together determining a new substituent to the
positions of the phenyl ring. Similar conclusions for the
regioselectivity of sulfonation of the phenyl ring have also
1
Regarding the 400-MHz H NMR (in DMSO-d6) spec-
tra, the S-alkylated thiouracils 2a–j showed similar shifts,
and therefore, we discuss here the spectroscopic data only
of 2b as the representative of this series (see Supporting
Information). On the basis of structure of 2b, the methylene
¨
been reported in the studies (Schafer et al., 1984, 1991;
Angioni et al., 2014; Katritzky et al., 1984; Coates et al.,
1996).
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Med Chem Res
Scheme 1 Reagents and conditions: i K2CO3, DMF; ii concentrated H2SO4, 80 °C; iii concentrated H2SO4, 20 °C; iv Fe, NH4Cl, 2:1 ethanol/
water, 80 °C; v triethylamine, r.t., 2 h
Scheme 2 Possible
interconversion of S-alkylated
derivatives
The amines 5a–d were prepared by reducing the nitro
compounds 4a–b, 4e–f with iron in a mixture of NH4Cl,
ethanol and water following a literature (Dai et al., 2005).
However, the post-process described for the reduction was
not practical because the target compounds 5a–d were very
slightly soluble in water and slightly soluble in cool ethyl
acetate and dichloromethane. The completion of the reac-
tion was monitored by TLC. Without allowing the mixture
123

Med Chem Res
Antitubercular activity
to cool, the iron residue is removed by filtration and
washed with boiling ethanol until a clear wash was
obtained. The filtrate was concentrated under reduced
pressure until no more ethanol distilled, the resultant
mixture was cooled to room temperature, and the solution
was filtered. The crude product was recrystallized from
ethanol to afford the appropriate amines.
Antitubercular activity of compounds was assessed against
Mycobacterium smegmatis (M. smegmatis) using conven-
tional broth microdilution assay. MIC values are given in
Table 2.
Table 2 shows the antitubercular activity results which
depicted that compounds 6a–d containing substituted
benzoylamido at the C-7 position show good activity
against M. smegmatis. The presence of substituted ben-
zoylamido moiety with other groups like chloro fused to
5H-thiazolo[3,2-a]pyrimidin-5-ones may be accounted for
their antitubercular activity.
The amino substitution of compounds 4a–h could lead
to an amino conjugation effect of the cyclic a,b-unsatu-
rated ketone of 5H-thiazolo[3,2-a]pyrimidin-5-ones.
Apparently, the negative charge density of N atom
decreases, and consequently, the nucleophilicity of amino
group will decrease dramatically. A mild procedure for the
generation of amides 6a–d is based on the procedure in
reference Tang et al., (2013). Compounds 4a–h react with
m-methylbenzoyl chloride in the presence of triethylamine
to give amides 6a–d. However, the synthesis required
relatively high temperatures and/or long reaction times
because of the low nucleophilicity of the amine group.
Materials and methods
Melting points were determined in open capillary tubes
with a WRS-1B melting point apparatus and are uncor-
rected. IR spectra (KBr) were recorded on a FTIR920
spectrophotometer. The 1H and 13C NMR spectra were
obtained from a solution in DMSO-d6 unless otherwise
noted with TMS as internal standard using a 400/101 MHz
(1H/13C) spectrometer. Mass spectra were acquired from a
Agilent 6200 Series TOF and 6500 Series Q-TOF LC/MS
System B.05.01. (B5125).
Biological activity
Antibacterial activity
All of the synthesized compounds were evaluated in vitro
antibacterial activity against two Gram-positive bacterial
strains: Staphylococcus aureus (S. aureus) and Bacillus
subtilis (B. subtilis); two Gram-negative bacterial strains:
Escherichia coli (E. coli) and Pseudomonas aeruginosa
(P. aeruginosa), by conventional broth microdilution
assay. The MIC values of antibacterial activity are given in
Table 1.
General procedure for preparation of compounds 2
Anhydrous potassium carbonate (1.3821 g, 10 mmol) and
substituted phenacyl halides (10 mmol) were added in
succession to a suspension of 6-substituted-2-thiouracils
(10 mmol) in dry N,N-dimethylformamide (10 mL). After
stirring for 3 h at room temperature, the mixture was
quenched with water (100 mL) and filtered. The resulting
solid was crystallized from a suitable solvent.
The investigation of antibacterial screening data reveals
that all the tested compounds showed significant activity
against Gram-negative bacteria. However, most of the
compounds exhibited relatively weak activity against
Gram-positive bacteria. The sulfonic acid group in the
phenyl ring did not seem to have a remarkable contribution
to the antibacterial inhibition by compounds 3a–d; how-
ever, strong electron-withdrawing group such as nitro may
have improved their effect against Gram-negative bacteria,
and compounds 4e and 4f showed good activity against
E. coli. Compounds 5a–d containing a primary amino
substituent on phenyl group exhibited moderate potencies
against P. aeruginosa. Compounds 6a–d that are having
substituted benzoylamido at the C-7 position were found
to be the most active compounds against the test
microorganisms.
6-Methyl-2-((2-(3-nitrophenyl)-2-oxoethyl)thio)pyrimidin-
4(3H)-one 2a
White solid; yield: 86.27 %; m.p. 252.2–253.7 °C. HRMS
(m/z): calcd for C13H12N3O4S (neutral M ? H) 306.05485;
found 306.057780.
6-Methyl-2-((2-(4-nitrophenyl)-2-oxoethyl)thio)pyrimidin-
4(3H)-one 2b
White solid; yield: 87.78 %; m.p. 258.1–259.5 °C (lit.
(Hurst et al., 1988) 71 %; m.p. [ 315 °C). HRMS (m/z):
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Med Chem Res
Table 1 In vitro antibacterial activity (MIC lg/mL)
Compound
Gram-positive bacteria
Gram-negative bacteria
S. aureus
B. subtilis
E. coli
P. aeruginosa
3a
800
—
800
400
800
800
400
800
—
200
400
200
400
200
200
800
800
100
50
200
400
400
800
200
400
—
3b
3c
400
400
800
800
800
800
800
800
800
800
400
400
—
3d
4a
4b
4c
4d
—
800
400
400
800
—
4e
800
800
—
4f
4g
400
800
800
800
400
400
50
4h
—
5a
800
800
400
400
200
200
800
400
100
200
200
100
100
50
5b
5c
5d
800
200
200
100
200
25
6a
6b
50
100
200
400
50
6c
200
100
25
6d
Ciprofloxacin
‘‘—’’ indicates bacteria is resistant to the compounds at [800 lg/mL
calcd for C13H12N3O4S (neutral M ? H) 306.05485; found
calcd for C14H15N2O3S (neutral M ? H) 291.08034; found
306.056718.
291.088547.
6-Methyl-2-((2-oxo-2-(p-tolyl)ethyl)thio)pyrimidin-4(3H)-
6-Amino-2-((2-(3-nitrophenyl)-2-oxoethyl)thio) pyrimidin-
one 2c
4(3H)-one 2f
White solid; yield: 84.56 %; m.p. 187.3–187.6 °C (lit.
(Johnson et al., 1913) 52 %; m.p. 191–195 °C). HRMS (m/
z): calcd for C14H15N2O2S (neutral M ? H) 275.0842;
found 275.096403.
Yellow solid; yield: 73.45 %; m.p. 217.8–218.2 °C. HRMS
(m/z): calcd for C12H11N4O4S (neutral M ? H) 307.05010;
found 307.053381.
6-Amino-2-((2-(4-nitrophenyl)-2-oxoethyl)thio) pyrimidin-
2-((2-(4-Chlorophenyl)-2-oxoethyl)thio)-6-methylpyrimidin-
4(3H)-one 2g
4(3H)-one 2d
Yellow solid; yield: 73.45 %; m.p. 222.6–223.2 °C. HRMS
(m/z): calcd for C12H11N4O4S (neutral M ? H) 307.05010;
found 307.051107.
Yellow green solid; yield: 86.85 %; m.p. 218.7–220.0 °C
(lit.(Hurst et al., 1988) 80 %; m.p. 210–212 °C). HRMS
(m/z): calcd for C13H12ClN2O2S (neutral M ? H)
295.03080; found 295.033049.
6-Amino-2-((2-oxo-2-(p-tolyl)ethyl)thio)pyrimidin-4(3H)-
one 2h
2-((2-(4-Methoxyphenyl)-2-oxoethyl)thio)-6-methyl pyrimidin-
4(3H)-one 2e
White solid; yield: 85.0 %; m.p. 220.0–220.4 °C (lit.
(Hurst et al., 1988) 68 %; m.p. 204–206 °C). HRMS (m/z):
calcd for C13H14N3O2S (neutral M ? H) 276.08067; found
276.090015.
Yellow solid; yield: 74.05 %; m.p. 180.6–181.2 °C (lit.
(Hurst et al., 1988) 50 %; m.p. 186–189 °C). HRMS (m/z):
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Med Chem Res
2-Methoxy-5-(7-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-
Table 2 In vitro antitubercular activity (MIC lg/mL)
yl)benzenesulfonic acid 3a
Compound
M. smegmatis
3a
—
Yellow solid; yield: 88.96 %; m.p. 283.2–284.8 °C; IR
(mmax/cm-1): 3445 (SO3H), 1726 (C=O); 1H NMR
(400 MHz, DMSO-d6) d 7.68 (dd, J = 2.5, 1.1 Hz, 1H,
Ar–H), 7.36–7.28 (m, 1H, Ar–H), 7.22 (d, J = 1.2 Hz, 1H,
C2–H), 6.96 (dd, J = 8.6, 1.1 Hz, 1H, Ar–H), 6.05 (s, 1H,
C6–H), 3.45 (qd, J = 7.0, 1.2 Hz, 3H, CH3O), 2.28 (s, 3H,
7-CH3); 13C NMR (101 MHz, DMSO-d6) d 162.61 (N=C–
S), 156.81 (CON, C-5), 154.41 (C-7), 146.56 (C-3), 137.71,
134.77, 131.23, 129.52, 127.87, 123.17 (Ar–C), 110.87
(C-2), 104.92 (C-6), 55.90 (CH3O), 18.99 (CH3); HRMS
(m/z): calcd for C14H13N2O5S2 (neutral M ? H)
353.02659; found 353.029811.
3b
—
3c
—
3d
—
4a
—
4b
—
4c
—
4d
800
—
4e
4f
—
4g
—
4h
800
—
5a
2-Methyl-5-(7-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-
5b
—
3-yl)benzenesulfonic acid 3b
5c
—
5d
—
Yellow solid; yield: 83.20 %; m.p. 245.1–247.2 °C; IR
(mmax/cm-1): 3440 (SO3H), 1721 (C=O); 1H NMR
(400 MHz, DMSO-d6) d 7.74 (t, J = 1.5 Hz, 1H, Ar–H),
7.29 (d, J = 1.2 Hz, 1H, C2–H), 7.28–7.12 (m, 2H, Ar–H),
6.08 (s, 1H, C6–H), 2.57 (s, 3H, phenyl-CH3), 2.29 (s, 3H,
7-CH3); 13C NMR (101 MHz, DMSO-d6) d 163.93 (N=C–
S), 162.11 (CON, C-5), 158.98 (C-7), 145.36, 137.67,
136.39, 129.93, 128.89, 127.36 (Ar–C), 111.23 (C-2),
104.92 (C-6), 23.17 (CH3), 20.34 (CH3); HRMS (m/z):
calcd for C14H13N2O4S2 (neutral M ? H) 337.03167;
found 337.023641.
6a
100
100
400
50
6b
6c
6d
Rifampicin
25
‘‘—’’ indicates bacteria is resistant to the compounds at[800 lg/mL
6-Amino-2-((2-(4-chlorophenyl)-2-oxoethyl)thio) pyrimidin-
4(3H)-one 2i
5-(7-Amino-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)-2-
Yellow solid; yield: 84.53 %; m.p. 216.0–217.2 °C (lit.
(Hurst et al., 1988) 63 %; m.p. 220 °C (dec.)). HRMS (m/
z): calcd for C12H11ClN3O2S (neutral M ? H) 296.02605;
found 296.028652.
methoxybenzenesulfonic acid 3c
Yellow solid; yield: 86.46 %; m.p. (dec.) 223.7 °C; IR
(mmax/cm-1): 3332 (SO3H), 1659 (C=O); 1H NMR
(400 MHz, DMSO-d6) d 7.68 (q, J = 2.1 Hz, 1H, Ar–H),
7.32 (dq, J = 8.5, 2.1 Hz, 1H, Ar–H), 6.98–6.93 (m,1H,
Ar–H), 6.93–6.90 (m, 1H, C2–H), 6.12 (broad, s, 2H, NH2),
5.02–4.95 (m, 1H, C6–H), 3.80 (d, J = 2.6 Hz, 3H, CH3O);
13C NMR (101 MHz, DMSO-d6) d 164.74 (N=C–S),
162.75 (CON, C-5), 159.40 (C-7), 149.88 (C-3), 136.70,
131.27, 129.19, 128.47, 127.32, 111.34 (Ar–C), 108.42 (C-
2), 80.10 (C-6), 54.43 (CH3); HRMS (m/z): calcd for
C13H12N3O5S2 (neutral M ? H) 354.02184; found
354.025808.
6-Amino-2-((2-(4-methoxyphenyl)-2-oxoethyl)thio) pyrimidin-
4(3H)-one 2j
Yellow solid; yield: 80.32 %; m.p. 228.6–231.0 °C. HRMS
(m/z): calcd for C13H14N3O3S (neutral M ? H) 292.07559;
found 292.085934.
General procedure for preparation of compounds 3
S-alkylated thiouracils 2 (1 mmol) were carefully dissolved
in 3.0 mL of concentrated sulfuric acid, and the reaction
mixture was stirred at 80 °C for 24 h. The progress of the
reaction was monitored by TLC. After completion, the
reaction mixture was cooled and poured into ethyl acetate,
and the precipitate that separated was collected by filtra-
tion, washed with ethyl acetate and dried. The resulting
solid was recrystallized from ethyl acetate.
5-(7-Amino-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)-2-
methylbenzenesulfonic acid 3d
Yellow solid; yield: 87.52 %; m.p. 238.1–239.2 °C; IR
(mmax/cm-1): 3342 (SO3H), 1660 (C=O); 1H NMR
(400 MHz, DMSO-d6) d 7.71 (d, J = 1.9 Hz, 1H, Ar–H),
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Med Chem Res
7.21 (dd, J = 7.7, 2.1 Hz, 1H, Ar–H), 7.13 (s, 1H, C2–H),
6.98 (s, 1H, Ar–H), 5.73 (broad, s, 2H, NH2), 5.01 (s, 1H,
C6–H), 2.56 (s, 3H, phenyl-CH3); 13C NMR (101 MHz,
DMSO-d6) d 164.89 (N=C–S), 162.65 (CON, C-5), 159.39
(C-7), 147.06 (C-3), 137.77, 136.61, 131.74, 129.83,
127.30, 124.26 (Ar–C), 109.96 (C-2), 80.33 (C-6), 20.31
(CH3); HRMS (m/z): calcd for C13H12N3O4S2 (neutral
M ? H) 338.02692; found 338.027661.
IR (mmax/cm-1): 1649 (C=O); 1H NMR (400 MHz, DMSO-
d6) d 7.30 (s, 1H, C2–H), 7.28 (d, J = 1.0 Hz, 2H, Ar–H),
7.18 (d, J = 7.9 Hz, 2H, Ar–H), 6.06 (t, J = 0.9 Hz, 1H,
C6–H), 2.36 (s, 3H, CH3), 2.29 (s, 3H, CH3); 13C NMR
(101 MHz, DMSO-d6) d 163.96 (N=C–S), 162.30 (CON,
C-5), 159.12 (C-7), 138.23 (C-3), 137.95, 129.54, 129.46,
128.08 (Ar–C), 111.00 (C-2), 104.96 (C-6), 23.28 (CH3),
21.34 (CH3); HRMS (m/z): calcd for C14H13N2OS (neutral
M ? H) 257.07486; found 257.088294.
General procedure for preparation of compounds 4
3-(4-Chlorophenyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-
S-alkylated thiouracils 2 (1 mmol) were carefully dissolved
in 3.0 mL of concentrated sulfuric acid, and the reaction
mixture was stirred at room temperature for 72 h. The
progress of the reaction was monitored by TLC. After
completion, the reaction mixture was cooled and poured
into ice-cold water, and the precipitate that separated was
collected by filtration, washed with ethyl acetate and dried.
The resulting solid was recrystallized from ethyl acetate.
one 4d
Yellow solid; yield: 92.91 %; m.p. 210.9–211.5 °C (lit.
(Galasko and Israelstam, 1969) 80 %; m.p. 210–212 °C);
IR (mmax/cm-1): 1647 (C=O); 1H NMR (400 MHz, DMSO-
d6) d 7.45 (d, J = 1.1 Hz, 4H, Ar–H), 7.39 (d, J = 1.1 Hz,
1H, C2–H), 6.08 (d, J = 0.9 Hz, 1H, C6–H), 2.29
(d, J = 1.1 Hz, 3H, CH3); 13C NMR (101 MHz, DMSO-
d6) d 163.83 (N=C–S), 162.73 (CON, C-5), 159.23 (C-7),
136.46 (C-3), 133.59, 131.49, 131.21, 127.48 (Ar–C),
112.03 (C-2), 104.96 (C-6), 23.42 (CH3); HRMS (m/z):
calcd for C13H10ClN2OS (neutral M ? H) 277.02024;
found 277.022425.
7-Methyl-3-(3-nitrophenyl)-5H-thiazolo[3,2-a]pyrimidin-
5-one 4a
Yellow solid; yield: 91.15 %; m.p. 260.1.1–261.7 °C; IR
(mmax/cm-1): 1702 (C=O); 1H NMR (400 MHz, DMSO-d6)
d 8.35–8.25 (m, 2H, Ar–H), 7.91 (d, J = 7.7 Hz, 1H, Ar–
H), 7.69 (t, J = 7.9 Hz, 1H, Ar–H), 7.55 (s, 1H, C2–H),
6.10 (s, 1H, C6–H), 2.31 (s, 3H, CH3); 13C NMR
(101 MHz, DMSO-d6) d 163.70 (N=C–S), 163.14 (CON,
C-5), 159.42 (C-7), 146.92 (C-3), 136.18, 135.19, 133.84,
128.93, 124.57, 123.54 (Ar–C), 113.37 (C-2), 104.96 (C-6),
23.56 (CH3); HRMS (m/z): calcd for C13H10N3O3S (neu-
tral M ? H) 288.04429; found 288.047339.
7-Amino-3-(3-nitrophenyl)-5H-thiazolo[3,2-a]pyrimidin-5-
one 4e
Yellow solid; yield: 92.01 %; m.p. 256.1.1–258.0 °C; IR
(mmax/cm-1): 3404, 3389 (NH), 1693 (C=O); H NMR
1
(400 MHz, DMSO-d6) d 8.28–8.20 (m, 2H, Ar–H), 7.86
(dt, J = 7.6, 1.3 Hz, 1H, Ar–H), 7.70–7.60 (m, 1H, Ar–
H), 7.23 (s, 1H, C2–H), 6.78 (s, 2H, 7-NH2), 4.95 (s, 1H,
C6–H); 13C NMR (101 MHz, DMSO-d6) d 164.64 (N=C–
S), 162.91 (CON, C-5), 159.50 (C-7), 146.85 (C-3),
135.98, 135.47, 134.38, 128.77, 124.30, 123.23 (Ar–C),
109.76 (C-2), 80.05 (C-6); HRMS (m/z): calcd for
C12H9N4O3S (neutral M ? H) 289.03954; found
289.041969.
7-Methyl-3-(4-nitrophenyl)-5H-thiazolo[3,2-a]pyrimidin-
5-one 4b
Yellow solid; yield: 92.72 %; m.p. 215.1–216.7 °C (lit.
(Hurst et al., 1988) 86 %; m.p. 238–242 °C); IR (mmax
/
cm-1): 1731(C=O); 1H NMR (400 MHz, DMSO-d6) d
8.27–8.19 (m, 2H, Ar–H), 7.75–7.66 (m, 2H, Ar–H), 7.57
(d, J = 1.7 Hz, 1H, C2–H), 6.11 (d, J = 1.5 Hz, 1H, C6–
H), 2.30 (d, J = 1.6 Hz, 3H, CH3); 13C NMR (101 MHz,
DMSO-d6) d 163.73 (N=C–S), 163.05 (CON, C-5), 159.24
(C-7), 147.44 (C-3), 138.64, 135.38, 130.90, 122.55 (Ar–
C), 113.94 (C-2), 104.96 (C-6), 23.51 (CH3); HRMS (m/z):
calcd for C13H10N3O3S (neutral M ? H) 288.04429; found
288.048423.
7-Amino-3-(4-nitrophenyl)-5H-thiazolo[3,2-a]pyrimidin-5-
one 4f
Yellow solid; yield: 91.14 %; m.p. 241.1–242.4 °C; IR
(mmax/cm-1): 3445, 3337 (NH), 1683 (C=O); 1H NMR
(400 MHz, DMSO-d6) d 8.23–8.18 (m, 2H, Ar–H),
7.70–7.63 (m, 2H, Ar–H), 7.24 (s, 1H, C2–H), 6.79 (s, 2H,
7-NH2), 4.95 (s, 1H, C6–H); 13C NMR (101 MHz,
DMSO-d6) d 164.65 (N=C–S), 162.91 (CON, C-5),
159.34 (C-7), 147.21 (C-3), 139.29, 135.69, 130.63,
122.42 (Ar–C), 110.31 (C-2), 79.97 (C-6); HRMS (m/z):
calcd for C12H9N4O3S (neutral M ? H) 289.03954; found
289.041732.
7-Methyl-3-(p-tolyl)-5H-thiazolo[3,2-a]pyrimidin-5-one 4c
Yellow solid; yield: 92.22 %; m.p. 210.7–210.9 °C (lit.
(Galasko and Israelstam, 1969) 84 %; m.p. 196–198 °C);
123

Med Chem Res
7-Amino-3-(p-tolyl)-5H-thiazolo[3,2-a]pyrimidin-5-one 4g
3-(4-Aminophenyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-
5-one 5b
Yellow solid; yield: 90.71 %; m.p. 201.5–202.3 °C; IR
(mmax/cm-1): 3380, 3341 (NH), 1721 (C=O); 1H NMR
(400 MHz, DMSO-d6) d 7.25 (d, J = 7.8 Hz, 2H, Ar–H),
7.15 (d, J = 7.9 Hz, 2H, Ar–H), 6.96 (d, J = 1.1 Hz, 1H,
C2–H), 4.95 (s, 1H, C6–H), 2.34 (s, 3H, CH3); 13C NMR
(101 MHz, DMSO-d6) d 162.61 (N=C–S), 159.41 (CON,
C-5), 157.37 (C-7), 137.82 (C-3), 129.78, 129.34, 127.93,
126.56 (Ar–C), 107.43 (C-2), 80.22 (C-6), 21.30 (CH3);
HRMS (m/z): calcd for C13H12N3OS (neutral M ? H)
258.07011; found 258.081756.
Yellow solid; yield: 80.16 %; m.p. 205.3–206.2 °C; IR
(mmax/cm-1): 3419, 3318(NH), 1688 (C=O), 1623 (NH); 1H
NMR (400 MHz, DMSO-d6) d 7.08–7.06 (m, 1H, C2–H),
7.04 (dd, J = 8.4, 1.8 Hz, 2H, Ar–H), 6.52 (dt, J = 8.3,
1.6 Hz, 2H, Ar–H), 6.02 (d, J = 1.8 Hz, 1H, C6–H), 5.36
(s, 2H, phenyl-NH2), 2.26 (d, J = 1.8 Hz, 3H, CH3); 13C
NMR (101 MHz, DMSO-d6) d 164.06 (N=C–S), 162.47
(CON, C-5), 159.41 (C-7), 149.49 (C-3), 139.19, 130.56,
119.42, 112.52 (Ar–C), 108.56 (C-2), 104.93 (C-6), 23.43
(CH3); HRMS (m/z): calcd for C13H12N3OS (neutral
M ? H) 258.07011; found 258.070469.
7-Amino-3-(4-chlorophenyl)-5H-thiazolo[3,2-a]pyrimidin-
5-one 4h
7-Amino-3-(3-aminophenyl)-5H-thiazolo[3,2-a]pyrimidin-
Yellow solid; yield: 90.66 %; m.p. 175.0–177.4 °C(lit.
(Hurst et al., 1988) 75 %; m.p. 186–188 °C); IR (mmax
5-one 5c
/
cm-1): 3374, 3341 (NH), 1717 (C=O); 1H NMR
(400 MHz, DMSO-d6) d 8.19 (s, 1H, Ar–H), 7.66 (s, 2H,
Ar–H), 7.31 (s, 1H, Ar–H), 7.00–6.92 (m, 1H, C2–H), 5.14
(s, 1H, C6–H); 13C NMR (101 MHz, DMSO-d6) d 164.65
(N=C–S), 159.81 (CON, C-5), 159.36 (C-7), 147.27 (C-3),
139.07, 130.69, 124.67, 122.47 (Ar–C), 112.99 (C-2),
80.21 (C-6); HRMS (m/z): calcd for C12H9ClN3OS (neutral
M ? H) 278.01549; found 278.017832.
Yellow solid; yield: 75.23 %; m.p. 198.0–199.1 °C; IR
(mmax/cm-1): 3464, 3304 (NH), 1671 (C=O), 1623(NH); 1H
NMR (400 MHz, DMSO-d6) d 6.97 (td, J = 7.8, 1.3 Hz,
1H, Ar–H), 6.88 (d, J = 1.3 Hz, 1H, C2–H), 6.66 (s, 2H,
7-NH2), 6.58–6.45 (m, 3H, Ar–H), 5.12 (s, 2H, phenyl-
NH2), 4.91 (d, J = 1.3 Hz, 1H, C6–H); 13C NMR
(101 MHz, DMSO-d6) d 164.91 (N=C–S), 162.66 (CON,
C-5), 159.21 (C-7), 147.89 (C-3), 138.94, 133.53, 127.94,
117.20, 114.98, 114.07 (Ar–C), 106.81 (C-2), 80.14 (C-6);
HRMS (m/z): calcd for C12H11N4OS (neutral M ? H)
259.06536; found 259.065181.
General procedure for preparation of compounds 5
A suspension of nitro compounds 4 (3.53 mmol) in ethanol
(60 mL) and water (30 mL) was treated with ammonium
chloride (0.1888 g, 3.53 mmol) and iron powder (0.9857 g,
17.65 mmol). After being stirred at 80 °C for 2 h, the
mixture was filtered while hot. The filtrate was washed
with hot ethanol and concentrated. The resulting concen-
trate was allowed to in an ice bath, and the precipitate was
filtered.
7-Amino-3-(4-aminophenyl)-5H-thiazolo[3,2-a]pyrimidin-
5-one 5d
Yellow solid; yield: 75.0 %; m.p. 201.3–202.8 °C; IR
(mmax/cm-1): 3323, 3162 (NH), 1650 (C=O), 1633 (NH);
1H NMR (400 MHz, DMSO-d6) d 7.01 (dd, J = 8.3,
1.5 Hz, 2H, Ar–H), 6.74 (d, J = 1.4 Hz, 1H, C2–H), 6.62
(s, 2H, 7-NH2), 6.49 (dd, J = 8.3, 1.5 Hz, 2H, Ar–H), 5.29
(s, 2H, phenyl-NH2), 4.93–4.88 (m, 1H, C6–H); 13C NMR
(101 MHz, DMSO-d6) d 165.03 (N=C–S), 162.54 (CON,
C-5), 159.64 (C-7), 149.22 (C-3), 139.51, 130.38, 120.18,
112.46 (Ar–C), 105.01 (C-2), 80.29 (C-6); HRMS (m/z):
calcd for C12H11N4OS (neutral M ? H) 259.06536; found
259.064633.
3-(3-Aminophenyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-
5-one 5a
Yellow solid; yield: 78.84 %; m.p. 231.6–237.3 °C; IR
(mmax/cm-1): 3426, 3316(N–H), 1685 (C=O), 1621 (N–H);
1H NMR (400 MHz, DMSO-d6) d 7.21 (d, J = 1.7 Hz, 1H,
C2–H), 7.01 (td, J = 7.8, 1.6 Hz, 1H, Ar–H), 6.59 (dd,
J = 7.5, 1.8 Hz, 1H, Ar–H), 6.60–6.47 (m, 2H, Ar–H),
6.05 (d, J = 1.6 Hz, 1H, C6–H), 5.17 (s, 2H, phenyl-NH2),
2.28 (d, J = 1.6 Hz, 3H, CH3); 13C NMR (101 MHz,
DMSO-d6) d 163.97 (N=C–S), 162.69 (CON, C-5), 158.98
(C-7), 148.02 (C-3), 138.57, 132.89, 128.09, 117.30,
115.01, 114.32 (Ar–C), 110.40 (C-2), 104.91 (C-6), 23.49
(CH3); HRMS (m/z): calcd for C13H12N3OS (neutral
M ? H) 258.07011; found 258.071755.
General procedure for preparation of compounds 6
A mixture of compounds 4 (1.0 mmoL), 3-methylbenzoyl
chloride (0. 1855 g, 1.2 equiv., 1.2 mmol) and triethy-
lamine (0.2024 g, 2 equiv., 2.0 mmol) was refluxed at
80 °C for 2 h. After the completion of reaction, the reaction
was quenched with water and extracted with dichlor-
omethane. Finally, the combined organic layer was washed
123

Med Chem Res
with brine and dried over anhydrous Na2SO4. After
removal of the solvent in vacuum, the residue was purified
by recrystallization.
21.29 (CH3); HRMS (m/z): calcd for C21H18N3O2S (neutral
M ? H) 376.11197; found 376.112952.
N-(3-(4-Chlorophenyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-
3-Methyl-N-(3-(3-nitrophenyl)-5-oxo-5H-thiazolo[3,2-
yl)-3-methylbenzamide 6d
a]pyrimidin-7-yl)benzamide 6a
White solid; yield: 89.10 %; m.p. 228.1–230.6 °C. IR
(mmax/cm-1): 3380 (NH), 1688 (C=O); 1H NMR
(400 MHz, DMSO-d6) d 10.88 (s, 1H, CONH), 7.89–7.75
(m, 2H, Ar–H), 7.51–7.38 (m, 6H, Ar–H), 7.36 (s, 1H, C2–
H), 7.04 (s, 1H, C6–H), 2.40 (s, 3H, CH3); 13C NMR
(101 MHz, DMSO-d6) d 167.12 (CONH), 163.76 (N=C–
S), 160.28 (CON, C-5), 155.26 (C-7), 138.22 (C-3), 136.71,
133.80, 133.64, 133.41, 131.53, 131.12, 129.16, 128.76,
127.51, 125.73 (Ar–C), 111.21 (C-2), 91.82 (C-6), 21.31
(CH3); HRMS (m/z): calcd for C20H15ClN3O2S (neutral
M ? H) 396.05735; found 396.057856.
White solid; yield: 89.73 %; m.p. 297.1–298.4 °C. IR
(mmax/cm-1): 3428 (NH), 1685 (C=O); 1H NMR
(400 MHz, DMSO-d6) d 10.91 (s, 1H, CONH), 8.35 (t,
J = 2.0 Hz, 1H, Ar–H), 8.30 (ddd, J = 8.2, 2.4, 1.1 Hz,
1H, Ar–H), 7.94 (dt, J = 7.7, 1.3 Hz, 1H, Ar–H), 7.87 (s,
1H, Ar–H), 7.82 (d, J = 7.4 Hz, 1H, Ar–H), 7.71 (t,
J = 8.0 Hz, 1H, Ar–H), 7.53 (d, J = 0.9 Hz, 1H, C2–H),
7.48–7.35 (m, 2H, Ar–H), 7.06 (d, J = 0.9 Hz, 1H, C6–H),
2.40 (s, 3H, CH3); 13C NMR (101 MHz, DMSO-d6) d
167.17 (CONH), 163.68 (N=C–S), 160.45 (CON, C-5),
155.42 (C-7), 146.98 (C-3), 138.26, 136.25, 135.48,
133.81, 133.75, 133.47, 129.20, 129.00, 128.80, 125.77,
124.64, 123.63 (Ar–C), 112.65 (C-2), 91.85 (C-6), 21.34
(CH3); HRMS (m/z): calcd for C20H15N4O4S (neutral
M ? H) 407.08140; found 407.081802.
Biological activity
The standard strains were obtained from National Center for
Medical Culture Collection. The antibacterial activity of the
synthesized compounds was performed by conventional
broth microdilution method against two Gram-positive
bacterial strains: Staphylococcus aureus [CMCC (B) 26003]
and Bacillus subtilis [CMCC(B) 63501]; two Gram-negative
bacterial strains: Escherichia coli [CMCC (B) 44102] and
Pseudomonas aeruginosa [CMCC (B) 10104].
A standard inoculum (1.5 9 107 c.f.u/mL 0.5 McFar-
land standards) was introduced onto the surface of sterile
agar plates. The tested compounds and reference drugs
were dissolved in MeOH to get a solution of 2 mg/mL
concentration. The series diluted compounds in Mueller–
Hinton Broth were dispensed into 96-well microtiter plates
(200 lL/well), and then, an aliquot of 5 9 105 c.f.u/mL of
bacterial culture was added to each well to final concen-
trations in a range of 1–800 lg/mL. After incubating at
37 °C for 24 h, the lowest concentration required to arrest
the growth of bacteria was recorded as the MIC value.
MeOH showed no inhibition effect. Ciprofloxacin was used
as reference antibacterial agent.
3-Methyl-N-(3-(4-nitrophenyl)-5-oxo-5H-thiazolo[3,2-
a]pyrimidin-7-yl)benzamide 6b
White solid; yield: 84.79 %; m.p. 306.0–306.8 °C. IR
(mmax/cm-1): 3368 (NH), 1685 (C=O); 1H NMR
(400 MHz, DMSO-d6) d 10.92 (s, 1H, CONH), 8.31–8.22
(m, 2H, Ar–H), 7.90–7.78 (m, 2H, Ar–H), 7.83–7.71 (m,
2H, Ar–H), 7.55 (s, 1H, C2–H), 7.49–7.37 (m, 2H, Ar–H),
7.07 (s, 1H, C6–H), 2.40 (s, 3H, CH3); 13C NMR
(101 MHz, DMSO-d6) d 167.14 (CONH), 163.68 (N=C–
S), 160.26 (CON, C-5), 155.38 (C-7), 147.49 (C-3), 138.56,
138.22, 135.65, 133.77, 133.44, 130.94, 129.16, 128.77,
125.73, 122.57 (Ar–C), 113.11 (C-2), 91.76 (C-6), 21.29
(CH3); HRMS (m/z): calcd for C20H15N4O4S (neutral
M ? H) 407.08140; found 407.081674.
3-Methyl-N-(5-oxo-3-(p-tolyl)-5H-thiazolo[3,2-a]pyrimidin-
7-yl)benzamide 6c
Mycobacterium smegmatis [CGMCC (B) 1.2621] was
obtained from China General Microbiological Culture Col-
lection Center. MIC of compounds was determined against
Mycobacterium smegmatis strain by using broth microdilu-
tion assay. Rifampicin was used as a reference drug.
White solid; yield: 85.84 %; m.p. 231.8–232.9 °C. IR (mmax
/
cm-1): 3431 (NH), 1683 (C=O); 1H NMR (400 MHz,
DMSO-d6) d 10.86 (s, 1H, CONH), 7.86 (s, 1H, Ar–H), 7.81
(dt, J = 7.6, 1.7 Hz, 1H, Ar–H), 7.47–7.37 (m, 2H, Ar–H),
7.33 (d, J = 7.8 Hz, 2H, Ar–H), 7.25 (s, 1H, C2–H), 7.20 (d,
J = 7.8 Hz, 2H, Ar–H), 7.03 (d, J = 1.1 Hz, 1H, C6–H),
2.38 (d, J = 9.1 Hz, 6H, two CH3); 13C NMR (101 MHz,
DMSO-d6) d 167.09 (CONH), 163.87 (N=C–S), 160.21
(CON, C-5), 155.13 (C-7), 138.23 (C-3), 138.20, 138.16,
133.83, 133.38, 129.56, 129.41, 129.15, 128.74, 128.08,
125.71 (Ar–C), 110.11 (C-2), 91.83 (C-6), 21.33 (CH3),
Conclusion
The present research study reports the successful synthetic
method leading to 7-substituted-5H-thiazolo[3,2-a]pyrim-
idin-5-ones or corresponding sulfonic acid derivatives at
123

Med Chem Res
Cai J (2004) Structural chemistry and properties of metal arenesul-
fonates. Coord Chem Rev 248:1061–1083
Coates J, Sammes PG, West RM (1996) Enhancement of lumines-
cence of europium (III) ions in water by use of synergistic
chelation. Part 1. 1: 1 and 2: 1 complexes. J Chem Soc Perkin
Trans 2:1275–1282
Dai Y, Guo Y, Frey RR (2005) Thienopyrimidine ureas as novel and
potent multitargeted receptor tyrosine kinase inhibitors. J Med
Chem 48:6066–6083
Dallinger D, Gorobets NY, Kappe CO (2003) High-throughput
synthesis of N-3-acylated dihydropyrimidines combining micro-
wave-assisted synthesis and scavenging techniques. Org Lett
5:1205–1208
different temperature in high yield and purity. The struc-
tures are fully supported by spectroscopic data. All the
synthesised compounds were tested for their antibacterial
and antitubercular activities. These compounds showed
significant activity against Gram-negative bacteria, and the
sulfonic acid group in the phenyl ring did not seem to have
a remarkable contribution to the antibacterial activity. The
presence of substituted benzoylamido moiety at the C-7
position of 5H-thiazolo[3,2-a]pyrimidin-5-ones showed
enhanced their antibacterial and antitubercular activities.
Danel K, Pedersen EB, Nielsen C (1998) Synthesis and anti-HIV-1
activity of novel 2, 3-dihydro-7H-thiazolo[3, 2-a] pyrimidin-7-
ones. J Med Chem 41:191–198
Dhapalapur M, Sabnis S, Deliwala C (1968) Potential anticancer
agents. II. Schiff bases from benzaldehyde nitrogen mustards.
J Med Chem 11:1014–1019
Acknowledgments The authors thank the Liaoning Medical
University Principal Fund (No. XZJJ20130104-03) for the financial
support of this research.
Compliance with ethical standards
Doria G, Passarotti C, Sala R, Magrini R, Sberze P, Tibolla M,
Ceserani R, Arcari G, Castello R, Toti D (1985) 7-trans-(2-
Pyridylethenyl)-5H-thiazolo[3, 2-a] pyrimidine-5-ones: synthe-
sis and pharmacological activity. II Farmaco 40:885–894
El-Bayouki KA, Basyouni WM (2010) Thiazolopyrimidines without
bridge-head nitrogen: thiazolo [4, 5-d] pyrimidines. J Sulfur
Chem 31:551–590
El-Emary T, Abdel-Mohsen SA (2006) Synthesis and antimicrobial
activity of some new 1, 3-diphenylpyrazoles bearing pyrimidine,
pyrimidinethione, thiazolopyrimidine, triazolopyrimidine, thio-
and alkylthiotriazolop-yrimidinone moieties at the 4-position.
Phosphorus Sulfur Silicon 181:2459–2474
Conflict of interest The authors declare no conflict of interest.
References
Abdel-Mohsen HT, Conrad JR, Beifuss U (2013) Laccase-catalyzed
domino reaction between catechols and 6-substituted 1, 2, 3,
4-tetrahydro-4-oxo-2-thioxo-5-pyrimidinecarbonitriles for the
synthesis of pyrimidobenzothiazole derivatives. J Org Chem
78:7986–8003
Allen C, Beilfuss H, Burness D, Reynolds G, Tinker J, VanAllan J
(1959) The structure of certain polyazaindenes. II. The product
from ethyl acetoacetate and 3-amino-1, 2, 4-triazole. J Org Chem
24:787–793
Al-Omary FA, Hassan GS, El-Messery SM, El-Subbagh HI (2012)
Substituted thiazoles V. Synthesis and antitumor activity of
novel thiazolo[2, 3-b] quinazoline and pyrido [4, 3-d] thiazolo
[3, 2-a] pyrimidine analogues. Eur J Med Chem 47:65–72
Andrew HF, Bradsher CK (1967) A new synthesis of thiazolo[3,2-a]
pyrimidinones. J Heterocycl Chem 4:577–581
Angioni S, Villa DC, Dal Barco S, Quartarone E, Righetti PP, Tomasi C,
Mustarelli P (2014) Polysulfonation of PBI-based membranes for
HT-PEMFCs: a possible way to maintain high proton transport at a
low H3PO4 doping level. J Mater Chem A 2:663–671
Awadallah FM (2008) Synthesis, pharmacophore modeling, and
biological evaluation of novel 5H-Thiazolo[3, 2-a] pyrimidin-5-
one derivatives as 5-HT2A receptor antagonists. Sci Pharm
76:415–438
Bakavoli M, Raissi H, Tajabadi J, Karimi M, Davoodnia A, Nikpour
M (2008) Investigation into the regioisomeric composition of
some fused pyrimidines: 1H NMR and theoretical studies.
J Sulphur Chem 29:25–30
Balkan A, Uma S, Ertan M, Wiegrebe W (1992) Thiazolo[3, 2-a]-
pyrimidine derivatives as calcium antagonists. Pharmazie
47:687–688
Bondock S, El-Azab H, Kandeel E-EM, Metwally MA (2013)
Efficient synthesis of new functionalized 2-(hetaryl) thiazoles.
Synth Commun 43:59–71
Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice
LB, Scheld M, Spellberg B, Bartlett J (2009) Bad bugs, no drugs:
no ESKAPE! An update from the Infectious Diseases Society of
America. Clin Infect Dis 48:1–12
Flefel E, Salama M, El-Shahat M, El-Hashash M, El-Farargy A
(2007)
A novel synthesis of some new pyrimidine and
thiazolopyrimidine derivatives for anticancer evaluation. Phos-
phorus Sulfur Silicon 182:1739–1756
Fujiwara M, Inoi T (1992) Syntheses and anti-inflammatory activity
of novel oximes and O-acyloximes. Chem Pharm Bull
40:2419–2422
Galasko GTF, Israelstam SS (1969) Reaction of aminoheterocycles
with reactive esters. 2. 2-aminothiazoles. J South Afr Chem Inst
22:121–127
¨
Geist JG, Lauw S, Illarionova V, Illarionov B, Fischer M, Grawert T,
Rohdich F, Eisenreich W, Kaiser J, Groll M (2010) Thiazolopy-
rimidine inhibitors of 2-methylerythritol 2, 4-cyclodiphosphate
synthase (IspF) from mycobacterium tuberculosis and plasmod-
ium falciparum. ChemMedChem 5:1092–1101
Ghorab M, Abdel-Gawad S, El-Gaby M (2000) Synthesis and
evaluation of some new fluorinated hydroquinazoline derivatives
as antifungal agents. II Farmaco 55:249–255
Hurst D, Beaumont C, Jones D, Kingsley D, Patridge J, Rutherford T
(1988) The chemistry of pyrimidinethiols. II. The preparation
and reactions of some 2-arenecarbonylmethylthiopyrimidines.
Aust J Chem 41:1209–1219
Janietz D, Goldmann B, Rudorf WD (1988) Chlormethyl-substituierte
¨
heterocyclen aus chlortetrolsauremethylester. J Prakt Chem
330:607–616
Jeanneau-Nicolle E, Benoit-Guyod M, Namil A, Leclerc G (1992)
New thiazolo[3, 2-a] pyrimidine derivatives, synthesis and
structure–activity relationships. Eur J Med Chem 27:115–120
Johnson TB, Moran RC, Kohmann EF (1913) 1, 4-Dithienes. I. J Am
Chem Soc 35:447–452
Katritzky AR, Yang Y-K, Gabrielsen B, Marquet J (1984) Pyrylium-
mediated transformations of natural products. Part 3. Synthesis
of water-soluble pyrylium salts and their preparative reactions
with amines. J Chem Soc Perkin Trans 2:857–866
Brown D, Hoerger E, Mason S (1955) Simple pyrimidines. Part II. 1:
2-Dihydro-1-methylpyrimidines and the configuration of the
N-methyluracils. J Chem Soc 211–217. doi:10.1039/JR9550000211
123

Med Chem Res
Kaye PT, Meakin GD, Smith AK, Tirel MD (1983) N, N-disubstituted
2-aminothiazole-5-carboxylates: preparation and rotation of
functional groups. J Chem Soc Perkin Trans 1:1677–1680
Khan RH, Rastogi RC (1991) Condensed heterocycles: synthesis and
antifungal activity of p-deficient pyrimidines linked with p-rich
heterocycles. J Agric Food Chem 39:2300–2303
Design, synthesis, biological evaluation, and structure–activity
relationships. Eur J Med Chem 46:819–824
Parekh NM, Maheria KC (2012) Antituberculosis and antibacterial
evaluations of some novel phenyl pyrazolone-substituted 1H-
benzo[g]pyrazolo[3, 4-b] quinoline-3-ylamine derivatives. Med
Chem Res 21:4168–4176
´
Kolb S, Mondesert O, Goddard ML, Jullien D, Villoutreix BO,
Quan ZJ, Zhang Z, Wang JK, Wang XC, Liu YJ, Ji PY (2008)
Efficient synthesis of 5H-thiazolo [3, 2-a] pyrimidines from
reactions of 3, 4-dihydropyrimidine-thiones with a-bromoace-
tone in aqueous media. Heteroat Chem 19:149–153
Ducommun B, Garbay C, Braud E (2009) Development of novel
thiazolopyrimidines as CDC25B phosphatase inhibitors. Chem-
MedChem 4:633–648
Kwiatkowski J, Pullman B (1975) Taulomerism and electronic
structure of biological pyrimidines. Adv Heterocycl Chem
18:199–335
Lin Y, Seifert C, Kang S, Dusza J, Lang S (1979) The synthesis of
substituted 2-aminothiazoles. J Heterocycl Chem 16:1377–1383
Liu SJ, Shang R, Shi L, Wan DC-C, Lin H (2014) Synthesis and
biological evaluation of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one
derivatives as dual binding site acetylcholinesterase inhibitors.
Eur J Med Chem 81:237–244
Raval JP, Naik BN, Desai KR (2012) A convenient, rapid microwave-
assisted synthesis of 2-substituted phenyl-2, 3-dihydrobenzo
[B][1, 4] thiazepine-3-carboxamide derivatives and its antimicro-
bial activity. Phosphorus Sulfur Silicon Relat Elem 187:255–267
¨
Schafer H, Jablokoff H, Hentschel M, Gewald K (1984) 2-Arylamino-
¨
thiophen-3-carbonsaurederivate. J Prakt Chem 326:917–923
¨
Schafer H, Gewald K, Bellmann P, Gruner M (1991) Synthese und
reaktionen von 2-arylhydrazono-2-cyan-N, N-dialkyl-acetamidi-
nen. Monatsh Chem 122:195–207
Maddila S, Damu G, Oseghe E, Abafe O, Rao CV, Lavanya P (2012)
Synthesis and biological studies of novel biphenyl-3,5-dihydro-
Simmons KJ, Chopra I, Fishwick CW (2010) Structure-based
discovery of antibacterial drugs. Nat Rev Microbiol 8:501–510
Tang J, Lackey KE, Dickerson SH (2013) The discovery of potent and
selective 4-aminothienopyridines as B-Raf kinase inhibitors.
Bioorg Med Chem Lett 23:66–70
2H-thiazolopyrimidines derivatives.
56:334–340
J Korean Chem Soc
Matiichuk V, Potopnyk M, Obushak N (2008) Molecular design of
pyrazolo[3, 4-d] pyridazines. Russ J Org Chem 44:1352–1361
Meslin J-C, Quiniou H (1974) The syntheses of 6-oxo-(and 6-thioxo)-
6H-1, 3-thiazines and 5-aroylthiazoles from N0-thioaroyl N, N-
dimethylformamidines. Synthesis 1974:298–300
¨
Tozkoparan B, Ertan M, Krebs B, Lage M, Kelicen P, Demirdamar R
(1998) Condensed heterocyclic compounds: synthesis and anti-
inflammatory activity of novel thiazolo [3, 2-a] pyrimidines.
Arch Pharm 331:201–206
Meslin J, Quiniou H (1975) Enchainements heteroatomiques et leurs
produits de cyclisation—II: N, N-dimethyl N0-thioaroylfor-
Tozkoparan B, Ertan M, Kelicen P, Demirdamar R (1999) Synthesis
and anti-inflammatory activities of some thiazolo [3, 2-a]
pyrimidine derivatives. II Farmaco 54:588–593
Veretennikov E, Pavlov A (2013) Synthesis of 5H-[1,3] thiazolo [3,
2-a] pyrimidin-5-one derivatives. Russ J Org Chem 49:575–579
Wichmann J, Adam G, Kolczewski S, Mutel V, Woltering T (1999)
Structure–activity relationships of substituted 5H-thiazolo[3,
2-a] pyrimidines as group 2 metabotropic glutamate receptor
antagonists. Bioorg Med Chem Lett 9:1573–1576
mamidines, aroyl-5 thiazoles et 6H-thiazine-1,
(thiones)-6 substitues. Tetrahedron 31:3055–3058
3
ones
Mizutani M, Sanemitsu Y, Tamaru Y, Yoshida Z (1985) Palladium-
catalyzed polyhetero-Claisen rearrangement of 2-(allylthio)
pyrimidin-4 (3H)-ones. J Org Chem 50:764–768
Mohamed SF, Flefel EM, Amr AE-GE, El-Shafy DNA (2010) Anti-
HSV-1 activity and mechanism of action of some new synthe-
sized substituted pyrimidine, thiopyrimidine and thiazolopyrim-
idine derivatives. Eur J Med Chem 45:1494–1501
Nagarajaiah H, Khazi I, Begum NS (2012) Synthesis, characterization
and biological evaluation of thiazolopyrimidine derivatives.
J Chem Sci 124:847–855
Youssef MM, Youssef AMS (2003) Reactions with 2-thiothymine;
selective cyclization of S-substituted-2-thiothymine. Phosphorus
Sulfur Silicon Relat Elem 178:67–81
Pan B, Huang R, Zheng L, Chen C, Han S, Qu D, Zhu M, Wei P
(2011) Thiazolidione derivatives as novel antibiofilm agents:
123