Synthesis, characterization, and screening for antiamoebic activity of palladium(II), platinum(II), and ruthenium(II) complexes with NS-donor ligands

Article abstract of DOI:10.1002/1522-2675(200209)85:9<2713::AID-HLCA2713>3.0.CO;2-0

Reaction of [PdCl₂(DMSO)₂], [PtCl₂(DMSO)₂], and [RuCl₂(η⁴-C₈H₁₂) (MeCN)₂] with S-acetyl N^β-acetyldithiocarbazate (=2-acetylhydrazinecarbodithioic

Full text of DOI:10.1002/1522-2675(200209)85:9<2713::AID-HLCA2713>3.0.CO;2-0

Helvetica Chimica Acta Vol. 85 (2002)
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Synthesis, Characterization, and Screening for Antiamoebic Activity
of Palladium(II), Platinum(II), and Ruthenium(II) Complexes
with NS-Donor Ligands
by Shailendra, Neelam Bharti, Fehmida Naqvi, and Amir Azam*
Department of Chemistry, Jamia Millia Islamia, Jamia Nagar, New Delhi-110025, India
Reaction of [PdCl2(DMSO)2], [PtCl2(DMSO)2], and [RuCl2(h4-C8H12)(MeCN)2] with S-acetyl Nb-
acetyldithiocarbazate (ˆ2-acetylhydrazinecarbodithioic acid anhydrosulfide with ethanethioic acid; aadt; 1), S-
methyl Nb-[(5-nitrothiophene-2-yl)methylene]dithiocarbazate (ˆ S-methyl 2-[(5-nitrothiophene-2-yl)methyl-
ene]hydrazinecarbodithioate; mntdt; 2), and S-benzyl Nb-[(5-nitrothiophene-2-yl)methylene]dithiocarbazate
(ˆ S-benzyl 2-[(5-nitrothiophene-2-yl)methylene]hydrazinecarbodithioate; bntdt; 3) led to new complexes
[PdCl2(L)], [PtCl2(L)], and [RuCl2(h4-C8H12)(L)] (L ˆ ligands 1 3). All these compounds were characterized
by elemental analysis, IR, 1H- and 13C-NMR and UV/VIS spectra and thermogravimetric analysis. Ligand 1
coordinates through the thioxo S-atom and the carbazate N(b) atom, whereas in ligands 2 and 3 the thioxo S-
atom and the azomethine N-atom are coordinated to the metal ion. Screening of antiamoebic activity of these
compounds was performed in vitro against the HK-9 strain of E. histolytica. All the complexes were more active
than their respective ligands; compound 3a showed the most promising activity.
Introduction. Amoebiasis is the infection of the human gastrointestinal tract by
Entamoeba histolytica (E. histolytica). Invasive amoebiasis is more common in
developing countries and remains a significant threat to health in large parts of the
world. Approximately 50 million people develop intestinal disease or the major extra-
intestinal complication of amoebic liver abscess [1], which are responsible for up to
100000 deaths per year [2]. Nitroimidazole drugs such as metronidazole (ˆ2-methyl-5-
nitro-1H-imidazole-1-ethanol) is highly effective against the acute disease, but has
common side effects [3]. It is poorly tolerated, and mutagenic effects of metronidazole
in bacteria has raised fear that the drug may be carcinogenic in man [4]. There have
been a few reports of resistance of E. histolytica to metronidazole [5]. Therefore, it is
desirable to search new amoebicidal agents better than the actually available
medication. Metals have been used in medicine for centuries, the success of cis-
[PtCl2(NH3)2] (cisplatin) as an anticancer drug [6 8] has stimulated a renewed interest
in metal-based chemotherapies. The transition-metal complexes of Schiff bases derived
from dithiocarbazates are widely studied because of their potential for therapeutic uses
[9 12] and have applications in health and skin care [13]. The antitumor activity of
transition-metal chelates of Schiff base ligands derived from S-methyl dithiocarbazate
have been reported [14]. Carcinostatic activities also have been found for some metal
complexes of dithiocarbazoic acid and the Schiff bases derived from its S-methyl ester
[15]. However, the potential of Schiff bases derived from S-alkyl dithiocarbazate and
their PdII complexes as antiamoebic agents has so far been very little explored [16]. As
part of our ongoing research work on antiamoebic compounds [17][18], we report
herein the synthesis, characterization, and in vitro screening for amoebicidal activity of

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new PdII, PtII and RuII complexes with S-acetyl Nb-acetyldithiocarbazate (ˆ2-
acetylhydrazinecarbodithioic acid anhydrosulfide with ethanethioic acid; 1), S-methyl
Nb-[(5-nitrothiophene-2-yl)methylene]dithiocarbazate (ˆ S-methyl 2-[(5-nitrothio-
phene-2-yl)methylene]hydrazinecarbodithioate; 2), and S-benzyl Nb-[(5-nitrothio-
phene-2-yl)methylene]dithiocarbazate (ˆ S-benzyl 2-[(5-nitrothiophene-2-yl)methyl-
ene]hydrazinecarbodithioate; 3) (Fig. 1) against the HK-9 strain of E. histolytica.
Fig. 1. Structure of ligands S-acetyl Nb-acetyldithiocarbazate (ˆaadt; 1), S-methyl Nb-[(5-nitrothiophene-2-
yl)methylene]dithiocarbazate (mntdt; 2), and S-benzyl Nb-[(5-nitrothiophene-2-yl)methylene]dithiocarbazate
(bntdt; 3)
Experimental. 1. General. Palladium chloride, platinum chloride, and ruthenium chloride were purchased
from Aldrich chemical company (USA). S-Acetyl Nb-acetyldithiocarbazate, S-methyl dithiocarbazate, and S-
benzyl dithiocarbazate were prepared by the method described previously [19 21]. The complex precursors
[PdCl2(DMSO2)], [PtCl2(DMSO)2] and [RuCl2(h4-C8H12)(MeCN)2] were prepared by literature procedures
[22][23]. Melting points: KSW melting-point apparatus; uncorrected. UV/VIS Spectra: DMF solns.; Shimadzu
UV-1601-PC-UV-VIS spectrophotometer; lmax in cmÀ1. IR Spectra: KBr disks; Perkin-Elmer 1620-FT-IR
spectrophotometer; nÄmax in cmÀ1 1H- and 13C-NMR Spectra: Bruker Spectrospin-DPX-300-MHz spectropho-
.
tometer; at r.t. in CDCl3 and (D6)DMSO; d in ppm rel. to SiMe4 as internal standard. Thermograms of the
complexes were recorded under N2 with a TG-51 thermogravimetricanalyser by 10 8 temp. increase/min.
Elemental analyses (C, H, N) were carried out by the Central Drug Research Institute, Lucknow, India; the Cl-
content was determined by the standard method.
2. Ligands. S-Acetyl Nb-Acetyldithiocarbazate (aadt; 1). Ligand 1 was prepared according to [19]. Yield
64%. Yellow solid. M.p. 2158. UV/VIS: 23095, 29154. IR: 3310 (NH), 1620 (CˆO), 1053 (CˆS). 1H-NMR
(CDCl3): 3.34 (s, 2 Me); 10.53 (d, 2 NH). 13C-NMR ((D6)DMSO): 202.47 (CˆS); 162.63 (CˆO); 27.49 (Me).
Anal. calc. for C5H8N2O2S2: C 31.21, H 4.20, N 14.40; found: C 31.25, H 4.16, N 14.58.
S-Methyl Nb-[(5-Nitrothiophene-2-yl)methylene]dithiocarbazate (mntdt; 2) and S-Benzyl Nb-[(5-Nitro-
thiophene-2-yl)methylene]dithiocarbazate (bntdt; 3). A soln. of S-methyl dithiocarbazate or S-benzyl
dithiocarbazate (3 mmol) in abs. EtOH (15 ml) was mixed with a soln. of 5-nitrothiophene-2-carboxaldehyde
(3 mmol) in EtOH (15 ml). The mixture was heated on a water bath for 4 h and then allowed to stand for 2 h at
r.t. The solid that separated out was filtered, washed with cold EtOH and dried in vacuo over silica gel.
Data of 2. Yield 54%. Orange solid. M.p. 1558. UV/VIS: 24093, 33223. IR: 3180 (NH), 1520 (CˆN), 1064
1
(CˆS). H-NMR (CDCl3): 8.24 (s, CHˆN); 2.53 (s, Me); 11.01 (s, NH); 7.38 7.97 (m, 2 arom. H). 13C-NMR
((D6)DMSO): 199.53 (CˆS); 17.84 (Me); 140.45 (CˆN); 125.95 129.47, 142.26 (arom. C). Anal. calc. for
C7H7N3O2S3: C 32.18, H 2.68, N 16.09; found: C 32.04, H 2.85, N 15.79.
Data of 3. Yield 79%. Orange solid. M.p. 1768. UV/VIS: 24272, 33445. IR: 3495 (NH), 1515 (CˆN), 1045
(CˆS). 1H-NMR (CDCl3): 7.91 (s, CHˆN); 4.54 (s, PhCH2); 10.18 (s, NH); 7.21 7.53 (m, 7 arom. H).
13C-NMR ((D6)DMSO): 197.47 (CˆS); 37.64 (PhCH2); 151.27 (CˆN); 127.32 130.95, 139.34, 145.20 (arom.
C). Anal. calc. for C13H11N3O2S3: C 46.29, H 3.26, N 12.46; found: C 46.54, H 3.14, N 12.22.
3. Metal Complexes. A soln. of ligand 1, 2, or 3 (1 mmol) in MeOH (10 ml) was added with stirring to a
suspension of the appropriate metal precursor (1 mmol) in hot MeOH (10 ml). The mixture obtained was
refluxed on a water bath for 4 h. On keeping the mixture overnight at 08, a colored compound precipitated; it
was filtered, washed with cold EtOH, and dried in vacuo over silica gel.
(2-Acetylhydrazinecarbodithioic acid-kN2,kS' anhydrosulfide with ethanethioic acid)dichloropalladium
([PdCl2(aadt)]; 1a): Yield 67%. Dark brown solid. M.p. 2808. UV/VIS: 37453. IR: 3190 (NH), 1624 (CˆO),
1
1031 (CˆS). H-NMR ((D6)DMSO): 3.21 (s, 2 Me); 3.56 (d, 2 NH). 13C-NMR ((D6)DMSO): 185.35 (CˆS);
163.27 (CˆO); 29.16 (Me). Anal. calc. for C5H8N2S2O2Cl2Pd: C 16.41, H 2.04, N 7.76, Cl 19.39; found: C 16.26,
H 2.16, N 7.58, Cl 19.24.

Helvetica Chimica Acta Vol. 85 (2002)
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(2-Acetylhydrazinecarbodithioic acid-kN2,kS' anhydrosulfide with ethanethioic acid)dichloroplatinum
[PtCl2(aadt)]; 1b): Yield 48%. Brown solid. M.p. 2508. UV/VIS: 37313. IR: 3175 (NH), 1627 (CˆO), 1033
(CˆS). 1H-NMR ((D6)DMSO): 3.27 (s, 2 Me); 3.63 (d, 2 NH). 13C-NMR ((D6)DMSO): 192.56 (CˆS); 162.95
(CˆO); 27.85 (Me). Anal. calc. for C5H8Cl2N2O2PtS2: C 13.02, H 1.86, N 6.30, Cl 15.33; found: C 13.10, H 1.74,
N 6.11, Cl 15.50.
(2-Acetylhydrazinecarbodithioic acid-kN2,kS' anhydrosulfide with ethanethioic acid)dichloro[(1,2,5,6-h)-
cycloocta-1,5-diene]ruthenium ([RuCl2(aadt)(h4-C8H12)]; 1c): Yield 52%. Dark brown solid. M.p. 2708. UV/
VIS: 37736. IR: 3150 (NH), 1625 (CˆO), 1035 (CˆS). 1H-NMR ((D6)DMSO): 3.19 (s, 2 Me); 3.49 (d, 2 NH);
2.59 (m, 4 −exo× H, CH2); 2.07 (m, 4 −endo× H, CH2). 13C-NMR ((D6)DMSO): 196.72 (CˆS); 164.18 (CˆO);
28.23 (Me). Anal. calc. for C13H20Cl2N2O2RuS2: C 33.22, H 4.08, Cl 14.91, N 5.70; found: C 33.05, H 4.23,
Cl 15.04, N 5.93.
Dichloro[S-methyl 2-[(5-nitrothiophene-2-yl)methylene]hydrazinecarbodithioate-kN2,kS']palladium
([PdCl2(mntdt)]; 2a): Yield 72%. Orange solid. M.p. 2788. UV/VIS: 23256, 25974, 36630. IR: 3395 (NH),
1
1498 (CˆN), 1041 (CˆS). H-NMR ((D6)DMSO): 8.17 (s, CHˆN); 2.56 (s, Me); 7.23 7.95 (m, 2 arom. H).
13C-NMR ((D6)DMSO): 187.85 (CˆS); 17.65 (Me); 145.27 (CˆN); 127.73 131.52, 138.41 (arom. C). Anal.
calc. for C7H7Cl2N3O2PdS3: C 19.22, H 1.60, Cl 16.24, N 9.61; found: C 18.97, H 1.75, Cl 16.27, N 9.47.
Dichloro[S-methyl
2-[(5-nitrothiophene-2-yl)methylene]hydrazinecarbodithioate-kN2,kS']platinum
([PtCl2(mntdt)]; 2b): Yield 68%. Brown solid. M.p. 2378. UV/VIS: 23310, 26178, 36496. IR: 3378 (NH),
1502 (CˆN), 1047 (CˆS). 1H-NMR ((D6)DMSO): 8.13 (s, CHˆN); 2.61 (s, Me); 3.47 (s, NH), 7.51 8.04
(m, 2 arom. H). 13C-NMR ((D6)DMSO): 195.78 (CˆS); 18.03 (Me); 148.63 (CˆN); 124.62 132.78 (arom. C).
Anal. calc. for C7H7Cl2N3O2PtS3: C 15.94, H 1.32, Cl 13.47, N 7.97; found: C 16.08, H 1.15, Cl 13.81, N 7.78.
Dichloro[(1,2,5,6-h)-cycloocta-1,5-diene][S-methyl 2-[(5-nitrothiophene-2-yl)methylene]hydrazine carbo-
dithioate-kN2,kS']ruthenium [RuCl2(h4-C8H12)(mntdt)]; 2c): Yield 54%. Black solid. M.p. 2168. UV/VIS: 23474,
26110, 36101. IR: 3364 (NH), 1489 (CˆN), 1052 (CˆS). 1H-NMR ((D6)DMSO): 8.35 (s, CHˆN); 2.49 (s, Me),
3.65 (s, NH); 7.26 7.79 (m, 2 arom. H); 2.49 (m, 4 −exo× H, CH2); 1.97 (m, 4 −endo× H, CH2). 13C-NMR
((D6)DMSO): 185.64 (CˆS); 17.18 (Me); 146.71 (CˆN); 127.53 130.81, 141.69 (arom. C). Anal. calc. for
C15H19Cl2N3O2RuS3: C 40.91, H 3.37, Cl 11.53, N 6.82; found: C 41.04, H 3.26, Cl 11.48, N 6.93.
[S-Benzyl 2-[(5-nitrothiophene-2-yl)methylene]hydrazinecarbodithioate-kN2,kS']dichloropalladium
([PdCl2(bntdt)]; 3a): Yield 75%. Orange solid. M.p. 2348. UV/VIS: 22988, 26316, 37037. IR: 3515 (NH),
1
1497 (CˆN), 1020 (CˆS). H-NMR ((D6)DMSO): 8.06 (s, CHˆN); 4.59 (s, PhCH2); 3.71 (s, NH); 7.37 7.82
(m, 7 arom. H). 13C-NMR ((D6)DMSO): 178.34 (CˆS); 36.45 (PhCH2); 159.18 (CˆN); 126.45 130.17, 137.59,
151.80 (arom. C). Anal. calc. for C13H11Cl2N3O2PdS3: C 30.41, H 2.14, Cl 13.84, N 8.19; found: C 30.23, H 2.31,
Cl 13.69, N 8.25.
[S-Benzyl
2-[(5-nitrothiophene-2-yl)methylene]hydrazinecarbodithioate-kN2,kS']dichloroplatinum
([PtCl2(bntdt)]; 3b): Yield 64%. Brown solid. M.p. 2658. UV/VIS: 23095, 26040, 36767. IR: 3482 (NH), 1503
(CˆN), 1025 (CˆS). 1H-NMR ((D6)DMSO): 7.96 (s, CHˆN); 4.42 (s, PhCH2); 7.15 7.68 (m, 7 arom. H).
13C-NMR ((D6)DMSO): 192.05 (CˆS); 37.27 (PhCH2); 154.92 (CˆN); 125.73 129.46, 135.42, 148.67 (arom. C).
Anal. calc. for C13H11Cl2N3O2PtS3: C 25.87, H 1.82, Cl 13.84, N 6.97; found: C 25.96, H 1.65, Cl 13.81, N 7.05.
[S-Benzyl 2-[(5-nitrothiophene-2-yl)methylene]hydrazinecarbodithioate-kN2,kS']dichloro[(1,2,5,6-h)-cy-
cloocta-1,5-diene]ruthenium ([RuCl2(bntdt)(h4-C8H12)]; 3c): Yield 58%. Dark brown solid. M.p. 2298. UV/
VIS: 22831, 26385, 37313. IR: 3499 (NH), 1493 (CˆN), 1014 (CˆS). 1H-NMR ((D6)DMSO): 8.02 (s, CHˆN);
4.47 (s, PhCH2); 3.57 (s, NH); 7.34 7.85 (m, 7 arom. H); 2.55 (m, 4 −exo× H, CH2); 1.94 (m, 4 −endo× H, CH2).
13C-NMR ((D6)DMSO): 187.81 (CˆS); 37.48 (PhCH2); 155.67 (CˆN); 126.61 134.54, 147.93 (arom. C). Anal.
calc. for C21H23Cl2N3O2RuS3: C 40.91, H 3.37, Cl 11.53, N 6.82; found: C 41.04, H 3.26, Cl 11.37, N 6.93.
4. In vitro Testing against E. histolytica. The ligands 1 3 and their PdII, PtII, and RuII complexes were
screened in vitro for antiamoebicactivity against the HK-9 strain of E. histolytica by the microdilution method
[24]. E. histolytica trophozoites were cultured in TYIS-33 growth medium as described previously [25] in wells
of 96-well microtiter plate. All the compounds were dissolved in DMSO (40 ml) [26][27], and the stock solns. of
the compounds were prepared freshly before use at a concentration of 1 mg/ml. Two-fold serial dilutions were
made in the wells of 96-well microtiter plates (Costar). Each test included metronidazole as a standard
amoebicidal drug, control wells (culture medium plus amoebae), and a blank (culture medium only). The cell
suspension used was diluted to 105 organism/ml by adding fresh medium, and 170 ml of this suspension was added
to the test and control wells in the plate. Plates were sealed and gassed for 10 min with N2 before incubation at
378 for 72 h. After incubation, the growth of amoebae in the plate was checked with a low-power microscope,
and the optical density of the soln. in each well was determined at 490 nm with a micro-plate reader. The %
inhibition of amoebal growth was calculated [24] from the optical densities of the control and tested well and

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was plotted against the logarithm of concentration of the drug tested. Linear regression analysis was used to
determine the best-fitting straight line from which the IC50 value was found. The results are reported in Table 1.
Results and Discussion. Reaction of ligands 1 3 (Fig. 1) with [PdCl2(DMSO)2],
[PtCl2(DMSO)2], and [Ru(cod)(MeCN)2]Cl2 (cod ˆ cycloocta-1,5-diene) gave amor-
phous solid compounds 1a c, 2a c, and 3a c, respectively, in good yield. All these
compounds are stable in both the solid and solution states, and their analytical data are
in good agreement with their composition. The complexes are insoluble in H2O,
MeOH, and EtOH, but soluble in DMF and DMSO. They do not undergo any weight
loss up to 2508, which suggests a fair thermal stability. The structures of the complexes
1a c, 2a c, and 3a c were established by comparing their spectral data (IR, UV/VIS,
1H- and 13C-NMR) with those of the corresponding free ligand and were further
supported by their thermogravimetricanalysis ( Figs. 2 and 3).
Fig. 2. Proposed structures of the complexes 1a, 1b, and 1c
Fig. 3. Proposed structures of the complexes 2a c and 3a
c
UV/VIS Spectral Studies. The UV/VIS spectrum of ligand 1 exhibits a broad band at
29150 cmÀ1 and a sharp band at 23095 cmÀ1 due to intraligand transitions. Complexes
1a c show a single band in the region 37736 37313 cmÀ1 due to a charge-transfer

Helvetica Chimica Acta Vol. 85 (2002)
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transition, which is in a higher-energy region with respect to ligand 1. The ligands 2 and
3 exhibit broad bands at 24272 24093 cmÀ1, which is assigned to the p-p* transition of
the azomethine moiety [28]. Bands at higher energies (33223 33445 cmÀ1) are
attributed to the p-p* transition of the thiophene ring. In complexes 2a c and 3a c,
the p-p* transition due to the azomethine chromophore is shifted to 25974 26385 cmÀ1
indicating that the imino N-atom is involved in the coordination. An intense charge-
transfer band is observed for the complexes in the 22831 23474 cmÀ1 region.
IR Spectral Studies. The IR spectrum of ligand 1 shows characteristic bands at 1053
and 3310 cmÀ1 attributed to the stretching vibrations nÄ(CˆS) and nÄ(NÀH), respec-
tively. A significant shift of nÄ(CˆS) to lower wave numbers indicates the coordination
of the thioxo S-atom. The coordination of N(b) of the hydrazine moiety is evident from
the shift of nÄ(NÀH) of the free ligand (ca. 3310 cmÀ1) to lower wave numbers (3150
3190 cmÀ1) in the complexes. The nÄ(CˆO) mode of the free ligand remains unchanged
in complexes 1a c, which excludes the possibility of the coordination of the oxo O-
atom to the metal ion. The far-IR spectra of the complexes exhibit bands in the region
480 415 cmÀ1, which are tentatively attributed to nÄ(MÀN) and nÄ(MÀS), respectively.
The ligands 2 and 3 can exhibit thione>thiol tautomerism (Scheme). However, the
existence of a strong band in the region 1045 1064 cmÀ1 due to nÄ(CˆS) and no band
due to nÄ(CÀSH) near 2570 cmÀ1 suggests their existence only in the thione form. The
downward shift of nÄ(CˆS) in the corresponding metal complexes suggests coordination
of ligands 2 and 3 to the metal ion through the CˆS group. The ligands 2 and 3 also
exhibit a strong band in the 1515 1520 cmÀ1 region due to nÄ(CˆN) of the azomethine
moiety. In the corresponding metal complexes, this band is shifted to lower frequency,
thereby suggesting that the unsaturated N-atom of the azomethine moiety is
coordinated to the metal. The far-IR spectra of the complexes exhibit bands in the
region 497 430 cmÀ1 tentatively attributed to nÄ(MÀN) and nÄ(MÀS), respectively.
Scheme
1H-NMR Spectral Studies. Further evidence for the coordinating mode of the
ligands 1 3 was obtained from the 1H-NMR spectra. The 1H-NMR spectra of ligands 2
and 3 in (D6)DMSO do not show any SH resonance (expected at ca. 4.0 ppm). The
appearance of a broad peak for NH (10.18 11.01 ppm) indicates that even in a polar
solvent, 2 and 3 remain in their thione form. The NH signal of 1 3 is usually shifted
upfield in the corresponding complexes (3.47 3.71 ppm). In complexes 2a and 3b, we
were unable to locate the NH signal. This either merges with aromatic protons or
resonates beyond 15 ppm, suggesting the coordination of the thioxo S-atom. A
negligible shift of the MeS or CH2S resonance on complexation indicates that the S-
atom of MeS or CH2S is not involved in coordination and that the group is still present
in the complexes. Aromatic protons of the complexes resonate nearly in the same
region as those of the free ligands.
13C-NMR Spectral Studies. 13C-NMR Spectra also provide diagnostic tools for the
elucidation of the coordinating mode of the ligands in complexes. Assignments of the

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signals are based on the chemical shifts and intensity patterns and on the coordination-
induced shift (CIS) Dd (Dd ˆ d(complex)À d(free ligand)) of the signals for C-atoms in
the vicinity of the coordinating functions [29]. Thus, the CˆS signal of ligand 1 (202.47 ppm)
experiences a Dd of 5 17 ppm in complexes 1a c, indicating the coordination of the
thioxo S-atom. The position of the CˆO signal remains unchanged and thus excludes
the coordination of the CˆO group to the metal. Also the d(C) of the Me group
appears in the same region as that of free ligand. In the 13C-NMR spectra of ligands 2
and 3, the proposed assignments are based on those suggested by Giuliani et al. [30].
The signals at 197.47 199.53 ppm of 2 and 3 are assigned to the CˆS group, while the signals at 140.45
151.27 ppm are assigned to the azomethine C-atom. The latter signal is shifted downfield by 3 8 ppm in the
corresponding complexes, which indicates the coordination of the N-atom lone pair to the metal as a result of
complex formation. Further, an upfield shift of the CˆS signal by 4 19 ppm for the complexes 2a c and 3a
c
as compared to the free ligands also suggests the coordination of the thioxo S-atom to the metal. Other C-atoms
(Me, CH2, and arom. C-atoms) of these complexes resonate in nearly the same region as those of the free
ligands.
Thermogravimetric Analysis. The thermogravimetricanalysis (under N , rate 108/
2
min) profiles of the PdII, PtII, and RuII complexes along with the % weight at different
temperatures were recorded. These complexes did not lose weight up to 2508. Further
increments of temperature caused decomposition of the complexes in two steps. The
first step occurred at 250 4058 implying loss of mixed fragments, the second step
started immediately after the first one and continued until the complete decomposition
of the ligand and formation of MS (M ˆ PdII, PtII, and RuII) as the end product. The
total % weight loss corresponds to the loss of the respective ligand after consideration
of the transfer of one S-atom to the metal ion, and the residue corresponds to the
respective metal sulfide.
Biological Activity. Metronidazole had a 50% inhibitory concentration (IC50) of
0.33 mg/ml in our experiment, which is within the range (0.17 0.37 mg/ml) of previously
reported IC50s obtained against the same strain of E. histolytica [31]. As shown in
Table 1, complexes 1a c, 2a c, and 3a c cause a marked inhibition as compared to
their respective ligands 1, 2, and 3, respectively. Compound 2a was as active as
metronidazole, while 3a had a better IC50 value. The IC50 values of Pd-, Pt-, and Ru-
complex precursors were also determined establishing that these metal-complex
precursors have no activity against E. histolytica (Table 2). These activities indicate
that the complexation to Pd not only increases the activity of the parent drug but also
modifies it from amoebostatic to amoebicidal. Detailed studies on the mechanism of
action of these complexes as well as further modifications of these and other related
metal derivatives are in progress.
N. Bharti acknowledges a Senior Research Fellowship from the Council of Scientific and Industrial Research
(CSIR), New Delhi, India. The authors are thankful to Prof. Alok Bhattacharya and Dr. Sudha Bhattacharya,
School of Life Sciences and School of Environmental Sciences, respectively, Jawaharlal Nehru University, New
Delhi, for providing laboratory facilities for the determination of biological activities.

Helvetica Chimica Acta Vol. 85 (2002)
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Table 1. In vitro Screening for Amoebicidal Activity of Ligands and Their PdII, PtII, and RuII Complexes against
the HK-9 Strain of E. histolytica
Compound
IC50 [mg/ml]a)
1
aadt
0.94 Æ 0.15
0.53 Æ 0.09
0.61 Æ 0.08
0.70 Æ 0.10
0.59 Æ 0.07
0.32 Æ 0.08
0.39 Æ 0.06
0.43 Æ 0.06
0.57 Æ 0.13
0.28 Æ 0.07
0.37 Æ 0.06
0.40 Æ 0.09
0.33 Æ 0.06
1a
1b
1c
2
2a
2b
2c
3
[PdCl2(aadt)]
[PtCl2(aadt)]
[RuCl2(aadt)(h4-C8H12
mntdt
[PdCl2(mntdt)]
[PtCl2(mntdt)]
[RuCl2(h4-C8H12)(mntdt)]
bntdt
[PdCl2(bntdt)]
[PtCl2(bntdt)]
[RuCl2(bntdt)(h4-C8H12)]
metronidazole
)
3a
3b
3c
a) Mean Æ 2 s.d.
Table 2. IC50 Values Obtained for Metal-Complex Precursors and Metronidazole Against the HK-9 Strain of E.
histolytica
IC50 [mg/ml]a)
[PdCl2(DMSO)2]
[PtCl2(DMSO)2]
[RuCl2(h4-C8H12)(MeCN)2]
Metronidazole
2.66 Æ 0.70
3.90 Æ 0.80
5.17 Æ 1.25
0.31 Æ 0.06
a) Mean Æ 2 s.d.
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Received July 10, 2002