Design, synthesis, and in vitro evaluation of cytotoxic activity of new substituted 1,4-benzoquinones and hydroquinones

Article abstract of DOI:10.1007/s00044-007-9001-3

A new series of p-benzoquinones, hydroquinones, and quinol dimethyl ethers substituted by a pyrazole ring either directly or after an oxoethyl linker was synthesized and screened for in vitro cytotoxic activity. Compounds 8d, f, g, i, and 9c, f, and 13c exhibited broad-spectrum activity (GI₅₀ MG-MID values 9.27-14.72 μM). With regard to sensitivity, compounds 8f and 9c, f have proved to possess a remarkable activity against leukemia tumor cell lines (GI₅₀ = 3.43-5.03 μM). Indeed, compound 13c showed the highest activity profile against individual leukemia subpanel cell line SR (GI ₅₀ = 0.91 μM).

Full text of DOI:10.1007/s00044-007-9001-3

Med Chem Res (2007) 16:49–77
DOI 10.1007/s00044-007-9001-3
ORIGINAL RESEARCH
Design, synthesis, and in vitro evaluation of cytotoxic
activity of new substituted 1,4-benzoquinones and
hydroquinones
Ibrahim Chaaban Æ El-Sayeda El-Khawass Æ Mona Mahran Æ Ola El-Sayed Æ
Hassan El-Saidi Æ Hassan Aboul-Enen
Received: 27 October 2006 / Accepted: 9 January 2007 / Published online: 12 July 2007
¨
Ó Birkhauser Boston 2007
Abstract A new series of p-benzoquinones, hydroquinones, and quinol dimethyl
ethers substituted by a pyrazole ring either directly or after an oxoethyl linker was
synthesized and screened for in vitro cytotoxic activity. Compounds 8d, f, g, i, and
9c, f, and 13c exhibited broad-spectrum activity (GI50 MG-MID values 9.27–
14.72 mM). With regard to sensitivity, compounds 8f and 9c, f have proved to
possess a remarkable activity against leukemia tumor cell lines (GI50 = 3.43–
5.03 mM). Indeed, compound 13c showed the highest activity profile against indi-
vidual leukemia subpanel cell line SR (GI50 = 0.91 mM).
Keywords 1,4-Benzoquinone Á Cytotoxic agents Á Hydroquinone Á
Pyrazole Á Pyrazolidendione Á Quinol dimethyl ether
Introduction
Quinones as well as hydroquinones represent an important class of compounds with
diverse pharmacological activities. Among the most important biological activities
reported are anticancer (Radeke et al., 1997; Rozek et al., 2001; Stahl et al., 2001;
Afrasiabi et al., 2005; Ward et al., 2005; Hasinoff and Begleiter, 2006),
antimicrobial (Chabaan et al., 1984a,b, 1989; Kaneshiro et al., 2000; Habib and
Mahran, 2004; Tapia et al., 2004), antiviral (Urbam and Capon, 1996; Iwashima
et al., 2005), and anti-inflammatory (Ospina et al., 2001) activities. Mitomycins
comprise a group of substituted indoloquinone antibiotics with potent antitumor
I. Chaaban Á E.-S. El-Khawass Á M. Mahran (&) Á O. El-Sayed Á H. El-Saidi
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Alexandria,
Alexandria, 21215, Egypt
e-mail: monamahran@Yahoo.com
H. Aboul-Enen
Biological and Medical Research Department, MBC-03 King Faisal Specialist Hospital and
Research Center, Rhyiad, Saudi Arabia

50
Med Chem Res (2007) 16:49–77
activity (Iyer and Szyblaski, 1963; Misra et al., 1977). These compounds act as
bifunctional alkylating agents that add across both strands of the DNA double helix
leading to cancer cell death (Iyer and Szyblaski, 1963). Reduction of benzoquinone
ring of mitomycins to the corresponding hydroquinone ring was proved to be an
essential step for attaining the biological activity (Schwartz et al., 1963). Moreover,
evidence was provided indicating that the carbamoyl group and the aziridine ring of
mitomycin C (Fig. 1) are not essential for its activity (Iyer and Szyblaski, 1963). In
view of these facts, the pharmacophoric groups of the structural backbone of
mitomycin could be simplified to a combined b-aminoketone and a cyclic a,b-
unsaturated ketone. These two parts were previously combined into one chemical
structure in the design of several piperidone derivatives (El-Subbagh et al., 2000)
(Fig. 1) as anticancer agents. These analogs were synthesized to fulfill such
structural requirements and proved to be very promising cytotoxic agents (IC50
values < 10 mM). Those compounds were shown to possess a higher affinity for the
thiol rather than the amino or the hydroxyl function of the nucleic acids, thus
decreasing host toxicity.
Fig. 1
Based on the aforementioned rationale, a new series of 1,4-benzoquinones and
hydroquinones was designed, synthesized, and screened for anticancer activity. The
proposed compounds were designed to include both the a,b-unsaturated ketone and/
or the b-aminoketone moieties in their structures.
Results and Discussion
Chemistry
The starting material 1-aryl-3-(2,5-dimethoxyphenyl) propenones 5a–c were
synthesized via Claisen–Schmidt condensation (Wattanasin and Murrphy, 1980)
(Scheme 1). The prepared quinol dimethylethers 5a–c were demethylated with 48%

Med Chem Res (2007) 16:49–77
51
hydrobromic acid (Borgman et al., 1973) to yield the dihydroxy chalcones 6a–c.
Subsequent oxidation of the dihydric phenolic compounds 6a–c to the correspond-
ing p-benzoquinones 7a–c was carried out using ceric ammonium nitrate in aqueous
acetonitrile (Ho et al., 1972). The target pyrazole derivatives 8a–i (Scheme 2) were
obtained through cyclocondensation of the a,b-unsaturated ketones 5a–c with the
selected 4-substituted phenylhydrazine hydrochlorides in boiling glacial acetic acid
containing an equimolar amount of anhydrous sodium acetate. Similarly, demethy-
lation of 8a–i by boiling with 48% hydrobromic acid yielded the corresponding
hydroquinones 9a–i, which on treatment with ceric ammonium nitrate in aqueous
acetonitrile yielded the corresponding quinones 10a–i.
OMe
O
H
O
OH
OMe
H
O
H3C
O
H +
R
R
KOH
HBr
H
H
R
4
OMe
3
OH
OMe
O
5a-c
H
6a-c
O
Ce(NH4)2(NO3)6
R
R = C6H5, 4-CH3C6H4, 4-ClC6H4
H
O
7a-c
Scheme 1
R
N
R
OMe
OH
OH
N
N
R1NHNH2
HBr
N
R1
5a-c
R1
OMe
8a-i
9a-i
R
Ce(NH4)2(NO3)6
O
N
N
R1
O
10a-i
R
R
= C6H5, 4-CH3C6H4, 4-CIC6H4
1
= C6H5, 4-SO2NH2C6H4, 4-SO2NHCOCH3C6H4
Scheme 2

52
Med Chem Res (2007) 16:49–77
The starting material, 2,5-dihydroxyphenacylbromide 11, was prepared accord-
ing to a reported method (King and Ostrum, 1964). Heating a solution of
acetylacetone, ethyl acetoacetate, or diethyl malonate in absolute ethanol with
metallic sodium and an equimolar amount of 2,5-dihydroxyphenacyl bromide 11
gave the expected 3-(2,5-dihydroxyphenacyl)pentane-2,4-dione 12, ethyl 2-(2,5-
dihydroxyphenacyl)-3-oxobutanoate 15 and diethyl 2-(2,5-dihydroxyphenacyl)
propanedioate 18, respectively (Schemes 3, 4, and 5). Cyclocondensation of the
prepared 1,3-dicarbonyl compounds 12, 15, and 18 with the selected 4-substituted
phenylhydrazine hydrochloride in the presence of anhydrous sodium acetate (Mong
et al., 1991) yielded the target substituted pyrazole, pyrazoline, and pyrazolidin-
edione derivatives 13, 16, and 19, respectively. On the other hand, reaction of the
aforementioned 1,3-diketone with some selected 4-arylthiosemicarbazides in glacial
acetic acid and anhydrous sodium acetate (Farghaly et al., 1981) yielded the
corresponding N-arylthiocarbamoylpyrazoles 14, 17, and 20.
R
H3
O
C
N
O
CH3
OH
OH
O
OH
O
N
Br
CH3
RNHNH2
CH3 COCH2 COCH3
CH3
O
OH
OH
OH
12
13a-e
11
R1 NHCSNHNH2
CSNH R1
R = C
H
, 4-CH
C
H
, 4-ClC H ,
6 4
H3
O
C
6
5
3
6
4
N
OH
4-SO NH
C
H
, 4-SO NHCOCH
C
H
2
2
6
4
2
3
6
4
N
1
R
= C
H
, 4-CH
C
H
, 4-ClC H
6 4
6
5
3
6
4
CH3
OH
O
14a-c
Scheme 3
R
CH3
OEt
O
N
OH
OH
O
OH
OH
O
N
CH3 COCH2 COOC2 H5
RNHNH2
11
CH3
O
15
16a-e
R1 NHCSNHNH2
CSNH R1
R = C
H
, 4-CH
C
H
, 4-ClC H
,
O
6
5
3
6
4
6 4
N
OH
OH
O
4-SO NH
C
H
, 4-SO NHCOCH
C
H
2
2
6
4
2
3
6
4
N
1
R
= C
H
, 4-CH
C
H
, 4-ClC H
6 4
6
5
3
6
4
CH3
17a-c
Scheme 4

Med Chem Res (2007) 16:49–77
53
R
O
OEt
O
O
N
OH
O
OH
OH
O
NH
OEt
CH2 (COOC2 H5
)
RNHNH2
2
11
O
OH
18
19a-e
R1 NHCSNHNH2
CSNH R1
R = C
H , 4-CH C H , 4-ClC H ,
5 3 6 4 6 4
O
6
N
OH
OH
O
4-SO NH C
H
, 4-SO NHCOCH C
H
2
2
6
4
2
3
6
4
NH
1
R
= C
H
, 4-CH C
H
, 4-ClC H
6 4
6
5
3
6
4
O
20a-c
Scheme 5
Attempts to oxidize the dihydroxy compounds, i.e., 1-aryl and 1-(N-
arylthiocarbamoyl)-4-(2,5-dihydroxyphenacyl)-3,5-dimethylpyrazoles 13 and 14,
1-aryl and 1-(N-arylthiocarbamoyl)- 4-(2,5-dihydroxyphenacyl)-3-methyl-4,
5-dihydropyrazolin-5-ones 16 and 17 or 1-aryl and 1-(N-arylthiocarbamoyl)-4-
(2,5-dihydroxyphenacyl) pyrazolidine-3,5-diones 19 and 20, were all unsuccessful.
Many procedures were tried using different oxidizing agents and reaction
conditions, including silver oxide, mercuric oxide, ceric ammonium nitrate, ferric
chloride, and potassium permanganate. It was presumed that these series of
compounds would exhibit clear strong intramolecular hydrogen bonding due to the
presence of a carbonyl group in the ortho position to the hydroxyl group, which
would create a system that can capture metals, giving stable six-membered ring
water-soluble colored chelates. Thus, such compounds would undergo chelate
formation reactions with the oxidizing metals rather than undergoing the expected
oxidation reactions. To examine this assumption, solutions of dihydroxy derivatives
13a, 14a, 16a, 17a, 19a, or 20a in dimethylformamide (DMF) were treated with 5%
aqueous solutions of CuSO4, CoSO4, or NiSO4 yielded colored chelates The
recorded kmax for the chelates and blank experiments are listed in Table 1. The
results obtained proved the formation of stable chelates between the aforementioned
derivatives and the different metals used, thus accounting for the difficulty faced in
oxidizing the dihydroxy compounds to their corresponding quinones.
Biological results
The in vitro antitumor evaluation of the tested compounds revealed that compounds
8d, f, g, i, 9c, f, and 13c exhibited a significantly high activity (GI50 = 9.27–14.72
mM; Table 2), with mild cytotoxicity (LC50 = 48.76–79.16 mM; Table 3).
Compounds 8c, 9a, i, 10c, f, 16c, and 19c showed moderate activity (GI50 = 23.03–
36.31 mM; Table 2). However, compounds 9d, g, and 10e, g possessed a weak
activity (GI50 = 53.19–90.06 mM; Table 2). Among all tested compounds, 9c

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Med Chem Res (2007) 16:49–77
Table 1
Comp. no.
kmax (in nm)
Cu2+ (505b)
Co2+ (510b)
Ni2+ (720b)
13a
14a
16a
17a
19a
20a
a
593 (351a)
598 (342a)
596 (351a)
594 (355a)
609 (351a)
615 (353a)
673 (351a)
675 (342a)
576 (351a)
574 (355a)
673 (351a)
674 (353a)
670 (351a)
673 (342a)
671 (351a)
675 (355a)
679 (351a)
677 (353a)
Blank of the compound in DMF–water
b
Blank of the metal ion in DMF–water
showed the highest activity (GI50 = 9.27 mM) with a weak cytotoxic activity
(LC50 = 76.14 mM, Table 3). Moreover, compound 13c proved to be effective
against individual leukemia subpanel cell lines SR (GI50 = 0.91 mM; results are not
shown), whereas compound 8g possessed a high activity against colon subpanel
tumor cell lines (GI50 = 3.74 mM; Table 2), and compound 8i exhibited growth
inhibition (GI50) potency against prostate cancer subpanel tumor cell lines at 3.61
mM (Table 2). With regard to selectivity, compounds 8c, g, and i, i.e., the 1,3-diaryl-
5-(2,5-dimethoxyphenyl) pyrazoles, possessed a moderate selectivity against
various tumor cell lines (Table 2). Compound 8c was selective against leukemia
subpanel tumor cell lines (selectivity ratio of 3.03), compound 8g was selective
against colon subpanel tumor cell lines (selectivity ratio of 3.21), while compound
8i showed selectivity against prostate subpanel tumor cell lines (selectivity ratio of
4.07).
The attempts to rationalize the structural variations of the synthesized
compounds and the obtained antitumor data facilitated the deduction of the
following general considerations. Direct attachment of the pyrazole moiety to the
dihydroxyphenyl ring is required for optimal activity. This argument is based on the
reported anticancer activity for the pyrazole ring (Abdou et al., 2004). The
introduction of sulfamoyl or an N-acetylsulfamoyl group at position 4 of the phenyl
ring at the N1 of the pyrazole ring resulted in the highest potency within the quinol
dimethyl ether derivatives, whereas a chlorine atom at position 4 of the phenyl ring
at C3 of the pyrazole ring resulted in the highest potency within the hydroquinone
and quinone series. However, the observed weak activity of the quinone derivatives
as compared to hydroquinones or quinol dimethyl ethers was unexpected, because
those quinones comprise both pharmacophores the a,b-unsaturated ketone and the
b-aminoketone that are believed to be essential for the sought for activity. However,
the evidence provided by Schwartz et al. (1963) demonstrated that reduction of the
benzoquinone ring of mitomycins to the corresponding hydroquinone was an
essential step for attaining the biological activity.
In the case of the second series of compounds that comprise a hydroquinone
moiety connected to the pyrazole counterpart through an oxoethyl linker, it was

Med Chem Res (2007) 16:49–77
55
Table 2 Median growth inhibitory concentrations GI50 (mM) of in vitro subpanel tumor cell lines and
GI50 (mM) full panel mean-graph midpoints (MG-MID)
a
Comp. no. Subpanel tumor cell lines
II III
Full-panel GI50
MG-MIDb
I
IV
V
VI
VII
VIII
IX
8c
11.11 40.63 25.17 29.23 34.93 49.00 34.89 60.45 17.68 33.67
(3.03)c (0.83) (1.34) (1.15) (0.96) (0.69) (0.96) (0.55) (1.92)
8d
8f
6.94
(1.84) (0.95) (1.07) (0.85) (0.83) (0.94) (0.98) (0.92) (1.04)
4.44 10.87 0.95 16.20 12.85 16.95 13.52 7.86 11.49 11.01
(2.47) (1.01) (2.22) (0.67) (0.85) (0.64) (0.81) (1.40) (0.95)
7.40 15.26 3.74 18.10 15.41 13.27 13.34 11.99 9.70
(1.62) (0.79) (3.21) (0.66) (0.78) (0.90) (0.90) (1.00) (1.24)
7.45 17.72 8.18 19.35 10.68 23.39 17.72 3.61 25.45 14.72
31.38 11.92 14.96 15.33 13.60 12.95 13.90 12.28 12.80
8g
8i
12.02
(1.97) (0.83) (1.79) (0.76) (1.37) (0.65) (0.83) (4.07) (0.57)
35.70 26.86 28.51 18.62 22.57 37.65 22.58 16.70 17.05 25.13
(0.70) (0.93) (0.88) (1.35) (1.11) (0.67) (1.11) (1.50) (1.47)
9a
9c
3.43
6.85
5.75
17.90 8.79
8.01
8.86
14.64 9.25
9.27
(2.70) (1.35) (1.61) (0.52) (1.05) (1.15) (1.04) (0.63) (1.00)
9d
9f
49.57 88.92 75.68 86.60 61.88 81.32 88.07 77.60 83.87 77.05
(1.55) (0.86) (1.02) (0.89) (1.25) (0.95) (0.87) (0.99) (0.92)
5.03
(2.69) (1.04) (0.90) (0.76) (0.93) (0.92) (1.13) (1.01) (0.81)
93.63 93.88 78.63 90.40 84.77 100 78.06 100 91.31 90.06
12.98 15.07 17.83 14.58 14.68 11.99 13.43 16.66 13.58
9g
9i
(0.96) (0.96) (1.14) (0.99) (1.06) (0.90) (1.15) (0.90) (0.98)
37.35 36.19 37.60 38.46 36.16 44.62 23.46 17.65 55.30 36.31
(0.97) (1.00) (0.96) (0.94) (1.00) (0.81) (1.54) (2.05) (0.65)
27.80 53.47 42.38 65.35 69.37 67.27 55.57 36.50 51.46 25.43
(0.91) (1.01) (1.00) (0.98) (0.95) (0.79) (1.14) (1.18) (1.11)
37.38 53.47 42.38 65.35 69.37 67.37 55.57 36.50 51.46 53.19
(1.42) (0.99) (1.25) (0.81) (0.76) (0.79) (0.95) (1.45) (1.03)
31.75 23.90 17.55 23.73 26.66 26.50 23.05 21.55 21.86 24.05
(0.75) (1.00) (1.37) (1.01) (0.90) (0.90) (1.04) (1.11) (1.10)
10c
10e
10f
10g
13c
57.80 100
(1.53) (0.88) (1.12) (0.88) (0.96) (0.88) (0.98) (0.88) (1.12)
7.71 12.01 11.18 11.31 13.08 14.05 12.03 12.39 11.37 11.68
(1.52) (0.97) (1.04) (1.03) (0.89) (0.83) (0.97) (0.94) (1.02)
78.35 100
92.02 100
89.97 100
78.53 88.51
obvious that the best activity was obtained when the substituent R for the N1 of the
pyrazole ring is a 4-bromophenyl group. Changing the substituent R with a phenyl, a
p-tolyl, or a p-sulfamoylphenyl group resulted in a dramatic loss of activity.
Interestingly, methyl groups attached to the pyrazole ring result in a higher activity,
as shown in the order of activity of compounds: 13c > 16c > 19c. This might be

56
Med Chem Res (2007) 16:49–77
Table 2 Continued
a
Comp. no. Subpanel tumor cell lines
Full-panel GI50
MG-MIDb
I
II
III
IV
V
VI
VII
VIII
IX
16c
19c
a
7.75
38.21 35.96 25.84 28.01 34.20 39.77 42.20 19.14 30.12
(3.89) (0.79) (0.84) (1.16) (1.08) (0.88) (0.76) (0.71) (1.57)
34.13 21.68 17.68 18.83 22.02 26.22 23.73 22.65 16.09 23.03
(0.67) (1.06) (1.28) (1.22) (1.05) (0.88) (0.83) (1.02) (1.43)
I, Leukemia; H, non-small cell lung cancer; III, colon cancer; IV, CNS cancer; V, melanoma; VI,
ovarian cancer; VII, renal cancer; VIII, prostate cancer; IX, breast cancer
b
GI50 (mM) full-panel mean-graph midpoints (MG-MID) = the average sensitivity of all cell lines toward
the test agent
c
Selectivity ratio of the nine tumor cell lines toward the active compounds
Table 3 Median total growth inhibitory concentrations (TGI, mM) of in vitro subpanel tumor cell lines,
TGI (mM) full panel mean-graph mid-points (MG-MID) and LC50 (mM) full panel mean-graph midpoints
(MG-MID)
Comp no. Subpanel tumor cell linesa
II III IV
78.15 100 82.80 84.33 70.00 85.15 77.44 100
Full panel TGI
MG-MIDb
I
V
VI
VII
VIII
XI
8c
78.56 84.04 (99.82)c
8d
8f
68.53 40.67 27.50 31.10 40.84 43.70 29.75 28.75 32.93 38.19 (73.02)
52.14 44.32 38.37 37.20 36.72 50.77 39.50 20.80 33.96 39.35 (74.68)
53.44 49.75 18.19 42.56 36.16 50.73 37.65 28.75 44.51 40.19 (77.06)
50.14 52.58 35.99 49.97 28.66 67.07 53.18 21.90 70.16 47.74 (79.16)
8g
8i
9a
9c
100
49.72 33.21 16.82 34.63 32.46 60.35 32.02 30.70 41.05 36.77 (76.14)
100 100 100 100 92.00 98.15 99.31 100 96.00 98.38 (100)
61.41 39.05 43.07 35.46 38.90 50.85 35.40 29.80 54.45 43.15 (76.61)
100 100 100 100 100 100 100 100 100 100 (100)
63.65 77.40 71.17 63.91 75.25 67.27 100
75.68 77.14 (91.28)
9d
9f
9g
9i
92.63 73.72 66.55 93.86 60.06 81.22 59.80 38.75 82.13 72.08 (91.16)
87.13 70.12 69.67 55.80 55.36 81.67 53.28 66.35 69.26 67.62 (95.61)
10c
10e
10f
10g
13c
16c
19c
a
94.04 100
84.58 71.07 37.40 53.00 52.66 65.67 50.16 71.85 62.63 61.00 (92.28)
91.23 100 100 100 100 100 100 100 100 95.32 (100)
88.83 100
97.27 100
86.78 100
95.46 95.82 (99.23)
46.58 32.92 42.08 29.80 31.38 42.40 36.70 47.30 36.30 38.38 (48.76)
35.81 48.55 45.46 45.96 42.57 50.00 46.15 50.00 38.18 44.67 (49.57)
50.00 48.36 43.33 40.50 42.44 44.34 46.92 50.00 40.91 45.21 (49.87)
I, Leukemia; II, non-small cell lung cancer; III, colon cancer; IV, CNS cancer; V, melanoma; VI,
ovarian cancer; VII, renal cancer; VIII, prostate cancer; IX, breast cancer
b
GI50 (mM) full-panel mean-graph mid-points (MG-MID) = The average sensitivity of all cell lines
toward the test agent
c
LC50 (mM) full-panel mean-graph midpoint (MG-MID) are shown in parentheses

Med Chem Res (2007) 16:49–77
57
attributed to the increase in lipid solubility that may facilitate absorption and
penetration of the compound to the target active site of its action.
Conclusion
In this study, compounds 9c, i.e., the 3-(4-chlorophenyl)-5-(2,5-dihydroxyphe-
nyl)-1-phenylpyrazole and 13c, i.e., the 1-(4-bromophenyl)-4-(2,5-dihydroxyphe-
nacyl)-3,5-dimethylpyrazole, exhibited remarkable antitumor activity against
leukemia subpanel tumor cell lines. These two compounds could be considered
as useful templates or leads for future development and further derivation or
structural variation to obtain more potent selective and less toxic antitumor
agents.
Experimental Procedures
Biological methods
For the past decade, the Development Therapeutic Program (DTP), Division of
Cancer Treatment and Diagnosis (DCTD), National Cancer Institute (NCI),
Bethesda, MD, has used an in vitro model consisting of 60 human tumor cell
lines as a primary anticancer screening (Paul et al., 1989; Monks et al., 1991;
Grever et al., 1992; Acton et al., 1994; Boyd and Paull, 1995). Out of the newly
synthesized pyrazole derivatives in the present work, 29 compounds (5c, 8c, d, f, g,
i, 9a, c, d, f, g, i, 10c, d, g, h, i, 13a–d, 16a–d, 19a–d) were selected by the National
Cancer Institute (NCI) for the in vitro disease–oriented human cells screening panel
assay to investigate their antitumor activities.
Primary anticancer assay (3-cell line/one dose assay). The three-cell line one-
dose assay has been in use by DTP for several years for evaluation of the
combinatorial libraries and has proved to be an effective prescreen. The inclusion
of this assay in the decision-making process will allow for more detailed
evaluation of agents that have exhibited some level of ability to inhibit the
growth of human tumor cells in culture. In this assay, a panel of three cell lines
consisting of MCF-7 (breast), NCI-H460 (lung), and SF-268 (CNS) was used.
Each cell line was seeded and preincubated on a microtiter plate. Test agents
were then added at a single concentration dose and the culture was incubated for
additional 48 h. End points were determined with Alamar blue, and the results
for each test agent were reported as the percent of growth of treated cells
compared to untreated control cells. Compounds that reduced the growth of any
of the cell lines up to 32% or less (negative numbers indicate cell kill) were then
evaluated for their anticancer activity (over a 5-log dose range) using an
extended panel of 60 cell lines. Eighteen compounds (8c, d, f, g, i, 9a, c, d, f, g,
i, 10c, e,f, g, 13c, 16c, 19c) showed promising activity and reduced the growth
of lung, breast, and/or CNS cell lines to <32%. The active compounds have been

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Med Chem Res (2007) 16:49–77
automatically scheduled for evaluation against full panel 60 human cell lines
(Grever et al., 1992).
Full-panel anticancer assay (60-cell lines/five dose assay). The NCI’s in vitro
full-panel antitumor screen consisting of 60 cell lines derived from nine tumor
subpanels, including leukemia, non-small-cell lung, colon, CNS, melanoma,
ovarian, renal, prostate, and breast cancer cell lines were incubated with five
concentrations (0.01–100 mM) for each compound and were used to create log
concentration–% growth inhibition curves (Paull et al., 1989; Monks et al., 1991;
Grever et al., 1992; Acton et al., 1994; Boyd and Paull, 1995). Cell viability and
growth were then estimated using the sulforhodamine B (SRB) protein assay.
Sulforhodamine B is a bright pink anionic dye that, in dilute acetic acid, binds
electrostatically to the basic amino acids. This reagent gives the best combination of
stain intensity, signal-to-noise ratio and linearity with cell number. Three responses
parameters—GI50, TGI, and LC50—were calculated for each cell line. GI50 value
(median growth inhibitory concentration) corresponds to the concentration of the
compound that causes 50% decrease in net cell growth. TGI value (total growth
inhibitory concentration; cytostatic activity) corresponds to the concentration of the
compound that results in total growth inhibition. LC50 value (mean lethal
concentration; cytotoxic activity) is the concentration of the compound causing
50% loss of initial cells at the end of the incubation period (48 hours). Subpanel or
full panel mean-graph midpoint values (MG-MID) are the average of individual real
and default GI50, TGI, and LC50 values of all cell lines in the subpanel or the full
panel, respectively. The ratio obtained by dividing the compound full-panel MG-
MID (mM) by its individual MG-MID (mM) is considered as a measure of compound
selectivity (Boyd and Paull, 1995). Ratios between 3 and 6 referred to moderate
selectivity; ratios greater than 6 indicated high selectivity toward the corresponding
cell line.
The median growth inhibitory concentrations (GI50, mM) of in vitro subpanel
tumor cell lines and GI50 (mM) full-panel mean-graph midpoints (MG-MID) are
listed in Table 2. The median total growth inhibitory concentrations (TGI, mM) of
in vitro subpanel tumor cell lines TGI (mM), full-panel mean-graph midpoints (MG-
MID), and LC50 (mM) full-panel mean-graph midpoints (MG-MID) are recorded in
Table 3.
The selectivity ratios of the active compounds toward the nine tumor cell lines
are shown in Table 2.
Chemistry
General
Melting points were determined in open glass capillaries on a Griffin melting point
apparatus and are all uncorrected. Infrared spectra (IR) were recorded, for KBr
discs, on a Perkin Elmer 1430 Infrared spectrophotometer. Nuclear magnetic
resonance (1H-NMR and 13C-NMR) was scanned on a Jeol-NMR 400 MHZ
spectrophotometer and are reported as d values (ppm) relative to tetramethylsilane

Med Chem Res (2007) 16:49–77
59
(TMS) as internal standard. The type of signal is indicated by one of the following
letters: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of
doublet. Mass spectra were run on a Finnigan mass spectrometer model SSQ/700
(70 ev). Microanalyses were performed on Perkin Elmer 2400 elemental analyzer, at
King Faisal Specialist Hospital and Research Center, Saudi Arabia. The absorption
spectra of the formed colored chelates were recorded on Shimadzu U.V–Vis.
recording spectrophotometer U.V–160A. Reactions were monitored via thin-layer
chromatography (TLC) on silica gel (60 GF254, Merck), using glass plates, and the
spots were visualized by exposure to iodine vapor or UV lamp at k254 nm for few
seconds.
General procedure for the preparation of 1-aryl-3-(2,5-dimethoxyphenyl)
propenones (5a–c)
A solution of 2,5-dimethoxybenzaldehyde 3 (1.66 g, 10 mmol) in absolute ethanol
(10 ml) was added to a well stirred solution of an equimolar amount of 4-substituted
acetophenones (10 mmol) in 4% ethanolic sodium hydroxide (10 ml). Stirring was
continued for 24 h at room temperature. The formed yellow crystalline product was
filtered, washed with cold ethanol, dried in a vacuum desiccator and finally
recrystallized.
3-(2,5-Dimethoxyphenyl)-1-phenylpropenone (5a)
Reagents: acetophenone (1.2 g, 10 mmol). Crystallization: dioxane. Yellow crystals
(2.51 g, 94%), mp 118 8C. IR (KBr, cmÀ1): 1663, 1603, 1266, 1053. Anal. %
(C17H16O3) C, H, calcd. 76.10, 6.01, found, 76.09, 6.00.
3-(2,5-Dimethoxyphenyl)-1-p-tolylpropenone (5b)
Reagents: 4-methylacetophenone (1.34 g, 10 mmol). Crystallization: dioxane.
Yellow crystals (2.76 g, 98%), mp 1228C. IR (KBr, cmÀ1): 1658, 1598, 1255, 1050.
1H-NMR (DMSO-d6, 400MHz): 2.42 (s, 3H), 3.80, 3.85 (two s, each 3H), 6.86 (d,
1H, J = 8.80Hz,), 6.92 (dd, 1H, J = 8.80, 2.92 Hz), 7.15 (d, 1H, J = 2.92 Hz), 7.28 (d,
2H , J = 8.08 Hz), 7.57 (d, 1H, J = 16.12 Hz), 7.92 (d, 2H, J = 8.08 Hz), 8.06 (d, 1H,
J = 16.16 Hz). Anal. % (C18H18O3) C, H, calcd. 76.57, 6.43, found, 76.57, 6.42.
1-(4-Chlorophenyl)-3-(2,5-dimethoxyphenyl)propenone (5c)
Reagents: 4-chloroacetophenone (1.54 g, 10 mmol). Crystallization: dioxane.
Yellow crystals (2.9 g, 96%), mp 578C, with decomposition. IR (KBr, cmÀ1): 1653,
1590, 1226, 1042. H-NMR (CDCl3, 400 MHz): 3.79, 3.84 (two s, each 3H), 6.85
1
(d, 1H, J = 8.8 Hz), 6.92 (dd, 1H, J = 8.80, 2.92 Hz), 7.13 (d, 1H, J = 2.92 Hz), 7.45
(d, 2H, J = 11.00 Hz), 7.51 (d, 1H, J = 16.12 Hz), 7.92 (d, 2H, J = 11.00 Hz), 8.05 (d,
1H, J = 16.12 Hz). Anal. % (C17H15ClO3) C, H, calcd. 67.44, 4.99, found, 67.43,
4.98.

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Med Chem Res (2007) 16:49–77
General procedure for the preparation of 1-aryl-3-(2,5-dihydroxyphenyl)
propenones (6a–c)
Under anhydrous condition, a mixture of 1-aryl-3-(2,5-dimethoxyphenyl)propenones
5a–c (1.0 mmol) and hydrobromic acid 48% (9 ml) was kept for 20 h at a temperature
˚
of 90C via an oil bath. The excess hydrobromic acid was removed under reduced
pressure and the formed dark residue was recrystallized.
3-(2,5-Dihydroxyphenyl)-1-phenylpropenone (6a)
Reagents: compound 5a (0.27 g, 1.0 mmol) Crystallization: 90% aqueous ethanol.
Brown solid (0.17 g, 70%), mp 1868C, with decomposition. IR (KBr, cmÀ1): 3375-
2980, 1625, 1537. Anal. % (C15H12O3) C,H, calcd. 74.99, 5.03, found, 74.97, 5.03.
3-(2,5-Dihydroxyphenyl)-1-p-tolylpropenone (6b)
Reagents: compound 5b (0.28 g, 1.0 mmol). Crystallization: 90% aqueous ethanol.
Dark brown crystals (0.18 g, 72%), mp 2238C. IR (KBr, cmÀ1): 3250–2900, 1612,
1520. 1H-NMR (DMSO-d6, 400 MHz): 2.42(s, 3H), 6.86 (d, 1H, J = 8.80 Hz), 6.92
(dd, 1H, J = 8.80, 2.92 Hz), 7.15 (d, 1H, J = 2.92 Hz), 7.28 (d, 2H, J = 8.08 Hz), 7.93
(d, 2H, J = 8.08 Hz), 7.57 (d, 1H, J = 16.12 Hz), 8.05 (d, 1H, J = 16.16 Hz), 9.33,
9.71 (two s, each 1H, D2O-exch). Anal. % (C16H14O3) C, H, calcd. 75.58, 5.55,
found, 75.57, 5.54.
3-(2,5-Dihydroxyphenyl)-1-(4-chlorophenyl)propenone (6c)
Reagents: compound 5c (0.3 g, 1.0 mmol). Crystallization: 90% aqueous ethanol.
Dark brown solid (0.178 g, 66%), melting with decomposition at 2548C. IR (KBr,
1
cmÀ1): 3250–2870, 1612, 1516. H-NMR (DMSO-d6, 400 MHz): 6.85 (d, 1H,
J = 8.80 Hz), 6.92 (dd, 1H, J = 8.80, 2.92 Hz), 7.13 (d, 1H, J = 2.92 Hz), 7.45 (d,
2H, J = 11.00 Hz), 7.93 (d, 2H, J = 11.00 Hz), 7.51 (d, 1H, J = 16.12 Hz), 8.05 (d,
1H, J = 16.12Hz), 9.23, 9.73 (two s, each 1H, two D2O-exch.). Anal. %
(C15H11ClO3), C,H, calcd. 65.59, 4.04, found 65.58, 4.03.
General procedure for the preparation of 2-(3-aryl-3-oxopropenyl)-1,4-
benzoquinones (7a–c)
A cold solution of ceric ammonium nitrate (2.74 g, 5 mmol) in (1:1) aqueous
acetonitrile (40 ml) was gradually added to a cooled and vigorously stirred solution
of 1-aryl-3-(2,5-dihydroxy-phenyl)propenones 6a–c (1.0 mmol) dissolved in a
mixture of acetonitrile (28 ml) and water (12 ml) over a period of 30 min. Cooling
and stirring were continued for another further hour. The reaction mixture was
allowed to attain room temperature, diluted with water (40 ml), and then extracted
five times each with 20 ml portions of dichloromethane. The combined dichlorom-
ethane extracts were washed with an equal volume of water and dried over

Med Chem Res (2007) 16:49–77
61
anhydrous sodium sulfate, and the solvent was removed under diminished pressure.
The crude dark brown precipitate was recrystallized.
2-(3-Oxo-3-phenylpropenyl)-1,4-benzoquinone (7a)
Reagents: 3-(2,5-dihydroxyphenyl)-1-phenylpropenone 6a (0.24 g, 1.0 mmol)
Crystallization: 10% aqueous DMF. Brown solid (0.17 g, 71%), mp 2608C, with
decomposition. IR (KBr, cmÀ1): 1725, 1637, 1525. Anal. % (C15H10O3), C,H, calcd.
75.62, 4.23, found, 75.61, 4.22.
2-(3-oxo–ptolylpropenyl)-1,4-benzoquinone (7b)
Reagents: compound 6b (0.25 g, 1.0 mmol). Crystallization: 10% aqueous DMF.
Brown solid (0.16 g, 63%), mp >3608C. IR (KBr, cmÀ1): 1720, 1635, 1522.
1H-NMR (DMSO-d6, 400 MHz): 2.42(s, 3H), 6.85 (d, 1H, J = 8.80 Hz), 6.92 (dd,
1H, J = 8.80, 2.92 Hz), 7.15 (d,1H, J = 2.92 Hz), 7.28 (d, 2H , J = 8.08 Hz), 7.56 (d,
1H, J = 8.80 Hz), 7.92 (d, 2H, J = 8.08 Hz), 8.07 (d, 1H, J = 8.80 Hz). Anal. %
(C16H12O3) C, H, calcd. 76.18, 4.79, found, 76.17, 4.77.
2-[3-(4-Chlorophenyl)-3-oxopropenyl]-1,4-benzoquinone (7c)
Reagents: compound 6c (0.27 g, 1.0 mmol). Crystallization: 10% aqueous DMF.
Brown solid (0.16 g, 59%), mp >3608C. IR (KBr, cmÀ1): 1718, 1635, 1512.
1H-NMR (DMSO-d6, 400 MHz): 6.86 (d, 1H, J = 8.80 Hz), 6.93 (dd, 1H, J = 8.80,
2.92 Hz), 7.13 (d,1H, J = 2.92 Hz), 7.44 (d, 2H , J = 8.08 Hz), 7.51(d, 1H, J = 16.12
Hz), 7.92 (d, 2H, J = 8.08 Hz), 8.05 (d, 1H, J = 16.12 Hz). Anal. % (C15H9ClO3) C,
H, calcd. 66.07, 3.33, found, 66.06, 3.33.
General procedure for the preparation of 1,3-diaryl-5-(2,5-dimethoxy-
phenyl)pyrazoles (8a–i)
A mixture of 1-aryl-3-(2,5-dimethoxyphenyl)propenone 5a–c (1.0 mmol) and the
appropriate 4-substituted phenylhydrazine hydrochloride (1.05 mmol) or the
selected 4-hydrazino-N-substituted benzenesulfonamide hydrochlorides (1.05
mmol) in glacial acetic acid (20 ml) containing an equimolar amount of anhydrous
sodium acetate (0.086 g, 1.05 mmol) was heated under reflux for 12 h. The reaction
mixture was concentrated, cooled and poured with stirring onto cold water (30 ml).
The yellow precipitate formed was filtered, washed with water, air-dried, and finally
recrystallized.
1,3-Diphenyl-5-(2,5-dimethoxyphenyl)pyrazole (8a)
Reagents: compound 5a (0.27 g, 1.0 mmol) and phenylhydrazine hydrochloride
(0.15 g, 1.05 mmol). Crystallization: chloroform–ethanol mixture (3:1). Yellow
solid (0.25 g, 70%), mp 1598C. IR (KBr, cmÀ1): 1598, 1500, 1215, 1048. Anal.
% (C23H20N2O2) C, H, N, calcd. 77.51, 5.66, 7.86, found, 77.50, 5.63, 7.85.

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Med Chem Res (2007) 16:49–77
5-(2,5-Dimethoxyphenyl)-3-(p-tolyl)-1-phenylpyrazole (8b)
Reagents: compound 5b (0.28 g, 1.0 mmol) and p-tolylhydrazine hydrochloride,
(0.17 g, 1.05 mmol). Crystallization: chloroform–ethanol mixture (3:1). Yellow
solid (0.24 g, 65%), mp 1728C. IR (KBr, cmÀ1): 1595, 1498, 1214, 1046. Anal. %
(C24H22N2O2) C, H, N calcd. 77.81, 5.99, 7.56, found, 77.79, 5.89, 7.55.
3-(4-Chlorophenyl)-5-(2,5-dimethoxyphenyl)-1-phenylpyrazole (8c)
Reagents: compound 5c (0.30 g, 1.0 mmol) and 4-chlorophenylhydrazine hydro-
chloride, (0.187 g, 1.05 mmol). Crystallization: chloroform–ethanol mixture (3:1).
Yellow solid (0.27 g, 69%), mp 1858C. IR (KBr, cmÀ1): 1593, 1499, 1214, 1045.
1H-NMR (DMSO-d6, 400 MHz): 3.81, 3.89 (two s, each 3H), 7.08 (dd, 1H, J = 9.52,
2.92 Hz), 7.25 (s, 1H), 7.20 (d, 1H, J = 9.52 Hz), 7.29 (d, 1H, J = 2.92 Hz), 7.41–
7.43 (m, 3H), 7.52 (d, 2H, J = 11.76 Hz), 7.65 (d, 2H, J = 11.76 Hz), 7.74 (d, 2H,
J = 11.00 Hz). Anal. (C23H19ClN2O2) C, H, N, calcd. 70.68, 4.90, 7.17, found,
70.66, 4.89, 7.17.
4-[5-(2,5-Dimethoxyphenyl)-3-phenylpyrazol-1-yl]benzenesulfonamide (8d)
Reagents: compound 5a (0.27 g, 1.0 mmol) with 4-hydrazinobenzenesulfonamide
hydrochloride, (0.234 g, 1.05 mmol). Crystallization: chloroform–ethanol mixture
(3:1). Yellow solid (0.28 g, 64%), mp 1408C. IR (KBr, cmÀ1): 3490, 1616, 1601,
1
1496, 1337, 1224, 1097, 1178. H-NMR (DMSO-d6, 400 MHz): 3.80, 3.85 (two s,
each 3H), 4.65 (s, 2H, D2O- exch), 6.86 (d, 1H, J = 8.80 Hz), 6.93 (dd, 1H, J = 8.80,
2.92 Hz), 7.15 (d, 1H, J = 2.92 Hz), 7.25(s, 1H), 7.48–7.50 (m, 3H), 7.56 (d, 2H,
J = 16.12 Hz), 7.99 (d, 2H, J = 8.80 Hz), 8.05 (d, 2H, J = 16.12 Hz). Anal. %
(C23H21N3O4S) C, H, N, calcd. 63.43, 4.86, 9.65, found, 63.39, 4.84, 9.63.
4-[5-(2,5-Dimethoxyphenyl)-3-p-tolylpyrazol-1-yl]benzenesulfonamide (8e)
Reagents: compound 5b (0.28 g, 1.0 mmol) with 4-hydrazinobenzenesulfonamide
hydrochloride, (0.234 g, 1.05 mmol). Crystallization: chloroform–ethanol mixture
(3:1). Yellow solid (0.87 g, 64%), mp 1688C. IR (KBr, cmÀ1): 3488, 1616, 1600,
1497, 1330, 1220, 1176, 1088. 1H-NMR (DMSO-d6, 400 MHz): 2.41 (s, 3H), 3.80,
3.84 (two s, each 3H), 4.46 (s, 2H, D2O exch), 6.85 (d, 1H, J = 8.80 Hz), 6.93 (dd,
1H, J = 8.80, 2.92 Hz), 7.13 (d, 1H, J = 2.92 Hz), 7.25 (s, 1H), 7.44 (d, 2H, J = 11.00
Hz), 7.51 (d, 2H, J = 16.12 Hz), 7.92 (d, 2H, J = 11.00 Hz), 8.04 (d, 2H, J = 16.12
Hz). Anal. % (C24H23N3O4S) C, H, N, calcd. 64.13, 5.16, 9.35, found, 64.09, 5.13,
9.32.
4-[3-(4-Chlorophenyl)-5-(2,5-dimethoxyphenyl)pyrazol-1-
yl]benzenesulfonamide (8f)
Reagents: compound 5c (0.30 g, 1.0 mmol) with 4-hydrazinobenzenesulfonamide
hydrochloride, (0.234 g, 1.05 mmol). Crystallization: chloroform–ethanol mixture

Med Chem Res (2007) 16:49–77
63
(3:1). Yellow solid (0.32 g, 68%), mp. 1828C. IR (KBr, cmÀ1): 3489, 1616, 1598,
1496, 1328, 1224, 1175, 1086. H-NMR (DMSO-d6, 400 MHz): 3.80, 3.89 (two s,
1
each 3H), 4.22 (s, 2H, D2O exch.), 6.86 (d, 1H, J = 9.56 Hz), 6.93 (dd, 1H, J = 9.56,
2.92 Hz), 7.13 (d, 1H, J = 2.92 Hz), 7.25 (s, 1H), 7.45 (d, 2H, J = 8.80 Hz), 7.52 (d,
2H, J = 16.16 Hz), 7.94 (d, 2H, J = 8.80 Hz), 8.06 (d, 2H, J = 16.16 Hz). Anal. %
(C23H20ClN3O4S) C, H, N, calcd. 58.78, 4.29, 8.94, found, 58.72, 4.19, 8.90.
N-Acetyl-4-[5-(2,5-dimethoxyphenyl)-3-phenylpyrazol-1-
yl]benzenesulfonamide (8g)
Reagents: compound 5a (0.27 g, 1.0 mmol) and N-acetyl-4-hydrazinobenzenesulf-
onamide hydrochloride, (0.28 g, 1.05 mmol). Crystallization: chloroform–ethanol
mixture (3:1). Yellow solid (0.3 g, 63%), mp 1588C. IR (KBr, cmÀ1): 3495, 1615,
1
1597, 1488, 1321, 1218, 1175, 1085. H-NMR (DMSO-d6, 400 MHz): 3.79, 3.83
(two s, each 3H), 2.32 (s, 3H), 6.86 (d, 1H, J = 8.80 Hz), 6.92 (dd, 1H, J = 8.80, 2.92
Hz), 7.15 (d, 1H, J = 2.92 Hz), 7.25 (s, 1H), 7.48–7.50 (m, 3H), 7.57 (d, 2H,
J = 16.12 Hz), 7.99 (d, 2H, J = 8.80 Hz), 8.06 (d, 2H, J = 16.16 Hz), 10.25 (s, 1H,
D2O-exch.). Anal. % (C25H23N3O5S) C, H, N, calcd. 62.88, 4.85, 8.80, found,
62.79, 4.78, 8.78.
N-Acetyl-4-[5-(2,5-dimethoxyphenyl)-3-p-tolylpyrazol-1-
yl]benzenesulfonamide (8h)
Reagents: compound 5b (0.28 g, 1.0 mmol) and N-acetyl-4-hydrazinobenzenesulf-
onamide hydrochloride, (0.28 g, 1.05 mmol). Crystallization: chloroform–ethanol
mixture (3:1). Yellow solid (0.39 g, 79%), mp 1908C. IR (KBr, cmÀ1): 3490, 1616,
1598, 1486, 1322, 1219, 1175, 1089. 1H-NMR (DMSO-d6, 400 MHz): 1.99 (s, 3H),
3.80, 3.84 (two s, each 3H), 2.35 (s, 3H), 7.06 (d, 1H, J = 8.80 Hz), 7.14 (dd, 1H,
J = 8.80, 2.92 Hz), 7.25 (s, 1H), 7.33 (d, 1H, J = 2.92 Hz), 7.64 (d, 2H, J = 8.80 Hz),
7.88 (d, 2H, J = 16.00 Hz), 8.05 (d, 2H, J = 16.00 Hz), 8.17 (d, 2H, J = 8.80 Hz),
10.11 (s, 1H, D2O-exch.). Anal. % (C26H25N3O5S) C, H, N, calcd. 63.53, 5.13, 8.55,
found, 63.48, 5.07, 8.53.
N-Acetyl-4-[3-(4-chlorophenyl)-5-(2,5-dimethoxyphenyl)pyrazol-1-
yl]benzenesulfon-amide (8i)
Reagents: compound 5c (0.30 g, 1.0 mmol) with N-acetyl-4-hydrazinobenzenesulf-
onamide hydrochloride, (0.28 g, 1.05 mmol). Crystallization: chloroform–ethanol
mixture (3:1). Yellow solid (0.38 g, 74%), mp 2068C. IR (KBr, cmÀ1): 3497, 1616,
1595, 1489, 1335, 1228, 1180, 1092. 1H-NMR (DMSO-d6, 400 MHz): 2.42 (s, 3H),
3.81, 3.85 (two s, each 3H), 6.85 (d, 1H, J = 8.80 Hz), 6.92 (dd, 1H, J = 8.80, 2.92
Hz), 7.15 (d, 1H, J = 2.92 Hz), 7.25 (s, 1H), 7.28 (d, 2H, J = 8.80 Hz), 7.57 (d, 2H,
J = 15.40 Hz), 7.92 (d, 2H, J = 8.80 Hz), 8.06 (d, 2H, J = 15.40 Hz), 10.01 (s, 1H,
D2O-exch.). Anal. % (C25H22ClN3O5S) C, H, N, calcd. 58.65, 4.33, 8.21, found,
58.58, 4.26, 8.19.

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General procedure for the preparation of 1,3-diaryl-5-(2,5-dihydroxy-
phenyl)pyrazoles (9a–i)
Under anhydrous condition, a mixture of the appropriate 1,3-diaryl-5-(2,5-dimeth-
oxyphenyl) pyrazoles 8a–i (1.0 mmol) and 48% hydrobromic acid (9 ml) was heated
˚
for 4 h, keeping the temperature between 120 and 125C with an oil bath. The
reaction mixture was allowed to cool and poured with stirring onto cold water. The
brown precipitate formed was filtered, air-dried, and finally recrystallized.
5-(2,5-Dihydroxyphenyl)-1,3-diphenylpyrazole (9a)
Reagents: compound 8a (0.356 g, 1.0 mmol). Crystallization: chloroform–ethanol
mixture (3:1). Brown solid (0.246 g, 75%), mp 1808C. IR (KBr, cmÀ1): 3414–3190,
1615, 1505. Anal. % (C21H16N2O2) C, H, N, calcd. 76.81, 4.91, 8.53, found, 76.80,
4.90, 8.53.
5-(2,5-Dihydroxyphenyl)-3-(p-tolyl)-1-phenylpyrazole (9b)
Reagents: compound 8b (0.37 g, 1.0 mmol). Crystallization: 10% aqueous DMF.
Brown solid (0.26 g, 76%), mp 2898C. IR (KBr, cmÀ1): 3420–3112, 1600, 1500.
1H-NMR (DMSO-d6, 400 MHz): 2.19 (s, 3H), 6.88 (d, 1H, J = 8.80 Hz), 6.93 (dd,
1H, J = 8.80, 2.92 Hz), 7.16 (d, 1H, J = 2.92 Hz), 7.27 (s, 1H), 7.45–7.49 (m, 3H),
7.57 (d, 2H, J = 16.00 Hz), 7.92 (d, 2H, J = 8.08 Hz), 8.05 (d, 2H, J = 16.00 Hz),
9.17, 9.6 (two s, each 1H, two D2O-exch.). Anal. % (C22H18N2O2) C, H, N, calcd.
77.17, 5.30, 8.18, found, 77.15, 5.28, 8.18.
3-(4-Chlorophenyl)-5-(2,5-dihydroxyphenyl)-1-phenylpyrazole (9c)
Reagents: compound 8c (0.39 g, 1.0 mmol). Crystallization: 10% aqueous DMF.
Brown solid (0.29 g, 80%), mp >3608C. IR (KBr, cmÀ1): 3425–3100, 1598, 1493.
1H-NMR (DMSO-d6, 400 MHz): 6.08 (dd, 1H, J = 9.52, 2.92 Hz), 7.19 (d, 1H,
J = 9.52 Hz), 7.25 (s, 1H), 7.29 (d, 1H, J = 2.92 Hz), 7.42–7.44 (m, 3H), 7.52 (d, 2H,
J = 11.76 Hz), 7.66 (d, 2H, J = 11.76 Hz), 7.75 (d, 2H, J = 11.00 Hz), 9.20, 9.63 (two
s, each 1H, two D2O-exch.). Anal. % (C21H15ClN2O2) C, H, N, calcd. 69.52, 4.17,
7.72, found, 69.50, 4.15, 7.71.
4-[5-(2,5-Dihydroxyphenyl)-3-phenylpyrazol-1-yl]benzenesulfonamide (9d)
Reagents: compound 8d (0.435 g, 1.0 mmol). Crystallization: 10% aqueous DMF.
Brown solid (0.33 g, 87%), mp 2908C. IR (KBr, cmÀ1): 3409–3239 (several bands),
1640, 1593, 1499, 1215, 1188. H-NMR (DMSO-d6, 400 MHz): 4.67 (s, 2H, D2O
1
exch), 6.84 (d, 1H, J = 8.80 Hz), 6.93 (dd, 1H, J = 8.80, 2.92 Hz), 7.15 (d, 1H,
J = 2.92 Hz), 7.26 (s, 1H), 7.48–7.51 (m, 3H), 7.57 (d, 2H, J = 16.12 Hz), 7.99 (d,
2H, J = 8.80 Hz), 8.06 (d, 2H, J = 16.12 Hz), 9.17, 9.63 (two s, each 1H, two D2O-
exch.). Anal. % (C21H17N3O4S) C, H, N, calcd. 61.91, 4.21, 10.31, found, 61.88,
4.19, 10.28.

Med Chem Res (2007) 16:49–77
65
4-[5-(2,5-Dihydroxyphenyl)-3-p-tolylpyrazol-1-yl]benzenesulfonamide (9e)
Reagents: compound 8e (0.45 g, 1.0 mmol). Crystallization: chloroform–ethanol
mixture (3:1). Brown solid (0.33 g, 78%), mp > 3608C. IR (KBr, cmÀ1): 3420–3230
(several bands), 1635, 1590, 1497, 1215, 1165. H-NMR (DMSO-d6, 400 MHz):
1
2.41 (s, 3H), 4.46 (s, 2H, D2O exch), 6.86 (d, 1H, J = 8.80 Hz), 6.92 (dd, 1H,
J = 8.80, 2.92 Hz), 7.14 (d, 1H, J = 2.92 Hz), 7.28 (s, 1H), 7.44 (d, 2H, J = 11.00
Hz), 7.51 (d, 2H, J = 16.12 Hz), 7.92 (d, 2H, J = 11.00 Hz), 8.04 (d, 2H, J = 16.12
Hz), 9.17, 9.63 (two s, each 1H, two D2O-exch.). Anal. % (C22H19N3O4S) C, H, N,
calcd. 62.69, 4.54, 9.97, found, 62.65, 4.52, 9.95.
4-[3-(4-Chlorophenyl)-5-(2,5-dihydroxyphenyl)pyrazol-1-
yl]benzenesulfonamide (9f)
Reagents: compound 8f (0.47 g, 1.0 mmol). Crystallization: 10% aqueous DMF.
Dark brown solid (0.322 g, 73%), mp >3608C. IR (KBr, cmÀ1): 3465–3230 (several
bands), 1605, 1590, 1491, 1219, 1128. 1H-NMR (DMSO-d6, 400 MHz): 4.36 (s, 2H,
D2O exch.), 6.86 (d, 1H, J = 9.56 Hz), 6.93 (dd, 1H, J = 9.56, 2.92 Hz), 7.13 (d, 1H,
J = 2.92 Hz), 7.25 (s, 1H), 7.45 (d, 2H, J = 8.80 Hz), 7.50 (d, 2H, J = 16.16 Hz), 7.92
(d, 2H, J = 8.80 Hz), 8.05 (d, 2H, J = 16.16 Hz), 9.23, 9.73(two s, each 1H, two
D2O-exch.). Anal. % (C21H16Cl N3 O4S) C, H, N, calcd. 57.08, 3.65, 9.51, found,
57.06, 3.62, 9.49.
N-Acetyl-4-[5-(2,5-dihydroxyphenyl)-3-phenylpyrazol-1-
yl]benzenesulfonamide (9g)
Reagents: compound 8g (0.477 g, 1.0 mmol). Crystallization: 10% aqueous DMF.
Brown solid (0.32 g, 71%), mp >3608C. IR (KBr, cmÀ1): 3400–3250, 1687, 1600,
1500, 1487, 1250, 1153. 1H-NMR (DMSO-d6, 400 MHz): 2.33 (s, 3H), 6.86 (d, 1H,
J = 8.80 Hz), 6.93 (dd, 1H, J = 8.80, 2.92 Hz), 7.15 (d, 1H, J = 2.92 Hz), 7.25 (s,
1H), 7.48–7.50 (m, 3 H), 7.57 (d, 2H, J = 16.12 Hz), 7.99 (d, 2H, J = 8.80 Hz), 8.06
(d, 2H, J = 16.12 Hz), 9.17, 9.36, 10.25 (three s, each 1H, two D2O-exch.). Anal. %
(C23H19 N3O5S) C, H, N, calcd. 61.46, 4.26, 9.35, found, 61.46, 4.25, 9.33.
N-Acetyl-4-[5-(2,5-dihydroxyphenyl)-3-(4-methylphenyl)pyrazol-1-yl]benzene
sulfonamide (9h)
Reagents: compound 8h (0.491 g, 1.0 mmol). Crystallization: 10% aqueous DMF.
Brown solid (0.34 g, 73%), mp >3608C. IR (KBr, cmÀ1): 3400–3280, 1670, 1598,
1498, 1455, 1245, 1138. 1H-NMR (DMSO-d6, 400 MHz): 2.05 (s, 3H), 2.43 (s, 3H),
7.08 (dd, 1H, J = 9.52, 2.92 Hz), 7.19 (d, 1H, J = 9.52 Hz), 7.30 (d, 2H, J = 16.00
Hz), 7.35 (s, 1H), 7.44 (d, 2H, J = 16.00 Hz), 7.52 (d, 2H, J = 11.76 Hz), 7.65 (d, 2H,
J = 11.76 Hz), 7.73 (d, 1H, J = 2.92 Hz), 9.02, 9.65, 10.43(three s, each 1H, two
D2O-exch.). Anal.% (C24H21N3O5S) C, H, N, calcd. 62.19, 4.57, 9.07, found, 62.09,
4.55, 9.06.

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N-Acetyl-4-[3-(4-chlorophenyl)-5-(2,5-dihydroxyphenyl)pyrazol-1-yl]benzene-
sulfonamide (9i)
Reagents: compound 8i (0.51 g, 1.0 mmol). Crystallization: 10% aqueous DMF.
Brown solid (0.37 g, 77%), mp >3608C. IR (KBr, cmÀ1): 3400–3286, 1678,
1594, 1490, 1459, 1243, 1137. 1H-NMR (DMSO-d6, 400 MHz): 2.42 (s, 3H),
6.88 (d, 1H, J = 8.76 Hz), 6.94 (dd, 1H, J = 8.76, 2.92 Hz), 7.15 (d, 1H, J = 2.92
Hz), 7.21 (s, 1H), 7.28 (d, 2H, J = 8.80 Hz), 7.57 (d, 2H, J = 15.20 Hz), 7.92 (d,
2H, J = 8.80 Hz), 8.07 (d, 2H, J = 15.2 Hz), 9.17, 9.63, 10.35 (three s, each 1H,
two D2O-exch.). Anal. % (C23H18ClN3O5S) C, H, N, calcd. 57.09, 3.75, 8.68,
found, 57.07, 3.69, 8.67.
General procedure for the preparation of 1,3-(diaryl)-5-(1,4-benzo-quinonyl)
pyrazoles (10a–i)
To a solution of the appropriate 1,3-diaryl-5-(2,5-dihydroxyphenyl)pyrazoles 9a–i
(1.0 mmol) dissolved in a mixture of acetonitrile (28 ml) and water (6 ml), a cooled
solution of ceric ammonium nitrate (2.74 g, 5 mmol) in a mixture of acetonitrile
(20 ml) and water (20 ml) was slowly added with vigorous stirring over a period of
30 min. During addition, the reaction mixture was kept in an ice water bath
whereupon the violet crystalline product separated out. Compound was filtered,
washed with ether, and finally recrystallized.
5-(1,4-Benzoquinonyl)-1,3-diphenylpyrazole (10a)
Reagents: compound 9a (0.328 g, 1.0 mmol). Crystallization: DMF/water (5:1).
Violet solid (0.22 g, 67%), mp >3608C. IR (KBr, cmÀ1): 1712, 1612, 1512. Anal. %
(C21H14N2O2) C, H, N, calcd. 77.29, 4.32, 8.58, found, 77.26, 4.28, 8.54.
5-(1,4-Benzoquinonyl)-3-(p-tolyl)-1-phenylpyrazole (10b)
Reagents: compound 9b (0.342 g, 1.0 mmol). Crystallization: 10% aqueous
DMF. Violet solid (0.22 g, 65%), mp >3608C. IR (KBr, cmÀ1): 1710, 1612,
1500. H-NMR (DMSO-d6, 400 MHz): 2.19 (s, 3H), 6.86 (d, 1H, J = 8.80 Hz),
1
6.92 (dd, 1H, J = 8.80, 2.92 Hz), 7.15 (d, 1H, J = 2.92 Hz), 7.27 (s, 1H), 7.46–
7.49 (m, 3H), 7.57 (d, 2H, J = 16.12 Hz), 7.93 (d, 2H, J = 8.08 Hz), 8.06 (d, 2H,
J = 16.12 Hz). Anal. % (C22H16N2O2) C, H, N, calcd. 77.63, 4.74, 8.23, found,
77.60, 4.71, 8.20.
5-(1,4-Benzoquinonyl)-3-(4-Chlorophenyl)-1-phenylpyrazole (10c)
Reagents: compound 9c (0.362 g, 1.0 mmol). Crystallization: 10% aqueous DMF.
Violet solid (0.25 g, 69%), mp >3608C. IR (KBr, cmÀ1): 1706, 1609, 1498. Anal. %
(C21H13ClN2O2) C, H, N, calcd. 69.91, 3.63, 7.76, found, 69.88, 3.59, 7.75.

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67
4-[5-(1,4-Benzoquinonyl)-3-phenylpyrazol-1-yl]benzenesulfonamide (10d)
Reagents: compound 9d (0.407 g, 1.0 mmol). Crystallization: 10% aqueous DMF.
Violet solid (0.235 g, 58%), mp 3218C with decomposition. IR (KBr, cmÀ1): 3250,
1728, 1593, 1500, 1450, 1250, 1162. H-NMR (DMSO-d6, 400 MHz): 4.67 (s, 2H,
1
D2O exch.), 6.63 (d, 1H, J = 9.52 Hz), 6.93 (dd, 1H, J = 9.52, 2.92 Hz), 7.15 (d, 1H,
J = 2.92 Hz), 7.26 (s, 1H), 7.48–7.50 (m, 3H), 7.56 (d, 2H, J = 16.12 Hz), 7.99 (d,
2H, J = 8.80 Hz), 8.06 (d, 2H, J = 16.12 Hz). Anal. % (C21H15N3O4S) C, H, N,
calcd. 62.21, 3.73, 10.36, found, 62.18, 3.70, 10.35.
4-[5-(1,4-Benzoquinonyl)-3-p-tolyl-pyrazol-1-yl]benzenesulfonamide (10e)
Reagents: compound 9e (0.421 g, 1.0 mmol). Crystallization: 10% aqueous DMF.
Violet solid (0.26 g, 62%), mp >3608C. IR (KBr, cmÀ1): 3250, 1725, 1593, 1498,
1448, 1250, 1158. H-NMR (DMSO-d6, 400 MHz): 2.41 (s, 3H), 4.60 (s, 2H, D2O
1
exch.), 7.08 (dd, 1H, J = 9.56, 2.92 Hz), 7.19 (d, 1H, J = 9.56 Hz), 7.24 (s, 1H), 7.34
(d, 2H, J = 11.96 Hz), 7.42 (d, 2H, J = 11.96 Hz), 7.52 (d, 2H, J = 11.76 Hz), 7.65 (d,
2H, J = 11.76 Hz), 7.73 (d, 1H, J = 2.92 Hz). Anal. % (C22H17N3O4S) C, H, N,
calcd. 63.00, 4.09, 10.02, found, 62.97, 4.06, 10.00.
4-[5-(1,4-Benzoquinonyl)-3-(4-chlorophenyl)pyrazol-1-yl]benzenesulfonamide (10f)
Reagents: compound 9f (0.442 g, 1.0 mmol). Crystallization: DMF–water (5:1).
violet solid (0.26 g, 59%), mp 3408C with decomposition. IR (KBr, cmÀ1): 3255,
1709, 1594, 1495, 1445, 1241, 1148. H-NMR (DMSO-d6, 400 MHz): 4.45 (s, 2H,
1
D2O exch.), 6.85 (d, 1H, J = 8.80 Hz), 6.96 (dd, 1H, J = 8.80, 2.92 Hz), 7.14 (d, 1H,
J = 2.92 Hz), 7.22 (s, 1H), 7.33 (d, 2H, J = 15.40 Hz), 7.51 (d, 2H, J = 15.40 Hz),
7.79 (d, 2H, J = 9.52 Hz), 7.90 (d, 2H, J = 9.52 Hz). Anal. % (C21H14ClN3O4S) C,
H, N, calcd. 57.34, 3.21, 9.55, found, 57.29, 3.18, 9.54.
N-Acetyl-4-[5-(1,4-benzoquinonyl)-3-phenylpyrazol-1-yl]benzenesulfonamide
(10g)
Reagents: compound 9g (0.449 g, 1.0 mmol). Crystallization: 10% aqueous DMF.
Violet solid (0.26 g, 58%), mp >3608C. IR (KBr, cmÀ1): 3375, 1731, 1662, 1584,
1496, 1437, 1250, 1175. 1H-NMR (DMSO-d6, 400 MHz): 2.32 (s, 3H), 6.86 (d, 1H,
J = 8.80 Hz), 6.93 (dd, 1H, J = 8.80, 2.92 Hz), 7.15 (d, 1H, J = 2.92 Hz), 7.27 (s,
1H), 7.48–7.50 (m, 3H), 7.56 (d, 2H, J = 16.12 Hz), 7.99 (d, 2H, J = 8.80 Hz), 8.05
(d, 2H, J = 16.12 Hz), 10.26 (s, 1H, D2O-exch.). Anal. % (C23H17N3O5S) C, H, N,
calcd. 61.74, 3.83, 9.39, found, 61.70, 3.79, 9.38.
N-Acetyl-4-[5-(1,4-benzoquinonyl)-3-(p-tolyl)pyrazol-1-yl]benzenesulfonamide
(10h)
Reagents: compound 9h (0.463 g, 1.0 mmol). Crystallization: DMF–water (5:1).
Violet solid (0.30 g, 65%), mp >3608C. IR (KBr, cmÀ1): 3370, 1730, 1660,
1580, 1495, 1430, 1245, 1170. 1H-NMR (DMSO-d6, 400 MHz): 2.06 (s, 3H),

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2.44 (s, 3H), 7.08 (dd, 1H, J = 9.52, 2.92 Hz), 7.20 (d, 1H, J = 9.52 Hz), 7.30 (d,
2H, J = 16.00 Hz), 7.35 (s, 1H), 7.45 (d, 2H, J = 16.00 Hz), 7.52 (d, 2H,
J = 11.76 Hz), 7.67 (d, 2H, J = 11.76 Hz), 7.73 (d, 1H, J = 2.92 Hz), 10.35 (s,
1H, D2O-exch.). Anal. % (C24H19N3O5S) C, H, N, calcd. 62.46, 4.15, 9.11,
found, 62.39, 4.11, 9.09.
N-Acetyl-4-[5-(1,4-benzoquinonyl)-3-(4-chlorophenyl))pyrazol-1-yl]benzene-
sulfonamide (10i)
Reagents: compound 9i (0.483 g, 1.0 mmol). Crystallization: DMF–water (5:1).
Violet solid (0.30 g, 62%), mp >3608C. IR (KBr, cmÀ1): 3368, 1725, 1662, 1588,
1493, 1446, 1240, 1173. 1H-NMR (DMSO-d6, 400 MHz): 2.45 (s, 3H), 6.88 (d, 1H,
J = 8.76 Hz), 6.94 (dd, 1H, J = 8.76, 2.92 Hz), 7.15 (d, 1H, J = 2.92 Hz), 7.21 (s,
1H), 7.28 (d, 2H, J = 8.08 Hz), 7.57 (d, 2H, J = 15.24 Hz), 7.93 (d, 2H, J = 8.80 Hz),
8.07 (d, 2H, J = 15.24 Hz), 10.35(s, 1H, D2O-exch.). Anal. % (C23H16ClN3O5S) C,
H, N, calcd. 57.32, 3.35, 8.72, found, 57.31, 3.32, 8.68.
3-(2,5-Dihydroxyphenacyl)pentane-2,4-dione (12)
To a well stirred solution of acetyl acetone (1.0 g, 10 mmol) in absolute ethanol
(10 ml) was added (0.23 g, 10 mmol) of metallic sodium. The reaction mixture was
stirred for 1 h under anhydrous condition until sodium was completely dissolved. A
solution of 2,5-dihdroxyphenacylbromide 11 (2.31 g, 10 mmol) in absolute ethanol
(20 ml) was then added to the previously prepared solution and the reaction mixture
was stirred while heating under reflux for 16 h. The formed dark brown precipitate
was filtered, washed with diethyl ether, and recrystallized from ethanol to yield 12
(1.92 g, 77%): mp >3608C. IR (KBr, cmÀ1): 3425, 1625. . 1H-NMR (DMSO-d6, 400
MHz): 2.39 (s, 6H), 3.56 (s, 1/2H, D2O-exch.), 5.08 (s, 1/2H), 5.33 (s, 2H), 7.09 (dd,
1H, J = 9.56, 3.86 Hz), 7.19 (d, 1H, J = 9.56 Hz), 7.54 (d, 1H, J = 3.86 Hz), 9.19,
9.63 (two s, each 1H, D2O-exch.). Anal. % (C13H14O5) C, H, calcd, 62.39, 5.64,
found, 62.38, 5.62.
Compounds 14 and 19 were prepared via the same procedure.
Ethyl 2-(2,5-dihydroxyphenacyl)-3-oxobutanoate (15)
Reagents: ethylacetoacetate (1.30 g, 10 mmol) and compound 11 (2.31 g,
10 mmol), reaction time: 18 hours. Crystallization: ethanol. Brown solid (2.24 g,
1
80%), mp > 3608C. IR(KBr, cmÀ1): 3425, 1700, 1612, 1225. H-NMR (DMSO-
d6, 400 MHz): 1.28 (t, 3H, J = 7.00 Hz), 2.39 (s, 3H), 3.50 (s, 1/2H, D2O-exch.),
4.06 ( q, 2H J = 7.00 Hz), 5.08 (s, 1/2H), 5.33 (s, 2H), 7.08 (dd, 1H, J = 9.56,
3.86 Hz), 7.19 (d, 1H, J = 9.56 Hz), 7.54 (d,1H, J = 3.80 Hz), 9.19, 9.63 (two s,
each 1H, D2O-exch.). Anal. % (C14H16O6) C, H, calcd. 60.00, 5.75, found, 59.99,
5.74.

Med Chem Res (2007) 16:49–77
69
Diethyl 2-(2,5-dihydroxyphenacyl)propanedioate (18)
Reagents: diethyl malonate (1.60 g, 10 mmol) and compound 11 (2.31 g, 10 mmol).
Crystallization: Brown solid (2.45 g, 79%), reaction time: 22 h, mp >3608C. IR
(KBr, cmÀ1): 3412, 1703, 1609, 1275. 1H-NMR (DMSO-d6, 400 MHz): 1.28 (t, 6H,
J = 7.00 Hz), 3.56 (s, 1/2H, D2O-exch.), 4.06 (q, 4H, J = 7.00 Hz), 5.08 (s, ½ H),
5.33 (s, 2H), 7.09 (dd, 1H, J = 9.56, 3.86 Hz), 7.19 (d, 1H, J = 9.56 Hz), 7.54 (d, 1H,
J = 3.86 Hz), 9.19, 9.63 (two s, each 1H, D2O-exch.). Anal. % (C15H18O7 ) C, H,
calcd. 58.06, 5.85, found, 58.06, 5.82.
General procedure for the preparation of 1-aryl-4-(2,5-dihyroxyphenacyl)-3,5-
dimethylpyrazoles (13a–e)
A solution of substituted arylhydrazine hydrochloride (1.05 mmol) in absolute
ethanol (10 ml) was gradually added to a solution of compound 12 (0.25 g, 1.0
mmol) in absolute ethanol (10 ml) containing few drops of glacial acetic acid and an
equimolar amount of anhydrous sodium acetate (0.123 g, 1.05 mmol). The reaction
mixture was stirred while heating under reflux for 18 h and set aside for an overnight
at room temperature. The formed brown precipitate was filtered, washed several
times with cold water, dried, and finally recrystallized.
4-(2,5-Dihyroxyphenacyl)-1-pheyl-3,5-dimethylpyrazole (13a)
Reagents: phenylhydrazine hydrochloride (0.15 g, 1.05 mmol). Crystallization: 10%
aqueous ethanol. Brown solid (0.19 g, 59%), melting with decomposition at 2248C.
1
IR (KBr, cmÀ1): 3425–2800, 1606, 1584, 1525. H-NMR (DMSO-d6, 400 MHz):
2.08, 2.20 (two s, each 3H), 5.20 (s, 2H), 6.85 (d, 1H, J = 8.8Hz), 6.95 (dd, 1H,
J = 8.80, 3.68 Hz), 7.24 (d, 1H, J = 3.68 Hz), 7.36–7.41 (m, 3H), 7.66 (d, 2H,
J = 8.08 Hz), 9.17, 9.53 ( two s, each 1H, D2O-exch.). Anal. % (C19H18N2O3) C, H,
N, calcd. 70.79, 5.63, 8.69, found, 70.76, 5.62, 8.68.
4-(2,5-Dihyroxyphenacyl)-1-(p-tolyl)-3,5-dimethylpyrazole (13b)
Reagents: p-tolylhydrazine hydrochloride (0.166 g, 1.05 mmol). Crystallization:
10% aqueous ethanol. Brown crystals (0.19 g, 57%), melting with decomposition at
1
2608C. IR (KBr, cmÀ1): 3450–2875, 1662, 1575, 1512. H- NMR (DMSO-d6, 400
MHz): 2.08, 2.20 (two s, each 3H), 2.40 (s, 3H), 5.30 (s, 2H), 7.08 (dd, 1H, J = 9.56,
2.92 Hz), 7.19 (d, 1H, J = 9.56 Hz), 7.53 (d, 2H, J = 11.76 Hz), 7.65 (d, 2H,
J = 11.76 Hz), 7.73 (d, 1H, J = 2.92 Hz), 9.20, 9.36 (two s, each 1H, D2O-exch.).
Anal. % (C20H20N2O3) C, H, N, calcd, 71.41, 5.99, 8.33, found, 71.40, 5.97, 8.32.
1-(4-Bromophenyl)-4-(2,5-dihyroxyphenacyl)-3,5-dimethylpyrazole (13c)
Reagents: 4-bromophenylhydrazine hydrochloride (0.234 g, 1.05 mmol). Crystal-
lization: 10% aqueous DMF. Brown crystals (0.24 g, 60%), mp > 3608C. IR (KBr,
1
cmÀ1): 3412–2800, 1650, 1575, 1512. H-NMR (DMSO-d6, 400MHz): 1.80, 1.94

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Med Chem Res (2007) 16:49–77
(two s, each 3H), 5.20 (s, 2H), 6.99 (dd, 1H, J = 8.08, 2.92 Hz), 7.07 (d, 2H, J = 8.80
Hz), 7.18 (d, 1H, J = 2.92 Hz), 7.31 (d, 1H, J = 8.08 Hz), 7.44 (d, 2H, J = 8.08 Hz),
9.30, 9.63 (two s, each 1H, D2O-exch.). Anal. % (C19H17BrN2O3) C, H, N, calcd.
56.87, 4.27, 6.98, found, 56.84, 4.25, 6.96.
4-(2,5-Dihydroxyphenacyl)-1-(4-sulfamoylphenyl)-3,5-dimethylpyrazole (13d)
Reagents: 4-hydrazinobenzenesulfonamide hydrochloride (0.234 g, 1.05 mmol).
Crystallization: 10% aqueous DMF. Brown crystals (0.25 g, 62%), mp > 3608C. IR
1
(KBr, cmÀ1): 3550–2805, 1600, 1556, 1525, 1481, 1250, 1162. H-NMR (DMSO-
d6, 400 MHz): 2.09, 2.21 (two s, each 3H), 4.00 (s, 2H, D2O-exch.), 5.20 (s, 2H),
7.08 (dd, 1H, J = 9.52, 2.92 Hz), 7.19 (d, 1H, J = 9.52 Hz), 7.53 (d, 2H, J = 11.76
Hz), 7.65 (d, 2H, J = 11.76 Hz), 7.73 (d, 1H, J = 2.92 Hz), 9.17, 9.53 (two s, each
1H, D2O-exch.). Anal. % (C19H19N3O5S) C, H, N, calcd. 56.85, 4.77, 10.47, found,
56.83, 4.77, 10.47.
1-[4-(N-acetylsulfamoyl)phenyl]-4-(2,5-dihydroxyphenacyl)-3,5-
dimethylpyrazole (13e)
Reagents: 4-(N-acetylsulfamoyl)phenylhydrazine hydrochloride (0.278 g, 1.05
mmol). Crystallization: 10% aqueous DMF. Brown solid (0.28 g, 63%), mp >
3608C. IR (KBr, cmÀ1): 3480–2820, 1650, 1602, 1555, 1520, 1480, 1255, 1160.
Anal. % (C21H21N3O6S) C, H, N, calcd. 56.88, 4.77, 9.48, found, 56.84, 4.74, 9.45.
General procedure for the preparation of 1-(N-arylthiocarbamoyl)-4-(2,5-
dihydroxyphenacyl)-3,5-dimethylpyrazoles (14a–c)
A solution of selected 4-arylthiosemicarbazides (1.0 mmol) in glacial acetic acid (20
ml) was gradually added with stirring over a period of 30 minutes to a boiling
solution of an equimolar amount of compound 12 (0.25 g, 1.0 mmol) in glacial
acetic acid (20 ml) containing an equimolar amount of anhydrous sodium acetate
(0.082 g, 1.0 mmol). The reaction mixture was stirred while heating under reflux for
24 h and then left for an overnight at room temperature. The formed dark precipitate
was filtered, washed several times with water, dried, and finally recrystallized.
4-(2,5-Dihydroxyphenacyl)-1-(N-phenylthiocarbamoyl)-3,5-dimethylpyrazole
(14a)
Reagents: phenylthiosemicarbazide (0.167 g, 1.0 mmol). Crystallization: 10%
aqueous DMF. Dark brown crystals (0.19 g, 50%), mp > 3608C. IR (KBr, cmÀ1):
3525–2775, 1656, 1618, 1575, 1515, 1478, 1262, 1112, 984. H-NMR (DMSO-d6,
1
400 MHz): 2.10, 2.18 (two s, each 3H), 5.21 (s, 2H), 6.71 (dd, 1H, J = 8.80, 2.96
Hz), 6.78 (d, 1H, J = 8.80 Hz), 7.00 (s, 1H), 7.22–7.25 (m, 3H), 7.48 (d, 2H,
J = 10.28 Hz), 9.07, 9.37, 9.93 (three s, each 1H, D2O-exch.). Anal. %
(C20H19N3O3S) C, H, N, calcd. 62.98, 5.02, 11.02, found, 62.96, 5.01, 11.02.

Med Chem Res (2007) 16:49–77
71
4-(2,5-Dihydroxyphenacyl)-1-[N-(p-tolyl)thiocarbamoyl]-3,5-dimethyl-pyrazole
(14b)
Reagents: p-tolylthiosemicarbazide (0.18 g, 1.0 mmol). Crystallization: 10%
aqueous DMF. Brown solid (0.217 g, 55%), mp > 3608C. IR (KBr, cmÀ1): 3425–
2650, 1687, 1637, 1598, 1543, 1500, 1262, 1118, 987. H-NMR (DMSO-d6, 400
1
MHz): 2.10, 2.18 (two s, each 3H), 2.65(s, 3H), 5.21 (s, 2H), 6.91–7.68 (m, 7H),
9.07, 9.27, 9.93 (three s, each 1H, D2O-exch.). Anal. % (C21H21N3O3S) C, H, N,
calcd. 63.78, 5.35, 10.62, found, 63.78, 5.33, 10.60.
1-[N-(4-Bromophenyl)thiocarbamoyl]-4-(2,5-dihydroxyphenacyl)-3,5-dimethyl-
pyrazole (14c)
Reagents: 4-bromophenylthiosemicarbazide (0.246 g, 1.0 mmol). Crystallization:
10% aqueous DMF. Black solid (0.26 g, 57%), mp > 3608C. IR (KBr, cmÀ1): 3487–
2975, 1662, 1625, 1587, 1525, 1487, 1287, 1109, 1287. Anal. % (C20H18BrN3O3S)
C, H, N, calcd. 52.18, 3.94, 9.13, found, 52.16, 3.92, 9.13.
General procedure for the preparation of 1-aryl-4-(2,5-dihydroxy-phenacyl)-3-
methyl-4,5-dihydropyrazol-5-ones (16a–e)
A solution of substituted phenylhydrazine hydrochloride (1.05 mmol) in absolute
ethanol (10 ml) was gradually added over a period of 30 min to a well stirred
solution of compound 15 (0.28 g, 1.0 mmol) in a mixture of 20 ml of absolute
ethanol–glacial acetic acid (1:1) containing an equimolar amount of anhydrous
sodium acetate (0.123 g). The reaction mixture was stirred while heating under
reflux for 14 h and then concentrated under diminished pressure. The formed brown
precipitate was filtered, washed several times with water, dried, and finally
recrystallized.
4-(2,5-Dihydroxyphenacyl)-3-methyl-1-phenyl-4,5-dihydropyrazol-5-one (16a)
Reagents: phenylhydrazine hydrochloride (0.15 g, 1.05 mmol). Crystallization: 10%
aqueous DMF. Brown solid (0.194 g, 60%), mp > 360 8C. IR (KBr, cmÀ1): 3450–
2650, 1648, 1562,1503. Anal. % (C18H16N2O4) C, H, N, calcd. 66.66, 4.97, 8.64,
found, 66.64, 4.95, 8.62.
4-(2,5-Dihydroxyphenacyl)-3-methyl-1-p-tolyl-4,5-dihydropyrazol-5-one (16b)
Reagents: p-tolylhydrazine hydrochloride (0.166 g, 1.05 mmol). Crystallization:
dioxane/ water (3:1). Brown solid (0.20 g, 59%), mp > 3608C. IR (KBr, cmÀ1):
3475–2825, 1662, 1584, 1518. H-NMR (DMSO-d6, 400 MHz): 2.07 (s, 3H), 2.21
1
(s, 3H), 3.55 (s, 1/2H, D2O-exch.), 4.91 (s, 1/2H), 5.15 (s, 2H), 6.65 (dd, 1H,
J = 8.08, 2.92 Hz), 6.69 (d, 1H, J = 8.08 Hz), 6.90(d, 1H, J = 2.92 Hz), 7.00 (d, 2H,
J = 8.80 Hz), 7.43 (d, 2H, J = 8.80 Hz), 9.15, 9.44 (two s, each 1H, two D2O-exch.).
Anal. % (C19H18N2O4) C, H, N, calcd. 67.45, 5.36, 8.28, found, 67.40, 5.36, 8.26.

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Med Chem Res (2007) 16:49–77
1-(4-Bromophenyl)-4-(2,5-dihydroxyphenacyl)-3-methyl-4,5-dihydropyrazol-5-
one (16c)
Reagents: 4-bromophenylhydrazine hydrochloride (0.234 g, 1.05 mmol). Crystal-
lization: 10% aqueous DMF. Brown solid (0.27 g, 67%), mp > 3608C. IR (KBr,
1
cmÀ1): 3450–2720, 1648, 1573, 1511. H-NMR (DMSO-d6, 400 MHz): 2.07 (s,
3H), 3.55 (s, ½ H, D2O-exch.), 4.94 (s, ½ H), 5.15 (s, 2H), 6.78 (s, 1H), 6.83 (dd,
1H, J = 8.80, 2.96 Hz), 6.99 (d, 1H, J = 8.80 Hz), 7.49 (d, 2H, J = 8.80 Hz), 7.75 (d,
2H, J = 8.80 Hz), 9.15, 9.44 (two s, each 1H, two D2O-exch.). Anal. %
(C18H15BrN2O4) C, H, N, calcd. 53.62, 3.75, 6.95, found,53.62, 3.70, 6.94.
4-(2,5-Dihydroxyphenacyl)-3-methyl-1-(4-sulfamoylphenyl)-4,5-
dihydropyrazol-5-one (16d)
Reagents: 4-sulfamoylphenylhydrazine hydrochloride (0.234 g, 1.05 mmol).
Crystallization: 10% aqueous DMF. Brown solid (0.282 g, 70%), mp > 3608C.
IR (KBr, cmÀ1): 3500–2950, 1600, 1550, 1525, 1487, 1268, 1175. Anal. %
(C18H17N3O6S) C, H, N, calcd. 53.59, 4.25, 10.42, found, 53.57, 4.21, 10.41.
1-[4-(N-acetylsulfamoyl)phenyl]-4-(2,5-dihydroxyphenacyl)-3-methyl-4,5-
dihydro-pyrazol-5-one (16e)
Reagents: 4-(N-acetylsulfamoyl)phenylhydrazine hydrochloride (0.278 g, 1.05
mmol).
Crystallization: 10% aqueous DMF. Brown solid (0.315 g, 71%), mp > 3608C. IR
1
(KBr, cmÀ1): 3589–2880, 1650, 1600, 1554, 1524, 1488, 1275, 1170. H-NMR
(DMSO-d6, 400 MHz): 2.07 (s, 3H), 2.19 (s, 3H), 3.55 (s, 1/2H, D2O-exch.), 4.94 (s,
1/2H), 5.15 (s, 2H), 7.08 (dd, 1H, J = 9.56, 2.92 Hz), 7.19 (d,1H, J = 9.56 Hz), 7.53
(d, 2H, J = 11.76 Hz), 7.65 (d, 2H, J = 11.76 Hz), 7.73 (d, 1H, J = 2.92 Hz), 9.15,
9.44, 10.04 (three s, each 1H, D2O-exch.). Anal. % (C20H19N3O7S) C, H, N, calcd.
53.93, 4.30, 9.43, found, 53.91, 4.28, 9.43.
General procedure for the preparation of 1-(N-arylthiocarbamoyl)-4-(2,5-
dihydroxyphenacyl)-3-methyl-3,4-dihydropyrazol-5-ones (17a–c)
A solution of selected 4-arylthiosemicarbazide (1.00 mmol) in glacial acetic acid
was gradually added over a period of 30 min to a boiling well stirred solution of an
equimolar amount of compound 15 (0.28 g, 1.00 mmol) in glacial acetic acid (20
ml) containing two drops of conc. sulfuric acid. The reaction mixture was heated
under reflux for 19 h, after which the excess solvent was evaporated under
diminished pressure. The formed sticky mass was triturated five times with 10-ml
˚
portions of petroleum ether (60–80C) and then the formed solid was filtered, dried,
and finally recrystallized.

Med Chem Res (2007) 16:49–77
73
4-(2,5-Dihydroxyphenacyl)-3-methyl-1-(N-phenylthiocarbamoyl)-3,4-
dihydropyrazol-5-one (17a)
Reagents: phenylthiosemicarbazide (0.167 g, 1.0 mmol). Crystallization:
DMSO–water (9:1). Dark brown crystals (0.23 g, 60%), mp > 3608C. IR (KBr,
cmÀ1): 3325–2750, 1675, 1625, 1587, 1525, 1484, 1284, 1112, 998. Anal. %
(C19H17N3O4S) C, H, N, calcd. 59.52, 4.47, 10.96, found, 59.50, 4.44, 10.96.
4-(2,5-Dihydroxyphenacyl)-3-methyl-1-[N-(p-tolyl)thiocarbamoyl]-3,4-
dihydropyrazol-5-one (17b)
Reagents: p-tolylthiosemicarbazide (0.181 g, 1.00 mmol). Crystallization: 10%
aqueous DMF. Brown solid (0.25 g, 63%), mp > 3608C. IR (KBr, cmÀ1): 3575–
2975, 1662, 1625, 1587, 1518, 1481, 1275, 1112.5, 993. H-NMR (DMSO-d6, 400
1
MHz): 2.07 (s, 3H), 2.21 (s, 3H), 3.55 (s, 1/2H, D2O-exch.), 4.94 (s, 1/2H), 5.15 (s,
2H), 6.93 (d, 2H, J = 12.44 Hz), 6.98 (dd, 1H, J = 8.80, 2.92 Hz), 7.01 (d, 1H,
J = 8.80 Hz), 7.38 (d, 2H, J = 12.44 Hz), 7.79 (d, 1H, J = 2.92 Hz), 9.15, 9.44, 10.07
(three s, each 1H, D2O-exch.). Anal. % (C20H19N3O4S) C, H, N, calcd. 60.44, 4.82,
10.57, found, 60.42, 4.80, 10.56.
1-[N-(4-Bromophenyl)thiocarbamoyl]-4-(2,5-dihydroxyphenacyl)-3-methyl-3,4-
dihydropyrazol-5-one (17c)
Reagents: 4-bromophenylthiosemicarbazide (0.246 g, 1.00 mmol). Crystallization:
10% aqueous DMSO. Brown solid (0.29 g, 63%), mp > 3608C. IR (KBr, cmÀ1):
3400–2800, 1675, 1612, 1553, 1506, 1287, 1112, 987. H-NMR (DMSO-d6, 400
1
MHz): 2.00 (s, 3H), 3.56 (s, 1/2H, D2O-exch.), 5.04 (s, 1/2H,), 5.19 (s, 2H), 7.10 (d,
2H, J = 8.08 Hz), 7.30 (d, 1H, J = 8.80 Hz), 7.35 (s, 1H), 7.43 (d, 2H, J = 8.08 Hz),
7.51 (d, 1H, J = 8.80 Hz), 9.01, 9.14, 9.71 (three s, each 1H, D2O-exch.). Anal. %
(C19H16BrN3O4S) C, H, N, calcd. 49.36, 3.49, 9.09, found, 49.35, 3.48, 9.08.
General procedure for the preparation of 2-aryl-4-(2,5-dihydroxy-phenacyl)-
pyrazolidine-3,5-diones (19a–e)
A solution of 4-substituted phenylhydrazine hydrochloride (1.05 mmol) in dry
dioxane (10 ml) was gradually added with stirring over a period of 30 min to a
solution of compound 18 (0.31g, 1.0 mmol) in dry dioxane (10 ml) containing an
equimolar amount of anhydrous sodium acetate (0.123 g). The reaction mixture was
stirred while heating under reflux for 18 h, after which it was allowed to attain room
temperature. The formed precipitate was filtered, washed with water, dried, and
finally recrystallized.
4-(2,5-Dihydroxyphenacyl)-2-phenylpyrazolidine-3,5-dione (19a)
Reagents: phenylhydrazine hydrochloride (0.15 g, 1.05 mmol). Crystallization:
ethanol. Dark brown solid (0.185 g, 57%), melting with decomposition at

74
Med Chem Res (2007) 16:49–77
1
290–2918C. IR (KBr, cmÀ1): 3700–2675, 1662, 1575, 1500. H-NMR (DMSO-
d6, 400 MHz): 3.59 (s, ½ H, D2O-exch.), 4.90 (s, ½ H), 5.15 (s, 2H), 6.74 (dd,
1H, J = 8.80, 2.96 Hz), 7.78(d, 1 H, J = 8.80 Hz), 7.00(s, 1H), 7.22–7.25 (m,
3H), 7.48 (d, 2H, J = 10.28 Hz), 9.19, 9.59, 11.28 (three s, each 1H, D2O-exch.).
Anal. % (C17H14N2O5) C, H, N, calcd. 62.58, 4.32, 8.58, found, 62.57, 4.30,
8.58.
4-(2,5-Dihydroxyphenacyl)-2-(p-tolyl)pyrazolidine-3,5-dione (19b)
Reagents: p-tolylhydrazine hydrochloride (0.166 g, 1.05 mmol). Crystallization:
10% aqueous DMF. Dark brown solid (0.20 g, 59%), melting with decomposition at
320–3218C. IR (KBr, cmÀ1): 3425–2650, 1675, 1581, 1512. Anal. % (C18H16N2O5)
C, H, N, calcd. 63.53, 4.74, 8.23, found, 63.52, 4.72, 8.20.
2-(4-Bromophenyl)-4-(2,5-dihydroxyphenacyl)pyrazolidine-3,5-dione (19c)
Reagents: 4-bromophenylhydrazine hydrochloride (0.234 g, 1.05 mmol). Crystal-
lization: 10% aqueous DMF. Dark brown solid (0.263 g, 65%), mp >3608C. IR
(KBr, cmÀ1): 3450–2675, 1675, 1575, 1500. 1H-NMR (DMSO-d6, 400 MHz): 3.59
(s, ½ H, D2O-exch.), 4.90 (s, ½ H), 5.15 (s, 2H), 6.80 (d, 2H, J = 8.80 Hz), 6.90 (s,
1H), 6.98 (d, 1H, J = 2.92 Hz), 7.01 (d, 1H, J = 2.92 Hz), 7.19 (d, 2H, J = 8.80 Hz),
9.19, 9.59, 11.28 (three s, each 1H, D2O-exch.). Anal. % (C17H13BrN2O5) C, H, N,
calcd. 50.39, 3.23, 6.91, found, 50.38, 3.22, 6.90.
4-(2,5-Dihydroxyphenacyl)-2-(4-sulfamoylphenyl)pyrazolidine-3,5-dione (19d)
Reagents: 4-sulfamoylphenylhydrazine hydrochloride (0.234 g, 1.05 mmol).
Crystallization: 10% aqueous DMF. Dark brown solid (0.27 g, 67%), mp
>3608C. IR (KBr, cmÀ1): 3525–2998, 1600, 1525, 1484, 1243, 1146. Anal. %
(C17H15N3O7S) C, H, N, calcd. 50.37, 3.73, 10.37, found, 50.36, 3.73, 10.36.
2-[4-(N-acetylsulfamoyl)phenyl]-4-(2,5-dihydroxyphenacyl)pyrazolidine-3,5-
dione (19e)
Reagents: N-acetylsulfamoylphenylhydrazine hydrochloride (0.278 g, 1.05 mmol).
Crystallization: 10% aqueous DMF. Dark brown solid (0.31 g, 69%), mp >3608C.
IR (KBr, cmÀ1): 3575–2980, 1650, 1619, 1550, 1495, 1247, 1146. 1H-NMR
(DMSO-d6, 400 MHz): 2.10 (s, 3H), 3.59 (s, ½ H, D2O-exch.), 4.85 (s, ½ H), 5.15
(s, 2H), 7.09 (dd, 1H, J = 9.52, 3.68 Hz), 7.20 (d, 1H, J = 9.52 Hz), 7.54 (d, 2H,
J = 11.76), 7.66 (d, 2H, J = 11.76 Hz), 7.73 (d, 1H, J = 3.68 Hz), 9.20, 9.59, 10.05,
11.20 (four s, each 1H, D2O-exch.). Anal. % (C19H17N3O8S) C, H, N, calcd. 51.01,
3.83, 9.39, found, 51.00, 3.81, 9.39.

Med Chem Res (2007) 16:49–77
75
General procedure for the preparation of 2-(N-arylthiocarbamoyl-4-(2,5-
dihydroxyphenacyl)-pyrazolidine-3,5-diones (20a–c)
A mixture of compound 18 (1.0 mmol) and selected 4-arylthiosemicarbazide (1.0
˚
mmol) was fused at 140C in an oil bath for 4 h, whereupon the reaction mixture
melted and then solidified The formed crude mass was allowed to attain the room
temperature and then recrystallized.
4-(2,5-Dihydroxyphenacyl)-2-(N-phenylthiocarbamoyl)pyrazolidine-3,5-dione
(20a)
Reagents: phenylthiosemicarbazide (0.167 g, 1.0 mmol). Crystallization: DMF–
water (6:1). Dark brown solid (0.30 g, 78%), mp > 360 8C. IR (KBr, cmÀ1): 3400–
2675, 1675, 1587, 1550, 1475, 1287, 1125, 993. Anal. % (C18H15N3O5S) C, H, N,
calcd. 56.10, 3.92, 10.90, found, 56.10, 3.90, 10.90.
4-(2,5-Dihydroxyphenacyl)-2-[N-(p-tolyl)thiocarbamoyl]pyrazolidine-3,5-dione
(20b)
Reagents: p-tolylthiosemicarbazide (0.181 g, 1.0 mmol). Crystallization: 15%
aqueous DMF. Dark brown solid (0.31 g, 83%), mp > 3608C. IR (KBr, cmÀ1):
3400–2750, 1687, 1606, 1550, 1500, 1268, 1112, 987. H-NMR (DMSO-d6, 400
1
MHz): 2.40 (s, 3H), 3.59 (s, ½ H, D2O-exch.), 4.90 (s, ½ H), 5.15 (s, 2H), 7.08 (dd,
1H, J = 9.52, 3.68 Hz), 7.19 (d, 1H, J = 9.52 Hz), 7.53 (d, 2H, J = 11.76 Hz), 7.65 (d,
2H, J = 11.76 Hz), 7.73 (d, 1H, J = 3.68 Hz), 9.20, 9.59, 10.30, 11.28 (four s, each
1H, D2O-exch.). Anal. % (C19H17N3O5S) C, H, N, calcd. 57.13, 4.29, 10.52, found,
57.13, 4.27, 10.50.
2-[N-(4-Bromophenyl)thiocarbamoyl]-4-(2,5-dihydroxyphenacyl)pyrazolidine-
3,5-dione (20c)
Reagents: 4-bromophenylthiosemicarbazide (0.246 g, 1.0 mmol). Crystallization:
15% aqueous DMF. Dark brown solid (0.4 g, 86%), mp > 3608C. IR (KBr, cmÀ1):
3450–2980, 1662, 1587, 1525, 1484, 1265, 1112, 981. H-NMR (DMSO-d6, 400
1
MHz): 3.59 (s, ½ H, D2O-exch.), 4.90 (s, ½ H), 5.15 (s, 2H), 6.95–7.68 (m, 7H),
9.20, 9.52, 10.40, 11.25 (four s, each 1H, D2O-exch.). Anal. % (C18H14BrN3O5S)
C, H, N, calcd. 46.57, 3.04, 9.05 , found, 46.54, 2.03, 9.05.
Formation of colored metal chelates of compounds; 13a, 14a, 16a, 17a, 19a, and
20a with Cu2+, Co2+ and Ni2+
A solution of 1-aryl and 1-(N-arylthiosemicarbamoyl)-4-(2,5-dihydroxyphenacyl)-3,
5-dimethyl-pyrazole; 13a and 14a, 1-aryl and 1-(N-arylthiosemicarbamoyl)-
3-methyl-4,5-dihydro-pyrazol-5-one; 16a and 17a or 1-aryl and 1-(N-arylthiose-
micarbamoyl)-4-(2,5-dihydroxyphenacyl) pyrazolidine-3,5-dione; 19a and 20a (1
mmol) in DMF (7 ml) was treated with 5% aqueous solution (5 ml) of CuSO4,

76
Med Chem Res (2007) 16:49–77
CoSO4 and NiSO4 . The corresponding blank experiments were carried out
simultaneously. The formed colored chelates; were light blue for Cu2+, purple for
Co2+ and bluish violet for Ni2+. The reported kmax for the chelates and for the blank
experiments are listed in Table 1.
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