Antileishmanial agents part-IV: Synthesis and antileishmanial activity of novel terpenyl pyrimidines

Article abstract of DOI:10.1016/j.ejmech.2005.01.004

Some novel N- and O-substituted terpenyl pyrimidines 4 (a-j) have been synthesized and screened for in vitro antileishmanial activity profile in promastigote model. Some of the compounds exhibited 100% inhibition at 10:μg:ml^-1 concentration.

Full text of DOI:10.1016/j.ejmech.2005.01.004

European Journal of Medicinal Chemistry 40 (2005) 552–556
www.elsevier.com/locate/ejmech
Antileishmanial agents part-IV: synthesis and antileishmanial activity
of novel terpenyl pyrimidines
Naveen Chandra a, Ramesh b, Ashutosh c, Neena Goyal c, S.N. Suryawanshi a,*, Suman Gupta b
a Division of Medicinal Chemistry, Central Drug Research Institute, Lucknow 226001, India
b Division of Parasitology, Central Drug Research Institute, Lucknow 226001, India
c Division of Biochemistry, Central Drug Research Institute, Lucknow 226001, India
Received and accepted 19 January 2005
Available online 02 March 2005
Abstract
Some novel N- and O-substituted terpenyl pyrimidines 4 (a–j) have been synthesized and screened for in vitro antileishmanial activity
profile in promastigote model. Some of the compounds exhibited 100% inhibition at 10 µg ml–1 concentration.
© 2005 Elsevier SAS. All rights reserved.
Keywords: a-Ionone; Terpenyl pyrimidine; Antileishmanial agents
1. Introduction
microtubule inhibitors [11] are under investigation at various
stages of drug development.
The leishmaniasis is a complex of diseases caused by at
least 17 species of the protozoan parasite Leishmania. The
disease is distributed worldwide, but mainly in the tropics
and subtropics, with a prevalence of 12 million cases and an
approximated incidence of 0.5 million cases of visceral (VL)
and 1.5 million cases of cutaneous leishmaniasis (CL). The
main drug treatments, pentavalent antimonials [1], which were
introduced some 50 years ago, are subject to development of
resistance. Although new drugs i.e. amphoterecin B and its
lipid complex [2] are quite effective but they are expensive
and out of reach of poor people. Newly introduced first orally
active drug miltefosine [3] is quite effective but shows terato-
genic effects and cannot be used in the pregnant women. The
search for new drugs continues, with bisphosphonates for
example residronate and pamidronate. Natural products are
not behind and derivatives of licochalcone A [4] and quino-
line alkaloids [5] are reported to have activity against experi-
mental animal infections.
Among the biochemical targets, DHFR is quite successful
in malaria (pyrimethamine and cycloguanil), bacteria (trime-
thoprim) and cancer (methotrexate). However, these classi-
cal DHFR inhibitors show no selectivity for the leishmanial
or trypanosomal enzymes. Computer aided modulation stud-
ies [12] between the leishmanial/trypanosomal and human
enzyme yielded some new chemical entities with in vitro bio-
logical profile [13]. In our continuation of studies on natural
product based pyrimidines [14], we synthesized some novel
terpene substituted diaminopyrimidines and evaluated them
for in vitro antileishmanial profile and the results are reported
in this communication.
2. Chemistry
The reported methodology [14] gives an excellent access
to oxygen substituted terpenyl pyrimidines. However, this
methodology is least applicable to the synthesis of diaminopy-
rimidines. Moreover, in the synthesis of oxygen substituted
pyrimidines, we used terpene based ketene acetals as key syn-
thons which involves use of carbon disulfide which is an envi-
ronmentally least friendly reaction. To do this, we visualized
1,3-ketoester 2 as a key synthon and can be extended to
required diaminopyrimidines as shown in Scheme 1.
Some biochemical targets trypanothione reductase [6], cys-
teine peptidases [7], sterol biosynthesis [8], dihydrofolate
reductase (DHFR) [9], ornithine decarboxylase [10], and
* Corresponding author. Tel.: +91 522 221 2411 18; fax: +91 522 222
3405/3938/9504.
E-mail address: shivajins@yahoo.co.in (S.N. Suryawanshi).
0223-5234/$ - see front matter © 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2005.01.004

N. Chandra et al. / European Journal of Medicinal Chemistry 40 (2005) 552–556
553
Scheme 1
.
The commercially available a-ionone 1 on reaction with
dimethyl carbonate and sodium hydride in refluxing toluene
furnished 1,3-ketoester 2 in 72% yield [15]. The classical con-
densation of 1,3-ketoester 2 with pre-prepared guanidine in
isopropanol (D, 16 h) furnished pyrimidone 3 in 54% yield.
The poor yield of pyrimidone 3 forced us to undertake few
exploratory studies. However, the results were not very
encouraging. The modified method [16] using guanidine car-
bonate and azeotropic removal of water did not help us to
improve the yield. The synthesis of chloride 4 was also prob-
lematic in the beginning. The classical methods used for the
aryl substituted pyrimidines [16] were not very useful on labile
terpenyl pyrimidone 3. However, the reaction of 3 with POCl3
in the presence of diisopropylethylamine [17] furnished chloro
compound 4 in quantitative yield. Having achieved the syn-
thesis of chloro compound on a comfortable scale it was used
for the synthesis of a chemical library of diamino pyrim-
idines as shown in Scheme 1.
3. Biological activities
3.1. Material and methods
Parasite: Luciferase transfected Leishmania donovani pro-
mastigotes (MHOM/IN/80/Dd-8, obtained from Imperial Col-
lege, London) which are more stable under the influence of G
418 [18] were maintained at 25 1 °C in Medium 199 (Sigma
Chemical Co., USA) supplemented with 10% foetal calf
serum (GIBCO).
3.2. In vitro assay
3.2.1. For extracellular (against promastigotes)
leishmanicidal activity
The effect of compounds on the growth of promastigotes
was assessed by monitoring the luciferase activity of viable
cells after treatment. The transgenic promastigotes of late log

554
N. Chandra et al. / European Journal of Medicinal Chemistry 40 (2005) 552–556
phase were seeded at 5 × 105/100 µl medium 199 per well in
96-well flat bottom microtitre (MT) plates (CELLSTAR) and
were incubated for 72 h in medium alone or in presence of
serial dilutions of drugs (250 ng ml–1 to 10 µg ml–1) in DMSO
[18]. Parallel dilutions of DMSO were used as controls.After
incubation, an aliquot (50 µl) of promastigote suspension was
aspirated from each well of 96-well plate and mixed with
equal volume of Steady Glo reagent (Promega) and lumines-
cence was measured in luminometer. The values were ex-
pressed as relative luminescence unit (RLU).
5.1. Methyl-5-(2,6,6-trimethyl-cyclohex-2-enyl)-3-keto-4-
pentenoate (2)
Sodium hydride (0.70 g, 29.00 mmol) was added to
a-ionone 1 (1.49 g, 1.50 ml, 7.29 mmol) and dimethyl car-
bonate (1.70 g, 1.59 ml, 18.8 mmol) in dry toluene (15.00 ml).
The magnetically stirred reaction mixture was held at 110 °C
for 3 h. Upon cooling a mixture of ether (25.00 ml), conc.
HCl (3.50 ml) and water (8.50 ml) was carefully added. After
vigorous stirring, the organic layer and a subsequent ether
extract of the aqueous phase were combined, dried (Na2SO4)
and evaporated to yield 2 as a pale yellow oil (1.31 g, 72%).
1H NMR (CDCl3, 200 MHz) d 0.80 (s, 3H), 0.90 (s, 3H),
1.25 (m, 1H), 1.45 (m, 1H), 1.55 (s, 3H), 2.00 (m, 2H), 2.20
(m, 1H), 3.60 (s, 2H), 3.70 (s, 3H), 5.45 (m, 1H), 5.72 (d,
J = 16.00 Hz, 0.5H), 6.10 (d, J = 16.00 Hz, 0.5H), 6.50 (dd,
J = 16.00, 10.00 Hz, 0.5H), 6.75 (dd, J = 16.00, 10.00 Hz,
0.5H).
4. Results and discussion
The diaminopyrimidines 5 (a–g) and oxygen substituted
pyrimidines 5 (h–j) were subjected to in vitro antileishma-
nial screening in the promastigote model (Table 1). The com-
pounds 5 (a–j) showed 100% inhibition at 10 µg ml–1 con-
centration. There is very little differentiation between anilino,
morpholino and pyrrolidino substitution. p-anisidino substi-
tution as in 5c proved better which showed 98.8% inhibition
at a 1 µg ml–1 concentration. The oxygen substituted pyrimi-
dine 5i and 5j showed 99% inhibition at 5 µg ml–1 concen-
tration. More compounds need to be prepared on a diami-
nopyrimidine and they will have to be subjected to in vitro
screening followed by the in vivo testing.
5.2. 2-Amino-6-[2-(2,6,6-trimethyl-cyclohex-2-enyl)-ethe-
nyl]-3H-pyrimidine-4-one (3)
To a solution 2 (2.50 g, 10 mmol) in dry isopropanol
(20 ml) was added guanidine solution in isopropanol (20 ml,
10 mmol) and refluxed at 90 °C for 16 h. The reaction mix-
ture was filtered through celite and the filtrate was extracted
with ethylacetate (2 × 30 ml). The combined extract was
washed with H2O (2 × 30 ml), brine (2 × 30 ml) and dried
(Na2SO4). The solvent was removed in vacuo. The crude prod-
uct thus obtained was column chromatographed (SiO2,
60–120 mesh). Elution with 2% MeOH in CHCl3 furnished 3
(1.40 g, 54%) as a white crystalline compound. IR (cm–1,
KBr): 2918, 1631, 1465, 1366; 1H NMR (CDCl3, 200 MHz)
d 0.80 (s, 3H), 0.90 (s, 3H), 1.20 (m, 1H), 1.40 (m, 3H), 1.50
(s, 3H), 2.00 (m, 2H), 2.25 (d, J = 10.00 Hz, 1H), 5.40 (m,
2H), 5.50 (s, 1H), 6.00 (d, J = 16.00 Hz, 1H), 6.50 (m, 1H);
13C NMR (CDCl3, 200 MHz) d 2 × 22.958 (q), 26.925 (q),
27.959 (q), 31.303 (t), 32.349 (s), 54.056 (d), 100.367 (d),
121.439 (d), 130.283 (d), 133.378 (s), 138.584 (d), 155.575
(s), 161.439 (s), 163.755 (s); MS: m/z 260 (M+ + 1).
5. Experimental
The reported melting points (°C) are the uncorrected ones.
The infrared spectra were recorded in KBr on a Perkin Elmer
model 881. NMR spectra were obtained in CDCl3 (with Me4Si
internal standard, Aldrich) and are reported in ppm down-
field from Me4Si. Proton, carbon NMR spectra were recorded
on Bruker Advance DRX 2000 instrument. Electron impact
(EI) mass spectra were recorded on a JEOL JMS-D-300 spec-
trometer with the ionization potential of 70 eV. Elemental
analyses were carried out on a Carlo-Erba EA 1108 instru-
ment.
5.3. 3-Chloro-5-[2-(2,6,6-trimethyl-cyclohex-2-enyl)-ethe-
Table 1
In vitro antileishmanial profile in promastigote model
nyl]-phenyl amine (4)
Compound numbers Concentration
Percent inhibition
71.0, 57.50, 19.0
100, 94, 30
4
5, 2, 1 µg ml–1
To a solution of 3 (500 mg, 1.92 mmol) in POCl3 (1.16 ml,
9.40 mmol) was added N,N-diisopropylethylamine (0.40 ml,
1.92 mmol) dropwise and the resulting mixture stirred at room
temperature for 8 h. Excess of POCl3 was removed in vacuo
and crude product was taken in dichloromethane (20 ml). It
was neutralized with aq. sol. of NH3. The combined extract
was washed with H2O (2 × 20 ml), brine (2 × 20 ml), dried
(Na2SO4) and solvent was removed in vacuo to yield 4 as a
brown oil (530 mg, 99%). IR (neat, cm–1): 2924, 1628, 1554,
1461, 1307, 758; 1H NMR (CDCl3, 200 MHz) d 0.87 (s, 3H),
0.94 (s, 3H), 1.52 (m, 1H), 1.58 (m, 1H), 1.70 (s, 3H), 2.00
(m, 2H), 2.25 (d, J = 10.00 Hz, 1H), 5.10 (m, 2H), 5.49 (bs,
5a
5b
5c
10, 5, 2.5 µg ml–1
10, 5, 2, 1 µg ml–1
10, 5, 2, 1 µg ml–1
500, 250 ng ml–1
10, 5, 2, 1 µg ml–1
10, 5, 2, 1 µg ml–1
10, 5, 2, 1 µg ml–1
500, 250 ng ml–1
100, 99.22, 22.85, 10.4
100, 98.89, 99.86, 98.8,
78.72, 21.49
,
,
5d
5e
5f
100, 99.94, 92.17, 61.47
100, 97.6, 58.7, 18.41
100, 99.8, 96.98, 88.06,
33.29, 30.31
5g
5h
5i
25, 10, 5, 1 µg ml–1
ND
100, 84.0, 92.38, 50.1
ND
10, 5, 2, 1 µg ml–1
10, 5, 2, 1 µg ml–1
100, 99.27, 58.0, 29.18
100, 99.1, 75.6, 39.6
5j

N. Chandra et al. / European Journal of Medicinal Chemistry 40 (2005) 552–556
555
1H), 6.17 (d, J = 16.00 Hz, 1H), 6.60 (s, 1H), 6.90 (dd,
5.3.4. 4-(4-Phenyl-piprazine-1-yl)-6-[2-(2,6,6-trimethyl-
cyclohex-2-enyl)-ethenyl]-pyrimidine-2-ylamine (5d)
J = 16.00, 10.00 Hz, 1H); 13C NMR (CDCl3, 200 MHz) d
22.159 (q), 23.467 (t), 29.295 (q), 30.070 (q), 33.059 (s),
33.761 (t), 54.075 (d), 108.048 (d), 122.645 (d), 129.160 (d),
132.984 (s), 142.959 (d), 161.896 (s), 163.230 (s), 165.916
(s); MS: m/z 278 (M+ + 1).
Yield: 41%. IR (neat, cm–1): 3409, 2925, 1574, 1536, 1499,
1447, 1228, 992, 759; 1H NMR (CDCl3, 200 MHz) d 0.88 (s,
3H), 0.95 (s, 3H), 1.30 (m, 2H), 1.60 (s, 3H), 2.00 (m, 2H),
2.30 (d, J = 10.00 Hz, 1H), 3.25 (m, 4H), 3.80 (m, 4H), 4.80
(bs, 2H), 5.50 (m, 1H), 5.95 (s, 1H), 6.15 (d, J = 16.00 Hz,
1H), 6.60 (dd, J = 16.00, 10.00 Hz, 1H), 6.95 (m, 3H), 7.30
(m, 2H); 13C NMR (CDCl3, 200 MHz) d 23.424 (q), 23.552
(t), 27.311 (q), 28.380 (q), 29.735 (t), 30.073 (d), 2 × 44.284
(t), 2 × 49.559 (t), 55.056 (d), 91.938 (d), 2 × 116.822 (d),
120.628 (d), 122.077 (d), 2 × 130.955 (d), 133.731 (s),
138.786 (d), 151.547 (s), 2 × 163.131 (s), 164.186 (s) MS:
m/z 404 (M+ + 1).
5.3.1. N4-(4-methoxy-phenyl)-6-[2-(2,6,6-trimethyl-cyclo-
hex-2-enyl)-ethenyl]-pyrimidine-2,4-diamine (5a)
To a solution of 4 (530 mg, 1.91 mmol) in isopropanol
(25.00 ml) was added p-methoxyaniline (472 mg, 3.84 mmol)
and stirred for 12 h at room temperature. After completion of
the reaction, it was concentrated in vacuo and the extract was
taken in EtOAc (20 ml) followed by washing with H2O (2 ×
15 ml), brine (2 × 15 ml) dried (Na2SO4) and it was concen-
trated in vacuo. The crude product thus obtained was column
chromatographed (SiO2, 60–120 mesh). Elution with 30%
ethyl acetate in hexane furnished 5a as a crystalline com-
pound (293 mg, 43%). M.p. 123–125 °C; IR (KBr, cm–1):
5.3.5. N4-phenyl-6-[2-(2,6,6-trimethyl-cyclohex-2-enyl)-
ethenyl]-pyrimidine-2,4-diamine (5e)
Yield: 44%. IR (neat, cm–1): 3488, 3309, 3185, 2923, 1571,
1449, 1404, 756; 1H NMR (CDCl3, 200 MHz) d 0.86 (s, 3H),
0.91 (s, 3H), 1.25 (m, 2H), 1.60 (s, 2H), 1.70 (s, 3H), 2.00
(m, 2H), 5.00 (m, 2H), 6.00 (s, 1H), 6.15 (d, 1H), 7.36 (m,
6H); 13C NMR (CDCl3, 200 MHz) d 23.358 (q), 23.495 (t),
27.259 (q), 28.288 (q), 32.992 (t), 33.684 (s), 55.058 (d),
93.049 (d), 122.273 (d), 2 × 122.885 (d), 124.886 (d), 3 ×
129.695 (d), 133.389 (s), 138.951 (s), 140.386 (d), 162.617
(s), 2 × 162.810 (s); MS: m/z 336 (M+ + 2).
1
3369, 3213, 2955, 1572, 1508, 1240; H NMR (CDCl3,
200 MHz) d 0.85 (s, 3H), 0.91 (s, 3H), 1.42 (m, 2H), 1.73 (s,
3H), 2.00 (m, 2H), 2.25 (d, J = 10.00 Hz, 1H), 5.85 (s, 1H),
6.10 (d, J = 16.00 Hz, 1H), 6.40 (m, 1H), 6.55 (dd, J = 16.00,
10.00 Hz, 1H), 6.90 (d, J = 8.00 Hz, 2H), 7.26 (d, J = 8.00 Hz,
2H); 13C NMR (CDCl3, 200 MHz) d 23.409 (q), 23.504 (t),
27.285 (q), 28.336 (q), 31.674 (t), 32.674 (t), 32.969 (s),
54.967 (d), 55.903 (q), 92.950 (d), 2 × 114.983 (d), 122.124
(d), 2 × 125.948 (d), 130.510 (d), 133.560 (s), 134.797 (s),
139.322 (d), 157.523 (s), 163.248 (s), 163.345 (s), 163.873
(s); MS: m/z 365 (M+ + 1). Analysis calculated for
C22H28N4O: C, 72.50, H, 7.74, N, 15.37. Found: C, 72.62; H,
7.85, N, 15.49.
5.3.6. 4-Piperidin-1-yl-6-[2-(2,6,6-trimethyl-cyclohex-2-
enyl)-ethenyl]-pyrimidine-2-ylamine (5f)
Yield: 55%. IR (neat, cm–1): 3321, 2927, 2856, 1574, 1532,
1
1418; H NMR (CDCl3, 200 MHz) d 0.85 (s, 3H), 0.95 (s,
3H), 1.20 (m, 2H), 1.55 (s, 9H), 2.00 (m, 2H), 2.25 (d,
J = 10.00 Hz, 1H), 3.55 (m, 4H), 4.35 (m, 2H), 5.45 (m, 1H),
5.90 (s, 1H), 6.10 (d, J = 16.00, 1H), 6.60 (q, J = 16.00,
10.00 Hz, 1H); 13C NMR (CDCl3, 200 MHz) d 23.413 (q),
23.537 (t), 25.136 (t), 26.014 (t), 27.296 (q), 28.356 (q),
29.348 (s), 30.066 (t), 31.721 (t), 2 × 45.472 (t), 55.054 (d),
91.887 (d), 121.991 (d), 130.784 (d), 133.777 (s), 138.425
(d), 162.197 (s), 162.929 (s), 163.860 (s), ; MS: m/z 327
(M+ + 1).
5.3.2. N4-(4-chloro-phenyl)-6-[2-(2,6,6-trimethyl-cyclohex-
2-enyl)-ethenyl]-pyrimidine-2,4-diamine (5b)
Yield: 47%. IR (neat, cm–1): 3376, 2925, 1620, 1517, 1493,
1283, 761; 1H NMR (CDCl3, 200 MHz) d 0.86 (s, 3H), 0.92
(s, 3H), 1.25 (m, 2H), 1.45 (m, 2H), 1.60 (s, 3H), 2.00 (m,
2H), 5.00 (bs, 2H), 5.29 (s, 1H), 5.45 (bs, 1H), 6.00 (s, 1H),
6.15 (d, J = 16.00 Hz, 1H), 6.60 (d, J = 10.00 Hz, 1H), 6.70
(q, J = 16.00, 10.00 Hz, 1H), 7.08 (d, 2H); 13C NMR (CDCl3,
200 MHz) d 23.407 (t), 23.520 (q), 27.269 (q), 28.374 (q),
31.660 (t), 33.003 (s), 32.969 (s), 55.016 (d), 93.530 (d), 2 ×
116.650 (d), 122.309 (d), 123.622 (d), 129.648 (d), 133.386
(s), 137.825 (s), 140.176 (d), 145.403 (s), 162.546 (s), 162.546
(s), 162.989 (s), 163.376 (s).
5.3.7. 4-Morpholin-4-yl-6-[2-(2,6,6-trimethyl-cyclohex-2-
enyl)-ethenyl]-pyrimidine-2-ylamine (5g)
Yield: 40%. IR (neat, cm–1): 2922, 1643, 1484, 1446, 1392,
1228, 1115, 984, 757; 1H NMR (CDCl3, 200 MHz) d 0.90 (s,
3H), 0.95 (s, 3H), 1.30 (m, 2H), 1.60 (s, 3H), 2.00 (m, 2H),
2.30 (d, 1H), 3.60 (m, 4H), 3.75 (m, 4H), 4.90 (m, 2H), 5.45
(bs, 1H), 5.90 (s, 1H), 6.10 (d, J = 16.00, 1H), 6.60 (q,
J = 16.00, 10.00 Hz, 1H); MS: m/z 329 (M+ + 1).
5.3.3. 4-Piprazine-1-yl-6-[2-(2,6,6-trimethyl-cyclohex-2-
enyl)-ethenyl]-pyrimidine-2-ylamine (5c)
5.3.8. 4-Methoxy-6-[2-(2,6,6-trimethyl-cyclohex-2-enyl)-
ethenyl]-pyrimidine-2-ylamine (5h)
To a solution of 25% CH3ONa in methanol (2 ml) was
added 4 (320 mg, 1.23 mmol) in methanol (15.00 ml) and the
resulting mixture stirred at room temperature for 12 h. After
completion, it was concentrated in vacuo and the residue was
Yield: 38%. IR (neat, cm–1): 3344, 2925, 1581, 1417, 1356;
1H NMR (CDCl3, 200 MHz) d 0.80 (s, 3H), 0.85 (s, 3H),
1.35 (m, 2H), 1.50 (s, 3H), 1.90 (m, 2H), 2.20 (d, J = 10.00 Hz,
1H), 2.60 (m, 4H), 3.35 (m, 4H), 5.40 (m, 1H), 6.00 (m, 5H),
6.50 (dd, J = 16.00, 10.00 Hz, 1H); MS: m/z 328 (M+ + 1).

556
N. Chandra et al. / European Journal of Medicinal Chemistry 40 (2005) 552–556
taken in EtOAc (15 ml) followed by washing with H2O (2 ×
20 ml), brine (2 × 10 ml) dried (Na2SO4) and it was concen-
trated in vacuo. The crude product thus obtained was column
chromatographed (SiO2, 60–120 mesh). Elution with 10%
ethyl acetate in hexane furnished 5h (150 mg, 57%). IR (KBr,
cm–1): 3332, 2925, 1575, 1450, 1369, 1199; 1H NMR (CDCl3,
200 MHz) d 0.90 (s, 3H), 0.95 (s, 3H), 1.30 (m, 2H), 1.60 (s,
3H), 2.00 (m, 2H), 2.30 (d, J = 10.00 Hz, 1H), 3.90 (s, 3H),
4.90 (m, 2H), 5.50 (m, 1H), 6.00 (s, 1H), 6.20 (d, J = 16.00 Hz,
1H), 6.65 (dd, J = 16.00, 10.00 Hz, 1H); 13C NMR (CDCl3,
200 MHz) d 23.363 (q), 23.503 (t), 27.285 (q), 28.277 (q),
31.731 (t), 32.977 (s), 53.757 (q), 54.969 (d), 95.101 (d),
122.213 (d), 129.993 (d), 133.468 (s), 140.050 (d), 163.116
(s), 164.579 (s), 171.834 (s); MS: m/z 275 (M+ + 1).Analysis
calculated for C16H23N3O: C, 70.23; H, 8.48; N, 15.37. Found:
C, 70.42; H, 8.65; N, 15.50.
Acknowledgements
Financial support to N.C. by MOH (India), Ramesh and
Ashutosh by CSIR, New Delhi and technical support by Mrs.
Manju and Mr. Shiv Ram are gratefully acknowledged.
References
[1] E. Moore, D. O’Flaherty, H. Heuvelmans, J. Seaman, H. Veeken,
S. De Wit, R.N. Davidson, Bull. World Health Organ. 79 (2001)
388–393.
[2] D.R. Goldsmith, C.M. Perry, Drugs 64 (2004) 1905–1911.
[3] S.L. Croft, K. Seifert, M. Duchene, Mol. Biochem. Parasitol. 126
(2003) 165–172.
[4] M. Chen, L. Zhai, S.B. Christensen, T.G. Theander, A. Kharazmi,
Antimicrob. Agents Chemother. 45 (2001) 2023–2029.
[5] C. Yates, Curr. Opin. Invest. Drugs 3 (2002) 1446–1452.
[6] D.S. Fries,A.H. Fairlamb, in: D.J.Abraham (Ed.), Burger’s Medicinal
Chemistry and Drug Discovery, vol. 5, sixth ed., Wiley, pp. 1033–
1087.
[7] M. Sajid, J.R. Mckerro, Mol. Biochem. Parasitol. 120 (2002) 1–21.
[8] C.W. Roberts, R. Mc Leod, D.W. Rice, M. Ginger, M.L. Chance,
L.J. Goad, Mol. Biochem. Parasitol. 126 (2003) 129–142.
[9] I.H. Gilbert, Biochem. Biophys. Acta 1587 (2002) 249–257.
[10] S. Muller, G.H. Coombs, R.D. Walter, Trends Parasitol. 17 (2001)
242–249.
5.3.9. 4-Ethoxy-6-[2-(2,6,6-trimethyl-cyclohex-2-enyl)-
ethenyl]-pyrimidine-2-ylamine (5i)
Yield: 58%. M.p. 102–104 °C; IR (KBr, cm–1): 3343, 3168,
2924, 1659, 1576, 1340; 1H NMR (CDCl3, 200 MHz) d 0.88
(s, 3H), 0.90 (s, 3H), 1.25 (m, 2H), 1.40 (t, 3H), 1.70 (s, 3H),
2.05 (m, 2H), 2.30 (d, J = 10.00 Hz, 1H), 4.30 (dd, 2H), 4.40
(m, 2H), 5.50 (m, 1H), 6.00 (s, 1H), 6.20 (d, J = 16.00 Hz,
1H), 6.60 (dd, J = 16.00, 10.00 Hz, 1H); MS: m/z 288
(M+ + 1). Analysis calculated for C17H25N3O: C, 71.04; H,
8.77; N, 14.62. Found: C, 71.22; H, 8.67; N, 14.77.
[11] K.G. Jayanarayan, C.S. Dey, J. Clin. Pharm. Ther. 27 (2002) 313–320.
[12] F. Shafinaz Chowdhury, R. Di Lucrezia, R. Hurtado Guerrero,
R. Brun, J. Goodman, L.M. Ruiz-Perez, et al., Bioorg. Med. Chem.
Lett. 11 (2001) 977–980.
[13] D. Pez, I. Leal, F. Zuccotto, C. Boussard, R. Brun, S.L. Croft, et al.,
Bioorg. Med. Chem. 11 (2003) 4693–4711.
[14] S. Pandey, S.N. Suryawanshi, S. Gupta, V.M.L. Srivastava, Eur. J.
Med. Chem. 39 (2004) 969–973.
[15] D. Herlem, J. Kervagoret, D. Yu, F. Khuong Huu, A.S. Kende, Tetra-
hedron 49 (1993) 607–618.
[16] D.R. Hannah, E.C. Sherer, R.V. Davies, R.B. Titman, C.A. Laughton,
M.F.G. Stevens, Bioorg. Med. Chem. 8 (2000) 739–750.
[17] E.O. Osmo Hormi, A.M. Paakkanen, J. Org. Chem. 52 (1987) 5275–
5276.
[18] Ashutosh et al., Poster presented in Chemistry Biology Interface:
Synergistic New Frontiers Nov. 21–26, 2004, New Delhi, India.
5.3.10. 4-Butoxy-6-[2-(2,6,6-trimethyl-cyclohex-2-enyl)-
ethenyl]-pyrimidine-2-ylamine (5j)
Yield: 55%. IR (Neat, cm–1): 3341, 3172, 2923, 1669,
1646, 1325; 1H NMR (CDCl3, 200 MHz) d 0.88 (s, 6H), 0.90
(s, 3H), 1.25 (m, 4H), 1.40 (t, 3H), 1.70 (s, 5H), 2.05 (m, 2H),
2.30 (d, J = 10.00 Hz, 1H), 4.30 (dd, 4H), 4.40 (m, 2H), 5.52
(m, 1H), 6.10 (s, 1H), 6.20 (d, J = 16.00 Hz, 1H), 6.65 (dd,
J = 16.00, 10.00 Hz, 1H); MS: m/z 315 (M+ + 1).