Synthesis and antileishmanial profile of some novel terpenyl pyrimidines

Article abstract of DOI:10.1016/j.ejmech.2004.03.007

Some novel terpenyl pyrimidine derivatives 2(a-d) and 6(a-b) have been synthesised from α/β-ionone keteneacetals 1 and 5. The terpenyl pyrimidine 2e has been synthesised from β-ionone 3 in two steps in quantitative yield. The pyrimidine derivatives were s

Full text of DOI:10.1016/j.ejmech.2004.03.007

European Journal of Medicinal Chemistry 39 (2004) 969–973
www.elsevier.com/locate/ejmech
Short communication
Synthesis and antileishmanial profile
of some novel terpenyl pyrimidines>
Susmita Pandey a, S.N. Suryawanshi a,*, Suman Gupta b, V. M.L. Srivastava b
a Division of Medicinal Chemistry, Central Drug Research Institute, Lucknow, India
b Division of Parasitology, Central Drug Research Institute, Lucknow, India
Received 22 September 2003; received in revised form 5 March 2004; accepted 11 March 2004
Available online 30 September 2004
Abstract
Some novel terpenyl pyrimidine derivatives 2(a–d) and 6(a–b) have been synthesised from a/b-ionone keteneacetals 1 and 5. The terpenyl
pyrimidine 2e has been synthesised from b-ionone 3 in two steps in quantitative yield. The pyrimidine derivatives were screened for in-vivo
antilesihmanial activity. The compounds 2d, 2e, 6a and 6b showed promising in-vivo antileishmanial activity.
© 2004 Elsevier SAS. All rights reserved.
Keywords: Ionones; Terpenyl pyrimidines; Antileishmanial activity
1. Introduction
therapy [4]. Although pentamidine is less toxic than antimo-
nials but still it is not free from side effects such as hypogly-
cemia, diabetes, nephrotoxicity and pain at site of infection.
Antibiotic amphoterecin-B is the second line of drug for the
treatment of visceral leishmaniasis. It shows better response
even in cases resistant to the antimonials and diamidines [5],
but it is quite toxic such as nephrotoxicity and cardiotoxicity
[6]. The development of new antileishmanial agents is ex-
tremely important, considering the high toxicity of the exist-
ing clinical drugs.
Currently, efforts are being made to search for new mol-
ecules from the natural sources and in this endeavour. Diaryl
heptanoids [7], oxygenated abietanes [8], diterpene quinones
[9] are showing promise as new lead molecules. Randomly
designed heterocyclic ionone like molecules [10] and some
novel terpenyl 2,4-diamino pyrimidines [11] are showing
promising antimicrobial and dihydrofolate reductase inhibi-
tory activities. Rationally designed 2,4-diaminopyrimidines
[12] and some computer aided molecules [13] are also giving
further inputs in the leishmanial dihydrofoliate reductase
activity. Prompted with these literature reports we designed
some novel terpenyl pyrimidines and evaluated for their in
vivo antileishmanial activity and the results are reported in
this communication (Scheme 1).
Leishmaniasis is an infection caused by protozoa of the
genus Leishmania presenting several forms of the disease
such as cutaneous (CL), mucocutaneous (MCL) and visceral
leishmaniasis (VL), which can be fatal when untreated. The
disease is endemic in some tropical areas of the world and in
under developed countries, directly affecting about 2 million
people per annum, with approximately 350 million people
under the risk of contracting the disease worldwide [1,2]. The
incidence for new cases of leishmaniasis is increasing daily
and currently is emerging as a common and serious opportu-
nistic infection in human immuno deficiency virus (HIV)
infected patients [3]. The current treatment for the leishma-
niasis is now based on the pentavalent antimonials, as sodium
stibogluconate (pentostam), meglumine antimonate (glucan-
time). The long course of treatment with antimonials leads to
the accumulation of the drug in the liver and spleen. The
lengthy treatment with antimonials often causes side effects
such as myalgia, pancreatitis, cardiac arrhythmia and hepati-
tis leading to the reduction or cessation of treatment. Penta-
midine is a second line of drug for the treatment of visceral
leishmaniasis in patients who failed to respond to antimony
2. Chemistry
> CDRI Communication No. 6451.
a-oxoketene dithioacetals of aromatic substrates are very
* Corresponding author.
E-mail address: shivajins@yahoo.co.in (S.N. Suryawanshi).
useful synthons in the synthesis of variety of heterocyclic and
© 2004 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2004.03.007

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S. Pandey et al. / European Journal of Medicinal Chemistry 39 (2004) 969–973
.
Scheme 1
carbocyclic compounds [14]. However, a-oxoketene dithio-
acetals of terpene substrates are some what more labile but
can be realised on a multigram scale [15]. The reaction of
a-oxoketene dithioacetal 1 with guanidine in refluxing etha-
nol furnished 2a in 50% yield. Similarly, the reaction of
a-oxoketene dithioacetal 1 with guanidine in n-butanol and
or benzyl alcohol under reflux conditions furnished 2b and or
2c in good yields. Initially, the preparation of 2d proved to be
problematic. However, after some experimentation the reac-
tion of a-oxoketene dithioacetal 1 with guanidine in isopro-
pyl alcohol at 140 °C (steel bomb, 24 h) furnished 2d in 50%
yield. The terpenyl pyrimidine 2e was prepared as shown in
Scheme 2. The reaction of b-ionone with sodium hydride and
dimethyl carbonate in toluene at reflux temperature (6 h)
furnished 4 in near quantitative yield [16]. The reaction of
ketoester 4 with guanidine in refluxing ethanol furnished 2e
in quantitative yield. a-ionone based a-oxoketene dithioac-
etal 5 on reaction with guanidine in refluxing ethanol (48 h)
furnished 6a in 52% yield. The reaction of 5 with guanidine
in isopropanol (140 °C, steel bomb, 24 h) furnished 6b in
23% yield (Scheme 3).
3. Biological activities
The in vivo leishmanicidal activity against amastigote
stage of Leishmania donovani was determined in Golden
hamsters
(Mesocricotus
aurctus)
infected
with
HOM/IN/80/DD8 strain of L. donovani obtained by courtesy
of PCC Garnham, Imperial College, London (UK). Male
hamsters weighing 35–40 g were infected with 1 × 107
amastigotes and the intensity of infection was assessed by
spleen biopsy. Animals with 2+ infections (5–
15 amastigote/100 cell nuclei) were chosen for screening
drugs. Usually 4–6 animals were used for each dose of the
drug and the same numbers were kept as controls. The treat-
.
Scheme 2
.
Scheme 3

S. Pandey et al. / European Journal of Medicinal Chemistry 39 (2004) 969–973
971
Table 1
1-yl)-penta-1,4-(z)-dien-3-one (5.92 g, 20 mmol) was added
to the reaction mixture and stirred for 48 h. The reaction
mixture was concentrated in vacuo, poured into water and
extracted with ethylacetate (100 ml × 3). The combined
extract was washed with water (100 ml × 3), brine solution
(100 ml), dried (Na2SO4) and the solvent was removed in
vacuo. The crude product was chromatographed (SiO2, 60–
120 mesh). Elution with 7% ethylacetate in hexane furnished
starting compound (2.00 g). Further elution with 15% ethy-
lacetate in hexane furnished 2a (2.5 g, 50%) as a white
crystalline solid. m.p. 135–138 °C. IR (KBr, cm–1) 3332,
3216, 2926, 1642, 1566, 1448. 1H NMR (CDCl3, 200 MHz)
d 1.06 (s, 6H), 1.35 (t, J = 7.00 Hz, 3H) 1.50 (m, 2H) 1.60 (m,
2H), 1.75 (s, 3H), 2.05 (m, 2H), 4.30 (q, 2H), 4.90 (m, 2H),
6.05 (s, 1H), 6.20 (d, J = 16.00 Hz, 1H), 7.30 (d, J = 16.00 Hz,
1H). 13C NMR (CDCl3, 200 MHz) d 14.872 (q), 19.515 (t),
22.130 (q), 2 × 29.300 (q), 33.621 (t), 34.597 (s), 40.083 (t),
62.228 (t), 95.324 (d), 130.774 (d), 132.439 (s), 135.228 (d),
137.343 (s), 163.171 (s), 164.804 (s), 171.471 (s). MS: (m/e),
288 (M+ + 1) (M+–CH3).
Antileishmanial activity of compounds against amastigotes of Leishmania
donovani in hamsters
Sr. no.
Compound number
Dose (mg/kg) In vivo inhibition (%)
Day-7
47
Day-28
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
6a
6b
50
50
50
50
50
50
50
–
53
–
40
–
66
–
22
63
–
64
64
–
ment of test animals was carried out by giving injection of the
drug suspension daily for 5 days intraperitoneally. The post-
treatment spleen biopsies were performed on each animal
after 7 and 28 days of drug administration. On the basis of the
intensity of infection (number of amastigote/100 spleen cell
nuclei) in treated animal in comparison to control animals.
The percentage inhibition was calculated in individual
treated animals.
The leishmanicidal activity of various screened com-
pounds 2(a–e), 6(a–b) is presented in Table 1. The com-
pounds were screened at 50 mg/kg/day × 5 and the activity
found is expressed at the minimum effective dose.
5.2. 6-(2,6,6-trimethyl-1-cyclohex-1-yl)
ethenyl-2-amino-4-n-butyloxy pyrimidine (2b)
To a solution of sodium butoxide (prepared by dissolving
(0.12 g of sodium metal in 80 ml of dry n-butanol) was added
guanidine hydrochloride (0.32 g, 0.5 mmol) and stirred the
reaction mixture for 0.5 h at room temperature. 1,1-
dimethylmercapto-5-(2,6,6-trimethyl-1-cyclohex-2-en-1-
yl)penta-1,4-(z)-dien-3-one (1.48 gm, 5 mmol )was added to
the reaction mixture and stirred at room temperature for 48 h.
It was concentrated in vacuo, poured into water and extracted
with ethylacetate (50 ml × 3). The combined extract was
washed with water (50 ml × 3), brine solution (50 ml), dried
(Na2SO4) and the solvent was removed in vacuo. The crude
product after column chromatography (SiO2, 60–120 mesh)
furnished colourless thick liquid (0.560 g, 39%) which after
crystallisation from ether–hexane furnished 2b as a colorless
crystalline solid. m.p. 105–106 °C, IR (KBr, cm–1) 3388,
3207, 2929, 1647, 1568. 1H NMR (CDCl3, 200 MHz) d 0.90
(t, 3H), 1.00 (s, 6H), 1.50 (m, 2H) 1.70 (m, 2H), 1.75 (s, 3H),
2.00 (t, 2H), 4.20 (t, 2H), 4.80 (m, 2H), 6.00 (s, 1H), 6.15 (d,
J = 16.00 Hz, 1H), 7.25 (d, J = 16.00 Hz, 1H). 13C NMR
(CDCl3, 200 MHz) d 14.208 (q), 19.532 (t), 19.577 (t),
22.130 (q), 2 × 29.307 (q), 33.586 (t), 34.588 (s), 40.070 (t),
66.187 (t), 95.257 (d), 131.013 (d), 132.285 (s), 135.054 (d),
137.356 (s), 163.305 (s), 164.986 (s), 171.622 (s). MS: (m/e),
316 (M+ + 1) 300 (M+–CH3), 260 (M+–CH3CH2CH=CH2).
4. Results and discussion
Out of all the compounds screened 2b, 2d, 6a and 6b
found most active showing 50–65% activity at 50 mg/kg
doses. Interestingly, compound 2e showed 63% activity on
day 28, which probably is acting through immunostimulation
[17]. Rest of the compounds showed moderate activity.
5. Experimental protocol
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
downfield from Me4Si. Proton, carbon NMR spectra were
recorded on BrukerAdvance DRX 2000 instrument. Electron
impact (EI) mass spectra were recorded on a Jeol JMS-D-300
spectrometer with the ionisation potential of 70 eV. Elemen-
tal analysis was carried out on a Carlo-Erba EA 1108 instru-
ment, and agrees within 0.4% with calculated values.
5.1. 6-(2,6,6-trimethyl-1-cyclohexene-1-yl)
ethenyl-2-amino-4-ethoxyl pyrimidine (2a)
5.3. 6-(2,6,6-trimethyl-cyclohex-1-yl)ethenyl-2-amino-4-n-
benzyloxy pyrimidine (2c)
To a solution of sodium ethoxide (prepared by dissolving
sodium metal 0.72 g, in absolute alcohol (60 ml) was added
guanidine hydrochloride (1.04 g, 22 mmol) and stirred the
reaction mixture for 0.5 h at room temperature. 1,1-
dimethylmercapto-5-(2,6,6-trimethyl-1-cyclohex-2-ene-
To a solution of sodium benzyloxide (prepared by dissolv-
ing sodium metal (0.80 g) in dry benzyl alcohol (20 ml) was
added guanidine hydrochloride (0.32 g, 0.5 mmol) and

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S. Pandey et al. / European Journal of Medicinal Chemistry 39 (2004) 969–973
stirred the reaction mixture for 0.5 h. 1,1-dimethylmercapto-
5-(2,6,6-trimethyl-1-cyclohex-2-en-1-yl)penta-1,4-(z)-dien-
3-one (1.48 gm, 5.00 mmol) was added. Resulting reaction
mixture was magnetically stirred for 36 h at room tempera-
ture. It was concentrated in vacuo, poured into water and
extracted with ethylacetate (50 ml × 3), dried (Na2SO4) and
the solvent was removed in vacuo. The crude product was
column chromatographed (SiO2, 60–120 mesh) to furnish 2c
as a white crystalline solid (0.786 g, 21%), m.p. 120–121 °C.
sodium sulfate, concentrated in vacuo and purified by col-
umn chromatography (SiO2, 60–120 mesh) to furnish 4 as a
thick liquid (13.00 g, 90%). IR (neat, cm–1): 2954, 1744,
1650. 1H NMR (200 MHz, CDCl3): d 1.00 (s, 6H), 1.50 (m,
2H), 1.60 (m, 2H), 1.80 (s, 3H), 2.01 (m, 2H), 3.70 (s, 2H),
3.75 (s, 3H), 6.20 (d, J = 16.00 Hz), 7.35 (d, J = 16.00 Hz,
1H). MS: m/e 250 (M+), 235 (M+–CH3).
5.6. 6-(2,6,6-trimethyl-1-cyclohexene-1-yl)-ethenyl-2-
amino-pyrimidine-4-one (2e)
1
IR (KBr, cm–1) 3328, 3214, 2924, 1636, 1564. H NMR
(200 MHz, CDCl3) d 1.10 (s, 6H), 1.50 (m, 2H), 1.65 (m,
2H), 1.85 (s, 3H), 2.10 (m, 2H), 4.90 (bs, 2H), 5.35 (s, 2H),
6.10 (s, 1H), 6.20 (d, J = 16 Hz, 1H), 7.40 (m, 6H). 13C NMR
(CDCl3, 200 MHz) d 19.540 (t), 22.174 (q), 2 × 29.343 (q),
33.644 (t), 34.627 (s), 40.100 (t), 67.925 (t), 95.710 (d), 3 ×
128.437 (d), 2 × 128.906 (d), 130.912 (d), 132.482 (s),
135.322 (d), 137.171 (s), 137.354 (s), 163.125 (s),
165.302 (s), 171.254 (s). MS: (m/e), 350 (M+ + 1), 334
(M+–CH3).
To a solution of methyl-5-(2′,6′,6′-trimethylcyclohex-1′-
enyl)-3-keto-4-pentenoate 4 (5.00 g, 20 mmol) in dry isopro-
panol (10 ml) was added guanidine solution in isopropanol
(3.80 g, 40 mmol, 40 ml) and the reaction mixture was heated
in a steel bomb at 130–140 °C for 16 h. It was concentrated in
vacuo, poured into water (30 ml) and extracted with dichlo-
romethane (100 ml × 2), brine solution (50 ml), dried
(Na2SO4) and the solvent was removed in vacuo. The crude
product was column chromatographed (SiO2, 60–120 mesh)
to furnish 2e as white crystalline solid (2.00 g, 40%), m.p.
5.4. 6-(2,6,6-trimethyl-1-cyclohexene-1-yl)
ethenyl-2-amino-4-thiomethyl pyrimidine (2d)
1
250–253 °C. IR (KBr, cm–1): 3331, 3171, 2928, 1599. H
NMR (200 MHz, CDCl3) d 1.028 (m, 6H), 1.50 (m, 2H), 1.60
(m, 2H), 1.71 (s, 3H), 2.10 (m, 2H), 5.60 (s, 1H), 6.10 (d,
J = 16.00 Hz, 1H), 6.50 (m, 2H), 7.20 (d, J = 16.00 Hz, 1H),
10.69 (m, 1H). 13C NMR (200 MHz, CDCl3) d 18.327 (t),
21.105 (q), 2 × 28.420 (q), 32.336 (s), 33.470 (t), 39.571 (t),
100.108 (d), 130.520 (s), 130.884 (d), 132.946 (d),
136.235 (s), 154.857 (s), 161.066 (s), 163.054 (s). MS: m/e
(259).
To
a
solution of 1,1-dimethylmercapto-5-(2,6,6-
trimethyl-1-cyclohex-1-ene-1-yl) penta-1,4-(z)-diene-3-one
(5.92 g, 20 mmol )in dry isopropanol (20 ml) was added
guanidine solution in isopropanol (1.90 g, 20 mmol,
20 ml)and the reaction mixture was heated in steel bomb at
120–130 °C for 24 h. It was concentrated in vacuo, poured
into water (30 ml) and extracted with ethylacetate (50 ml ×
4). Combined extract was washed with water (50 ml × 2),
brine solution (50 ml) dried (Na2SO4) and the solvent was
removed in vacuo. The crude product was column chromato-
graphed (SiO2, 60–120 mesh) to furnish 2d as a white crys-
talline solid (2.80 g, 50%). m.p. 98–100 °C. IR (KBr, cm–1)
3314, 2922, 1628, 1516, 1432, 1312, 1H NNR (CDCl3,
200 MHz) d 1.07 (s, 6H), 1.60 (m, 2H), 1.63 (m, 2H), 1.66 (s,
3H) 2.08 (m, 2H), 2.50 (s, 3H), 5.00 (s, 2H), 6.27 (d,
J = 17.00 Hz, 1H), 6.56 (s, 1H), 7.34 (d, J = 17.00 Hz, 1H).
13C NMR (CDCl3, 200 MHz) d 12.76 (q), 19.49 (t), 22.16
(q), 2 × 29.32 (q), 33.66 (t), 34.61 (s), 40.10 (t), 106.24 (d),
130.53 (d), 132.89 (s), 136.06 (d), 137.34 (s), 162.37 (s),
162.66 (s), 171.63 (s). MS (m/e): 290 (M+ + 1), 275 (M+–
CH3). Anal. C16H23N3S (C,H,N).
5.7. 6-(2,6,6-Trimethyl-1-cyclohexen-1-yl)
ethenyl-2-amino-4-ethoxylpyrimidine (6a)
To a solution of sodium ethoxide (prepared by the reaction
of sodium 6.72 g in absolute alcohol (60 ml) was added
guanidine hydrochloride (1.04 g, 22 mmol) and stirred the
reaction mixture for 0.5 h at room temperature. 1,1-
dimethylmercapto-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-
penta-1,4-(z)-dien-3-one (5.92 g, 20 mmol) was added and
the resulting reaction mixture was stirred for 48 h at room
temperature. The reaction mixture was poured into water
(50 ml) and extracted with ethylacetate (50 ml × 4). Com-
bined extract was washed with water (50 ml × 2), brine
solution (50 ml), dried (Na2SO4) and the solvent was re-
moved in vacuo. The crude product was column chromato-
graphed (SiO2, 60–120 mesh). Elution with 7% ethylacetate
in hexane furnished starting compound (2.00 g, 33%). Con-
tinued elution with 15% ethylacetate in hexane furnished 6a
(2.72 g, 52%) as a white crystalline solid. m.p. 109–110 °C.
5.5. Methyl-5-(2′,6′,6′-trimethylcyclohex-1′-enyl)-3-keto-4-
pentenoate (4)
Sodium hydride (3.5 g, 50% suspension in oil, 73 mmol)
was added to a solution of b-ionone (14.00 g, 72 mmol) and
dimethyl carbonate (13.00 g, 144 mmol) in toluene (150 ml)
and the stirred reaction mixture was held at 100 °C for 1.5 h.
After cooling, a mixture of ether (250 ml), cone. HCl (35 ml),
water (85 ml) was carefully added with vigorous stirring. The
organic layer and subsequent ether extract of aqueous phase
were combined washed with water (50 ml × 2), dried on
1
IR (KBr cm–1) 3350, 3176, 2916, 1664, 1579. H NMR
(CDCl3, 200 MHz) d 0.90 (s, 3H), 1.00 (s, 3H), 1.60 (s, 3H),
2.00 (bs, 2H), 2.30 (d, J = 8.00 Hz, 1H), 6.20 (d, J = 16.00 Hz,
1H), 6.70 (dd, J = 16.00, 10.00 Hz, 1H). 13C NMR (CDCl3,
200 MHz) d 14.864 (q), 23.343 (q), 23.495 (t), 27.291 (q),
28.239 (q), 31.757 (s), 32.953 (t), 54.959 (d), 62.139 (t),

S. Pandey et al. / European Journal of Medicinal Chemistry 39 (2004) 969–973
973
95.128 (d), 122.140 (d), 130.273 (d), 133.527 (s),
References
139.734 (d), 163.259 (s), 164.826 (s), 171.434 (s). MS (m/e):
287 (M+) 272(M+–CH3). Anal. C17H25ON3 (C,H,N).
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5.8. 6-(2,6,6-trimethyl-2-cyclohexen-1-yl)
ethenyl-2-amino-4-thiomethyl pyrimidine (6b)
To a solution of 1,1-dimethylmercapto-5-(2,6,6-trimethyl-
2-cyclohexen-1-yl)-penta-1,4-(z)-dien-3-one
(6.53
g,
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22 mmol) in dry isopropanol (20 ml) was added guanidine
solution in isopropanol (1.90 g, 20 ml, 20 mmol) and the
reaction mixture was heated in a steel bomb at 120–130 °C for
24 h. It was concentrated in vacuo, poured into water and
extracted with ethylacetate (50 ml × 4). The combined extract
was washed with water (50 ml × 2), brine solution (50 ml),
dried (Na2SO4) and the solvent was removed in vacuo. The
crude product was column chromatographed (SiO2, 60–
120 mesh). Elution with 10% ethylacetate in hexane furnished
6b as a white crystalline solid (2.00 g, 33%). m.p. 74–75 °C.
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IR (KBr, cm–1) 3510, 3410, 3314, 2940, 1540, 1440. H
1
NMR (CDCl3, 200 MHz) d 0.75 (s, 3H), 1.15 (m, 1H), 1.40
(m, 1H), 1.55 (s, 3H), 2.00 (m, 2H), 2.25 (d, J = 10.00 Hz,
1H), 2.40 (s, 3H), 4.85 (bs, 2H), 5.40 (bs, 1H), 6.05 (d,
J = 16.00 Hz, 1H), 6.50 (s, 1H), 6.65 (dd, J = 16.00, 10.00 Hz,
1H). 13C NMR (CDCl3, 200 MHz) d 12.747 (q), 23.358 (q),
23.504 (t), 27.27 (q), 28.329 (t), 31.692 (s), 33.002 (t),
55.044 (d), 105.926 (d), 122.306 (d), 129.980 (d),
133.378 (s), 140.813 (d), 162.088 (s), 162.668 (s),
171.641 (s). MS: (m/e) 289 (M+), 274 (M+–CH3).
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Financial support to Susmita Pandey by ICMR, New
Delhi and technical support by Mrs. Manju is gratefully
acknowledged.