Chemotherapy of leishmaniasis part-VIII: Synthesis and bioevaluation of novel chalcones

Article abstract of DOI:10.1016/j.ejmech.2007.12.014

Some novel dihydro-α-ionone based chalcones have been synthesized and evaluated for their in vitro antileishmanial activity in promastigote and amastigote model. Some of the compounds showed 100% inhibition at 5 and 2 μm/ml concentration.

Full text of DOI:10.1016/j.ejmech.2007.12.014

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European Journal of Medicinal Chemistry 43 (2008) 2473e2478
http://www.elsevier.com/locate/ejmech
Original article
Chemotherapy of leishmaniasis part-VIII: Synthesis
and bioevaluation of novel chalcones*
a
a
a
b
S.N. Suryawanshi a, , Naveen Chandra , Pawan Kumar , Jyoti Porwal , Suman Gupta
*
a Division of Medicinal Chemistry, Central Drug Research Institute, Chatter Manzil, Lucknow 226001, India
b Division of Parasitology, Central Drug Research Institute, Chatter Manzil, Lucknow 226001, India
Received 21 August 2007; accepted 11 December 2007
Available online 27 December 2007
Abstract
Some novel dihydro-a-ionone based chalcones have been synthesized and evaluated for their in vitro antileishmanial activity in promastigote
and amastigote model. Some of the compounds showed 100% inhibition at 5 and 2 mm/ml concentration.
Ó 2008 Elsevier Masson SAS. All rights reserved.
Keywords: Dihydro-a-ionone; Chalcones; In vitro antileishmanial activity
1. Introduction
antileishmanial studies. Curcumin 1 isolated from Curcuma
longa Linn. (Fig. 1) is not only showing promise as anticancer
agent [5a] but it is showing antileishmanial activity profile in
the in vitro studies [5b,10]. Exhaustive analoging of curcumin
has generated some interesting results [11]. Licochalcone 2 iso-
lated from Glycerrhiza spp. was first reported for its antibacte-
rial activity [12] is also showing promising antileishmanial
activity [13]. Chemical library generated on the basis of Licho-
chalcone as a lead molecule is showing promise in the in vitro
antileishmanial studies [9a]. Phenolic diketone 3 isolated from
Zingiber officinale [14] is a structural mimic of 1 and 2 and
shows radical scavenging activities quite comparable to Curcu-
min 1. In continuation of our efforts to generate natural product
based novel antileishmanial agents [15] coupled with encourag-
ing results on 1e3, we synthesized some novel dihydro-a-ion-
one based chalcones and evaluated them for in vitro
antileishmanial activity and the results are reported in this
paper.
Leishmaniasis is an infection caused by protozoa of the ge-
nus Leishmania presenting several forms of the disease such as
cutaneous (CL), mucocutaneous (MCL) and visceral leish-
maniasis (VL), which can be fatal when untreated. The che-
motherapy currently available for leishmaniasis is far from
satisfactory. Resistance to the pentavalent antimonials [1,2],
which have been recommended drugs for the treatment of
both visceral (VL) and cutaneous leishmaniasis (CL) for
>50 years, is now widespread in India. Although new drugs
have become available in recent years for the treatment of
(VL) including amphotericin B lipid complex [3] and the
oral drug miltefosine [4], treatment problems remain.
In view of the high toxicity associated with the existing anti-
leishmanial drugs, efforts are being made to search for new
molecules from natural sources, which can act as a new lead
in the chemotherapy of Leishmania. In this endeavour, diaryl
heptanoids [5], oxygenated abietanes [6], diterpene quinones
[7,8], and chalcones [9] are showing promise in the in vitro
2. Chemistry
The dihydro-a-ionone 4 was made available using our pub-
lished method [16]. The reaction of dihydro-a-ionone 4 with
p-benzyloxy benzaldehyde 5a in the presence of KF/Al2O3 un-
der microwave irradiation (4e5 min) furnished chalcone 6a in
*
CDRI Communication no. 7317.
* Corresponding author. Tel.: þ91 2212411 18; fax: þ91 0522 2223405/938/
504.
E-mail address: shivajins@yahoo.co.in (S.N. Suryawanshi).
0223-5234/$ - see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.12.014

2474
S.N. Suryawanshi et al. / European Journal of Medicinal Chemistry 43 (2008) 2473e2478
O
O
transfected with firefly luciferase gene, and the transfectants
were maintained in medium 199 (Sigma Chemical Co.,
USA) supplemented with 10% foetal calf serum (GIBCO)
and 1% penicillin (50 mg/ml), streptomycin (50 mg/ml) solu-
tion (Sigma) under pressure of G418 (Sigma) [18]. The in vitro
effect of the compounds on the growth of promastigotes was
assessed by monitoring the luciferase activity of viable cells
after treatment. The transgenic promastigotes of late log phase
were seeded at 5 ꢂ 105/100 ml medium 199 in 96-well flat bot-
tomed microtitre (MT) plates (CELLSTAR) and incubated for
72 h in medium alone or in the presence of serial dilutions of
drugs (0.25e10 mg/ml) in DMSO. Parallel dilutions of DMSO
were used as controls. After incubation, an aliquot (50 ml) of
promastigote suspension was aspirated from each well of a
96-well plate and mixed with an equal volume of stready GloÒ
reagent (Promega) and luminescence was measured by a lumin-
ometer. The values were expressed as relative luminescence unit
(RLU). The inhibition of parasitic growth was determined by
comparing the luciferase activity of drug treated parasites with
that of untreated controls by the general formula:
HO
OH
OMe
HO
OMe
OH
1
OMe
O
O
2
(CH2)n CH3
HO
3
Fig. 1.
N ꢃ n
72% yield as a pale yellow crystalline solid, m.p. 99e101 ꢀC.
% Inhibition ¼
ꢂ 100
N
1
The H NMR spectrum of 6a displayed a three proton singlet
at 1.60 for a C-2 methyl, a singlet at 5.08 for a benzylic CH2,
a broad singlet at 5.35 for a C-3 proton, and it confirmed the
assigned structure of 6a. Under identical reaction conditions,
alkoxy aldehydes 5(bed) reacted smoothly with dihydro-a-
ionone 4 to furnish chalcones 6(bed) in respectable yields
(Scheme 1). Aldehydes with electron withdrawing group
5(eeh) also reacted with dihydro-a-ionone 4 under identical
reaction conditions to furnish 6(eeh) in respectable yields.
Base labile aldehyde, p-hydroxy benzaldehyde 5i under
classical conditions (aq. KOH, methanol) was not a very clean
reaction. However, under solvent free microwave conditions it
furnished chalcone 6i in good yield. Under identical reaction
conditions pyridine-3-aldehyde 7 reacted smoothly with dihy-
dro-a-ionone 4 to furnish E/Z unseparable mixture of chalcone
8 in good yield. The furano aldehyde 9 under identical reac-
tion conditions reacted with dihydro-a-ionone 4 to furnish
chalcone 10 in quantitative yield.
where N is average relative luminescence unit (RLU) of con-
trol wells; n is average RLU of treated wells.
3.2.2. Antiamastigote activity
For assessing the activity of compounds against the amas-
tigote stage of the parasite, mouse macrophage cell line (J-
774A.1) infected with promastigotes expressing luciferase
firefly reporter gene was used [18]. Cells were seeded in
a 96-well plate (5 ꢂ 104 cell/100 ml/well) in RPMI-1640 con-
taining 10% foetal calf serum and the plates were incubated
at 37 ꢀC in a CO2 incubator. After 24 h, the medium was re-
placed with fresh medium containing stationary-phase pro-
mastigotes (2.5 ꢂ 105/100 ml/well). Promastigotes invade the
macrophage and are transformed into amastigote. The taste
material in appropriate concentrations (0.25e10 mg/ml) in
complete medium was added after replacing the previous me-
dium and the plates were incubated at 37 ꢀC in a CO2 incuba-
tor for 24 h or more. After incubation, the drug containing
medium was decanted and 50 ml PBS was added in each
well and mixed with an equal volume of steady GloÒ reagent.
After gentle shaking for 1e2 min, the reading was taken in
a luminometer. The inhibition of parasitic growth was deter-
mined as described above.
3. Biological activities
3.1. Material and method
Parasite: luciferase transfected Leishmania donovani promasti-
gotes (MHOM/IN/80/Dd-8, obtained from Imperial College, Lon-
don) which are more stable under the influence of G 418 [17] were
maintained at 25 ꢁ 1 ꢀC in medium 199 (Sigma Chemical Co.,
USA) supplemented with 10% foetal calf serum (GIBCO).
4. Results and discussion
In our earlier studies we have shown that ketene acetals of ar-
omatic substrates [19] and ketene acetals and their S, N, and N,N-
acetals of terpene substrates [20] showed pronounced invitro and
in vivo antileishmanial profile. In view to further optimise the ac-
tivity profile, we synthesized series of dihydro-a-ionone based
simple chalcones 6(aei), 8 and 10 as shown in Scheme 1. The
compounds were subjected to in vitro antileishmanial activity
3.2. In vitro assay
3.2.1. Antipromastigote activity
The L. donovani promastigotes (MHOM/IN/Dd-8; origi-
nally obtained from Imperial college, London) were

S.N. Suryawanshi et al. / European Journal of Medicinal Chemistry 43 (2008) 2473e2478
2475
R4
CHO
R3
R2
R1
R2
KF / Al2O3
Microwave
+
R4
O
O
R1
R3
4
5
6
a) R1 = R2 = R4 = H, R3 = OBn
b) R1 = R2 = R4 = H, R3 = OMe
c) R1 = R4 = H, R2= R3 = OMe
d) R1 = H, R2 = R3 = R4 = OMe
e) R1 = R2 = R4 = H, R3 = Cl
f) R1 = NO2, R2 = R3 = R4 = H
g) R1 = R3= R4 = H, R2 = NO2
h) R1 = R2 = R4 = H, R3 = NO2
i) R1 = R2 = R4 = H, R3 = OH
CHO
KF / Al2O3
Microwave
+
+
N
N
O
O
O
4
7
8
KF / Al2O3
Microwave
OH
O
OHC
O
OH
O
4
9
10
Scheme 1.
Table 1
Antileishmanial activity of compounds against L. donovani
profile as shown in Table 1. From the results we found that the
substitution on aromatic ring has profound role to play in the bi-
ological activity of these compounds. The chalcones having p-
methoxy and 3,4-dimethoxy substitution as in 6b and 6c showed
very good activity in promastigote as well as amastigote model.
However, 3,4,5,-trimethoxy substitution as in 6d showed activity
in promastigote model but was found inactive in the amastigote
model. Electron withdrawing substituents on the aromatic ring
have role to play in the activity profile as 6e and 6h which showed
very good activity in the promastigote as well as amastigote
model. Next, we synthesized pyridine and furan based chalcones
8 and 10 as shown in Scheme 1. Among them pyridine based
chalcone 8 (Table 1) showed very good profile in the promasti-
gote as well as amastigote model. However, chalcones 6b, 6c,
6e and 8 showed marginal in vivo activity in the hamster model.
Serial Compound Antipromastigote activity Antiamastigote activity
number number
Concentration
(mg/ml)
% Concentration
Inhibition (mg/ml)
%
Inhibition
Nl
1
6a
6b
6c
6d
6e
6f
5
2
5
2
5
2
5
2
5
2
5
2
5
2
5
2
5
2
5
2
5
2
100
61
5
2
5
2
5
2
5
2
5
2
5
2
5
e
5
2
5
2
5
2
5
2
2
98
98
81
40
95
79
Nl
Nl
93
88
Nl
Nl
65
e
3
100
100
90
4
50
5
100
100
53
6
34
99
7
6g
6h
6i
98
99
5. Experimental
8
80
74
Nl
Nl
92
33
Nl
Nl
95
The reported melting points are the uncorrected ones. The
infrared spectra were recorded in KBr on a PerkineElmer
model 881. 1H NMR spectra and 13C NMR (in CDCl3) spectra
(chemical shift in d, ppm downfield from TMS) were recorded
on Bruker Advance DRX-2000 instrument. Electron impact
(EI) mass spectra were recorded on a Joel JMS-D-300
9
100
76
10
11
8
100
100
93
10
65

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S.N. Suryawanshi et al. / European Journal of Medicinal Chemistry 43 (2008) 2473e2478
spectrometer with the ionization potential 70 eV. The reaction
was carried out in unmodified microwave oven (LG made,
850 W, 2450 MHz) at medium power 450 W for 4e5 min.
(15 ml) and filtered. The filterate was concentrated in vacuo.
The light yellow oil thus obtained was chromatographed
(SiO2; 60e120 mesh). Elution with 5% ethylacetate in hexane
furnished thick yellow liquid which on crystallization (ether:-
hexane) furnished white solid 6c (1.28 g, 73%). M.p. 99e
100 ꢀC; IR (KBr, cmꢃ1): 3020, 2936, 1685, 1592, 1512,
5.1. 1-(4-Benzyloxy-phenyl)-5-(2,6,6-trimethylcyclohex-
2-enyl)-pent-1-en-3-one (6a)
1
1460; H NMR (200 MHz, CDCl3): d 0.89 (s, 3H), 0.96 (s,
A mixture of dihydro-a-ionone 4 (1.00 g, 5.15 mmol), 4-
benzyloxy benzaldehyde 5a (1.28 g, 6 mmol) and KF/Al2O3
(1.00 g) was subjected to microwave irradiation for 5 min. On
cooling, the crude product was taken up in ethylacetate
(15 ml) and filtered. The filterate was concentrated in vacuo.
The pale yellow crude liquid thus obtained was chromato-
graphed (SiO2; 60e120 mesh). Elution with 4% ethylacetate
in hexane furnished yellow solid which on crystallization
(ether:hexane) gave 6a as a pale yellow crystalline solid
(1.43 g, 72%). M.p. 99e101 ꢀC; IR (KBr, cmꢃ1): 2940, 1639,
1599, 1510; 1H NMR (200 MHz, CDCl3): d 0.89 (s, 3H), 1.00
(s, 3H), 1.45 (m, 5H), 1.60 (s, 3H), 2.00 (m, 2H), 2.70 (m,
2H), 5.08 (s, 2H), 5.35 (m, 1H), 6.60 (d, J ¼ 16.00 Hz, 1H),
7.00 (d, J ¼ 8.00 Hz, 2H), 7.45 (m, 8H); 13C NMR (200 MHz,
CDCl3): d 23.427 (q), 24.005 (t), 25.608 (t), 2 ꢂ 28.095 (q),
31.995 (s), 33.045 (t), 41.483 (t), 49.108 (d), 70.518 (t),
2 ꢂ 115.720 (d), 121.397 (d), 124.611 (d), 124.924 (s),
127.858 (d), 127.927 (d), 128.567 (d), 2 ꢂ 129.075 (d),
2 ꢂ 130.357 (d), 136.176 (s), 136.869 (s), 142.369 (d),
161.097 (s), 200.905 (s); MS (m/z): 389 (Mþ þ 1).
3H), 1.25 (m, 2H), 1.50 (m, 2H), 1.75 (s, 3H), 1.90 (m, 1H),
2.00 (m, 2H), 2.70 (m, 2H), 3.95 (s, 3H), 3.97 (s, 3H), 5.36
(m, 1H), 6.61 (d, J ¼ 16.00 Hz, 1H), 6.87 (m, 2H), 7.01 (m,
2H), 7.41 (m, 3H) ; MS (m/z): 343 (Mþ þ 1).
5.4. 1-(3,4,5-Trimethoxy-phenyl)-5-(2,6,6-
trimethylcyclohex-2-enyl)-pent-1-en-3-one (6d)
A mixture of dihydro-a-ionone 4 (1.00 g, 5.15 mmol),
3,4,5-trimethoxy benzaldehyde 5d (1.18 g, 6 mmol) and KF/
Al2O3 (1.00 g) was subjected to microwave irradiation for
5 min. On cooling, the crude product was taken up in ethyla-
cetate (15 ml) and filtered. The filterate was concentrated in
vacuo. The pale yellow crude liquid thus obtained was chro-
matographed (SiO2; 60e120 mesh). Elution with 4% ethylace-
tate in hexane furnished thick yellow liquid which on
crystallization (ether:hexane) furnished white crystalline solid
6d (1.43 g, 76%). M.p. 89e90 ꢀC; IR (KBr, cmꢃ1): 2938,
1657, 1588, 1503, 1458; 1H NMR (200 MHz, CDCl3):
d 0.89 (s, 3H), 0.95 (s, 3H), 1.20 (m, 2H), 1.54 (m, 2H),
1.71 (s, 3H), 2.00 (m, 3H), 2.70 (m, 2H), 3.91 (s, 9H), 5.40
(m, 1H), 6.62 (d, J ¼ 16.00 Hz, 1H), 6.75 (s, 2H), 7.50 (d,
J ¼ 16.00 Hz, 1H); MS (m/z): 371 (Mþ ꢃ 1).
5.2. 1-(4-Methoxy-phenyl)-5-(2,6,6-trimethylcyclohex-2-
enyl)-pent-1-en-3-one (6b)
A mixture of dihydro-a-ionone 4 (1.00 g, 5.15 mmol), 4-
methoxy benzaldehyde 5b (0.82 g, 6 mmol) and KF/Al2O3
(1.00 g) was subjected to microwave irradiation for 5 min.
On cooling, the crude product was taken up in ethylacetate
(15 ml) and filtered. The filterate was concentrated in vacuo.
The pale yellow crude liquid thus obtained was chromato-
graphed (SiO2; 60e120 mesh). Elution with 4% ethylacetate
in hexane furnished thick yellow liquid 6b (1.12 g, 70%). IR
5.5. 1-(4-Chloro-phenyl)-5-(2,6,6-trimethylcyclohex-2-
enyl)-pent-1-en-3-one (6e)
A mixture of dihydro-a-ionone 4 (1.00 g, 5.15 mmol), 4-
chloro benzaldehyde 5e (0.84 g, 6 mmol) and KF/Al2O3
(1.00 g) was subjected to microwave irradiation for 4 min.
On cooling, the crude product was taken up in ethylacetate
(15 ml) and filtered. The filterate was concentrated in vacuo.
The crude liquid thus obtained was chromatographed (SiO2;
60e120 mesh). Elution with 3% ethylacetate in hexane fur-
nished 6d as a thick yellow liquid (1.28 g, 79%). IR (neat,
cmꢃ1): 2927, 1693, 1609; 1H NMR (200 MHz, CDCl3):
d 0.85 (s, 3H), 0.90 (s, 3H), 1.50 (m, 4H), 1.60 (s, 3H), 1.90
(m, 3H), 2.60 (m, 2H), 5.28 (m, 1H), 6.60 (d, J ¼ 16.00 Hz,
1H), 7.40 (m, 4H), 7.50 (d, J ¼ 16.00 Hz, 1H); 13C NMR
(200 MHz, CDCl3): d 21.985 (q), 22.480 (q), 23.890 (t),
26.605 (q), 30.565 (t), 31.534 (s), 40.253 (t), 47.510 (t),
52.433 (d), 120.067 (d), 125.893 (d), 2 ꢂ 128.156 (d),
2 ꢂ 128.349 (d), 132.153 (s), 134.590 (s), 135.180 (s),
139.373 (d), 199.239 (s); MS (m/z): 317 (Mþ þ 1).
1
(neat, cmꢃ1): 2949, 1700, 1655, 1601; 1512, 1457; H NMR
(200 MHz, CDCl3): d 0.93 (s, 3H), 0.96 (s, 3H), 1.60 (m,
5H), 1.70 (s, 3H), 1.80 (m, 2H), 2.70 (m, 2H), 3.90 (s, 3H),
5.40 (m, 1H), 6.65 (d, J ¼ 16.00 Hz, 1H), 6.95 (d,
J ¼ 8.00 Hz, 2H), 7.50 (m, 3H); 13C NMR (200 MHz,
CDCl3): d 23.402 (t), 23.981 (q), 25.577 (t), 2 ꢂ 28.060 (q),
31.964 (t), 33.020 (t), 49.068 (d), 53.826 (d), 55.783 (s),
114.417 (d), 114.801 (d), 121.368 (d), 124.472 (d), 127.653
(s), 2 ꢂ 130.331 (d), 136.156 (s), 142.433 (d), 161.920 (s),
200.959 (s); MS (m/z): 313 (Mþ þ 1).
5.3. 1-(3,4-Dimethoxy-phenyl)-5-(2,6,6-
trimethylcyclohex-2-enyl)-pent-1-en-3-one (6c)
5.6. 1-(2-Nitro-phenyl)-5-(2,6,6-trimethylcyclohex-2-
enyl)-pent-1-en-3-one (6f)
A mixture of dihydro-a-ionone 4 (1.00 g, 5.15 mmol), 3,4-
dimethoxy benzaldehyde 5c (0.99 g, 6 mmol) and KF/Al2O3
(1.00 g) was subjected to microwave irradiation for 5 min.
On cooling, the crude product was taken up in ethylacetate
A mixture of dihydro-a-ionone 4 (1.00 g, 5.15 mmol), 2-ni-
tro benzaldehyde 5f (0.91 g, 6 mmol) and KF/Al2O3 (1.00 g)

S.N. Suryawanshi et al. / European Journal of Medicinal Chemistry 43 (2008) 2473e2478
2477
was subjected to microwave irradiation for 4 min. On cooling,
5.9. 1-(4-Hydroxy-phenyl)-5-(2,6,6-trimethyl-cyclohex-2-
enyl)-pent-1-en-3-one (6i)
the crude product was taken up in ethylacetate (15 ml) and fil-
tered. The filterate was concentrated in vacuo. The pale yellow
crude liquid thus obtained was chromatographed (SiO2; 60e
120 mesh). Elution with 5% ethylacetate in hexane furnished
6f thick yellow liquid (1.16 g, 69%). IR (neat, cmꢃ1): 2928,
A mixture of dihydro-a-ionone 4 (1.00 g, 5.15 mmol), 4-
hydroxy benzaldehyde 5i (0.75 g, 6 mmol) and KF/Al2O3
(1.00 g) was subjected to microwave irradiation for 4 min.
On cooling, the crude product was taken up in ethylacetate
(15 m) and filtered. The filterate was concentrated in vacuo.
The pale yellow crude liquid thus obtained was chromato-
graphed (SiO2; 60e120 mesh). Elution with 5% ethylacetate
in hexane furnished 6i as a thick yellow liquid (0.55 g,
1
1699, 1611, 1528, 1348, 1216; H NMR (200 MHz, CDCl3):
d 0.82 (s, 3H), 0.92 (s, 3H), 1.40 (m, 4H), 1.62 (s, 3H), 1.90
(m, 3H), 2.66 (m, 2H), 5.28 (m, 1H), 6.51 (d, J ¼ 16.00 Hz,
1H), 7.71 (m, 3H), 8.00 (m, 2H); MS (m/z): 328 (Mþ þ 1).
1
36%). IR (neat, cmꢃ1): 3288, 2930, 1637, 1584; H NMR
5.7. 1-(3-Nitro-pheny)-5-(2,6,6-trimethylcyclohex-2-
enyl)-pent-1-en-3-one (6g)
(200 MHz, CDCl3): d 0.90 (s, 3H), 1.30 (m, 4H), 1.70 (s,
3H), 1.80 (s, 3H), 2.70 (m, 2H), 5.40 (m, 1H), 6.65 (d,
J ¼ 16.00 Hz, 1H), 6.90 (d, 2H), 7.50 (d, 2H), 7.60 (d,
J ¼ 16.00 Hz, 1H); 13C NMR (200 MHz, CDCl3): d 21.731
(q), 23.952 (q), 24.861 (t), 28.004 (q), 30.068 (t), 31.957 (s),
49.113 (d), 2 ꢂ 53.794 (d), 116.563 (s), 121.544 (d), 123.869
(d), 127.111 (s), 2 ꢂ 130.760 (d), 132.963 (s), 135.980 (s),
143.825 (d), 162.969 (s), 202.968 (s); MS (m/z): 299
(Mþ þ 1).
A mixture of dihydro-a-ionone 4 (1.00 g, 5.15 mmol), 3-ni-
tro benzaldehyde 5g (0.91 g, 6 mmol) and KF/Al2O3 (1.00 g)
was subjected to microwave irradiation for 3 min. On cooling,
the crude product was taken up in ethylacetate (15 ml) and fil-
tered. The filterate was concentrated in vacuo. The crude liq-
uid thus obtained was chromatographed (SiO2; 60e120
mesh). Elution with 5% ethylacetate in hexane furnished thick
yellow liquid which on crystallization (ether:hexane) fur-
nished 6g as a yellow crystalline solid (0.88 g, 68%). M.p.
114e116 ꢀC; IR (KBr, cmꢃ1): 2949, 1722, 1669, 1618;
5.10. 1-Pyridin-3-yl-5- (2,6,6-trimethyl-cyclohex-2-enyl)-
pent-1-en-3-one (8)
1
1532, 1449, 1352; H NMR (200 MHz, CDCl3): d 0.82 (s,
A mixture of dihydro-a-ionone 4 (1.00 g, 5.15 mmol), pyr-
idine-3-aldehyde 7 (0.64 ml, 6 mmol) and KF/Al2O3 (1.00 g)
was subjected to microwave irradiation for 5 min. On cooling,
the crude product was taken up in ethylacetate (15 ml) and fil-
tered. The filterate was concentrated in vacuo. The crude prod-
uct thus obtained was chromatographed (SiO2; 60e120 mesh).
Elution with 7% ethylacetate in hexane furnished 8 as a thick
brown liquid (0.75 g, 52%). IR (neat, cmꢃ1): 2932, 1664,
1617, 1341; 1H NMR (200 MHz, CDCl3): d 0.90 (s, 3H),
0.95 (s, 3H), 1.25 (m, 2H), 1.50 (m, 2 H), 1.60 (s, 3H), 2.00
(m, 3H), 2.75 (m, 2H), 5.40 (m, 1H), 6.35 (d, J ¼ 16.00 Hz,
1H), 7.15 (d, J ¼ 16.00 Hz, 1H), 7.60 (d, J ¼ 8.00 Hz, 2H);
13C NMR (200 MHz, CDCl3): d 21.127 (q), 23.935 (t),
2 ꢂ 25.127 (q), 33.049 (t), 40.186 (s), 41.722 (t), 48.945 (d),
123.208 (d), 124.142 (d), 130.788 (d), 2 ꢂ 132.201 (d),
139.488 (d) 2 ꢂ 149.425 (d); MS (m/z): 283 (Mþ þ 1).
3H), 0.87 (s, 3H), 1.15 (m, 2H), 1.40 (m, 2H), 1.70 (s, 3H),
1.90 (m, 3H), 2.70 (m, 2H), 5.30 (m, 1H), 6.70 (d,
J ¼ 16.00 Hz, 1H), 7.40 (d, J ¼ 16.00 Hz, 2H), 7.62 (d,
J ¼ 8.00 Hz, 2H), 8.18 (d, J ¼ 8.00 Hz, 2H); 13C NMR
(200 MHz, CDCl3): d 21.096 (q), 23.953 (t), 2 ꢂ 25.049 (q),
31.968 (t), 53.956 (d), 122.833 (d), 124.851 (d), 129.288 (d),
130.338 (d), 134.182 (d), 139.250 (d), 139.448 (d), 200.340
(s); MS (m/z): 328 (Mþ þ 1).
5.8. 1-(4-Nitro-phenyl)-5-(2,6,6-trimethylcyclohex-2-
enyl)-pent-1-en-3-one (6h)
A mixture of dihydro-a-ionone 4 (1.00 g, 5.15 mmol), 4-ni-
tro benzaldehyde 5h (0.91 g, 6 mmol) and KF/Al2O3 (1.00 g)
was subjected to microwave irradiation for 5 min. On cooling,
the crude product was taken up in ethylacetate (15 ml) and fil-
tered. The filterate was concentrated in vacuo. The crude liq-
uid thus obtained was chromatographed (SiO2; 60e120
mesh). Elution with 5% ethylacetate in hexane furnished thick
yellow liquid which on crystallization (ether:hexane) fur-
nished 6h as a yellow crystalline solid (1.14 g, 67 %). M.p.
107e08 ꢀC; IR (KBr, cmꢃ1): 2929, 1664, 1609, 1522, 1345,
5.11. 1-(5-Hydroxymethyl-furan-2-yl)-5-(2,6,6-trimethyl-
cyclohex-2-enyl)-pent-1-en-3-one (10)
A mixture of dihydro-a-ionone 4 (1.00 g, 5.15 mmol), hy-
droxymethyl furfuraldehyde 9 (0.76 ml, 6 mmol) and KF/
Al2O3 (1.00 g) was subjected to microwave irradiation for
5 min. On cooling, the crude product was taken up in ethyla-
cetate (15 ml) and filtered. The filterate was concentrated in
vacuo. The crude product thus obtained was chromatographed
(SiO2; 60e120 mesh). Elution with 6% ethylacetate in hexane
furnished 10 as a thick yellow liquid (1.18 g, 76%). IR (neat,
cmꢃ1): 3411, 2927, 1613, 1576; 1H NMR (200 MHz, CDCl3):
d 0.88 (s, 3H), 0.90 (s, 3H), 1.22 (m, 2H), 1.53 (m, 4H), 1.70
(s, 3H), 1.90 (m, 3H), 2.70 (m, 2H), 4.65 (s, 2H), 5.40 (m, 1H),
6.40 (m, 1H), 6.65 (s, 1H), 6.70 (d, J ¼ 14.00 Hz, 1H); 13C
1
1217; H NMR (200 MHz, CDCl3): d 0.85 (s, 3H), 0.95 (s,
3H), 1.20 (m, 2H), 1.50 (m, 2H), 1.65 (s, 3H), 1.90 (m, 3H),
2.70 (m, 2H), 5.35 (m, 1H), 6.80 (d, J ¼ 16.00 Hz, 1H), 7.50
(d, J ¼ 16.00 Hz, 1H), 7.65 (d, J ¼ 8.00 Hz, 2H), 8.20 (d,
J ¼ 8.00 Hz, 2H); 13C NMR (200 MHz, CDCl3): d 21.057
(q), 21.206 (t), 23.962 (t), 2 ꢂ 25.030 (q), 31.953 (t), 40.558
(s), 42.027 (t), 48.943 (d), 121.665 (d), 124.363 (d), 124.558
(d), 2 ꢂ 129.971 (d), 130.275 (d), 135.842 (d), 139.385 (s),
141.275 (s), 148.924 (s), 200.057 (s); MS (m/z): 328 (Mþ þ 1).

2478
S.N. Suryawanshi et al. / European Journal of Medicinal Chemistry 43 (2008) 2473e2478
[9] (a) M. Liu, P. Wilairat, S.L. Croft, A.L.-C. Tan, M.-L. Go, Bioorg. Med.
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NMR (200 MHz, CDCl3): d 23.367 (t), 23.949 (q), 25.377 (t),
28.019 (q), 28.045 (q), 30.065 (t), 32.987 (s), 41.994 (t),
49.003 (d), 57.929 (t) 110.738 (d), 116.996 (d), 121.446 (d),
123.585 (d), 128.674 (d), 136.024 (s), 151.335 (s), 157.296
(s), 200.768 (s); MS (m/z): 303 (Mþ þ 1).
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Acknowledgements
Financial support to Jyoti Porwal by MOH (India) and tech-
nical support by Mrs. Manju are gratefully acknowledged.
(b) Denise de C.F. Gomes, L.V. Alegrio, L.L. Leon, M.E. Freire de Lima,
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