Synthesis and studies of new 2-(coumarin-4-yloxy)-4,6-(substituted)-s- triazine derivatives as potential anti-HIV agents

Article abstract of DOI:10.1002/ardp.200800149

Novel 2-(coumarin-4-yloxy)-4,6-(substituted)-s-triazine derivatives i. e., diaryltriazine (DATA) are reported as novel non-nucleoside reverse transcriptase inhibitors (NNRTIs), were synthesized and their activities against human immunodeficiency virus HIV

Full text of DOI:10.1002/ardp.200800149

Arch. Pharm. Chem. Life Sci. 2009, 342, 281–290
D. H. Mahajan et al.
281
Full Paper
Synthesis and Studies of New 2-(Coumarin-4-yloxy)-4,6-
(substituted)-s-Triazine Derivatives as Potential Anti-HIV
Agents
Dharmesh H. Mahajan1, Christophe Pannecouque2, Erik De Clercq2, and Kishor H. Chikhalia3
1 Department of Chemistry, Veer Narmad South Gujarat University, Surat, Gujarat, India
2 Rega Institute for Medical Research, K.U.Leuven, Leuven, Belgium
3 Department of Chemistry, Gujarat University, Ahmedabad, Gujarat, India
Novel 2-(coumarin-4-yloxy)-4,6-(substituted)-s-triazine derivatives i.e., diaryltriazine (DATA) are
reported as novel non-nucleoside reverse transcriptase inhibitors (NNRTIs), were synthesized
and their activities against human immunodeficiency virus HIV-1 (III-B), HIV-2 (ROD), and the
double RT mutant HIV-1 (K103N and Y181C) were assessed. Modifications at positions 4 and 6 of
the coumarinyl-triazine scaffold generated interesting derivatives displaying good to moderate
anti-HIV activity against selected HIV strains as compared to nevirapine and efavirenz. The syn-
1
thesized compounds were characterized by FTIR, H-NMR, and mass spectral data together with
elemental analysis.
Keywords: Anti-HIV activity / 4-Hydroxycoumarin / NNRTIs / s-Triazines /
Received: August 15, 2008; accepted: January 16, 2009
DOI 10.1002/ardp.200800149
NNRTIs are bound in a hydrophobic pocket proximal
to the catalytic site of RT in HIV-1 [5]. X-ray crystallo-
graphic studies of NNRTIs in complex with RT [6, 7] have
shown that the NNRTIs maintain a very similar confor-
Introduction
Reverse transcriptase (RT) plays a critical role in the repli-
cative cycle of the human immunodeficiency virus (HIV),
and thus considerable effort has been directed toward
this enzyme as a target for the treatment of HIV / AIDS.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
have become the key components in the combination
regimens [1]. NNRTIs bind to an allosteric site of reverse
transcriptase (RT) in a noncompetitive manner which
causes distortion of the three-dimensional structure of
the enzyme and inhibits its catalytic function [2, 3]. Drug
resistance [4] is an important cause of failure for treat-
ment of HIV infection. The efficacy of non-nucleoside
reverse transcriptase inhibitors (NNRTIs) is impaired by
rapid emergence of drug-resistance mutations.
,
mational butterfly-like’ shape and appear to function as
p-electron donors to aromatic side-chain residues sur-
rounding the binding pocket [8, 9]. Part of our earlier
work in this field concerned the synthesis of novel cou-
marin based triazine derivatives, since compounds of
this structural framework have been found to possess dis-
tinct HIV RT inhibition properties. Alterations of the imi-
doylthiourea complexes led to the synthesis of a new dia-
ryltriazine (DATA) class of compounds [10]. Potent DATA
NNRTIs inhibited wild-type HIV-1 RT at nanomolar con-
centrations of EC50. Recently, the focal point of attention
has been the Het–NH–Ph–U motif, where Het is an aro-
matic heterocycle and U is an unsaturated, hydrophobic
group, such as triazinyl [11] derivatives. A specific HIV-1
RT-inhibitory profile has been described for PETT (Phenyl
Ethyl Thiazolyl Thiourea) derivatives [12, 13] (Fig. 1).
In continuation of our endeavor to develop new,
potent, selective, and less toxic anti-HIV agents, we report
here the synthesis of some related new substituted s-tria-
zine-based compounds and their in-vitro anti-HIV activity.
Correspondence: Prof. Kishor. H. Chikhalia, Department of Chemistry,
School of Sciences, Gujarat University, Navrangpura Ahmedabad – 380
009, Gujarat, India.
E-mail: chikhalia_kh@yahoo.com
Fax: +91 79 263 085 45
Abbreviations: diaryltriazine (DATA); non-nucleoside reverse transcrip-
tase inhibitors (NNRTIs); PETT (Phenyl Ethyl Thiazolyl Thiourea)
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

282
D. H. Mahajan et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 281–290
Figure 1. Structures of DATA, triazinyl derivatives, and PETT
analogues.
Reagents: (i) Acetone / 10% NaHCO3; (ii) acetone / 10% NaHCO3; (iii) dioxane / 10%
NaHCO3.
Scheme 1. Synthesis of 8a–m and 9a–m.
Results and discussion
Chemistry
parison with nevirapine (BIRG587) used as reference
drugs. The cytotoxicity of the compound was determined
in parallel. Comparisons of inhibitory concentration
(IC50), cytotoxic concentration (CC50), and SI (selectivity,
given by the CC50/IC50 ratio) values for different com-
pounds are depicted in Tables 1 and 2. The compounds
found active were also evaluated against HIV-RT double
mutant strain RES056 (K103N and Y181C) using efavirenz
(DMP-266) as standard drug and results are mentioned in
Table 3.
Some analogues of compound 9 (namely 9d and 9l)
were active against HIV-1 (IIIB) with IC50 values of 8.33 and
10 lg/mL, respectively. Compounds 9d and 9l exhibited
selectivity with selective indexes of SI = 6 and SI = 7,
respectively.
Of the second set of compounds (Scheme 2, Table 2),
the most potent and selective compound was found to be
13d having an IC50 value of 1.07 lg/mL (logP = 4.40)
against HIV-1(IIIB) with a selectivity index (SI) of 43. HIV-
1(IIIB) was also selectively inhibited by compound 13g
and 13j at IC50 = 6.86 lg/mL (logP = 4.47) and 7.16 lg/mL
(logP = 4.70), respectively, thus showing a SI = 7 for both
the compounds.
Considering the versatile chemistry of cyanuric chloride
[14] (as in 2,4,6-trichloro-1,3,5-triazine), and its reactions
with various nucleophiles [15] such as amines, ureas, phe-
nols, etc., here, we extend previous investigations in the
design of novel triazinyl containing NNRTIs (Schemes 1
and 2). 3,4-Dimethoxyphenylethyl-1,3,5-triazinyl amine
derivatives (8a–m / 9a–m) were prepared by the conden-
sation of 2,4,6-trichloro-1,3,5-s-triazine 1 with 4-hydroxy-
coumarin 2, 3,4-dimethoxyphenylethylamine 4 and vari-
ous substituted phenyl urea / thiourea compounds, 6a–
m / 7a–m, respectively, to obtain novel urea 8a–m and
9a–m (urea / thiourea) derivatives as shown in Scheme 1.
Further modification was done by replacing two chlorine
atoms of intermediate 3 as shown in Scheme 2. Com-
pound 3, on reaction with glycine ethylester hydrochlor-
ide gave key intermediate 11 which was further treated
with various aryl ureas to obtain the new compounds
12a–m. In parallel, 11 was further derivatized by treat-
ment with several aryl amines to afford 13a–m.
In-vitro anti-HIV activity
The synthesized compounds were evaluated for anti-HIV
activity by determining their ability to inhibit the repli-
cation of HIV-1 (IIIB) and HIV-2 (ROD) in MT-4 cells in com-
The four most active compounds 9d, 13d, 13g, and 13j
were further tested for their inhibitory effects (Table 3)
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Arch. Pharm. Chem. Life Sci. 2009, 342, 281–290
New S-Triazine Derivatives as Potential Anti-HIV Agents
283
Table 1. Anti-HIV-1 and HIV-2 activity (IC50 in lg/ml) and cyto-
toxicity of compounds 8a–m and 9a–m in MT-4 cells.
Com-
pound
Ar
HIV
strain
IC50
CC50
SIc)
logPd)
(lg/ml)a) (lg/ml)b)
8a
8b
8c
8d
8e
8f
C6H5
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
A86.93
A86.93
A16.90
A16.90
A22.45
A22.45
A74.98
A74.98
A51.15
A51.15
A25.23
A25.23
A35.43
A35.43
A25.48
A25.48
A61.60
A61.60
A47.63
A47.63
A19.75
A19.75
A30.15
A30.15
A12.85
A12.85
A15.45
A15.45
A20.03
A20.03
A61.20
A61.20
8.33
A53.66
A13.75
A13.75
A16.78
A16.78
A40.83
A40.83
A19.63
A19.63
A56.45
A56.45
A62.70
A62.70
A14.55
A14.55
10.00
86.93
86.93
16.90
16.90
22.45
22.45
74.98
74.98
51.15
51.15
25.23
25.23
35.43
35.43
25.48
25.48
61.60
61.60
47.63
47.63
19.75
19.75
30.15
30.15
12.85
12.85
15.45
15.45
20.03
20.03
61.20
61.20
53.66
53.66
13.75
13.75
16.78
16.78
40.83
40.83
19.63
19.63
56.45
56.45
62.70
62.70
14.55
14.55
66.05
66.05
54.60
54.60
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
6
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
a1
7
4.82
5.31
5.31
5.31
5.38
5.38
5.38
4.69
4.69
5.65
4.98
5.03
5.82
5.97
6.45
6.45
6.45
6.52
6.52
6.52
5.84
5.84
6.80
6.12
6.18
6.96
2-CH3 N C6H4
3-CH3 N C6H4
4-CH3 N C6H4
2-Cl N C6H4
3-Cl N C6H4
4-Cl N C6H4
2-OCH3 N C6H4
4-OCH3 N C6H4
4-Br N C6H4
4-F N C6H4
8g
8h
8i
8j
8k
8l
4-OEt N C6H4
C10H7
8m
9a
9b
9c
9d
9e
9f
Reagents: (i) Acetone / 10% NaHCO3; (ii) acetone / 10% NaHCO3; (iii) dioxane / 10%
NaHCO3.
C6H5
Scheme 2. Synthesis of 12a–m and 13a–m.
2-CH3 N C6H4
3-CH3 N C6H4
4-CH3 N C6H4
2-Cl N C6H4
3-Cl N C6H4
4-Cl N C6H4
2-OCH3 N C6H4
4-OCH3 N C6H4
4-Br N C6H4
4-F N C6H4
against the HIV-RT mutant strain RES056 (K103N and
Y181C). In contrast with the second generation NNRTI,
efavirenz, they did not show activity against this HIV-RT
mutant strain.
We previously reported that compounds with novel
coumarin-based triazine derivatives, containing an ethyl-
linked thiourea moiety displayed activity against the
HIV-1 and HIV-2 RTs. Further SAR studies were carried out
in the present work, the thiourea part being deleted
while keeping the remaining aryl-ethyl-amino substruc-
ture (Scheme 1). No significant improvement of activity
was achieved as the compounds having an ureido linkage
with the substituted ring system 8a–m did not show
selectivity. Thiourea derivatives 9d and 9l having a 4-CH3
or 4-OEt substitution to the phenyl nucleus, respectively,
displayed a selective inhibition effect. The calculated
logP values of synthesized compounds in Scheme 1
ranged from 4.69 to 6.96.
The modification carried out at position 4 and 6 by
introducing amino acid and various aryl ureas and aryl
amines led to compounds 12a–m and 13a–m. The incor-
poration of an aryl amino group having a para-substi-
tuted ring with lipophilic methyl and chloro groups at
position 6 led to selective inhibition of HIV-1 replication
(derivatives 13d and 13g). The improvement in lipophilic-
9g
9h
9i
9j
9k
9l
4-OEt N C6H4
C10H7
A66.05
A54.60
A54.60
a1
a1
a1
9m
a)
Concentration required to protect the cell against viral cytopathoge-
nicity by 50% in MT-4 cells.
Selectivity index: ratio CC50/IC50, a higher SI means a more selective
compound.
All data represent mean values for at least two separate experiments.
logP values calculated with Chem office 2005 software.
b)
c)
d)
ity (logP) of the synthesized compounds may render
them more capable of penetrating various biomem-
branes [16], and such compounds might be much better
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www.archpharm.com

284
D. H. Mahajan et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 281–290
Table 2. Anti-HIV-1 and HIV-2 activity (IC50 in lg/ml) and cyto-
toxicity of compounds 12a–m and 13a–m in MT-4 cells.
Table 3. Anti-HIV activity (IC50 in lg/ml) and cytotoxicity of potent
compounds against HIV-RT mutants strains RES056: (K103N
and Y181C).
Com-
pound
Ar
HIV
strain
IC50
CC50
SIc)
logPd)
(lg/ml)a) (lg/ml)b)
Compound
HIV strain RES056
IC50 (lg/ml)a) CC50 (lg/ml)b)
SIc)
12a
12b
12c
12d
12e
12f
12g
12h
12i
C6H5
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
A125.00 A125.00 X1
A125.00 A125.00 X1
2.93
3.42
3.42
3.42
3.49
3.49
3.49
2.80
2.80
3.76
3.09
3.14
3.93
3.91
4.40
4.40
4.40
4.47
4.47
4.47
3.79
3.79
4.74
4.07
4.13
4.91
2-CH3 N C6H4
3-CH3 N C6H4
4-CH3 N C6H4
2-Cl N C6H4
3-Cl N C6H4
4-Cl N C6H4
A73.53
A73.53
A14.23
A14.23
A11.27
A11.27
A78.80
A78.80
73.53 a1
73.53 a1
14.23 a1
14.23 a1
11.27 a1
11.27 a1
F78.80 X1
F78.80 X1
9d
13d
13g
13j
A53.66
A45.53
A45.60
A51.28
53.66
45.53
45.60
51.28
A2.00
a1
a1
a1
a1
A50
Efavirenz
0.0403
a), b) and c) for footnotes see in Table 1.
A125.00 A125.00 X1
A125.00 A125.00 X1
A125.00 A125.00 X1
A125.00 A125.00 X1
A125.00 A125.00 X1
A125.00 A125.00 X1
Conclusion
2-OCH3 N C6H4 III B
ROD
4-OCH3 N C6H4 III B
ROD
4-Br N C6H4
4-F N C6H4
4-OEt N C6H4
C10H7
In summary, we designed, synthesized, and evaluated a
series of 1-(4-(3,4-dimethoxyphenethylamino)-6-(2-oxo-2H-
chromen-4-yloxy)-1,3,5-triazin-2-yl)-3-aryl urea / aryl thio-
urea 8a–m / 9a–m and 2-(4-(2-oxo-2H-chromen-4-yloxy)-6-
(3-arylureido/arylamino)-1,3,5-triazin-2-ylamino)acetate
derivatives 12a–m / 13a–m as novel NNRTIs. Only com-
pounds 9d (IC50 = 8.33 lg/mL, SI = 6) and 9l (IC50 = 10 lg/
mL, SI = 7) (Scheme 1) and 13g (IC50 = 6.86 lg/mL, SI = 7)
and 13j (IC50 = 7.16 lg/mL, SI = 7) (Scheme 2) displayed a
selective activity against HIV-1, with 13d showing the
highest potency (IC50 = l1 lg/mL, SI = 43).
A85.90
A85.90
85.90 a1
85.90 a1
12j
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
A125.00 A125.00 X1
A125.00 A125.00 X1
A125.00 A125.00 X1
A125.00 A125.00 X1
A125.00 A125.00 X1
A125.00 A125.00 X1
A125.00 A125.00 X1
A125.00 A125.00 X1
12k
12l
12m
13a
13b
13c
13d
13e
13f
C6H5
A61.15
A61.15
A23.12
A23.12
A65.28
A65.28
1.07
A45.53
A67.70
A67.70
A56.00
A56.00
6.86
61.15 a1
61.15 a1
23.12 a1
23.12 a1
65.28 a1
65.28 a1
45.53 43
45.53 a1
67.70 a1
67.70 a1
56.00 a1
56.00 a1
2-CH3 N C6H4
3-CH3 N C6H4
4-CH3 N C6H4
2-Cl N C6H4
3-Cl N C6H4
4-Cl N C6H4
One of the authors (DHM) thanks the University Grants Com-
mission, New Delhi for providing financial assistance F. No. 30-
60/2004(SR) and a Research Fellowship. Authors (KHC and
DHM) are very thankful to Prof. Dr. K. R. Desai, Head, Depart-
ment of Chemistry, Veer Narmad South Gujarat University,
Surat, for providing support and research facility.
13g
13h
13i
45.60
7
A45.60
A72.30
A72.30
A58.60
A58.60
7.16
45.60 a1
72.30 a1
72.30 a1
58.60 a1
58.60 a1
2-OCH3 N C6H4 III B
ROD
4-OCH3 N C6H4 III B
ROD
4-Br N C6H4
4-F N C6H4
4-OEt N C6H4
C10H7
The authors have declared no conflict of interest.
13j
III B
ROD
III B
ROD
III B
ROD
III B
ROD
III B
ROD
51.28
7
A51.28
A67.60
A67.60
A62.13
A62.13
A46.53
A46.53
0.010
51.28 a1
67.60 a1
67.60 a1
62.13 a1
62.13 a1
46.53 a1
46.53 a1
A4.00 A415
13k
13l
Experimental
Chemistry
Melting points were determined on an electro thermal appara-
tus (capillary method) and are uncorrected. IR spectra were
recorded on a FT Shimadzu spectrophotometer (Shimadzu,
Tokyo, Japan) using potassium bromide technique. 1H-NMR spec-
tra were recorded on a Bruker Avance II 400 M Hz spectrometer
(Bruker Bioscience, USA) and chemical shifts were expressed in
ppm downfield from internal TMS and J values were reported in
Hertz. Elemental analyses were carried out on Heraeus Rapid
Analyser (Heraeus, Germany) and functions were within l 0.4%
of the theoretical value. Thin layer chromatography was per-
formed on silica gel coated (Merck Kiesel 60 GF-254, 0.2 mm
thickness; Merck, Germany) sheets. Solvents used for the chemi-
cal synthesis acquired from commercial sources were of analyti-
13m
Nevirapine
a), b), c) and c) for footnotes see in Table 1.
taken up by cells and have enhanced blood–brain barrier
penetration because of their increased accumulation in
lipids [17].
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Arch. Pharm. Chem. Life Sci. 2009, 342, 281–290
New S-Triazine Derivatives as Potential Anti-HIV Agents
285
cal grade and were used without further purification unless oth-
erwise stated.
2H, -CH2), 3.72 (t, J = 6.8 Hz, 2H, -CH2), 3.84 (s, 6H, 26 -OCH3), 6.68
(s, 1H, -C=CH), 7.28 (dd, J = 2.2 Hz, J = 8.3 Hz, 1H, Ar-H), 7.30 (s, 1H,
Ar-NH), 9.40 (br. s, 1H, CO-NH), 8.82 (s, 1H, Ar-NH), 7.74 (dd, J =
1.9 Hz, J = 8.2 Hz, 1H, Ar-H). ES-MS [m/z + 1]+: 569. Anal. calcd. for
C30H28N6O6: C, 63.37; H, 4.96; N, 14.78. Found: C, 63.42; H, 4.99;
N, 14.72.
4-(4,6-Dichloro-1,3,5-triazin-2-yloxy)-2H-chromen-2-one
3
To a stirred solution of cyanuric chloride (0.1 mol,18.4 g.) in ace-
tone (100 mL) at 0–58C, the solution of 4-hydroxy coumarin
(0.1 mol, 16.2 g.) in 10% NaHCO3 (90 mL) was added dropwise in
two hours. The progress of reaction was monitored by TLC using
acetone / toluene (10 : 1) as eluent. After completion of the reac-
tion, the stirring was stopped and the solution was treated with
crushed ice. The product obtained was filtered and dried. The
crude product was purified by recrystallization from acetone to
give the title compound 3. Yield: 85%; m.p.: 208–2108C.
C12H5N3O3Cl2 requires: N, 13.55. Found: N, 13.35.
1-(4-(3,4-Dimethoxyphenethylamino)-6-(2-oxo-2H-
chromen-4-yloxy)-1,3,5-triazin-2-yl)-3-m-tolylurea 8c
Yield: 65%; IR m (max)/cm– 1: 3356, 2838, 1727, 1694, 1518, 1341,
1250, 1022, 806. 1H-NMR d: 2.45 (s, 3H, -CH3), 2.74 (t, J = 7.1 Hz,
2H, -CH2), 3.76 (t, J = 6.8 Hz, 2H, -CH2), 3.84 (s, 6H, 26 -OCH3), 6.66
(s, 1H, -C=CH), 7.28 (dd, J = 2.4 Hz, J = 8.7 Hz, 1H, Ar-H), 7.30 (s, 1H,
Ar-NH), 7.72 (dd, J = 2.0 Hz, J = 8.0 Hz, 1H, Ar-H), 7.10–7.75 (m,
9H, Ar-H), 8.79 (s, 1H, Ar-NH), 9.40 (s, 1H, CO-NH). ES-MS [m/z + 1]+:
569. Anal. calcd. for C30H28N6O6: C, 63.37; H, 4.96; N, 14.78.
Found: C, 63.34; H, 4.95; N, 14.81.
4-(4-Chloro-6-(3,4-dimethoxyphenethylamino)-1,3,5-
triazin-2-yloxy)-2H-chromen-2-one 5
3,4-Dimethoxy phenyl ethyl amine (0.022 mol, 3.6 g) dissolved
in acetone / water (10 : 2, 60 mL) was slowly added to a well-
stirred slurry of 3 (0.022 mol, 7.0 g.) in acetone (90 mL), main-
taining the temperature at 458C. The pH was adjusted to neutral
by the addition of 10% NaHCO3 solution. The progress of reaction
was monitored by TLC using acetone / toluene (10 : 1) as eluent.
The temperature was gradually raised to 508C during two hours
and further maintained for two hours. After completion of reac-
tion, the solution was poured in ice-cold water. The solid prod-
uct obtained was filtered and dried. The crude product was puri-
fied by recrystallization from acetone / ethyl acetate (1 : 1) to
give the title compound 5. Yield: 72%; m.p.: 150–1558C.
C22H19ClN4O5 requires: N, 12.32. Found: N, 12.28.
1-(4-(3,4-Dimethoxyphenethylamino)-6-(2-oxo-2H-
chromen-4-yloxy)-1,3,5-triazin-2-yl)-3-p-tolylurea 8d
Yield: 63%; IR m (max)/cm– 1: 3307, 2835, 1727, 1680, 1518, 1348,
1
1235, 1028, 806. H-NMR d: 2.45 (s, 3H, -CH3), 2.62 (t, J = 7.4 Hz,
2H, -CH2), 3.78 (t, J = 6.6 Hz, 2H, -CH2), 3.80 (s, 6H, 26 -OCH3), 6.46
(s, 1H, -C=CH), 7.20 (d, J = 8.2 Hz, 2H, Ar-H), 7.21 (s, 1H, Ar-NH),
7.40 (d, J = 8.2 Hz, 2H, Ar-H), 8.88 (s, 1H, Ar-NH), 9.45 (s, 1H, CO-
NH), 7.12–7.74 (m, 7H, Ar-H). ES-MS [m/z + 1]+: 569. Anal. calcd.
for C30H28N6O6: C, 63.37; H, 4.96; N, 14.78. Found: C, 63.32; H,
4.98; N, 14.80.
1-(2-Chlorophenyl)-3-(4-(3,4-dimethoxyphenethylamino)-
6-(2-oxo-2H-chromen-4-yloxy)-1,3,5-triazin-2-yl) urea 8e
Yield: 59%; IR m (max)/cm– 1: 3351, 2840, 1727, 1688, 1526, 1240,
1028, 887, 806. 1H-NMR d: 2.75 (t, J = 7.2 Hz, 2H, -CH2), 3.76 (t, J =
7.3 Hz, 2H, -CH2), 3.84 (s, 6H, 26 -OCH3), 6.46 (s, 1H, -C=CH), 7.28
(dd, J = 2.4 Hz, J = 8.7 Hz, 1H, Ar-H), 7.31 (s, 1H, Ar-NH), 7.72 (dd, J
= 2.1 Hz, J = 8.2 Hz, 1H, Ar-H), 7.22–7.75 (m, 9H, Ar-H), 8.78 (s, 1H,
Ar-NH), 9.52 (s, 1H, CO-NH). ES-MS [m/z + 1]+: 590. Anal. calcd. for
C29H25ClN6O6: C, 59.14; H, 4.28; N, 14.27. Found: C, 59.17; H, 4.30;
N, 14.31.
General procedure for the preparation of 1-(4-(3,4-
dimethoxyphenethylamino)-6-(2-oxo-2H-chromen-4-
yloxy)-1,3,5-triazin-2-yl)-3-aryl urea/aryl thiourea 8a–m /
9a–m
A mixture of 5 (0.005 mol) and aryl urea (6a–m) / thiourea (7a–
m) (0.005 mol) in dioxane (50 mL) was refluxed on heating with
stirring at reflux temperature for four hours. The pH was
adjusted to neutral by the addition of 10% NaHCO3 solution. The
progress of reaction was monitored by TLC using acetone / hex-
ane (4 : 6) as eluent. After the completion of reaction, the con-
tent was added to cold water. The product obtained was purified
by recrystallization from absolute alcohol.
1-(3-Chlorophenyl)-3-(4-(3,4-dimethoxyphenethylamino)-
6-(2-oxo-2H-chromen-4-yloxy)-1,3,5-triazin-2-yl) urea 8f
Yield: 74%; IR m (max)/cm– 1: 3351, 2838, 1727, 1694, 1518, 1241,
1028, 882, 806. 1H-NMR d: 2.75 (t, J = 7.1 Hz, 2H, -CH2), 3.76 (t, J =
7.2 Hz, 2H, -CH2), 3.84 (s, 6H, 26 -OCH3), 6.46 (s, 1H, -C=CH), 7.28
(dd, J = 2.2 Hz, J = 8.3 Hz, 1H, Ar-H), 7.31 (s, 1H, Ar-NH), 7.74 (dd, J
= 1.9 Hz, J = 8.2 Hz, 1H, Ar-H), 8.80 (s, 1H, Ar-NH), 9.40 (s, 1H, CO-
NH). ES-MS [m/z + 1]+: 590. Anal. calcd. for C29H25ClN6O6: C, 59.14;
H, 4.28; N, 14.27. Found: C, 59.10; H, 4.25; N, 14.30.
1-(4-(3,4-Dimethoxyphenethylamino)-6-(2-oxo-2H-
chromen-4-yloxy)-1,3,5-triazin-2-yl)-3-phenylurea 8a
Yield: 60%; IR m (max)/cm– 1: 3351, 2838, 1727, 1694, 1518, 1347,
1241, 1028, 806. 1H-NMR d: 2.75 (t, J = 7.1 Hz, 2H, -CH2), 3.76 (t, J =
6.7 Hz, 2H, -CH2), 3.84 (s, 6H, 26 -OCH3), 6.46 (s, 1H, -C=CH), 7.28
(dd, J = 2.2 Hz, J = 8.3 Hz, 1H, Ar-H), 7.31 (s, 1H, Ar-NH), 7.74 (dd, J
= 1.9 Hz, J = 8.2 Hz, 1H, Ar-H), 8.80 (s, 1H, Ar-NH), 9.40 (s, 1H, CO-
NH). ES-MS [m/z + 1]+: 555. Anal. calcd. for C29H26N6O6: C, 62.81; H,
4.73; N, 15.15. Found: C, 62.75; H, 4.78; N, 15.19.
1-(4-Chlorophenyl)-3-(4-(3,4-dimethoxyphenethylamino)-
6-(2-oxo-2H-chromen-4-yloxy)-1,3,5-triazin-2-yl) urea 8g
Yield: 70%; IR m (max)/cm– 1: 3351, 2837, 1721, 1699, 1522, 1347,
1241, 1022, 885, 882, 805. 1H-NMR d: 2.77 (t, J = 7.4 Hz, 2H, -CH2),
3.80 (t, J = 7.3 Hz, 2H, -CH2), 3.84 (s, 6H, 26 -OCH3), 6.46 (s, 1H, -
C=CH), 7.31 (s, 1H, Ar-NH), 7.56 (d, J = 8.3 Hz, 2H, Ar-H), 7.66 (d, J =
8.4 Hz, 2H, Ar-H), 7.12–7.78 (m, 7H, Ar-H), 8.80 (s, 1H, Ar-NH),
9.45 (s, 1H, CO-NH). ES-MS [m/z + 1]+: 590. Anal. calcd. for
1-(4-(3,4-Dimethoxyphenethylamino)-6-(2-oxo-2H-
chromen-4-yloxy)-1,3,5-triazin-2-yl)-3-o-tolylurea 8b
Yield: 66%; IR m (max)/cm– 1: 3352, 2830, 1732, 1685, 1525, 1348,
1236, 1021, 809. 1H-NMR d: 2.45 (s, 3H, -CH3), 2.75 (t, J = 6.9 Hz,
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D. H. Mahajan et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 281–290
C29H25ClN6O6: C, 59.14; H, 4.28; N, 14.27. Found: C, 59.13; H, 4.24;
N, 14.25.
1-(4-(3,4-Dimethoxyphenethylamino)-6-(2-oxo-2H-
chromen-4-yloxy)-1,3,5-triazin-2-yl)-3-(naphthalen-1-
yl)urea 8m
1-(4-(3,4-Dimethoxyphenethylamino)-6-(2-oxo-2H-
chromen-4-yloxy)-1,3,5-triazin-2-yl)-3-(2-
methoxyphenyl)urea 8h
Yield: 70%; IR m (max)/cm– 1: 3351, 2838, 1727, 1694, 1528, 1347,
1241, 1028, 810. 1H-NMR d: 2.75 (t, J = 7.1 Hz, 2H, -CH2), 3.76 (t, J =
6.7 Hz, 2H, -CH2), 3.84 (s, 6H, 26 -OCH3), 6.46 (s, 1H, -C=CH), 7.28
(dd, J = 2.2 Hz, J = 8.3 Hz, 1H, Ar-H), 7.31 (s, 1H, Ar-NH), 9.40 (s, 1H,
CO-NH), 8.80 (s, 1H, Ar-NH), 7.74 (dd, J = 1.9 Hz, J = 8.2 Hz, 1H, Ar-
H). ES-MS [m/z + 1]+: 605. Anal. calcd. for C33H28N6O6: C, 65.55; H,
4.67; N, 13.90. Found: C, 65.59; H, 4.69; N, 13.98.
Yield: 65%; IR m (max)/cm– 1: 3360, 2838, 1696, 1727, 1520, 1349,
1236, 1032, 804. 1H-NMR d: 2.77 (t, J = 7.1 Hz, 2H, -CH2), 3.82 (t, J =
6.7 Hz, 2H, -CH2), 3.85 (s, 9H, 36 -OCH3), 6.66 (s, 1H, -C=CH), 7.23
(dd, J = 2.2 Hz, J = 8.3 Hz, 1H, Ar-H), 7.29 (s, 1H, Ar-NH), 6.70–7.74
(m, 9H, Ar-H), 7.76 (dd, J = 2.0 Hz, J = 8.2 Hz, 1H, Ar-H), 8.86 (s, 1H,
Ar-NH), 9.56 (s, 1H, CO-NH). ES-MS [m/z + 1]+: 585. Anal. calcd. for
C30H28N6O7: C, 61.64; H, 4.83; N, 14.38. Found: C, 61.58; H, 4.80;
N, 14.32.
1-(4-(3,4-Dimethoxyphenethylamino)-6-(2-oxo-2H-
chromen-4-yloxy)-1,3,5-triazin-2-yl)-3-phenylthiourea 9a
Yield: 75%; IR m (max)/cm– 1: 3511; 3334; 1723; 1685; 1519; 1345;
1236; 1028; 806. 1H-NMR d: 2.76 (t, J = 7.0 Hz, 2H, -CH2), 3.61 (t, J =
6.8 Hz, 2H, -CH2), 3.81 (s, 6H, 26 -OCH3), 6.46 (s, 1H, -C=CH), 7.26
(s, 1H, Ar-NH), 7.28 (dd, J = 2.2 Hz, J = 8.3 Hz, 1H, Ar-H), 7.72 (dd, J
= 1.8 Hz, J = 8.2 Hz, 1H, Ar-H), 9.25 (s, 1H, Ar-NH), 9.55 (s, 1H, CS-
NH). ES-MS [m/z + 1]+: 571. Anal. calcd. for C29H26N6O5S: C, 61.04;
H, 4.59; N, 14.73. Found: C, 61.15; H, 4.55; N, 14.80.
1-(4-(3,4-Dimethoxyphenethylamino)-6-(2-oxo-2H-
chromen-4-yloxy)-1,3,5-triazin-2-yl)-3-(4-methoxyphenyl)
urea 8i
Yield: 59%; IR m (max)/cm– 1: 3351, 2838, 1727, 1694, 1518, 1347,
1241, 1028, 806. 1H-NMR d: 2.75 (t, J = 7.1 Hz, 2H, -CH2), 3.76 (t, J =
7.7 Hz, 2H, -CH2), 3.84 (s, 9H, 36 -OCH3), 6.46 (s, 1H, -C=CH), 7.23
(d, J = 8.2 Hz, 2H, Ar-H), 7.31 (s, 1H, Ar-NH), 7.33 (d, J = 8.1 Hz, 2H,
Ar-H), 6.98–7.78 (m, 7H, Ar-H), 8.80 (s, 1H, Ar-NH), 9.48 (s, 1H, CO-
NH). ES-MS [m/z + 1]+: 585. Anal. calcd. for C30H28N6O7: C, 61.64; H,
4.83; N, 14.38. Found: C, 61.68; H, 4.86; N, 14.40.
1-(4-(3,4-Dimethoxyphenethylamino)-6-(2-oxo-2H-
chromen-4-yloxy)-1,3,5-triazin-2-yl)-3-o-tolylthiourea 9b
Yield: 67%; IR m (max)/cm– 1: 3522; 3345; 1738; 1690; 1528; 1352;
1
1231; 1028; 810. H-NMR d: 2.46 (s, 3H, -CH3), 2.75 (t, J = 6.9 Hz,
2H, -CH2), 3.66 (t, J = 6.8 Hz, 2H, -CH2), 3.80 (s, 6H, 26 -OCH3), 6.62
(s, 1H, -C=CH), 7.20 (dd, J = 2.3 Hz, J = 8.2 Hz, 1H, Ar-H), 7.23 (s, 1H,
Ar-NH), 7.78 (dd, J = 1.9 Hz, J = 8.2 Hz, 1H, Ar-H), 9.20 (s, 1H, Ar-
NH), 9.45 (br. s, 1H, CS-NH). ES-MS [m/z + 1]+: 585. Anal. calcd. for
C30H28N6O5S: C, 61.63; H, 4.83; N, 14.37. Found: C, 61.59; H, 4.90;
N, 14.31.
1-(4-Bromophenyl)-3-(4-(3,4-dimethoxyphenethylamino)-
6-(2-oxo-2H-chromen-4-yloxy)-1,3,5-triazin-2-yl)urea 8j
Yield: 56%; IR m (max)/cm– 1: 3365, 2842, 1731, 1690, 1524, 1348,
1230, 1022, 806, 582. 1H-NMR d: 2.77 (t, J = 7.1 Hz, 2H, -CH2), 3.72
(t, J = 7.3 Hz, 2H, -CH2), 3.86 (s, 6H, 26 -OCH3), 6.67 (s, 1H, -C=CH),
7.30 (s, 1H, Ar-NH), 7.39 (d, J = 8.2 Hz, 2H, Ar-H), 7.40 (d, J = 8.2 Hz,
2H, Ar-H), 7.22–7.78 (m, 7H, Ar-H), 8.86 (s, 1H, Ar-NH), 9.41 (s, 1H,
CO-NH). ES-MS [m/z + 1]+: 635. Anal. calcd. for C29H25BrN6O6: C,
54.99; H, 3.98; N, 13.27. Found: C, 55.05; H, 3.97; N, 13.22.
1-(4-(3,4-Dimethoxyphenethylamino)-6-(2-oxo-2H-
chromen-4-yloxy)-1,3,5-triazin-2-yl)-3-m-tolylthiourea 9c
Yield: 65%; IR m (max)/cm– 1: 3360; 2850; 1728; 1690; 1535; 1349;
1242; 1030; 808. 1H-NMR d: 2.46 (s, 3H, -CH3), 2.73 (t, J = 7.0 Hz,
2H, -CH2), 3.70 (t, J = 6.88 Hz, 2H, -CH2), 3.82 (s, 6H, 26-OCH3),
6.46 (s, 1H, -C=CH), 7.14 (dd, J = 2.4 Hz, J = 8.7 Hz, 1H, Ar-H), 7.20
(s, 1H, Ar-NH), 7.80 (dd, J = 2.2 Hz, J = 8.2 Hz, 1H, Ar-H), 8.81 (s, 1H,
Ar-NH), 9.42 (s, 1H, CS-NH). ES-MS [m/z + 1]+: 585. Anal. calcd. for
C30H28N6O5S: C, 61.63; H, 4.83; N, 14.37. Found: C, 61.59; H, 4.89;
N, 14.30.
1-(4-(3,4-Dimethoxyphenethylamino)-6-(2-oxo-2H-
chromen-4-yloxy)-1,3,5-triazin-2-yl)-3-(4-fluorophenyl)
urea 8k
Yield: 66%; IR m (max)/cm– 1: 3356, 2848, 1735, 1686, 1526, 1341,
1234, 1150, 1024, 805. 1H-NMR d: 2.65 (t, J = 7.2 Hz, 2H, -CH2), 3.78
(t, J = 7.4 Hz, 2H, -CH2), 3.82 (s, 6H, 26 -OCH3), 6.65 (s, 1H, -C=CH),
7.29 (s, 1H, Ar-NH), 7.45 (d, J = 8.3 Hz, 2H, Ar-H), 7.56 (d, J = 8.3 Hz,
2H, Ar-H), 7.18–7.78 (m, 7H, Ar-H), 8.89 (s, 1H, Ar-NH), 9.42 (s, 1H,
CO-NH). ES-MS [m/z + 1]+: 573. Anal. calcd. for C29H25FN6O6: C,
60.84; H, 4.40; N, 14.68. Found: C, 60.80; H, 4.38; N, 14.62.
1-(4-(3,4-Dimethoxyphenethylamino)-6-(2-oxo-2H-
chromen-4-yloxy)-1,3,5-triazin-2-yl)-3-p-tolylthiourea 9d
Yield: 69%; IR m (max)/cm– 1: 3312; 2832; 1722; 1684; 1519; 1345;
1
1235; 1028; 806. H-NMR d: 2.46 (s, 3H, -CH3), 2.65 (t, J = 7.4 Hz,
2H, -CH2), 3.77 (t, J = 6.8 Hz, 2H, -CH2), 3.82 (s, 6H, 26 -OCH3), 6.46
(s, 1H, -C=CH), 7.19 (s, 1H, Ar-NH), 7.20 (d, J = 8.1 Hz, 2H, Ar-H),
7.66 (d, J = 8.2 Hz, 2H, Ar-H), 8.91 (s, 1H, Ar-NH), 9.49 (s, 1H, CS-
NH). ES-MS [m/z + 1]+: 585. Anal. calcd. for C30H28N6O5S: C, 61.63;
H, 4.83; N, 14.37. Found: C, 61.58; H, 4.91; N, 14.32.
1-(4-(3,4-Dimethoxyphenethylamino)-6-(2-oxo-2H-
chromen-4-yloxy)-1,3,5-triazin-2-yl)-3-(4-
ethoxyphenyl)urea 8l
Yield: 62%; IR m (max)/cm– 1: 3351, 2838, 1727, 1694, 1530, 1347,
1241, 1028, 806. 1H-NMR d: 1.31 (t, 3H, -CH3), 2.65 (t, J = 7.2 Hz,
2H, -CH2), 3.78 (t, J = 7.4 Hz, 2H, -CH2), 3.82 (s, 6H, 26 -OCH3), 3.98
(q, 2H, -OCH2), 6.46 (s, 1H, -C=CH), 7.18 (d, J = 8.29 Hz, 2H, Ar-H),
7.23 (d, 2H, J = 8.29 Hz, Ar-H), 7.29 (s, 1H, Ar-NH), 7.18–7.78 (m,
7H, Ar-H), 8.82 (s, 1H, Ar-NH), 9.40 (s, 1H, CO-NH). ES-MS [m/z + 1]+:
599. Anal. calcd. for C31H30N6O7: C, 62.20; H, 5.05; N, 14.04.
Found: C, 60.25; H, 5.22; N, 13.98.
1-(2-Chlorophenyl)-3-(4-(3,4-dimethoxyphenethylamino)-
6-(2-oxo-2H-chromen-4-yloxy)-1,3,5-triazin-2-yl)thiourea
9e
Yield: 55%; IR m (max)/cm– 1: 3359; 2842; 1734; 1696; 1530; 1244;
1033; 808; 890. 1H-NMR d: 2.74 (t, J = 7.2 Hz, 2H, -CH2), 3.76 (t, J =
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Arch. Pharm. Chem. Life Sci. 2009, 342, 281–290
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7.31 Hz, 2H, -CH2), 3.85 (s, 6H, 26 -OCH3), 6.65 (s, 1H, -C=CH), 7.18
(dd, J = 2.3 Hz, J = 8.7 Hz, 1H, Ar-H), 7.29 (s, 1H, Ar-NH), 7.77 (dd, J
= 2.0 Hz, J = 8.2 Hz, 1H, Ar-H), 8.86 (s, 1H, Ar-NH), 9.61 (s, 1H, CS-
NH). ES-MS [m/z + 1]+: 606. Anal. calcd. for C29H25ClN6O5S: C,
57.57; H, 4.16; N, 13.89. Found: C, 57.52; H, 4.11; N, 13.94.
650. Anal. calcd. for C29H25BrN6O5S: C, 53.63; H, 3.88; N, 12.94.
Found: C, 53.58; H, 3.82; N, 12.98.
1-(4-(3,4-Dimethoxyphenethylamino)-6-(2-oxo-2H-
chromen-4-yloxy)-1,3,5-triazin-2-yl)-3-(4-
fluorophenyl)thiourea 9k
1-(3-Chlorophenyl)-3-(4-(3,4-dimethoxyphenethylamino)-
6-(2-oxo-2H-chromen-4-yloxy)-1,3,5-triazin-2-yl)thiourea
Yield: 62%; IR m (max)/cm– 1: 3352; 1738; 1689; 1539; 1347; 1234;
1154; 1028; 845; 805. 1H-NMR d: 2.68 (t, J = 7.2 Hz, 2H, -CH2), 3.74
(t, J = 7.3 Hz, 2H, -CH2), 3.86 (s, 6H, 26 -OCH3), 6.46 (s, 1H, -C=CH),
7.31 (s, 1H, Ar-NH), 7.49 (d, J = 8.3 Hz, 2H, Ar-H), 7.66 (d, J = 8.2 Hz,
2H, Ar-H), 8.91 (s, 1H, Ar-NH), 9.56 (s, 1H, CS-NH). ES-MS [m/z + 1]+:
589. Anal. calcd. for C29H25FN6O5S: C, 59.18; H, 4.28; N, 14.28.
Found: C, 59.25; H, 4.32; N, 14.21.
9f
Yield: 62%; IR m (max)/cm– 1: 3366; 2838; 1730; 1696; 1534; 1246;
1022; 889; 808. 1H-NMR d: 2.75 (t, J = 7.2 Hz, 2H, -CH2), 3.76 (t, J =
7.1 Hz, 2H, -CH2), 3.84 (s, 6H, 26 -OCH3), 6.46 (s, 1H, -C=CH), 7.29
(s, 1H, Ar-NH), 7.30 (dd, J = 2.2 Hz, J = 8.3 Hz, 1H, Ar-H), 7.72 (dd, J
= 1.9 Hz, J = 8.2 Hz, 1H, Ar-H), 8.86 (s, 1H, Ar-NH), 9.56 (s, 1H, CS-
NH). ES-MS [m/z + 1]+: 606. Anal. calcd. for C29H25ClN6O5S: C,
57.57; H, 4.16; N, 13.89. Found: C, 57.59; H, 4.18; N, 13.87.
1-(4-Chlorophenyl)-3-(4-(3,4-dimethoxyphenethylamino)-
6-(2-oxo-2H-chromen-4-yloxy)-1,3,5-triazin-2-yl)thiourea
1-(4-(3,4-Dimethoxyphenethylamino)-6-(2-oxo-2H-
chromen-4-yloxy)-1,3,5-triazin-2-yl)-3-(4-
9g
ethoxyphenyl)thiourea 9l
Yield: 70%; IR m (max)/cm– 1: 3366; 2837; 1721; 1690; 1535; 1352;
1244; 1029; 889; 882; 808. 1H-NMR d: 2.78 (t, J = 7.4 Hz, 2H, -CH2),
3.82 (t, J = 7.3 Hz, 2H, -CH2), 3.84 (s, 6H, 26 -OCH3), 6.46 (s, 1H, -
C=CH), 7.30 (s, 1H, Ar-NH), 7.46 (d, J = 8.3 Hz, 2H, Ar-H), 7.69 (d, J =
8.4 Hz, 2H, Ar-H), 8.89 (s, 1H, Ar-NH), 9.45 (s, 1H, CS-NH). ES-MS
[m/z + 1]+: 606. Anal. calcd. for C29H25ClN6O5S: C, 57.57; H, 4.16; N,
13.89. Found: C, 57.51; H, 4.20; N, 13.82.
Yield: 56%; IR m (max)/cm– 1: 3360; 2832; 1734; 1691; 1539; 1352;
1240; 1034; 809. 1H-NMR d: 1.30 (t, 3H, -CH3), 2.69 (t, J = 7.3 Hz,
2H, -CH2), 3.77 (t, J = 7.4 Hz, 2H, -CH2), 3.96 (q, 2H, -OCH2), 3.84 (s,
6H, 26 -OCH3), 6.66 (s, 1H, -C=CH), 7.15 (d, J = 8.1 Hz, 2H, Ar-H),
7.28 (d, J = 8.2 Hz, 2H, Ar-H), 7.38 (s, 1H, Ar-NH), 8.88 (s, 1H, Ar-
NH), 9.49 (s, 1H, CS-NH). ES-MS [m/z + 1]+: 615. Anal. calcd. for
C31H30N6O6S: C, 60.57; H, 4.92; N, 13.67. Found: C, 60.64; H, 4.95;
N, 13.69.
1-(4-(3,4-Dimethoxyphenethylamino)-6-(2-oxo-2H-
chromen-4-yloxy)-1,3,5-triazin-2-yl)-3-(2-
methoxyphenyl)thiourea 9h
1-(4-(3,4-Dimethoxyphenethylamino)-6-(2-oxo-2H-
chromen-4-yloxy)-1,3,5-triazin-2-yl)-3-(naphthalen-1-
yl)thiourea 9m
Yield: 72%; IR m (max)/cm– 1: 3362; 2833; 1727; 1691; 1540; 1352;
1233; 1034; 806. 1H-NMR d: 2.77 (t, J = 7.3 Hz, 2H, -CH2), 3.81 (t, J =
6.8 Hz, 2H, -CH2), 3.88 (s, 9H, 36 -OCH3), 6.65 (s, 1H, -C=CH), 7.21
(dd, J = 2.2 Hz, J = 8.3 Hz, 1H, Ar-H), 7.26 (s, 1H, Ar-NH), 7.78 (dd, J
= 2.2 Hz, J = 8.2 Hz, 1H, Ar-H), 8.87 (s, 1H, Ar-NH), 9.49 (s, 1H, CS-
NH). ES-MS [m/z + 1]+: 601. Anal. calcd. for C30H28N6O6S: C, 59.99;
H, 4.70; N, 13.99. Found: C, 60.01; H, 4.73; N, 14.04.
Yield: 60%; IR m (max)/cm– 1: 3359; 2838; 1729; 1690; 1536; 1350;
1244; 1032; 809. 1H-NMR d: 2.75 (t, J = 7.1 Hz, 2H, -CH2), 3.75 (t, J =
6.8 Hz, 2H, -CH2), 3.85 (s, 6H, 26 -OCH3), 6.46 (s, 1H, -C=CH), 7.21
(dd, J = 2.0 Hz, J = 8.3 Hz, 1H, Ar-H), 7.25 (s, 1H, Ar-NH), 7.74 (dd,
J = 1.9 Hz, J = 8.2 Hz, 1H, Ar-H), 8.82 (s, 1H, Ar-NH), 9.55 (s, 1H, CS-
NH). ES-MS [m/z + 1]+: 621. Anal. calcd. for C33H28N6O5S :C, 63.86;
H, 4.55; N, 13.54. Found: C, 63.91; H, 4.60; N, 13.60.
1-(4-(3,4-Dimethoxyphenethylamino)-6-(2-oxo-2H-
chromen-4-yloxy)-1,3,5-triazin-2-yl)-3-(4-
methoxyphenyl)thiourea 9i
Yield: 58%; IR m (max)/cm– 1: 3360; 2832; 1732; 1680; 1545; 1350;
1244; 1032; 807. 1H-NMR d: 2.77 (t, J = 7.1 Hz, 2H, -CH2), 3.72 (t, J =
7.6 Hz, 2H, -CH2), 3.84 (s, 9H, 36 -OCH3), 6.64 (s, 1H, -C=CH), 7.21
(d, J = 8.2 Hz, 2H, Ar-H), 7.32 (s, 1H, Ar-NH), 7.36 (d, J = 8.1 Hz, 2H,
Ar-H), 8.82 (s, 1H, Ar-NH), 9.56 (s, 1H, CS-NH). ES-MS [m/z + 1]+:
601. Anal. calcd. for C30H28N6O6S: C, 59.99; H, 4.70; N, 13.99.
Found: C, 59.96; H, 4.68; N, 13.95.
Ethyl 2-(4-chloro-6-(2-oxo-2H-chromen-4-yloxy)-1,3,5-
triazin-2-ylamino)acetate 11
Glycine ethylester hydrochloride (0.016 mol, 2.25 g) dissolved in
acetone / water (10 : 2, 60 mL) was slowly added to a well-stirred
slurry of 2-(coumarinyl-4-oxy)-4,6-dichloro-s-triazine (0.016 mol,
5.0 g.) in acetone (90 mL), maintaining the temperature at 458C.
The pH was adjusted to neutral by the addition of 10% NaHCO3
solution. The progress of reaction was monitored by TLC using
acetone / toluene (10 : 1) as eluent. The temperature was gradu-
ally raised to 508C during two hours and further maintained for
two hours. After completion of the reaction, the solution was
poured in ice-cold water. The solid product obtained was filtered
and dried. The crude product was purified by recrystallization
from acetone / ethyl acetate (1 : 1) to give the title compound 5.
Yield: 60%; m. p.: 222–2288C. C16H13ClN4O5 requires: N, 14.87.
Found N, 14.80.
1-(4-Bromophenyl)-3-(4-(3,4-dimethoxyphenethylamino)-
6-(2-oxo-2H-chromen-4-yloxy)-1,3,5-triazin-2-yl)thiourea
9j
Yield: 66%; IR m (max)/cm– 1: 3360; 2842; 1739; 1686; 1529; 1352,
1234; 1029; 809; 580. 1H-NMR d: 2.77 (t, J = 7.1 Hz, 2H, -CH2), 3.74
(t, J = 7.3 Hz, 2H, -CH2), 3.86 (s, 6H, 26 -OCH3), 6.46 (s, 1H, -C=CH),
7.30 (s, 1H, Ar-NH), 7.38 (d, J = 8.2 Hz, 2H, Ar-H), 7.44 (d, J = 8.2 Hz,
2H, Ar-H), 8.89 (s, 1H, Ar-NH), 9.49 (s, 1H, CS-NH). ES-MS [m/z + 1]+:
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Arch. Pharm. Chem. Life Sci. 2009, 342, 281–290
7.20 (s, 1H, Ar-NH), 7.32 (dd, J = 2.0 Hz, J = 8.0 Hz, 1H, Ar-H), 7.34
(dd, J = 2.3 Hz, J = 8.0 Hz, 1H, Ar-H), 8.20 (s, 1H, Ar-NH), 8.30 (s, 1H,
CO-NH). ES-MS [m/z + 1]+: 511. Anal. calcd. for C23H19ClN6O6: C,
54.07; H, 3.75; N, 16.45. Found: C, 53.98; H, 3.70; N, 16.52.
General procedure for the preparation of ethyl 2-(4-(2-
oxo-2H-chromen-4-yloxy)-6-(3-arylureido/arylamino)-
1,3,5-triazin-2-ylamino)acetate 12a–m / 13a–m
A mixture of ethyl 2-(4-chloro-6-(2-oxo-2H-chromen-4-yloxy)-1,3,5-
triazin-2-ylamino)acetate 11 (0.005 mol) and aryl urea / amine
(0.005 mol) in dioxane (50 mL) was refluxed on heating with stir-
ring at reflux temperature for four hours. The pH was adjusted
to neutral by the addition of 10% NaHCO3 solution. After comple-
tion of the reaction, the content was added to cold water. The
product obtained was purified by recrystallization from abso-
lute alcohol.
Ethyl 2-(4-(2-oxo-2H-chromen-4-yloxy)-6-(3-(3-
chlorophenyl) ureido)-1,3,5-triazin-2-ylamino)acetate 12f
Yield: 58%; IR m (max)/cm– 1: 3355; 2835; 1731; 1652; 1545; 1350;
1243; 1038; 885; 809. 1H-NMR d: 1.35 (t, J = 7.1 Hz, 3H, -CH3), 3.94
(s, 2H, -NHCH2), 4.23 (q, J = 7.1 Hz, 2H, -CH2), 6.65 (s, 1H, -C=CH),
7.19 (s, 1H, Ar-NH), 7.30 (dd, J = 2.3 Hz, J = 8.1 Hz, 1H, Ar-H), 7.34
(dd, J = 2.0 Hz, J = 8.1 Hz, 1H, Ar-H), 8.26 (s, 1H, Ar-NH), 8.33 (s, 1H,
CO-NH). ES-MS [m/z + 1]+: 511. Anal. calcd. for C23H19ClN6O6: C,
54.07; H, 3.75; N, 16.45. Found: C, 54.12; H, 3.72; N, 16.48.
Ethyl 2-(4-(2-oxo-2H-chromen-4-yloxy)-6-(3-
phenylureido)-1,3,5-triazin-2-ylamino) acetate 12a
Yield: 60%; IR m (max)/cm– 1: 3360; 2822; 1715; 1656; 1542; 1347;
1
1244; 1029; 810. H-NMR d: 1.37 (t, J = 7.1 Hz, 3H, -CH3), 3.98 (s,
Ethyl 2-(4-(2-oxo-2H-chromen-4-yloxy)-6-(3-(4-
2H, -NHCH2), 4.20 (q, J = 7.2 Hz, 2H, -OCH2), 6.46 (s, 1H, -C=CH),
7.26 (dd, J = 2.2 Hz, J = 8.3 Hz, 1H, Ar-H), 7.32 (s, 1H, Ar-NH), 7.65
(dd, J = 1.9 Hz, J = 8.2 Hz, 1H, Ar-H), 7.90 (s, 1H, Ar-NH), 8.07 (s, 1H,
CO-NH). ES-MS [m/z + 1]+: 477. Anal. calcd. for C23H20N6O6: C,
57.98; H, 4.23; N, 17.64. Found: C, 58.00; H, 4.20; N, 17.60.
chlorophenyl) ureido)-1,3,5-triazin-2-ylamino)acetate 12g
Yield: 60%; IR m (max)/cm– 1: 3361; 2840; 1738; 1656; 1547; 1359;
1248; 1044; 890; 806. 1H-NMR d: 1.33 (t, J = 7.1 Hz, 3H, -CH3), 3.96
(s, 2H, -NHCH2), 4.19 (q, J = 7.1 Hz, 2H, -CH2), 6.46 (s, 1H, -C=CH),
7.21 (s, 1H, Ar-NH), 7.66 (d, J = 8.1 Hz, 2H, Ar-H), 7.69 (d, J = 8.1 Hz,
2H, Ar-H), 8.30 (s, 1H, Ar-NH), 8.39 (s, 1H, CO-NH). ES-MS [m/z + 1]+:
511. Anal. calcd. for C23H19ClN6O6: C, 54.07; H, 3.75; N, 16.45.
Found: C, 54.15; H, 3.77; N, 16.49.
Ethyl 2-(4-(2-oxo-2H-chromen-4-yloxy)-6-(3-o-
tolylureido)-1,3,5-triazin-2-ylamino)acetate 12b
Yield: 62%; IR m (max)/cm– 1: 3365; 2824; 1720; 1654; 1535; 1351;
1
1243; 1032; 811. H-NMR d: 1.35 (t, J = 7.1 Hz, 3H, -CH3), 2.45 (s,
3H, -CH3), 3.95 (s, 2H, -NHCH2), 4.10 (q, J = 7.1 Hz, 2H, -CH2), 6.46 (s,
1H, -C=CH), 7.22 (dd, J = 2.2 Hz, J = 8.3 Hz, 1H, Ar-H), 7.28 (s, 1H,
Ar-NH), 7.32 (dd, J = 1.9 Hz, J = 8.3 Hz, 1H, Ar-H), 7.95 (s, 1H, Ar-
NH), 8.12 (s, 1H, CO-NH). ES-MS [m/z + 1]+: 491. Anal. calcd. for
C24H22N6O6: C, 58.77; H, 4.52; N, 17.13. Found: C, 58.70; H, 4.54;
N, 17.08.
Ethyl 2-(4-(2-oxo-2H-chromen-4-yloxy)-6-(3-(2-
methoxyphenyl) ureido)-1,3,5-triazin-2-ylamino)acetate
12h
Yield: 66%; IR m (max)/cm– 1: 3355; 2839; 1725; 1690; 1525; 1350;
1234; 1030; 807. 1H-NMR d: 1.32 (t, J = 7.1 Hz, 3H, -CH3), 3.81 (s,
3H, -OCH3), 3.91 (s, 2H, -NHCH2), 4.20 (q, J = 7.1 Hz, 2H, -CH2), 6.62
(s, 1H, -C=CH), 7.15 (s, 1H, Ar-NH), 7.19 (dd, J = 2.3 Hz, J = 8.0 Hz,
1H, Ar-H), 7.66 (dd, J = 2.0 Hz, J = 8.1 Hz, 1H, Ar-H), 8.22 (s, 1H, Ar-
NH), 8.31 (s, 1H, CO-NH). ES-MS [m/z + 1]+: 507. Anal Calcd for
C24H22N6O7: C, 56.92; H, 4.38; N, 16.59. Found: C, 57.03; H, 4.42;
N, 16.63.
Ethyl 2-(4-(2-oxo-2H-chromen-4-yloxy)-6-(3-m-
tolylureido)-1,3,5-triazin-2-ylamino)acetate 12c
Yield: 66%; IR m (max)/cm– 1: 3360; 2830; 1725; 1650; 1538; 1349;
1
1244; 1029; 810. H-NMR d: 1.33 (t, J = 7.1 Hz, 3H, -CH3), 2.40 (s,
3H, -CH3), 3.96 (s, 2H, -NHCH2), 4.12 (q, J = 7.1 Hz, 2H, -CH2), 6.65 (s,
1H, -C=CH), 7.20 (dd, J = 2.2 Hz, J = 8.3 Hz, 1H, Ar-H), 7.29 (s, 1H,
Ar-NH), 7.35 (dd, J = 1.9 Hz, J = 8.3 Hz, 1H, Ar-H), 7.98 (s, 1H, Ar-
NH), 8.20 (s, 1H, CO-NH). ES-MS [m/z + 1]+: 491. Anal. calcd. for
C24H22N6O6: C, 58.77; H, 4.52; N, 17.13. Found: C, 58.65; H, 4.48;
N, 17.17.
Ethyl 2-(4-(2-oxo-2H-chromen-4-yloxy)-6-(3-(4-
methoxyphenyl) ureido)-1,3,5-triazin-2-ylamino)acetate
12i
Yield: 62%; IR m (max)/cm– 1: 3356; 2832; 1730; 1690; 1520; 1347;
1243; 1025; 806. 1H-NMR d: 1.37 (t, J = 7.1 Hz, 3H, -CH3), 3.16 (s,
3H, -OCH3), 3.98 (s, 2H, -NHCH2), 4.00 (q, J = 7.1 Hz, 2H, -CH2), 6.47
(s, 1H, -C=CH), 6.80 (d, J = 8.0 Hz, 2H, Ar-H), 7.25 (s, 1H, Ar-NH),
7.28 (d, J = 8.1 Hz, 2H, Ar-H), 7.90 (s, 1H, CO-NH), 8.07 (s, 1H, Ar-
NH). ES-MS [m/z + 1]+: 507. Anal. calcd. for C24H22N6O7: C, 56.92; H,
4.38; N, 16.59. Found: C, 56.99; H, 4.34; N, 16.55.
Ethyl 2-(4-(2-oxo-2H-chromen-4-yloxy)-6-(3-p-
tolylureido)-1,3,5-triazin-2-ylamino)acetate 12d
Yield: 69%; IR m(max)/cm– 1: 3361; 2825; 1726; 1661; 1540; 1351;
1243; 1030; 808. 1H-NMR d: 1.38 (t, J = 7.1 Hz, 3H, -CH3), 2.40 (s,
3H, -CH3), 3.96 (s, 2H, -NHCH2), 4.10 (q, J = 7.1 Hz, 2H, -CH2), 6.46 (s,
1H, -C=CH), 7.20 (s, 1H, Ar-NH), 7.38 (d, J = 8.3 Hz, 2H, Ar-H), 7.55
(d, J = 8.41 Hz, 2H, Ar-H), 7.98 (s, 1H, Ar-NH), 8.15 (s, 1H, CO-NH).
ES-MS [m/z + 1]+: 491. Anal. calcd. for C24H22N6O6: C, 58.77; H,
4.52; N, 17.13. Found: C, 58.68; H, 4.54; N, 17.20.
Ethyl 2-(4-(2-oxo-2H-chromen-4-yloxy)-6-(3-(4-
bromophenyl) ureido)-1,3,5-triazin-2-ylamino)acetate 12j
Yield: 63%; IR m (max)/cm– 1: 3321; 2822; 1718; 1656; 1548; 1350;
1241; 1110; 817; 581. 1H-NMR d: 1.35 (t, J = 7.1 Hz, 3H, -CH3), 3.98
(s, 2H, -NHCH2), 4.22 (q, J = 7.2 Hz, 2H, -CH2), 6.46 (s, 1H, -C=CH),
7.25 (s, 1H, Ar-NH), 7.62 (d, J = 8.2 Hz, 2H, Ar-H), 7.68 (d, J = 8.1 Hz,
2H, Ar-H), 8.35 (s, 1H, Ar-NH), 8.40 (s, 1H, CO-NH). ES-MS [m/z + 1]+:
556. Anal. calcd. for C23H19BrN6O6: C, 49.74; H, 3.45; N, 15.13.
Found: C, 49.85; H, 3.52; N, 15.22.
Ethyl 2-(4-(2-oxo-2H-chromen-4-yloxy)-6-(3-(2-
chlorophenyl) ureido)-1,3,5-triazin-2-ylamino)acetate 12e
Yield: 55%; IR m (max)/cm– 1: 3360; 2832; 1726; 1658; 1540; 1347;
1243; 1034; 880; 809. 1H-NMR d: 1.38 (t, J = 7.1 Hz, 3H, -CH3), 3.92
(s, 2H, -NHCH2), 4.16 (q, J = 7.1 Hz, 2H, -CH2), 6.46 (s, 1H, -C=CH),
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Arch. Pharm. Chem. Life Sci. 2009, 342, 281–290
New S-Triazine Derivatives as Potential Anti-HIV Agents
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Ethyl 2-(4-(2-oxo-2H-chromen-4-yloxy)-6-(3-(4-
Ethyl 2-(4-(2-oxo-2H-chromen-4-yloxy)-6-(p-tolylamino)-
fluorophenyl) ureido)-1,3,5-triazin-2-ylamino)acetate 12k
Yield: 62%; IR m (max)/cm– 1: 3370; 2850; 1739; 1675; 1546; 1351;
1240; 1160; 1035; 808. 1H-NMR d: 1.38 (t, J = 7.1 Hz, 3H, -CH3), 4.00
(s, 2H, -NHCH2), 4.25 (q, J = 7.2 Hz, 2H, -CH2), 6.46 (s, 1H, -C=CH),
7.25 (s, 1H, Ar-NH), 7.65 (d, J = 8.2 Hz, 2H, Ar-H), 7.69 (d, J = 8.1 Hz,
2H, Ar-H), 8.39 (s, 1H, Ar-NH), 8.42 (s, 1H, CO-NH),. ES-MS [m/z +
1]+: 495. Anal. calcd. for C23H19FN6O6: C, 55.87; H, 3.87; N, 17.00.
Found: C, 55.98; H, 3.94; N, 17.15.
1,3,5-triazin-2-ylamino)acetate 13d
Yield: 62%; IR m (max)/cm– 1: 3300; 1714; 1340; 1226; 1109; 813.
1H-NMR d: 1.33 (t, J = 7.1 Hz, 3H, -CH3), 2.49 (s, 3H, -CH3), 3.94 (s,
2H, -NHCH2), 4.01 (q, J = 7.0 Hz, 2H, -OCH2), 6.46 (s, 1H, -C=CH),
7.13 (s, 1H, Ar-NH), 7.27 (d, J = 8.2 Hz, 2H, Ar-H), 7.40 (d, J = 8.1 Hz,
2H, Ar-H), 9.30 (s, 1H, Ar-NH-Ar). ES-MS [m/z + 1]+: 448. Anal. calcd.
for C23H21N5O5: C, 61.74; H, 4.73; N, 15.65. Found: C, 61.62; H,
4.67; N, 15.72.
Ethyl 2-(4-(2-oxo-2H-chromen-4-yloxy)-6-(3-(4-
Ethyl 2-(4-(2-oxo-2H-chromen-4-yloxy)-6-((2-
ethoxyphenyl) ureido)-1,3,5-triazin-2-ylamino)acetate 12l
Yield: 54%; IR m (max)/cm– 1: 3355; 2832; 1735; 1664; 1525; 1347;
1241; 1031; 806. 1H-NMR d: 1.30–1.35 (m, 6H, 26 -CH3), 4.00-4.15
(m, 6H, 36 -CH2), 6.50 (s, 1H, -C=CH), 6.98 (d, J = 8.2 Hz, 2H, Ar-H),
7.22 (d, J = 8.1 Hz, 2H, Ar-H), 7.28 (s, 1H, Ar-NH), 8.31 (s, 1H, Ar-
NH), 8.40 (s, 1H, CO-NH). ES-MS [m/z + 1]+: 521. Anal. calcd. for
C25H24N6O7: C, 57.69; H, 4.65; N, 16.15. Found: C, 57.75; H, 4.60;
N, 16.05.
chlorophenyl)amino)-1,3,5-triazin-2-ylamino)acetate 13e
Yield: 66%; IR m (max)/cm– 1: 3360; 1725; 1345; 1230; 1049; 884;
808. 1H-NMR d: 1.37 (t, J = 7.1 Hz, 3H, -CH3), 3.96 (s, 2H, -NHCH2),
4.18 (q, J = 7.1 Hz, 2H, -CH2), 6.46 (s, 1H, -C=CH), 7.15 (s, 1H, Ar-
NH), 7.28 (dd, J = 2.3 Hz, J = 8.0 Hz, 1H, Ar-H), 7.60 (dd, J = 2.0 Hz, J
= 8.2 Hz, 1H, Ar-H), 9.36 (s, 1H, Ar-NH-Ar). ES-MS [m/z + 1]+: 468.
Anal. calcd. for C22H18ClN5O5: C, 56.48; H, 3.88; N, 14.97. Found:
C, 56.55; H, 3.92; N, 14.90.
Ethyl 2-(4-(2-oxo-2H-chromen-4-yloxy)-6-(3-(1-naphthyl)
Ethyl 2-(4-(2-oxo-2H-chromen-4-yloxy)-6-((3-
ureido)-1,3,5-triazin-2-ylamino)acetate 12m
chlorophenyl)amino)-1,3,5-triazin-2-ylamino)acetate 13f
Yield: 56%; IR m (max)/cm– 1: 3366; 1728; 1349; 1235; 1052; 880;
810. 1H-NMR d: 1.35 (t, J = 7.1 Hz, 3H, -CH3), 3.98 (s, 2H, -NHCH2),
4.22 (q, J = 7.1 Hz, 2H, -CH2), 7.18 (s, 1H, Ar-NH), 6.46 (s, 1H, -
C=CH), 7.25 (dd, J = 2.2 Hz, J = 8.1 Hz, 1H, Ar-H), 7.64 (dd, J =
2.0 Hz, J = 8.2 Hz, 1H, Ar-H), 9.39 (s, 1H, Ar-NH-Ar). ES-MS [m/z +
1]+: 468. Anal. calcd. for C22H18ClN5O5: C, 56.48; H, 3.88; N, 14.97.
Found: C, 56.39; H, 3.74; N, 15.10.
Yield: 60%; IR m (max)/cm– 1: 3307; 2880; 1715; 1652; 1552; 1336;
1
1237; 1026; 865. H-NMR d: 1.35 (t, J = 7.1 Hz, 3H, -CH3), 4.02 (s,
2H, -NHCH2), 4.20 (q, J = 7.2 Hz, 2H, -CH2), 6.46 (s, 1H, -C=CH), 7.21
(s, 1H, Ar-NH), 7.28 (dd, J = 2.2 Hz, J = 8.3 Hz, 1H, Ar-H), 7.72 (dd, J
= 1.9 Hz, J = 8.2 Hz, 1H, Ar-H), 8.40 (s, 1H, Ar-NH), 8.47 (s, 1H, CO-
NH). ES-MS [m/z + 1]+: 527. Anal. calcd. for C27H22N6O6: C, 61.59; H,
4.21; N, 15.96. Found: C, 61.69; H, 4.15; N, 16.08.
Ethyl 2-(4-(2-oxo-2H-chromen-4-yloxy)-6-(phenylamino)-
1,3,5-triazin-2-ylamino)acetate 13a
Ethyl 2-(4-(2-oxo-2H-chromen-4-yloxy)-6-((4-
chlorophenyl)amino)-1,3,5-triazin-2-ylamino)acetate 13g
Yield: 67%; IR m (max)/cm– 1: 3366; 1728; 1349; 1235; 1052; 880;
810. 1H-NMR d: 1.35 (t, J = 7.1 Hz, 3H, -CH3), 3.98 (s, 2H, -NHCH2),
4.22 (q, J = 7.1 Hz, 2H, -CH2), 6.46 (s, 1H, -C=CH), 7.18 (s, 1H, Ar-
NH), 7.33 (d, J = 8.1 Hz, 2H, Ar-H), 7.69 (d, J = 8.1 Hz, 2H, Ar-H),
9.39 (s, 1H, Ar-NH-Ar). ES-MS [m/z + 1]+: 468. Anal. calcd. for
C22H18ClN5O5: C, 56.48; H, 3.88; N, 14.97. Found: C, 56.45; H, 3.85;
N, 14.89.
Yield: 70%; IR m (max)/cm– 1: 3360; 1720; 1347; 1244; 1029; 810.
1H-NMR d: 1.37 (t, J = 7.1 Hz, 3H, -CH3), 3.98 (s, 2H, -NHCH2), 4.10
(q, J = 7.2 Hz, 2H, -OCH2), 6.46 (s, 1H, -C=CH), 7.25 (s, 1H, Ar-NH),
7.22 (dd, J = 2.0 Hz, J = 8.2 Hz, 1H, Ar-H), 7.68 (dd, J = 1.9 Hz, J =
8.2 Hz, 1H, Ar-H), 9.38 (s, 1H, Ar-NH-Ar). ES-MS [m/z + 1]+: 434.
Anal. calcd. for C22H19N5O5: C, 60.97; H, 4.42; N, 16.16. Found: C,
61.15; H, 4.56; N, 16.02.
Ethyl 2-(4-(2-oxo-2H-chromen-4-yloxy)-6-(o-tolylamino)-
1,3,5-triazin-2-ylamino)acetate 13b
Ethyl 2-(4-(2-oxo-2H-chromen-4-yloxy)-6-((2-
methoxyphenyl)amino)-1,3,5-triazin-2-ylamino)acetate
13h
Yield: 56%; IR m (max)/cm– 1: 3365; 1729; 1347; 1246; 1025; 812.
1H-NMR d: 1.33 (t, J = 7.0 Hz, 3H, -CH3), 2.45 (s, 3H, -CH3), 3.95 (s,
2H, -NHCH2), 4.06 (q, J = 7.1 Hz, 2H, -OCH2), 6.47 (s, 1H, -C=CH),
7.21 (s, 1H, Ar-NH), 7.26 (dd, J = 2.1 Hz, J = 8.2 Hz, 1H, Ar-H), 7.71
(dd, J = 1.9 Hz, J = 8.2 Hz, 1H, Ar-H), 9.38 (s, 1H, Ar-NH-Ar). ES-MS
[m/z + 1]+: 448. Anal. calcd. for C23H21N5O5: C, 61.74; H, 4.73; N,
15.65. Found: C, 61.62; H, 4.85; N, 15.55.
Yield: 60%; IR m (max)/cm– 1: 3409; 1728; 1350; 1219; 1028; 807.
1H-NMR d: 1.32 (t, J = 7.1 Hz, 3H, -CH3), 3.18 (s, 3H, -OCH3), 3.92 (s,
2H, -NHCH2), 4.10 (q, J = 7.14 Hz, 2H, -OCH2), 6.47 (s, 1H, -C=CH),
7.19 (s, 1H, Ar-NH), 7.28 (dd, J = 2.1 Hz, J = 8.2 Hz, 1H, Ar-H), 7.69
(dd, J = 2.0 Hz, J = 8.2 Hz, 1H, Ar-H), 9.36 (s, 1H, Ar-NH-Ar). ES-MS
[m/z + 1]+: 464. Anal. calcd. for C23H21N5O6: C, 59.61; H, 4.57; N,
15.11. Found: C, 59.72; H, 4.65; N, 15.02.
Ethyl 2-(4-(2-oxo-2H-chromen-4-yloxy)-6-(m-tolylamino)-
1,3,5-triazin-2-ylamino)acetate 13c
Ethyl 2-(4-(2-oxo-2H-chromen-4-yloxy)-6-((4-
methoxyphenyl)amino)-1,3,5-triazin-2-ylamino)acetate
Yield: 62%; IR m (max)/cm– 1: 3370; 1735; 1352; 1249; 1032; 810.
1H-NMR d: 1.35 (t, J = 7.1 Hz, 3H, -CH3), 3.92 (s, 2H, -NHCH2), 2.41
(s, 3H, -CH3), 4.05 (q, J = 7.0 Hz, 2H, -OCH2), 6.50 (s, 1H, -C=CH),
7.18 (s, 1H, Ar-NH), 7.22 (dd, J = 2.1 Hz, J = 8.2 Hz, 1H, Ar-H), 7.71
(dd, J = 1.9 Hz, J = 8.2 Hz, 1H, Ar-H), 9.35 (s, 1H, Ar-NH-Ar). ES-MS
[m/z + 1]+: 448. Anal. calcd. for C23H21N5O5: C, 61.74; H, 4.73; N,
15.65. Found: C, 61.60; H, 4.66; N, 15.71.
13i
Yield: 59%; IR m (max)/cm– 1: 1730; 1355; 1222; 1026; 810. 1H-NMR
d: 1.35 (t, J = 7.1 Hz, 3H, -CH3), 3.18 (s, 3H, -OCH3), 3.95 (s, 2H, -
NHCH2), 4.16 (q, J = 7.1 Hz, 2H, -OCH2), 6.47 (s, 1H, -C=CH), 7.19 (s,
1H, Ar-NH), 7.30 (dd, J = 2.1 Hz, J = 8.2 Hz, 1H, Ar-H), 7.69 (dd, J =
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Arch. Pharm. Chem. Life Sci. 2009, 342, 281–290
2.0 Hz, J = 8.2 Hz, 1H, Ar-H), 9.36 (s, 1H, Ar-NH-Ar). ES-MS [m/z +
1]+: 464. Anal. calcd. for C23H21N5O6: C, 59.61; H, 4.57; N, 15.11.
Found: C, 59.70; H, 4.68; N, 15.22.
microtiter tray wells. Mock-infected cells were used to evaluate
the effect of test compound on uninfected cells in order to assess
the cytotoxicity of the test compound. Exponentially growing
MT-4 cells were centrifuged for 5 min at 1000 rpm, and the
supernatant was discarded. The MT-4 cells were resuspended at
66105 cells/mL, and an amount of 50 lL volume was transferred
to the microtiter tray wells. Five days after infection, the viabil-
ity of mock- and HIV-infected cells were examined spectrophoto-
metrically by the MTT assay.
The MTT assay is based on the reduction of yellow 3-(4,5-dime-
thylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (Across
Organics, Geel, Belgium) by mitochondrial dehydrogenase of
metabolically active cells to a blue-purple formazan that can be
measured spectrophotometrically. The absorbances were read
in an eight-channel computer-controlled photometer (Multiscan
Ascent Reader, Labsystem, Helsinki, Finland) at two wavelengths
(540 and 690 nm). All data were calculated using the median OD
(optical density) value of three wells.
Ethyl 2-(4-(2-oxo-2H-chromen-4-yloxy)-6-((4-
bromophenyl)amino)-1,3,5-triazin-2-ylamino)acetate 12j
Yield: 60%; IR m (max)/cm– 1: 3580; 1732; 1359; 1226; 1036; 811;
589. 1H-NMR d: 1.36 (t, J = 7.0 Hz, 3H, -CH3), 4.18 (s, 2H, -NHCH2),
4.25 (q, J = 7.0 Hz, 2H, -CH2), 6.48 (s, 1H, -C=CH), 7.26 (s, 1H, Ar-
NH), 7.67 (d, J = 8.1 Hz, 2H, Ar-H), 7.69 (d, J = 8.1 Hz, 2H, Ar-H),
9.41 (s, 1H, Ar-NH-Ar). ES-MS [m/z + 1]+: 513. Anal. calcd. for
C22H18BrN5O5: C, 51.58; H, 3.54; N, 13.67. Found: C, 51.72; H, 3.58;
N, 13.59.
Ethyl 2-(4-(2-oxo-2H-chromen-4-yloxy)-6-((4-
fluorophenyl)amino)-1,3,5-triazin-2-ylamino)acetate 13k
Yield: 63%; IR m (max)/cm– 1: 3565; 1736; 1345; 1222; 1165; 1030;
806. 1H-NMR d: 1.39 (t, J = 7.1 Hz, 3H, -CH3), 4.15 (s, 2H, -NHCH2),
4.27 (q, J = 7.2 Hz, 2H, -CH2), 6.46 (s, 1H, -C=CH), 6.90 (d, J = 7.9 Hz,
2H, Ar-H), 7.29 (s, 1H, Ar-NH), 7.45 (d, J = 8.0 Hz, 2H, Ar-H), 9.40 (s,
1H, Ar-NH-Ar). ES-MS [m/z + 1]+: 452. Anal. calcd. for C22H18FN5O5:
C, 58.54; H, 4.02; N, 15.51. Found: C, 58.53; H, 4.10; N, 15.45.
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i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com