Succinct and facile synthesis of innovative thiopyrimidines with antimicrobial and antitubercular investigation

Article abstract of DOI:10.1080/10426507.2012.692130

To develop a series of bioactive heterocycles in minimum number of steps, 3-methyl- 4-(substituted phenyl)-1-phenyl-4,8-dihydropyrazolo[4′,3′: 5,6]pyrano[2,3-d]pyrimidine-5,7 (1H,6H)-dithione 2(a-j), 4-(4-substituted phenyl)-5-imino-3-methyl-1,6-diphenyl-4,5,6,8-tetrahydropyrazolo[4′, 3′:5,6]pyrano[2,3-d]pyrimidine-7(1H)-thione 3(a-j), and N-[4-(subs- tituted phenyl)-3-methyl-1-phenyl-7-thioxo-1,4,7,8-hexahydropyrazolo[4′, 3′:5,6]pyrano[2,3-d]pyrimidine-5-yl]thiourea 4(a-j) have been synthesized from amino nitrile functionality 1(a-j). The structures of the compounds were elucidated by IR, ¹H NMR, elemental analysis, and some representative ¹³C NMR and mass spectra. All the title compounds were screened for antimicrobial and antitubercular activities, while some representative compounds were tested for antioxidant activity. Out of synthesized compounds, compounds 1j (4-CH3), 2d (4-F), 4c (4-OH), and 4i (3-Br) exhibited maximum inhibition against Mycobacterium Tuberculosis H37Rv. Compound 3c (4-OH) revealed elevated efficacy against all tested bacterial strain, while compounds 1i (3-Br), 2c (4-OH), and 3h (3-NO2) were found efficacious against Candida albicans as compared to standard drugs. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

Full text of DOI:10.1080/10426507.2012.692130

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Succinct and Facile Synthesis of
Innovative Thiopyrimidines With
Antimicrobial and Antitubercular
Investigation
Prashant T. Mistry a , Nimesh R. Kamdar a , Dhaval D. Haveliwala a &
Saurabh K. Patel a
a Department of Chemistry , Veer Narmad South Gujarat University ,
Surat , 395 007 , Gujarat , India
Accepted author version posted online: 17 May 2012.Published
online: 31 May 2013.
To cite this article: Prashant T. Mistry , Nimesh R. Kamdar , Dhaval D. Haveliwala & Saurabh K.
Patel (2013) Succinct and Facile Synthesis of Innovative Thiopyrimidines With Antimicrobial and
Antitubercular Investigation, Phosphorus, Sulfur, and Silicon and the Related Elements, 188:5,
561-572, DOI: 10.1080/10426507.2012.692130
To link to this article: http://dx.doi.org/10.1080/10426507.2012.692130
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Phosphorus, Sulfur, and Silicon, 188:561–572, 2013
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.692130
SUCCINCT AND FACILE SYNTHESIS OF INNOVATIVE
THIOPYRIMIDINES WITH ANTIMICROBIAL AND
ANTITUBERCULAR INVESTIGATION
Prashant T. Mistry, Nimesh R. Kamdar, Dhaval D. Haveliwala,
and Saurabh K. Patel
Department of Chemistry, Veer Narmad South Gujarat University, Surat 395 007,
Gujarat, India
GRAPHICAL ABSTRACT
R
R
R
S
NH
NHCSNH2
H3C
H3C
H3C
NH
N
N
N
N
N
N
O
N
H
S
N
N
O
N
H
S
O
N
H
S
2(a-j)
4(a-j)
3(a-j)
Abstract To develop a series of bioactive heterocycles in minimum number of steps, 3-methyl-
4-(substituted phenyl)-1-phenyl-4,8-dihydropyrazolo[4ꢁ,3ꢁ:5,6]pyrano[2,3-d]pyrimidine-5,7
(1H,6H)-dithione 2(a–j), 4-(4-substituted phenyl)-5-imino-3-methyl-1,6-diphenyl-4,5,6,8-
tetrahydropyrazolo[4ꢁ,3ꢁ:5,6]pyrano[2,3-d]pyrimidine-7(1H)-thione 3(a–j), and N-[4-(subs-
tituted phenyl)-3-methyl-1-phenyl-7-thioxo-1,4,7,8-hexahydropyrazolo[4ꢁ,3ꢁ:5,6]pyrano[2,3-
d]pyrimidine-5-yl]thiourea 4(a–j) have been synthesized from amino nitrile functionality
1(a–j). The structures of the compounds were elucidated by IR, 1H NMR, elemental
analysis, and some representative 13C NMR and mass spectra. All the title compounds
were screened for antimicrobial and antitubercular activities, while some representative
compounds were tested for antioxidant activity. Out of synthesized compounds, compounds
1j (4-CH3), 2d (4-F), 4c (4-OH), and 4i (3-Br) exhibited maximum inhibition against
Mycobacterium Tuberculosis H37Rv. Compound 3c (4-OH) revealed elevated efficacy
against all tested bacterial strain, while compounds 1i (3-Br), 2c (4-OH), and 3h
(3-NO2) were found efficacious against Candida albicans as compared to standard drugs.
Received 9 December 2011; accepted 29 April 2012.
The authors are thankful to the Department of Chemistry, V. N. S. G. University, Surat, for laboratory
and some analytical facilities, and Atul Ltd, Valsad, for library and chemical facilities. The authors also thank
Microcare Laboratory, Surat, for antimicrobial and antitubercular activities, and Biogenics, Research & Training
Centre in Biotechnology, Karnataka, for antioxidant activity. The authors are grateful to RTML, Vapi, SAIF,
Chandigarh and CDRI, Lucknow, for analytical facilities.
Address correspondence to Saurabh K. Patel, Department of Chemistry, Veer Narmad South Gujarat Uni-
versity, Surat 395-007, Gujarat, India. E-mail: saurabh@vnsgu.ac.in
561

562
P. T. MISTRY ET AL.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Keywords Thiopyrimidines; pyrimidine dithione; antimicrobial activity; antitubercular activ-
ity; antioxidant activity
INTRODUCTION
According to World Health Organization (WHO), the antimicrobial resistance is a
serious matter that contributes to health and economic losses throughout the world.1 The
current antimicrobial therapy needs crucial attention and continuing research to develop
new class of antimicrobial agents.2 Sulfur-based compounds constitute a major branch
of organic chemistry, among which thiopyrimidine compounds in particular possess sig-
nificant medicinal importance. Thiopyrimidines are privileged heterocycles due to their
synthetic versatility and extensive variety of pharmacological activities such as antimicro-
bial,3–5 radioprotective,6 antiproliferative,7 antiinflammatory,8,9 antitumor,10 antiplatelet,11
anti-lung cancer,12 antispasmodic,13 and molluscicidal activity.14 Thiopyrimidine deriva-
tives exhibited moderate antiviral activity against hepatitis-A virus and herpes simplex
virus type-1.15 Moreover, there has been considerable interest in the chemistry of 4H-pyran,
which are a core structure in various pharmaceuticals as it reveals diverse pharmacological
significance such as antimicrobial,16–18 antitubercular,19,20 anticancer,21 anticonvulsant,22
vasorelaxant,23 antihypertensive,24 antileishmanial,25 and antirheumatic26 activities.
It is expected that the two or more pharmacophores if allied together would create
different molecular templates with remarkable biological properties. Despite the enormous
pharmacological effects of fused pyrazole and thiopyrimidine derivatives, no systematic
study has been so far undertaken to focus the synthesis of a heterocycles incorporating both
of these bioactive scaffold with their biological properties. In view of our recent success on
pyran-based heterocycles with interesting antimicrobial and antituberculosis activities,27–30
we designed and synthesized novel thiopyrimidine derivatives using common sulfur reagent
and evaluated for their in vitro antimicrobial and antituberculosis activities.
RESULT AND DISCUSSION
Chemistry
The key precursors, o-aminonitrile of pyranopyrazole 1(a–j) were prepared by the
reported method of Jin et al. in presence of hexadecyltrimethyl ammonium bromide in
aqueous media.31 Structural elucidation of the synthesized compounds was performed by
IR, 1H NMR, elemental analysis, and some representative 13C NMR and mass spectra. In
IR spectrum of the starting molecules 1(a–j), sharp absorption bands of -NH2 and -C≡N
groups were observed in the region of 3445–3330 cm−1 and 2208–2174 cm−1, respectively.
The C-O-C ether linkage was found at 1145–1070 cm−1. The 1H NMR spectra exhibited
one singlet at 1.90–1.78 δ ppm attributed to the -CH3 protons of fused pyrazole ring. In
1H NMR spectra, common singlet signals appeared in the region of 5.24–4.68 δ ppm and
7.15–6.92 δ ppm corresponds to -CH and -NH2 of pyran ring, and multiplet at 7.80–6.90 δ
ppm corresponds to aromatic protons.
The entire compounds 2(a–j), 3(a–j), and 4(a–j) were synthesized by the reaction of
precursor 1(a–j) with carbon disulphide, phenyl isothiocyanate, and ammonium thiocyanate
under different reaction conditions, respectively.30,32,33 The structure of compounds 2(a–j)

SYNTHESIS OF INNOVATIVE THIOPYRIMIDINES
563
were elucidated by IR spectra which showed 2-NH band in the region of 3417–3398 cm−1
and 3338–3322 cm−1 and 2>C S band at around 1338–1306 cm−1 and 1276–1256 cm−1
with the agreement of two singlets at 8.44–8.41 δ ppm and 8.39–8.35 δ ppm accounted
1
for 2-NH protons in H NMR spectra, respectively. This was further substantiated by
the 13C NMR spectrum of 2c (4-OH), showed a signals at 174.70 and 197.66 δ ppm
due to two >C S of pyrimidine dithione with the agreement of molecular ion peak at
m/z 420 which confirmed its molecular weight by mass spectrum (MS). The structure of
compounds 3(a–j) were elucidated by IR spectra which showed 2-NH band in the region
of 3318–3294 cm−1 and 3217–3194 cm−1 and >C S band at around 1255–1236 cm−1
with the agreement of two singlets at 10.16–10.12 δ ppm and 8.43–8.39 δ ppm accounted
1
for 2-NH protons in H NMR spectra, respectively. This was further substantiated by the
13C NMR spectrum of 3j (4-CH3), showed a signal at 172.51 δ ppm due to >C S of
thiopyrimidine with the agreement of molecular ion peak at m/z 477 which confirmed
its molecular weight by MS. The structure of compounds 4(a–j) were elucidated by IR
spectra which showed -NH2 band in the region of 3375–3354 cm−1 and 3346–3327 cm−1
,
2-NH bands at around 3082–3062 cm−1 and 3204–3190 cm—1, and 2 >C S band at
1358–1336 cm−1 and 1247–1225 cm−1 with the agreement of singlet at around 5.43–5.40
δ ppm accounted for -NH2 protons in 1H NMR spectra. This was further substantiated by
the 13C NMR spectrum of 4d (4-F), showed a signal at 176.31 and 178.54 δ ppm due to
two >C S of thiopyrimidine with the agreement of molecular ion peak at m/z 464 which
1
confirmed its molecular weight by MS. In general, H NMR spectra showed singlet at
around 4.94–4.75 δ ppm which confirme -CH (methine) proton.
Biological Activity
The newly synthesized compounds were tested for their in vitro antibacterial and an-
tifungal activity (minimum inhibitory concentrations (MICs), μg mL−1) by broth dilution
method as described by A. Rattan34 against two Gram-positive bacteria (Staphylococcus
aureus MTCC 96 and Streptococcus pyogenes MTCC 442), two Gram-negative bacteria
(Escherichia coli MTCC 443 and Pseudomonas aeruginosa MTCC 1688), and three fungi
(Candida albicans MTCC 227, Aspergillus niger MTCC 282, and Aspergillus clavatus
MTCC 1323) organisms. Ampicillin and griseofulvin were used as standard drugs for an-
timicrobial activity. For in vitro antitubercular activity, primary screening of the compounds
has been conducted at 62.5 μg mL−1 for Mycobacterium Tuberculosis H37Rv strain using
Lowenstein–Jensen medium method.34 The antitubercular activity data were compared with
that of standard drug rifampicin. Some randomly selected, compounds were screened for
their in vitro antioxidant activity (free radical scavenging activity) at different concentra-
tions (10 μg, 50 μg, and 100 μg) using 1,1-diphenyl-2-picryl hydrazyl method.35 Butylated
hydroxyl anisole (BHA) was used as standard antioxidant agent. The antimicrobial, antitu-
bercular, and antioxidant activity data of the newly synthesized compounds were compared
with standard drugs as well as with corresponding precursors 1(a–j). Additional details are
provided in the online Supplementary Materials (Tables S1 and S2 and Figure S1).
Antibacterial Activity
Among the synthesized compounds, 1c (4 OH, pyran with free amino cyano group),
1i (3-Br), and 1j (4-CH3) exhibited MIC of 100 μg mL−1, 100 μg mL−1, and 150 μg mL−1
for S. aureus as compared to ampicillin 250 μg mL−1 and MIC of these compounds was

564
P. T. MISTRY ET AL.
decreased when converted into 2c (4-OH, pyrimidine dithione), 2i (3-Br), 2j (4-CH3), 3i
(3-Br, pyrimidine thione), 3j (4-CH3), 4c (4-OH, pyrimidine thione with thiourea linkage),
4i (3-Br), and 4j (4-CH3). MIC remains same when compound 1c (4-OH) converted
into 3c (4-OH). The compounds 1i (3-Br, pyran with free amino cyano group) and 3c
(4-OH, pyrimidine thione) demonstrated good MIC with 100 μg mL−1 for S. pyogenes
as compared to ampicillin but compound 1i (3-Br) converted to compounds 2i (3-Br,
pyrimidine dithione), 3i (3-Br, pyrimidine thione), and 4i (3-Br, pyrimidine thione with
thiourea linkage), MIC was slightly decreased. Compound 1c (4-OH) exhibited MIC of
200 μg mL−1 for S. pyogenes when converted to 3c (4-OH, pyrimidine thione), MIC
was significantly improved. The compounds 1j (4-CH3) and 3c (4-OH, pyrimidine thione)
showed maximum MIC with 62.5 μg mL−1 for E. coli as compared to standard drug but
compound 1j (4-CH3) converted to compounds 2j, 3j, and 4j MIC were slightly decreased.
The compounds 1h (3-NO2, pyran with free amino cyano group), 1j (4-CH3, pyran with
free amino cyano group), 2d (4-F, pyrimidine dithione), 3c (4-OH, pyrimidine thione), and
4i (3-Br, pyrimidine thione with thiourea linkage) showed equal MIC of 100 μg mL−1
for P. aeruginosa as compared to standard drug ampicillin but compounds 1h (3-NO2)
and 1j converted to 2h (3-NO2), 2j (4-CH3), 3h (3-NO2), 3j (4-CH3), 4h (3-NO2), and 4j
(4-CH3), MIC of these compound were slightly reduced. In case of P. aeruginosa, MIC of
compounds 1c (4-OH), 1d (4-F), and 1i (3-Br) were found to be equal or enhanced when
converted to 2c (4-OH), 2d (4-F), 2i (3-Br), 3c (4-OH), 3d (4-F), 3i (3-Br), 4d (4-F), and
4i (3-Br), while the remaining compounds showed moderate to poor activity than standard
drugs (Table S1).
Antifungal Activity
The results revealed that compounds 1b (4-OCH3, pyran with free amino cyano
group), 1d (4-F), and 1i (3-Br) demonstrated superior antifungal activity for C. albicans
as compared to greseofulvin. MIC were slightly reduced when converted to 2b (4-OCH3,
pyrimidine dithione), 2d (4-F), 2i (3-Br), 3b (4-OCH3, pyrimidine thione), 3d (4-F), 3i
(3-Br), 4b (4-OCH3, pyrimidine thione with thiourea linkage), 4d (4-F), and 4i (3-Br).
MIC of compounds 1a (-H), 1c (4-OH), 1e (2-Cl), and 1h (3-NO2), were enhanced when
converted to 2c (4-OH), 3e (2-Cl), 3h (3-NO2), and 4a (-H). All the remaining compounds
showed, moderate to poor antifungal activity for all three fungal species compared to that
of standards (Table S1).
Antitubercular Activity
The synthesized compounds were tested against M. Tuberculosis H37Rv. Among the
synthesized compounds, 1j (4-CH3, pyran with free amino cyano group) was revealed
highest inhibition for M. Tuberculosis H37Rv. When compound 1j converted to compounds
2j, 3j, and 4j, activity were slightly decreased. Inhibition activity was improved when
compounds 1b (4-OCH3), 1c (4-OH), and 1i (3-Br) were converted to 2b (pyrimidine
dithione), 2c (4-OH), 2i (3-Br), 3b (4-OCH3, pyrimidine thione), 3c (4-OH), 3i (3-Br), 4b
(4-OCH3, pyrimidine thione with thiourea linkage), 4c (4-OH), and 4i (3-Br), while all the
remaining compounds revealed, moderate to poor efficacy.

SYNTHESIS OF INNOVATIVE THIOPYRIMIDINES
565
Antioxidant Activity
One of the compound, 2g (4-Cl) revealed good antioxidant activity of 42.06% and
68.25% at 50 μg and 100 μg concentrations as compared to standard BHA (39.80%
and 59.16%), respectively, while the compound 4g (4-Cl) was found to be inactive at all
concentrations. Pyrimidine dithione nucleus showed comparatively better activity than the
thiopyrimidine derivative (Table S2).
CONCLUSION
Thiopyrimidines have been successfully synthesized and evaluated for their antimi-
crobial and antitubercular activities, while some representative compounds have been tested
for antioxidant activity. It is obvious from the biological screening result that the several
thiopyrimidines were interestingly found to be active compared to their corresponding
precursors. Among the synthesized compounds, compound 3c (4-OH) revealed elevated
efficacy against all tested bacterial strain, while compounds 1i (3-Br), 2c (4-OH), and 3h
(3-NO2) were found efficacious against C. albicans as compared to standard drugs. Anti-
tubercular activity of compounds 1j (4-CH3), 2d (4-F), 4c (4-OH), and 4i (3-Br) exhibited
remarkable inhibition against M. Tuberculosis H37Rv compared to that of rifampicin. Al-
though a generalization could not be made, the screened compound 2g (4-Cl) showed very
good antioxidant property. From the present study, it is concluded that the introduction of
thione (>C S) group in pyrimidine nucleus play vital role in enhancing the antimicrobial
activity. Some of the synthesized compounds may be helpful for the development of novel
alternative thearapeutic agents and open the possibility of finding new clinically effective
rich source of bioactive candidates.
EXPERIMENTAL
Melting points were taken in open capillary tubes and are uncorrected. The progress
of the reactions were monitored by thin layer chromatography using silica gel as adsorbent
[Mobile phase: toluene:ethyl acetate (7.5:2.5)] and visualization was accomplished by Ultra
violet light or iodine vapor. IR spectra were recorded on Thermo Scientific Nicolec iS 10 and
Shimadzu spectrophotometer using KBr pallets. The 1H NMR and representative 13C NMR
spectra were recorded on a Bruker Avance II 400 spectrometer using tetramethylsilane as
the internal standard in CDCl3 or dimethyl sulfoxide as solvent. Elemental analysis was
carried out on Carlo Erba 1108 analyzer. Mass spectra of some representative compounds
were recorded on Waters Q-Tof Micro (TOF MS ES+) mass spectrometer.
General Preparation of 3-Methyl-4-(substituted phenyl)-1-phenyl-4,8-
dihydropyrazolo[4’,3’:5,6]pyrano[2,3-d]pyrimidine-5,7(1H,6H)-dithione
2(a–j)
A mixture of 6-amino-4-(substituted phenyl)-5-cyano-3-methyl-1-phenyl-1,4-
dihydropyrano[2,3-c]pyrazole 1(a–j) (2.0 mmol) and carbon disulphide (3.0 mmol) in
pyridine (10 mL) was refluxed for 7–8 h. After completion of reaction, the reaction
mixture was left to cool to room temperature, poured into crushed ice, and neutralized with
dilute hydrochloric acid (1:1). The crude product was separated by filtration, washed with

566
P. T. MISTRY ET AL.
water, dried, and recrystallized from methanol to give 3-methyl-4-(substituted phenyl)-
1-phenyl-4,8-dihydropyrazolo[4ꢁ,3ꢁ:5,6]pyrano[2,3-d]pyrimidine-5,7(1H,6H)-dithione
2(a–j).
3-Methyl-1,4-diphenyl-4,8-dihydropyrazolo[4’,3’:5,6]pyrano[2,3-d]-pyrim
idine-5,7(1H,6H) dithione (2a). Reddish yellow; 59%; mp: 207 ◦C–209 ◦C;
(methanol) IR (KBr) υ (cm−1): 3417, 3322 (2-NH), 3078, 2969, 2852 (C-H str.), 1320,
1266 (2>C S), 1167, 1047 (C-O-C); 1H NMR (400 MHz, CDCl3) δ (ppm): 8.43 (s, 1H,
-NH), 8.37 (s, 1H, -NH), 7.93–6.96 (m, 10H, Ar-H), 4.82 (s, 1H, -CH), 2.24 (s, 3H, -CH3);
Anal. Calcd for C21H16N4OS2: C 62.35, H 3.99, N 13.85; Found: C 62.31, H 4.03, N
13.88.
3-Methyl-4-(4-methoxyphenyl)-1-phenyl-4,8-dihydropyrazolo[4’,3’:5,6]-
pyrano[2,3-◦d]pyrimidine-5,7(1H,6H)-dithione (2b). Turmeric yellow; 66%; mp:
◦
252 C–255 C; (methanol) IR (KBr) υ (cm−1): 3410, 3330 (2-NH), 3085, 2962, 2845
1
(C-H str.), 1315, 1262 (2>C S), 1180, 1035 (C-O-C); H NMR (400 MHz, CDCl3) δ
(ppm): 8.43 (s, 1H, -NH), 8.35 (s, 1H, -NH), 7.91–6.98 (m, 9H, Ar-H), 4.77 (s, 1H, -CH),
3.69 (s, 3H, -OCH3), 2.20 (s, 3H, -CH3); Anal. Calcd for C22H18N4O2S2: C, 60.81; H,
4.18; N, 12.89. Found: C, 60.85; H, 4.20; N, 12.84.
3-Methyl-4-(4-hydroxyphenyl)-1-phenyl-4,8-dihydropyrazolo[4’,3’:5,6]-py
rano[2,3-d]pyrimidine-5,7(1H,6H)-dithione (2c). Turmeric yellow; 53%; mp:
◦
>280 C; (methanol) IR (KBr) υ (cm−1): 3398, 3335 (2-NH), 3266 (-OH), 3076, 2968,
2838 (C-H str.), 1322, 1276 (2>C S), 1187, 1024 (C-O-C); 1H NMR (400 MHz, CDCl3)
δ (ppm): 8.43 (s, 1H, -NH), 8.35 (s, 1H, -NH), 7.92–6.97 (m, 9H, Ar-H), 5.21 (s, 1H,
-OH), 4.78 (s, 1H, -CH), 2.23 (s, 3H, -CH3); 13C NMR (400 MHz, CDCl3) δ (ppm): 15.2
(CH3), 37.0 (CH), 100.9 (C), 111.1 (C), 118.2 (CH), 121.8 (CH), 124.8 (CH), 128.4 (CH),
129.4 (CH), 138.0 (C), 142.3 (C), 143.6 (C), 151.5 (C-CH3), 154.1 (C-OH), 166.5 (C),
174.7, 197.7 (2>C S); MS (m/z): 420 (M+); Anal. Calcd for C21H16N4O2S2: C, 59.98;
H, 3.84; N, 13.32; Found: C, 59.97; H, 3.86; N, 13.33.
3-Methyl-1–4-(4-fluorophenyl)-phenyl-4,8-dihydropyrazolo[4’,3’:5,6]-pyr
ano[2,3-d]pyrimidine-5,7(1H,6H)-dithione (2d). Greenish yellow; 61%; mp:
◦
◦
269 C–273 C; (methanol) IR (KBr) υ (cm−1): 3412, 3334 (2-NH), 3080, 2956, 2852
1
(C-H str.), 1321, 1265 (2>C S), 1185, 1042 (C-O-C), 752 (C-F); H NMR (400 MHz,
CDCl3) δ (ppm): 8.44 (s, 1H, -NH), 8.37 (s, 1H, -NH), 7.90–7.05 (m, 9H, Ar-H), 4.77
(s, 1H, -CH), 2.23 (s, 3H, -CH3); Anal. Calcd for C21H15N4OFS2: C, 59.70; H, 3.58; N,
13.26; Found: C, 59.72; H, 3.54; N, 13.25.
3-Methyl-4-(2-chlorophenyl)-1-phenyl-4,8-dihydropyrazolo[4’,3’:5,6]-pyr
ano[2,3-d]pyrimidine-5,7(1H,6H)-dithione (2e). Turmeric yellow; 55%; mp:
◦
◦
239 C–242 C; (methanol) IR (KBr) υ (cm−1): 3402, 3324 (2-NH), 3076, 2968, 2856
1
(C-H str.), 1330, 1256 (2>C S), 1196, 1045 (C-O-C), 756 (C-Cl); H NMR (400 MHz,
CDCl3) δ (ppm): 8.43 (s, 1H, -NH), 8.38 (s, 1H, -NH), 7.92–7.04 (m, 9H, Ar-H), 4.79
(s, 1H, -CH), 2.21 (s, 3H, -CH3); Anal. Calcd for C21H15N4OClS2: C, 57.46; H, 3.44; N,
12.76; Found: C, 57.42; H, 3.48; N, 12.75.
3-Methyl-4-(3-chlorophenyl)-1-phenyl-4,8-dihydropyrazolo[4’,3’:5,6]-pyr
ano[2,3-d]pyrimidine-5,7(1H,6H)-dithione (2f). Light brown; 62%; mp:
260 ◦C–264 ◦C; (methanol) IR (KBr) υ (cm−1): 3416, 3332 (2-NH), 3080, 2962,
1
2854 (C-H str.), 1338, 1260 (2>C S), 1186, 1035 (C-O-C), 752 (C-Cl); H NMR
(400 MHz, CDCl3) δ (ppm): 8.42 (s, 1H, -NH), 8.35 (s, 1H, -NH), 7.90–7.00 (m, 9H,
Ar-H), 4.75 (s, 1H, -CH), 2.19 (s, 3H, -CH3); Anal. Calcd for C21H15N4OClS2: C, 57.46;
H, 3.44; N, 12.76; Found: C, 57.43; H, 3.49; N, 12.78.

SYNTHESIS OF INNOVATIVE THIOPYRIMIDINES
567
3-Methyl-4-(4-chlorophenyl)-1-phenyl-4,8-dihydropyrazolo[4’,3’:5,6]-pyr
ano[2,3-d]pyrimidine-5,7(1H,6H)-dithione (2g). Turmeric yellow; 65%; mp:
◦
◦
249 C–251 C; (methanol) IR (KBr) υ (cm−1): 3414, 3338 (2-NH), 3094, 2954, 2842
1
(C-H str.), 1306, 1267 (2>C S), 1177, 1028 (C-O-C), 755 (C-Cl); H NMR (400 MHz,
CDCl3) δ (ppm): 8.43 (s, 1H, -NH), 8.36 (s, 1H, -NH), 7.95–6.98 (m, 9H, Ar-H), 4.77
(s, 1H, -CH), 2.23 (s, 3H, -CH3); Anal. Calcd for C21H15N4OClS2: C, 57.46; H, 3.44; N,
12.76; Found: C, 57.41; H, 3.47; N, 12.77.
3-Methyl-4-(3-nitrophenyl)-1-phenyl-4,8-dihydropyrazolo[4’,3’:5,6]-pyra
no[2,3-d]pyrimidine-5,7(1H,6H)-dithione (2h). Dark brown; 53%; mp:
273 ◦C–277 ◦C; (methanol) IR (KBr) υ (cm−1): 3398, 3322 (2-NH), 3076, 2968,
2840 (C-H str.), 1540, 1363 (-NO2 asym, sym), 1327, 1258 (2>C S), 1188, 1034
1
(C-O-C); H NMR (400 MHz, CDCl3) δ (ppm): 8.41 (s, 1H, -NH), 8.35 (s, 1H, -NH),
7.92–6.97 (m, 9H, Ar-H), 4.78 (s, 1H, -CH), 2.21 (s, 3H, -CH3); Anal. Calcd for
C21H15N5O3S2: C, 56.11; H, 3.36; N, 15.58; Found: C, 56.15; H, 3.364; N, 15.57.
3-Methyl-4-(3-bromophenyl)-1-phenyl-4,8-dihydropyrazolo[4’,3’:5,6]-pyr
ano[2,3-d]pyrimidine-5,7(1H,6H)-dithione (2i). Orange; 58%; mp: >280 ◦C;
(methanol) IR (KBr) υ (cm−1): 3408, 3335 (2-NH), 3086, 2959, 2852 (C-H str.), 1315,
1266 (2>C S), 1181, 1035 (C-O-C), 755 (C-Br); 1H NMR (400 MHz, CDCl3) δ (ppm):
8.43 (s, 1H, -NH), 8.35 (s, 1H, -NH), 7.95–7.06 (m, 9H, Ar-H), 4.78 (s, 1H, -CH), 2.23
(s, 3H, -CH3); Anal. Calcd for C21H15N4OBrS2: C, 52.18; H, 3.13; N, 11.59; Found: C,
52.15; H, 3.14; N, 11.57.
3-Methyl-4-(4-methylphenyl)-1-phenyl-4,8-dihydropyrazolo[4’,3’:5,6]-py
rano[2,3-d]pyrimidine-5,7(1H,6H)-dithione (2j). Dark yellow; 54%; mp:
254 ◦C–258 ◦C; (methanol) IR (KBr) υ (cm−1): 3416, 3329 (2-NH), 3090, 2963,
2847 (C-H str.), 1309, 1265 (2>C S), 1177, 1045 (C-O-C); 1H NMR (400 MHz, CDCl3)
δ (ppm): 8.41 (s, 1H, -NH), 8.39 (s, 1H, -NH), 7.94–6.97 (m, 9H, Ar-H), 4.76 (s, 1H, -CH),
2.21 (s, 3H, -CH3), 2.00 (s, 3H, -CH3); Anal. Calcd for C22H18N4OS2: C, 63.13; H, 4.33;
N, 13.39; Found: C, 63.15; H, 4.35; N, 13.41.
General Preparation of 4-(4-Substituted phenyl)-5-imino-3-methyl-
1,6-diphenyl-4,5,6,8-tetrahydropyrazolo[4’,3’:5,6]pyrano[2,3-d]
pyrimidine-7(1H)-thione 3(a–j)
A mixture of 6-amino-4-(substituted phenyl)-5-cyano-3-methyl-1-phenyl-1,4-
dihydropyrano[2,3-c]pyrazole 1(a–j) (2.0 mmol) and phenyl isothiocyanate (2.0 mmol) in
pyridine (10 mL) was refluxed for 14–16 h. After completion of reaction, the reaction mix-
ture was left to cool to room temperature, poured into crushed ice and neutralized with dilute
hydrochloric acid (1:1). The crude product was separated by filtration, washed with water,
dried, and recrystallized from ethanol to give 4-(4-substituted phenyl)-5-imino-3-methyl-
1,6-diphenyl-4,5,6,8-tetrahydropyrazolo[4’,3’:5,6]pyrano[2,3-d]pyrimidine-7(1H)-thione
3(a-j).
5-Imino-3-Methyl-1,4,6-triphenyl-4,5,6,8-tetrahydropyrazolo[4’,3’:5,6]-py
rano[2,3-d]pyrimidine-7(1H)-thione (3a). Beige; 66%; mp: 227 ◦C–230 ◦C;
(ethanol) IR (KBr) υ (cm−1): 3310, 3205 (2-NH), 3070, 2995, 2935 (C-H str.), 1655
(-C N), 1245 (>C S), 1155, 1062 (C-O-C); 1H NMR (400 MHz, CDCl3) δ (ppm): 10.14
(s, 1H, -NH), 8.41 (s, 1H, -NH), 7.77–7.15 (m, 15H, Ar-H), 4.90 (s, 1H, -CH), 2.36 (s, 3H,
-CH3); Anal. Calcd for C27H21N5OS: C 69.96, H 4.57, N 15.11; Found: C 69.99, H 4.55,
N 15.07.

568
P. T. MISTRY ET AL.
4-(4-Methoxyphenyl)-5-imino-3-methyl-1,6-diphenyl-4,5,6,8-tetrahydro-
pyrazolo[4’,3’:5,6]pyrano[2,3-d]pyrimidine-7(1H)-thione (3b). Light yellow;
51%; mp: 241 ◦C–244 ◦C; (ethanol) IR (KBr) υ (cm−1): 3318, 3196 (2-NH), 3061, 3008,
2922 (C-H str.), 1666 (-C N), 1236 (>C S), 1222, 1029 (-OCH3), 1167, 1051 (C-O-C);
1H NMR (400 MHz, CDCl3) δ (ppm): 10.12 (s, 1H, -NH), 8.42 (s, 1H, -NH), 7.75–7.19
(m, 14H, Ar-H), 4.88 (s, 1H, -CH), 3.67 (s, 3H, -OCH3), 2.37 (s, 3H, -CH3); Anal. Calcd
for C28H23N5O2S: C 68.13, H 4.70, N 14.19; Found: C 68.09, H 4.66, N 14.23.
4-(4-Hydroxyphenyl)-5-imino-3-methyl-1,6-diphenyl-4,5,6,8-tetrahydro-
pyrazolo[4’,3’:5,6]pyrano[2,3-d]pyrimidine-7(1H)-thione (3c). Dark brown; 69%;
◦
mp: >280 C; (ethanol) IR (KBr) υ (cm−1): 3302, 3217 (2-NH), 3221 (-OH), 3079,
1
2988, 2941 (C-H str.), 1648 (-C N), 1253 (>C S), 1146, 1067 (C-O-C); H NMR
(400 MHz, CDCl3) δ (ppm): 10.15 (s, 1H, -NH), 8.40 (s, 1H, -NH), 7.76–7.13 (m, 14H,
Ar-H), 5.25 (s, 1H, -OH), 4.91 (s, 1H, -CH), 2.34 (s, 3H, -CH3); 13C NMR (400MHz,
CDCl3) δ (ppm): 15.3 (CH3), 36.2 (CH), 92.0 (C), 98.4 (C), 117.1 (CH), 122.5 (CH),
123.8 (CH), 126.1 (CH), 127.3 (CH), 128.8 (CH), 129.6 (CH), 139.0 (C), 140.8 (C), 143.4
(C), 147.7 (C-CH3), 148.9 (C), 151.9 (C), 155.0 (C-OH), 172.2 (>C S); Anal. Calcd for
C27H21N5O2S: C, 67.62; H, 4.41; N, 14.60; Found: C, 67.64; H, 4.43; N, 14.64.
4-(4-Fluorophenyl)-5-imino-3-methyl-1,6-diphenyl-4,5,6,8-tetrahydro-py
razolo[4’,3’:5,6]pyrano[2,3-d]pyrimidine-7(1H)-thione (3d). Cream; 71%; mp:
218 ◦C–220 ◦C; (ethanol) IR (KBr) υ (cm−1): 3312, 3211 (2-NH), 3064, 2998, 2934 (C-H
str.), 1659 (-C N), 1240 (>C S), 1154, 1057 (C-O-C), 746 (C-F); 1H NMR (400 MHz,
CDCl3) δ (ppm): 10.14 (s, 1H, -NH), 8.42 (s, 1H, -NH), 7.71–7.20 (m, 14H, Ar-H), 4.94
(s, 1H, -CH), 2.33 (s, 3H, -CH3); Anal. Calcd for C27H20N5OFS: C, 67.34; H, 4.19; N,
14.54; Found: C, 67.38; H, 4.22; N, 14.58.
4-(2-Chlorophenyl)-5-imino-3-methyl-1,6-diphenyl-4,5,6,8-tetrahydro-py
razolo[4’,3’:5,6]pyrano[2,3-d]pyrimidine-7(1H)-thione (3e). Light brown; 54%;
mp: 159 ◦C–162 ◦C; (ethanol) IR (KBr) υ (cm−1): 3299, 3214 (2-NH), 3070, 2990, 2930
1
(C-H str.), 1651 (-C N), 1250 (>C S), 1159, 1061 (C-O-C), 757 (C-Cl); H NMR
(400 MHz, CDCl3) δ (ppm): 10.16 (s, 1H, -NH), 8.40 (s, 1H, -NH), 7.75–7.19 (m, 14H,
Ar-H), 4.91 (s, 1H, -CH), 2.35 (s, 3H, -CH3); Anal. Calcd for C27H20N5OClS: C, 65.12;
H, 4.05; N, 14.06; Found: C, 65.10; H, 4.02; N, 14.03.
4-(3-Chlorophenyl)-5-imino-3-methyl-1,6-diphenyl-4,5,6,8-tetrahydro-py
razolo[4’,3’:5,6]pyrano[2,3-d]pyrimidine-7(1H)-thione (3f). Light brown; 64%;
mp: 207 ◦C–210 ◦C; (ethanol) IR (KBr) υ (cm−1): 3318, 3202 (2-NH), 3080, 3010, 2927
1
(C-H str.), 1656 (-C N), 1244 (>C S), 1148, 1072 (C-O-C), 751 (C-Cl); H NMR
(400 MHz, CDCl3) δ (ppm): 10.13 (s, 1H, -NH), 8.42 (s, 1H, -NH), 7.78–7.16 (m, 14H,
Ar-H), 4.89 (s, 1H, -CH), 2.35 (s, 3H, -CH3); Anal. Calcd for C27H20N5OClS: C, 65.12;
H, 4.05; N, 14.06; Found: C, 65.10; H, 4.07; N, 14.03.
4-(4-Chlorophenyl)-5-imino-3-methyl-1,6-diphenyl-4,5,6,8-tetrahydro-py
razolo[4’,3’:5,6]pyrano[2,3-d]pyrimidine-7(1H)-thione (3g). Beige; 57%; mp:
234 ◦C–237 ◦C; (ethanol) IR (KBr) υ (cm−1): 3305, 3194 (2-NH), 3067, 2989, 2944 (C-H
str.), 1661 (-C N), 1239 (>C S), 1151, 1058 (C-O-C), 756 (C-Cl); 1H NMR (400 MHz,
CDCl3) δ (ppm): 10.15 (s, 1H, -NH), 8.43 (s, 1H, -NH), 7.77–7.11 (m, 14H, Ar-H), 4.91
(s, 1H, -CH), 2.34 (s, 3H, -CH3); Anal. Calcd for C27H20N5OClS: C, 65.12; H, 4.05; N,
14.06; Found: C, 65.15; H, 4.03; N, 14.08.
4-(3-Nitrophenyl)-5-imino-3-methyl-1,6-diphenyl-4,5,6,8-tetrahydro-pyr
azolo[4’,3’:5,6]◦pyrano[2,3-d]pyrimidine-7(1H)-thione (3h). Turmeric yellow;
◦
53%; mp: 209 C–213 C; (ethanol) IR (KBr) υ (cm−1): 3294, 3212 (2-NH), 3070,

SYNTHESIS OF INNOVATIVE THIOPYRIMIDINES
569
2996, 2930 (C-H str.), 1648 (-C N), 1552, 1350 (-NO2 asym, sym), 1255 (>C S),
1160, 1062 (C-O-C); 1H NMR (400 MHz, CDCl3) δ (ppm): 10.13 (s, 1H, -NH),
8.39 (s, 1H, -NH), 7.79–7.16 (m, 14H, Ar-H), 4.92 (s, 1H, -CH), 2.35 (s, 3H, -CH3);
Anal. Calcd for C27H20N6O3S: C, 63.77; H, 3.96; N, 16.53; Found: C, 63.79; H, 3.93;
N, 16.55.
4-(3-Bromophenyl)-5-imino-3-methyl-1,6-diphenyl-4,5,6,8-tetrahydro-py
razolo[4’,3’:5,6]pyrano[2,3-d]pyrimidine-7(1H)-thione (3i). Black; 61%; mp:
>280 ◦C; (ethanol) IR (KBr) υ (cm−1): 3318, 3209 (2-NH), 3082, 3008, 2942 (C-H str.),
1
1654 (-C N), 1236 (>C S), 1154, 1068 (C-O-C), 748 (C-Br); H NMR (400 MHz,
CDCl3) δ (ppm): 10.14 (s, 1H, -NH), 8.40 (s, 1H, -NH), 7.75–7.18 (m, 14H, Ar-H), 4.90
(s, 1H, -CH), 2.35 (s, 3H, -CH3); Anal. Calcd for C27H20N5OBrS: C, 59.78; H, 3.72; N,
12.91; Found: C, 59.75; H, 3.70; N, 12.95.
4-(4-Methylphenyl)-5-imino-3-methyl-1,6-diphenyl-4,5,6,8-tetrahydro-py
razolo[4’,3’:5,6]pyrano[2,3-d]pyrimidine-7(1H)-thione (3j). Cream; 74%; mp:
259 ◦C–262 ◦C; (ethanol) IR (KBr) υ (cm−1): 3309, 3217 (2-NH), 3065, 2990, 2928 (C-H
1
str.), 1662 (-C N), 1248 (>C S), 1164, 1055 (C-O-C); H NMR (400 MHz, CDCl3) δ
(ppm): 10.13 (s, 1H, -NH), 8.39 (s, 1H, -NH), 7.76–7.15 (m, 14H, Ar-H), 4.92 (s, 1H,
-CH), 2.37 (s, 3H, -CH3), 1.96 (s, 3H, -CH3); 13C NMR (400 MHz, CDCl3) δ (ppm): 15.2
(CH3), 23.1 (CH3), 37.0 (CH), 93.0 (C), 98.3 (C), 122.2 (CH), 123.9 (CH), 125.9 (CH),
127.6 (CH), 128.3 (CH), 129.2 (CH), 130.7 (CH), 136.2 (C-CH3), 139.5 (C), 142.5 (C),
143.8 (C), 145.1 (C), 148.4 (C-CH3), 149.4 (C), 152.3 (C), 172.5 (>C S); MS (m/z): 477
(M+); Anal. Calcd for C28H23N5OS: C, 70.42; H, 4.85; N, 14.66; Found: C, 70.39; H,
4.87; N, 14.68.
General Preparation of N-[4-(Substituted phenyl)-3-methyl-1-phenyl-7-
thioxo-1,4,7,8-hexahydropyrazolo[4’,3’:5,6]pyrano[2,3-d] pyrimidine-5-yl]thi-
ourea 4(a–j)
A mixture of 6-amino-4-(substituted phenyl)-5-cyano-3-methyl-1-phenyl-1,4-
dihydropyrano[2,3-c]pyrazole 1(a–j) (2.0 mmol) and ammonium thiocyanate (4.0 mmol)
in dimethyl formamide (10 mL) was refluxed for 10–11 h. After completion of reaction,
the reaction mixture was left to cool to room temperature and poured into crushed ice.
The crude product was separated by filtration, washed with water, dried, and recrystallized
from ethanol to give N-[4-(substituted phenyl)-3-methyl-1-phenyl-7-thioxo-1,4,7,8-
hexahydropyrazolo[4’,3’:5,6]pyrano[2,3-d]pyrimidine-5-yl]thiourea 4(a–j).
N-(3-Methyl-1,4-diphenyl-7-thioxo-1,4,7,8-tetrahydropyrazolo[4’,3’:5,6]-
pyrano[2,3-d]pyrimidine-5-yl)thiourea (4a). Light brown; 46%; mp: >280 ◦C;
(ethanol) IR (KBr) υ (cm−1): 3365, 3335 (-NH2), 3062 (2-NH), 2935, 2880 (C-H str.),
1
1651 (-C N), 1348, 1238 (2>C S), 1141, 1062 (C-O-C); H NMR (400 MHz, CDCl3)
δ (ppm): 9.89 (s, 2H, 2-NH), 7.82–7.15 (m, 10H, Ar-H), 5.43 (s, 2H, -NH2), 4.91 (s, 1H,
-CH), 2.35 (s, 3H, -CH3); Anal. Calcd for C22H18N6OS2: C 59.17, H 4.06, N 18.82; Found:
C 59.20, H 4.10, N 18.79.
N-[4-(4-Methoxyphenyl)-3-methyl-1-phenyl-7-thioxo-1,4,7,8-tetrahydro-
pyrazolo[4’,◦3’:5,6]pyrano[2,3-d]pyrimidine-5-yl]thiourea (4b). Beige; 53%; mp:
◦
262 C–266 C; (ethanol) IR (KBr) υ (cm−1): 3354, 3338 (-NH2), 3082, 3195 (2-NH),
2944, 2872 (C-H str.), 1658 (-C N), 1336, 1225 (2>C S), 1230, 1038 (-OCH3), 1152,
1055 (C-O-C); 1H NMR (400 MHz, CDCl3) δ (ppm): 9.91 (s, 2H, 2-NH), 7.80–7.19 (m,
9H, Ar-H), 5.43 (s, 2H, -NH2), 4.92 (s, 1H, -CH), 3.62 (s, 3H, -OCH3), 2.35 (s, 3H, -CH3);

570
P. T. MISTRY ET AL.
Anal. Calcd for C23H20N6O2S2: C 57.97, H 4.23, N 17.63; Found: C 58.02, H 4.25, N
17.60.
N-[4-(4-Hydroxyphenyl)-3-methyl-1-phenyl-7-thioxo-1,4,7,8-tetrahydro-
pyrazolo[4’,3’:5,6]pyrano[2,3-d]pyrimidine-5-yl]thiourea (4c). Reddish brown;
57%; mp: >280 ◦C; (ethanol) IR (KBr) υ (cm−1): 3359, 3342 (-NH2), 3235 (-OH), 3076,
3190, (2-NH), 2932, 2884 (C-H str.), 1650 (-C N), 1352, 1240 (2>C S), 1145, 1066
1
(C-O-C); H NMR (400 MHz, CDCl3) δ (ppm): 9.90 (s, 2H, 2-NH), 7.78–7.16 (m, 9H,
Ar-H), 5.40 (s, 2H, -NH2), 5.22 (s, 1H, -OH), 4.89 (s, 1H, -CH), 2.38 (s, 3H, -CH3); 13
C
NMR (400 MHz, CDCl3) δ (ppm): 15.4 (CH3), 37.1 (CH), 92.0 (C), 98.4 (C), 116.3 (CH),
122.1 (CH), 123.7 (CH), 128.6 (CH), 129.4 (CH), 139.3 (C), 142.1 (C), 143.9 (C), 148.1
(C-CH3), 152.0 (C), 155.1 (C-OH), 157.1 (C-NHCSNH2), 176.4, 179.0 (2>C S); Anal.
Calcd for C22H18N6O2S2: C, 57.13; H, 3.92; N, 18.17; Found: C, 57.15; H, 3.96; N, 18.15.
N-[4-(4-Fluorophenyl)-3-methyl-1-phenyl-7-thioxo-1,4,7,8-tetrahydro-py
razolo[4’,3’:5,6]pyrano[2,3-d]pyrimidine-5-yl]thiourea (4d). Cream; 51%; mp:
◦
◦
271 C–274 C; (ethanol) IR (KBr) υ (cm−1): 3368, 3332 (-NH2), 3072, 3204 (2-NH),
2930, 2878 (C-H str.), 1648 (-C N), 1344, 1232 (2>C S), 1138, 1059 (C-O-C), 752
(C-F); 1H NMR (400 MHz, CDCl3) δ (ppm): 9.92 (s, 2H, 2-NH), 7.85–7.20 (m, 9H, Ar-H),
5.40 (s, 2H, -NH2), 4.93 (s, 1H, -CH), 2.37 (s, 3H, -CH3); 13C NMR (400 MHz, CDCl3) δ
(ppm): 15.5 (CH3), 37.1 (CH), 92.1 (C), 98.5 (C), 117.0 (CH), 122.5 (CH), 125.6 (CH),
128.6 (CH), 129.3 (CH), 139.2 (C), 143.5 (C), 144.7 (C), 148.2 (C-CH3), 152.1 (C), 156.8
(C-NHCSNH2), 158.9 (C-F), 176.3, 178.5 (2>C S); MS (m/z): 464 (M+); Anal. Calcd
for C22H17N6OFS2: C, 56.88; H, 3.69; N, 18.09; Found: C, 56.85; H, 3.67; N, 18.12.
N-[4-(2-Chlorophenyl)-3-methyl-1-phenyl-7-thioxo-1,4,7,8-tetrahydro-py
razolo[4’,3’:5,6]pyrano[2,3-d]pyrimidine-5-yl]thiourea (4e). Greenish white;
49%; mp: >280 ◦C; (ethanol) IR (KBr) υ (cm−1): 3358, 3346 (-NH2), 3080, 3196
(2-NH), 2941, 2886 (C-H str.), 1656 (-C N), 1358, 1244 (2>C S), 1150, 1072 (C-O-C),
1
754 (C-Cl); H NMR (400 MHz, CDCl3) δ (ppm): 9.91 (s, 2H, 2-NH), 7.77–7.14 (m,
9H, Ar-H), 5.43 (s, 2H, -NH2), 4.89 (s, 1H, -CH), 2.37 (s, 3H, -CH3); Anal. Calcd for
C22H17N6OClS2: C, 54.94; H, 3.56; N, 17.47; Found: C, 54.98; H, 3.61; N, 17.51.
N-[4-(3-Chlorophenyl)-3-methyl-1-phenyl-7-thioxo-1,4,7,8-tetrahydro-py
razolo[4’,3’:5,6]pyrano[2,3-d]pyrimidine-5-yl]thiourea (4f). Light brown; 55%;
mp: >280 ◦C; (ethanol) IR (KBr) υ (cm−1): 3365, 3342 (-NH2), 3069, 3192 (2-NH), 2934,
2878 (C-H str.), 1651 (-C N), 1350, 1237 (2>C S), 1135, 1064 (C-O-C), 758 (C-Cl);
1H NMR (400 MHz, CDCl3) δ (ppm): 9.92 (s, 2H, 2-NH), 7.82–7.15 (m, 9H, Ar-H), 5.40
(s, 2H, -NH2), 4.91 (s, 1H, -CH), 2.37 (s, 3H, -CH3); Anal. Calcd for C22H17N6OClS2: C,
54.94; H, 3.56; N, 17.47; Found: C, 54.98; H, 3.59; N, 17.50.
N-[4-(4-Chlorophenyl)-3-methyl-1-phenyl-7-thioxo-1,4,7,8-tetrahydro-py
razolo[4’,3’:5,6]pyrano[2,3-d]pyrimidine-5-yl]thiourea (4g). Dark brown; 64%;
mp: 258 ◦C–261 ◦C; (ethanol) IR (KBr) υ (cm−1): 3372, 3330 (-NH2), 3074, 3192
(2-NH), 2929, 2884 (C-H str.), 1646 (-C N), 1345, 1231 (2>C S), 1148, 1058 (C-O-C),
1
752 (C-Cl); H NMR (400 MHz, CDCl3) δ (ppm): 9.91 (s, 2H, 2-NH), 7.80–7.17 (m,
9H, Ar-H), 5.42 (s, 2H, -NH2), 4.91 (s, 1H, -CH), 2.37 (s, 3H, -CH3); Anal. Calcd for
C22H17N6OClS2: C, 54.94; H, 3.56; N, 17.47; Found: C, 54.99; H, 3.60; N, 17.50.
N-[4-(3-Nitrophenyl)-3-methyl-1-phenyl-7-thioxo-1,4,7,8-tetrahydro-pyr
azolo[4’,3’:5,6]pyrano[2,3-d]pyrimidine-5-yl]thiourea (4h). Black; 59%; mp:
◦
>280 C; (ethanol) IR (KBr) υ (cm−1): 3360, 3336 (-NH2), 3062, 3198 (2-NH), 2940,
2876 (C-H str.), 1658 (-C N), 1545, 1357 (-NO2 asym, sym), 1343, 1247 (2>C S),
1140, 1067 (C-O-C); 1H NMR (400 MHz, CDCl3) δ (ppm): 9.92 (s, 2H, 2-NH), 7.72–7.21

SYNTHESIS OF INNOVATIVE THIOPYRIMIDINES
571
(m, 9H, Ar-H), 5.41 (s, 2H, -NH2), 4.93 (s, 1H, -CH), 2.36 (s, 3H, -CH3); Anal. Calcd for
C22H17N7O3S2: C, 53.76; H, 3.49; N, 19.95; Found: C, 53.78; H, 3.47; N, 19.98.
N-[4-(3-bromophenyl)-3-methyl-1-phenyl-7-thioxo-1,4,7,8-tetrahydro-py
razolo[4’,3’:5,6]pyrano[2,3-d]pyrimidine-5-yl]thiourea (4i). Black; 53%; mp:
◦
>280 C; (ethanol) IR (KBr) υ (cm−1): 3375, 3342 (-NH2), 3069, 3204 (2-NH), 2931,
2886 (C-H str.), 1650 (-C N), 1353, 1236 (2>C S), 1129, 1050 (C-O-C), 753 (C-Br);
1H NMR (400 MHz, CDCl3) δ (ppm): 9.89 (s, 2H, 2-NH), 7.83–7.14 (m, 9H, Ar-H), 5.42
(s, 2H, -NH2), 4.93 (s, 1H, -CH), 2.37 (s, 3H, -CH3); Anal. Calcd for C22H17N6OBrS2: C,
50.29; H, 3.26; N, 15.99; Found: C, 50.25; H, 3.29; N, 15.95.
N-[4-(4-Methylphenyl)-3-methyl-1-phenyl-7-thioxo-1,4,7,8-tetrahydro-py
razolo[4’,3’:5,6]pyrano[2,3-d]pyrimidine-5-yl]thiourea (4j). Gray; 61%; mp:
◦
◦
266 C–270 C; (ethanol) IR (KBr) υ (cm−1): 3366, 3327 (-NH2), 3077, 3191 (2-NH),
1
2927, 2879 (C-H str.), 1643 (-C N), 1347, 1229 (2>C S), 1145, 1079 (C-O-C); H
NMR (400 MHz, CDCl3) δ (ppm): 9.91 (s, 2H, 2-NH), 7.76–7.15 (m, 9H, Ar-H), 5.40 (s,
2H, -NH2), 4.92 (s, 1H, -CH), 2.36 (s, 3H, -CH3), 1.97 (s, 3H, -CH3); Anal. Calcd for
C23H20N6OS2: C, 59.98; H, 4.38; N, 18.25; Found: C, 59.95; H, 4.35; N, 18.28.
REFERENCES
1. WHO, World Health Organization, www.searo.who.int/linkfiles/regional health forum rhf vol
15 no 1.pdf.
2. Leal, B.; Afonso, I. F.; Rodrigues, C. R.; Abreu, P. A.; Garrett, R.; Pinheiro, L. C. S.; Azevedo,
A. R.; Borges, J. C.; Vegi, P. F.; Santos, C. C. C.; Da Silveira F. C. A.; Cabral, L. M.; Frugulhetti,
I. C. P. P.; Bernardino, A. M. R.; Santos, D. O.; Castro, H. C. Bioorg. Med. Chem. 2008, 16,
8196–8204.
3. Hegab, M. I.; Hassan, N. A.; Rashad, A. E.; Fahmy, A. A.; Abdel-Megeid, F. M. E. Phosphorus,
Sulfur Silicon Relat. Elem. 2007, 182, 1535-1556.
4. Prachayasittikul, S.; Worachartcheewan, A.; Nantasenamat, C.; Chinworrungsee, M.; Sorn-
songkhram, N.; Ruchirawat, S.; Prachayasittikul, V. Eur. J. Med. Chem. 2011, 46, 738-742.
5. Prachayasittikul, S.; Sornsongkhram, N.; Pingaew, R.; Techatanachai, S.; Ruchirawat, S.;
Prachayasittikul, V. Eur. J. Sci. Res. 2009, 36, 236-245.
6. Ghorab, M. M.; Ragab, F. A.; Alqasoumi, S. I.; Alafeefy, A. M.; Aboulmagd, S. A. Eur. J. Med.
Chem. 2010, 45, 171-178.
7. Ranise, A.; Spallarossa, A.; Schenone, S.; Bruno, O.; Bondavalli, F.; Pani, A.; Marongiu, M. E.;
Mascia, V.; Collab, P. L.; Loddo, R. Bioorg. Med. Chem. 2003, 11, 2575-2589.
8. Sondhi, S. M.; Singh, N.; Johar, M.; Kumar, A. Bioorg. Med. Chem. 2005, 13, 6158-6166.
9. Sondhi, S. M.; Dinodi, M.; Rani, R.; Shukla, R.; Raghubir, R. Ind. J. Chem. 2009, 49B, 273-281.
10. Amr, A. E.; Mohamed, A. M.; Mohamed, S. F.; Abdel–Hafez, N. A.; Hammam, A. G. Bioorg.
Med. Chem. 2006, 14, 5481-5488.
11. Roma, G.; Cinone, N.; Braccio, M. D.; Grossi, G.; Leoncini, G.; Signorello, M. G.; Carotti, A.
Bioorg. Med. Chem. 2000, 8, 751-768.
12. Hammam, A. G.; Abd El-Salam, O. I.; Mohamed, A. M.; Hafez, N. A. Ind. J. Chem. 2005, 44B,
1887-1893.
13. Zorkun, I. S.; Sarac, S.; Celebi, S.; Erol, K. Bioorg. Med. Chem. 2006, 14, 8582-8589.
14. Abdelrazek, F. M.; Michael, F. A.; El-Mahrouky, S. F. Int. J. Phys. Sci. 2007, 2, 212-216.
15. Rashad, A. E.; Mohamed, M. S.; Zaki, M. E. A.; Fatahala, S. S. Arch. Pharm. Chem. Life Sci.
2006, 339, 664-669.
16. Ramiz, M. M. M.; El-Sayed, W. A.; El-Tantawy, A. I.; Abdel-Rahman, A. A. H. Arch. Pharm.
Res. 2010, 33, 647-654.

572
P. T. MISTRY ET AL.
17. Bedair, A. H.; El-Hady, N. A.; El-Latif, M. S. A.; Fakery, A. H.; El-Agrody, A. M. I1 Farmaco.
2000, 55, 708-714.
18. Bedair, A. H.; Emam, H. A.; El-Hady, N. A.; Ahmed, K. A. R.; El-Agrody, A. M. Il Farmaco.
2001, 56, 965-973.
19. Ferreira, S. B.; da Silva, F. C.; Bezerra, F. A. F. M.; Lourenco, M. C. S.; Kaiser, C. R.; Pinto, A.
C.; Ferreira, V. F. Arch. der. Pharm. 2010, 343, 81-90.
20. Vyas, D. H.; Tala, S. D.; Akbari, J. D.; Dhaduk, M. F.; Joshi, K. A.; Joshi, H. S. Ind. J. Chem.
2009, 48B, 833-839.
21. Kolokythas, G.; Kostakis, I. K.; Pouli, N.; Marakos, P.; Kousidou, O. C.; Tzanakakis, G. N.;
Karamanos, N. K. Eur. J. Med. Chem. 2007, 42, 307-319.
22. Aytemir, M. D.; Calis, U.; Ozalp, M. Arch. Pharm. Pharm. Med. Chem. 2004, 337, 281-288.
23. Chiou, W. F.; Li, S. Y.; Ho, L. K.; Hsien, M. L.; Don, M. J. Eur. J. Med. Chem. 2002, 37, 69-75.
24. Sanfilippo, P. J.; McNally, J. J.; Press, J. B.; Falotico, R.; Giardino, E.; Katz, L. B. Bioorg. Med.
Chem. Lett. 1993, 3, 1385-1388.
25. Xuesen, F.; Dong, F.; Yingying, Q.; Xinying, Z.; Wang, J.; Loiseau, P. M.; Andrei, G.; Snoeck,
R.; Clercq, E. D. Bioorg. Med. Chem. Lett. 2010, 20, 809-813.
26. Smith, C. W.; Bailey, J. M.; Billingham, M. E. J.; Chandrasekhar, S.; Dell, C. P.; Harvey, A. K.;
Hicks, C. A.; Kingston, A. E.; Wishart, G. N. Bioorg. Med. Chem. Lett. 1995, 5, 2783-2788.
27. Kamdar, N. R.; Haveliwala, D. D.; Mistry, P. T.; Patel, S. K. Eur. J. Med. Chem. 2010, 45,
5056-5603.
28. Kamdar, N. R.; Haveliwala, D. D.; Mistry, P. T.; Patel, S. K. Med. Chem. Res. 2011, 20, 854-864.
29. Mistry, P. T.; Kamdar, N. R.; Haveliwala, D. D.; Patel, S. K. Lett. Drug Des. Discov. 2011, 8,
750-757.
30. Haveliwala, D. D.; Kamdar, N. R.; Mistry, P. T.; Patel, S. K. J. Sulfur Chem. 2011, 32, 451-462.
31. Jin, T. S.; Wang, A. Q.; Cheng, Z. L.; Zhang, J. S.; Li, T. S. Synth. Commun. 2005, 35, 137-143.
32. Behalo, M. S. Phosphorus, Sulfur Silicon Relat. Elem. 2009, 184, 206-219.
33. El-Assiery, S. A.; Sayed, G. H.; Fouda, A. Acta Pharm. 2004, 54, 143-150.
34. Rattan, A. In: B. I. Churchill (Ed.), Antimicrobials in Laboratory Medicine; Livingstone: New
Delhi, 2000; pp. 85-108.
35. Kumar, S.; Manjusha, D. K.; Saroha, K.Singh, N.; Vashishta, B. Acta. Pharm. 2008, 58, 215-220.