Synthesis and antimalarial activity in vitro of new heterobimetallic complexes: Rh and Au derivatives of chloroquine and a series of ferrocenyl-4-amino-7-chloroquinolines

Article abstract of DOI:10.1016/j.jorganchem.2003.07.026

The reaction of chloroquine and several ferrocenyl derivatives of chloroquine with Au(PPh₃)NO₃, Au(C₆ F₅)(tht) and [Rh(COD)Cl]₂ have been investigated. The resulting products have been characterised by a range of techniques including NMR, mass spectrometry, elemental analysis, IR and cyclic voltammetry. The data suggests that the products are heterobimetallic complexes where the quinoline nitrogen coordinates to the Au or Rh. In vitro studies against Plasmodium falciparum are reported.

Full text of DOI:10.1016/j.jorganchem.2003.07.026

Journal of Organometallic Chemistry 688 (2003) 144ꢁ152
/
www.elsevier.com/locate/jorganchem
Synthesis and antimalarial activity in vitro of new heterobimetallic
complexes: Rh and Au derivatives of chloroquine and a series of
ferrocenyl-4-amino-7-chloroquinolines
Margaret A.L. Blackie a, Paul Beagley a, Kelly Chibale a, Cailean Clarkson b,
John R. Moss a,*, Peter J. Smith b
a Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
b Division of Pharmacology, Department of Medicine, University of Cape Town Medical School, Observatory 7925, South Africa
Received 4 March 2003; accepted 30 July 2003
Abstract
The reaction of chloroquine and several ferrocenyl derivatives of chloroquine with Au(PPh3)NO3, Au(C6F5)(tht) and
[Rh(COD)Cl]2 have been investigated. The resulting products have been characterised by a range of techniques including NMR,
mass spectrometry, elemental analysis, IR and cyclic voltammetry. The data suggests that the products are heterobimetallic
complexes where the quinoline nitrogen coordinates to the Au or Rh. In vitro studies against Plasmodium falciparum are reported.
# 2003 Elsevier B.V. All rights reserved.
Keywords: Antimalarial activity; Heterobimetallic complexes; Chloroquine
1. Introduction
selectivity for the cancer cells. Metal complexes have
now been investigated to treat numerous diseases
including malaria. This approach has been successfully
explored with 4-aminoquinolines, an important class of
antimalarial agents exemplified by chloroquine. A
number or transition metals e.g. Rh, Ru [4] and Au [5]
have been coordinated to chloroquine and other ami-
noquinolines [6]. It has also been shown that ferrocene
[7] and a ruthenocene [8] unit can also be incorporated
into the aminoalkyl side chain of chloroquine. The
coordination of a metal and the incorporation of an
organometallic moiety has a positive effect resulting in
higher activity against both the chloroquine-sensitive
and chloroquine-resistant strains of the parasite.
Metallic chloroquine analogues and derivatives show
considerable promise but the role of the metals is not
completely understood. The mechanism by which the
organometallic and coordination complexes operate is
likely to be different and we thought it would be
interesting to see if the two approaches were comple-
mentary. We wished to investigate the synthesis of
complexes of the type [Au(L)(PPh3)]NO3, [Au(C6F5)(L)]
and [Rh(Cl)(COD)(L)] where L is either chloroquine (1),
Malaria continues to be a major health problem,
especially in the Third World. Malaria is a vector-borne
parasitic disease, transmitted to humans by the female
Anopheles mosquito. Forty years ago, less than 10% of
the world’s population was at risk of contracting the
disease, today over 40% of the world’s population is at
risk [1] since various species of Plasmodium, the
causative agent of malaria, have developed resistance
to drugs like chloroquine (1).
The advent of cisplatin [2] sparked a worldwide
interest in metal-containing drugs, and as a result,
numerous inorganic/organometallic compounds have
been screened for anti-tumour activity. In many cases,
the platinum or organometallic moiety has been co-
ordinated to or incorporated into vectors like hormones,
drugs and metabolites [3]. Accumulation of these com-
plexes in the vicinity of the tumour results in higher
* Corresponding author. Tel.: ꢀ
7499.
E-mail address: jrm@science.uct.ac.za (J.R. Moss).
/
27-21-650-2535; fax: ꢀ27-21-689-
/
ferroquine
(2),
N-(7-chloro-quinolin-4-yl)-N?-[2-
0022-328X/03/$ - see front matter # 2003 Elsevier B.V. All rights reserved.
doi:10.1016/S0022-328X(03)00917-3

M.A.L. Blackie et al. / Journal of Organometallic Chemistry 688 (2003) 144ꢁ
/152
145
1
(N??,N??-dimethylaminomethyl)ferrocenylmethyl]-eth-
ane-1,2-diamine (3), or 3-benzyl-1-[2-(7-chloro-quinolin-
4-ylamino)-ethyl]-1-[2-(N??,N??-dimethylaminomethyl)-
ferrocenylmethyl]urea (4) (Fig. 1). The presence of the
two metal centres in the molecule could have an
additive, synergistic or antagonistic effect as far as the
antimalarial activity is concerned and we wished to
explore this.
at ambient temperature. H-NMR spectra were refer-
enced internally using the residual protons in the
deuterated solvent (CDCl3: d 7.27; CD3OD: d 5.84)
and are reported relative to Me4Si (d 0.00). 13C-NMR
spectra were referenced internally to the solvent reso-
nance (CDCl3: d 77.0; CD3OD: d 49.1) and are reported
relative to Me4Si (d 0.0). 19F-NMR spectra were
referenced externally to CFCl3. 31P-NMR spectra were
referenced externally to H3PO4. All chemical shifts are
quoted in d (ppm) and coupling constants, J, are given
in Hertz (Hz). Mass spectra were determined by Dr
Boshoff of the mass spectrometry unit at the Cape
Technikon. In all cases the isotopic distribution pattern
was checked against the theoretical distribution. Cyclic
voltammetry (CV) was carried out on a BAS-100B
electrochemical analyser in a one-compartment-three-
electrode system, comprising Ag/Agꢀ (0.01 M) as the
reference electrode, platinum wire as the auxiliary
electrode and a platinum disc as the working electrode.
The supporting electrolyte was a solution of 0.1 M
tetrabutylammonium perchlorate in anhydrous MeCN.
The potentials E were recorded without IR compensa-
tion. All potentials reported are relative to the half wave
potential (E1/2) of the ferrocene/ferrocenium couple run
under the same conditions. The experiments were
performed in 1.0 mM solutions under an atmosphere
of Ar at room temperature (r.t.). The solutions were
degassed by bubbling Ar through the solution for 5 min
prior to the CV run. The platinum disc electrode was
polished after every run. Conductivity measurements
were performed on a Metrohm 660 conductometer in
1.0 mM nitrobenzene solutions at 20 8C. Two strains of
P. falciparum were used in this study, a chloroquine-
sensitive strain, D10, and a chloroquine-resistant strain,
K1. The P. falciparum strains were cultured using a
modified version of the Trager and Jensen method [12].
Parasite viability was assessed using the lactate dehy-
drogenase assay [13].
2. Experimental
2.1. General experimental
The syntheses were performed using standard Schlenk
techniques. When applicable reactions were performed
in a centrifuge tube fitted with a nitrogen inlet. MeCN
and CH2Cl2 were distilled from CaH2; Et2O was distilled
from Na/benzophenone/tetraglyme. Chloroquine, free
base, was obtained from chloroquine diphosphate
according to a literature procedure [4]. Ferroquine (3)
[7a], [Au(PPh3)]NO3 [9], [Au(C6F5)(tht)] [10],
[Rh(Cl)(COD)]2 [11] and 13 [4] were prepared according
to literature procedures The synthesis of the previously
reported complexes 3 and 3-benzyl-1-[2-(7-chloro-qui-
nolin-4-ylamino)-ethyl]-1-[2-(N??,N??-dimethylamino-
methyl)-ferrocenylmethyl]urea 4 are described in the
supplementary information.
Melting points were recorded on a Kofler hotstage
microscope (Reichart Thermovar). Microanalyses were
performed using a Carlo Erba EA1108 elemental
analyser in the microanalytical laboratory at the Uni-
versity of Cape Town. Infrared spectra were recorded as
KBr discs on a PerkinꢁElmer Paragon 1000 FT-IR
/
spectrometer. NMR spectra were recorded on either a
Varian Unity-400 (1H: 400 MHz; 13C: 100.6 MHz; 19F:
376 MHz) spectrometer or a Varian Mercury-300 (1H:
300 MHz; 13C: 75.5 MHz; 31P: 121 MHz) spectrometer
2.2. Preparation of [Au(L)(PPh3)]NO3 complexes
[14]
Complex 5. Chloroquine (1) (62 mg, 0.19 mmol) and
triphenylphosphinegold(I) nitrate (100 mg, 0.19 mmol)
were dissolved in CH2Cl2 (5 cm3). Light was excluded
and the mixture was allowed to stir for 3 h at 25 8C. The
reaction vessel was cooled to ꢂ
/
78 8C and Â90% of the
/
solvent was removed in vacuo. The mixture was allowed
to warm to r.t. and Et2O (1 cm3) was added resulting in
a slurry which was cooled to ꢂ4 8C and allowed to
/
stand for 1 h. The mixture was then filtered, and the
solid washed with Et2O before drying the solid in vacuo
to yield a cream crystalline product (134 mg, 82%); m.p.:
Fig. 1. Ligands for metal complexation (chloroquine (1); ferroquine
(2);
N-(7-chloro-quinolin-4-yl)-N?-[2-(N??,N??-dimethylamino-
89ꢁ
[C35H40N3AuClP][NO3]: C, 51.47; H, 4.80; N, 6.67%; dH
(300 MHz; CDCl3) 8.44 (1H, d, 3JHH
9, ArC5-H), 8.33
/
90 8C; Found: C, 51.72; H, 5.01; N, 6.50. Calc. for
methyl)ferrocenylmethyl]-ethane-1,2-diamine (3); 3-benzyl-1-[2-(7-
chloro-quinolin-4-ylamino)-ethyl]-1-[2-(N??,N??-dimethylamino-
methyl)-ferrocenylmethyl]urea) (4).
ꢃ
/

146
M.A.L. Blackie et al. / Journal of Organometallic Chemistry 688 (2003) 144ꢁ152
/
3
8.14 (1H, d, JHH
4
9, ArC5-H), 7.85 (1H, d, JHH
(1H, d, 3JHH
ꢃ
/
6, ArC2-H), 8.06 (1H, d, 4JHH
ꢃ
/
2, ArC8-
ꢃ
/
ꢃ
/
2,
7.49 (15H, m, Ph), 7.38 (1H, dd, 3JHH
ꢃ/2 and
ArC8-H), 7.53 (15H, m, Ph), 7.12 (1H, dd, 4JHH
ꢃ
/
2 and
H), 7.63ꢁ
/
3JHH
ꢃ/9, ArC6-H), 6.48 (1H, d, JHH
ꢃ6, ArC3-H),
/
3
3JHH
ꢃ
/
9, ArC6-H), 6.49 (1H, d, JHH
ꢃ6, ArC3-H),
/
3
3.76 (1H, m, 6?), 2.79ꢁ
(4H, m, 5?, 4?), 1.35 (3H, d, JHH
3JHH
ꢃ6, 1?); dC{H} (75.5 MHz; CDCl3) 152.3 (ArC2),
/
2.56 (6H, m, 2?, 3?), 1.78ꢁ
/
1.57
4.31 (1H, m, Cp), 4.24 (1H, m, Cp), 4.12 (1H, m, Cp),
4.08 (5H, m, Cp?), 3.90 (1H, d, 2JHH
13, 2?a), 3.64 (3H,
m, 3?a, 5?), 3.50 (3H, m, 3?b, 4?), 2.82 (1H, d, 2JHH
13,
2?b), 2.09 (6H, s, 1?); dC{H} (75.5 MHz; CDCl3) 152.1
(ArC2), 151.0 (CIV), 148.2 (CIV), 135.4 (CIV), 134.0 (Ph),
133.9 (Ph), 132.3 (Ph), 129.5 (Ph), 129.3 (Ph), 128.0
(CIV), 127.1 (CIV), 126.7 (ArC8), 125.8 (ArC6), 123.7
(ArC5), 117.7 (CIV), 99.0 (ArC3), 71.4 (Cp), 69.4 (5C,
Cp?), 66.5 (Cp), 65.8 (Cp), 58.0 (2?), 44.4 (2C, 1?), 41.6
(5?); dP{H} (121 MHz; CDCl3) 30.71 (PPh3); nmax 3331br
3
ꢃ
/
6, 1??), 1.09 (6H, t,
ꢃ
/
/
ꢃ
/
151.8 (CIV), 147.5 (CIV), 136.3 (CIV), 134.1 (Ph), 134.0
(Ph), 132.5 (Ph), 129.7 (Ph), 129.5 (Ph), 126.1 (ArC5),
125.3 (ArC6), 124.7 (ArC8), 117.9 (CIV), 99.1 (ArC3),
52.6 (2?), 49.3 (6?), 47.0 (3?), 33.5 (5?), 23.1 (4?), 19.7 (1??),
10.6 (1?); dP{H} (121 MHz, CDCl3) 30.81 (PPh3); nmax
3404br m (n Nꢁ
noline, n CÄN), 1534m (7-chloroquinoline), 1478m,
1436m, 1382vs (n NꢁO), 1200w (NR), 1152m, 1100m,
1025w, 996w (n PꢁC), 807w, 749m, 711m, 693s, 546s,
503s; m/z (FAB) 781 (M(37Cl)ꢀH, 16), 780 (M(37Cl),
40), 779 (MꢀH, 16), 778 (M, 40), 748 (MꢂMe, 3), 721
(13), 459 (AuPPh3, 21), 320 (CQ, 8), 249 (CQ37Clꢂ
2CH2CH3, 13), 247 (35Cl-CQꢂ
2-CH2CH3, 36), 183
(39), 165 (12), 152 (15), 140 (30), 136 (17), 128 (11),
115 (18), 105 (11), 91 (26), 89 (30), 86 (47), 77 (60), 64
(27), 63 (59); L (C6H5NO2, 20 8C)ꢃ
Compound 6 was prepared by an analogous proce-
dure to 5 from ferroquine (2) and triphenylphosphine-
gold(I) nitrate and obtained as an orange crystalline
/H), 3070m, 2966m, 1579s (7-chloroqui-
/
/
m (NH), 3054m, 2940m, 1580s (7-chloroquinoline, n CÄ
N), 1478m (NCH3), 1436m, 1383vs (n NÃO), 1329s,
1205w, 1139w, 1102m (ferrocene), 1029w, 996m, 811m
/
/
/
/
/
/
(ferrocene), 747m (d CÃ
/
H aromatic), 714m (d CÃ
/
H
/
aromatic), 695s, 618w, 544s and 506m; m/z (FAB)
Found 935.20071 (Mꢀ, C43H44N4Au35ClFePꢀ requires
/
935.20069), 841.5 (2%), 770.6 (2), 721.5 (Mꢀ ꢂ
/
3Phꢀ
AuPPh3, 5),
459.3 (AuPPh3, 100), 213.1 (18), 185.1 (23); E1/2: not
found; ferrocene redox: Epa 294 mV and Epcꢃ186
mV; L (C6H5NO2, 20 8C)ꢃ
13 Vꢂ1 cm2 molꢂ1
/
Me, 25), 680.5 (3), 649.4 (3%), 475.3 (Mꢀ ꢂ
/
/
17 Vꢂ1 cm2 molꢂ1
.
ꢃ
/
/
/
.
Compound 8 was prepared by an analogous proce-
dure to 5 from 4 and triphenylphosphinegold(I) nitrate
solid (84%); m.p. 110ꢁ112 8C; dH (400 MHz; CDCl3)
/
3
8.68 (1H, d, JHH
4
7, ArC2-H), 8.26 (1H, d, JHH
ꢃ
/
ꢃ/2,
ArC8-H), 7.94 (1H, d, 3JHH
ꢃ
/
9, ArC5-H), 7.60 (15H, m,
as an orange crystalline solid (75%); m.p.: 102ꢁ105 8C;
/
4
3
Ph), 7.39 (1H, d, JHH
ꢃ
/
2 and JHH
7, ArC3-H), 4.59 (1H, d, 2JHH
ꢃ
/
9, ArC6-H), 6.97
14, 3?a),
14, 3?b), 4.37 (1H, m, Cp), 4.22 (1H,
m, Cp), 4.16 (5H, s, Cp?), 4.09 (1H, m, Cp), 3.99 (1H, d,
2JHH 12, 2?a), 3.11 (1H, d, 2JHH
12, 2?b), 2.32 (6H, s,
Found: C, 54.05; H, 4.14; N, 7.16. Calc. for
C51H50AuClFeN5OPNO3: C, 54.15; H, 4.54; N, 7.43%;
(1H, d, 3JHH
ꢃ
/
ꢃ
/
4.48 (1H, d, 2JHH
ꢃ
/
3
dH (300 MHz; CDCl3) 8.31 (1H, d, JHH
ꢃ7, ArC2-H),
/
4
3
8.18 (1H, d, JHH
ArC5-H), 7.66ꢁ7.50 (15H, m, Ph), 7.28ꢁ
ArC6-H, U), 6.81 (1H, d, JHH
(6H, m, 3Cp, 3?a, 4?), 4.12 (5H, s, Cp?), 4.11ꢁ
ꢃ
/
2, ArC8-H), 8.11 (1H, d, JHH
7.10 (8H, m, 1??,
7, ArC3-H), 4.51ꢁ4.20
3.61 (5H,
ꢃ
/
9,
ꢃ
/
ꢃ
/
/
/
3
1?); dC{H} (100.6 MHz; CDCl3) 154.2 (ArC2), 152.5
(CIV), 146.8 (CIV), 136.7 (CIV), 134.2 (Ph), 134.1 (Ph),
132.6 (Ph), 128.8 (Ph), 126.7 (Ph), 126.1 (ArC8), 124.6
(ArC6), 124.0 (ArC5), 118.0 (CIV), 100.4 (CIV), 95.5
(ArC3), 83.0 (CIV, Cp), 71.4 (Cp), 70.8 (Cp), 69.6 (5C,
Cp?), 66.7 (Cp), 57.8 (2?), 44.7 (2C, 1?), 42.5 (3?); dP{H}
ꢃ
/
/
/
m, 2?a, 2?b, 3?b, 5?), 2.01 (6H, s, 1?); dC{H} (75.5 MHz;
CDCl3) 159.9 (CO), 153.6 (CIV), 153.3 (ArC2), 146.3
(CIV), 140.5 (CIV), 136.8 (CIV), 134.2 (Ph), 134.0 (Ph),
132.6 (Ph), 129.8 (Ph), 129.6 (Ph), 128.2 (2C, U), 127.1
(U), 126.6 (2C, U), 124.9 (ArC8), 123.7 (ArC5) 117.8
(CIV), 99.5 (ArC3), 84.3 (CIV, Cp), 70.6 (Cp), 69.7 (Cp?),
68.6 (Cp), 67.8 (Cp), 58.7 (2?), 49.7 (3?), 45.5 (4?), 44.6
(1??), 44.2 (2C, 1?), 43.1 (5?); dP{H} (121 MHz; CDCl3)
(121 MHz, CDCl3) 30.60 (PPh3); nmax 3430br s (n NÃ
H), 3079s, 2941s, 2826s, 2776s, 1592vs (7-chloroquino-
line, n CÄN), 1480m, 1434m (d-as NCH3), 1384vs (n
NÃO), 1332s, 1209w, 1141w, 1102s (ferrocene), 1032w,
996m (n PÃ
aromatic, five adjacent hydrogens), 711m (d Cꢁ
/
/
/
/
C), 815m (ferrocene), 749m (d CÃ
/
H
30.58 (PPh3); nmax 3309br m (n NÃ
2820m, 2775m, 1595vs (7-chloroquinoline, n CÄ
1542s (7-chloroquinoline), 1480w, 1452m (NCH3),
1437m (d-as (NCH3)), 1381vs (n NÃO), 1336s, 1283m,
1205m, 1101m (ferrocene), 1028m, 999w (n PÃC), 814w
(d CÃH aromatic), 748m (d CÃH aromatic), 695s,
609w, 544s, 510m, 454w; m/z (FAB) 1068.2548 (Mꢀꢀ
H, C51H51N5Au35ClFeOPꢀ requires 1068.2535), 917
(2%), 721 (36), 610 (Mꢀ ꢂ
AuPPh3, 12), 565 (8), 459
(100), 213 (33), 185 (33), 91 (CH2ÃCpÃCH2, 54); E1/2
180 mV; ferrocene redox: Epa 219 mV and Epcꢃ141
mV; L (C6H5NO2, 20 8C)ꢃ
31 Vꢂ1 cm2 molꢂ1
/
H), 3057m, 2934m,
/H
/
N),
aromatic, five adjacent hydrogens), 544s, 505m, 456w;
m/z (EI) 892 (Mꢀ, 79%), 848.1 (Mꢂ
NMe2, 5), 757 (5),
721 (23), 637 (5), 459 (100), 432 (Mꢀ ꢂ
AuPPh3, 14),
388 (25), 262 (PPh3, 12), 213 (94), 185 (65), 183 (65), 134
(51), 91 (28); E1/2 147 mV; ferrocene redox: Epa 252
mV and Epcꢃ162 mV; L (C6H5NO2, 20 8C)ꢃ
21 Vꢂ1
cm2 molꢂ1
/
/
/
/
/
/
ꢃ
/
ꢃ
/
/
/
/
.
/
Compound 7 was prepared by an analogous proce-
dure to 5 from 3 and triphenylphosphinegold(I) nitrate
/
/
ꢃ
/
ꢃ
/
/
as an orange crystalline solid (90%); m.p.: 106ꢁ
/
108 8C;
3
dH (300 MHz; CDCl3) 8.41 (1H, d, JHH
ꢃ/6, ArC2-H),
/
.

M.A.L. Blackie et al. / Journal of Organometallic Chemistry 688 (2003) 144ꢁ
/152
147
2.3. Preparation of [Au(L)(C6F5)] complexes
955s (n CÃ
/
F), 862m, 804m, 605w, 527w and 490w
(ferrocene);
m/z (FAB) 798.0672 H,
(Mꢀꢀ
/
Synthesis of complex 9. (Pentafluorophenyl)(tetrahy-
drothiophene)gold (58 mg, 0.95 mmol) and chloroquine
(1) (100 mg, 0.18 mmol) were dissolved in CH2Cl2 (3
cm3) and stirred at 25 8C for 2 h in the absence of light.
Addition of hexane (2 cm3) resulted in a suspension
which was centrifuged and the supernatant was dec-
anted off the crystalline solid. The crystals were dried in
vacuo to yield a white crystalline solid; (91 mg, 63%);
C29H25N3Au35ClFeF5 requires 798.0672), 753 (8), 459
(9), 434 (71), 389 (100), 256 (27, HC-Fp-CH2-NMe2),
213 (65), 134 (29, Fe-Cp-CH2), 91 (66, CH2-Cp-CH2).
Compound 11 was prepared by an analogous proce-
dure to 9 from 3 and pentafluorophenyl(tetrahydrothio-
phene)gold(I) as a orange crystalline solid; (132 mg,
75%); m.p.: 76ꢁ78 8C; dH (300 MHz; CD3OD) 8.35 (1H,
/
3
3
d, JHH
7.78 (1H, d, JHH
and 3JHH 9, ArC6-H), 6.57 (1H, d, 3JHH
4.25ꢁ4.23 (1H, m, Cp), 4.15ꢁ
(1H, t, JHHH
2JHH
ꢃ
/
6, ArC2-H), 8.09 (1H, d, JHH
ꢃ9, ArC5-H),
/
4
4
m.p.: 114ꢁ
4JHH
2, ArC8-H), 8.37 (1H, d, JHH
8.23 (1H, d, JHH
and 3JHH 9, ArC6-H), 6.66 (1H, d, 3JHH
/
116 8C; dH (400 MHz; CD3OD) 8.58 (1H, d,
ꢃ
/
2, ArC8-H), 7.40 (1H, dd, JHH
ꢃ2
/
3
ꢃ
/
ꢃ
/
6, ArC2-H),
4
ꢃ
/
ꢃ
/
6, ArC3-H),
3
ꢃ
/
9, ArC5-H), 7.44 (1H, dd, JHH
ꢃ
/
2
6, ArC3-H),
/
/4.13 (1H, m, Cp), 4.07
3
ꢃ
/
ꢃ
/
ꢃ
/
2, Cp), 4.03 (5H, s, Cp?), 3.81 (1H, d,
2
3.95ꢁ
/
3.91 (1H, m, 6?), 3.24ꢁ
/
3.12 (6H, m, 2?, 3?), 1.92ꢁ
/
ꢃ
/
13, 3?a), 3.66 (1H, d, JHH
ꢃ
/
13, 2?a), 3.52 (2H,
1.74 (4H, m, 4?, 5?), 1.42 (3H, d, 3JHH
ꢃ
/
6, 1??), 1.32 (6H,
m, 5?), 3.44 (1H, d, JHH
ꢃ
/
13, 3?b), 2.95 (2H, m, 4?),
2
3
t, JHH
ꢃ
/
7, 1?); dC{H} (100 MHz; CD3OD) 153.5
2.88 (1H, d, 2JHH
ꢃ
/
13, 2?b), 1.97 (6H, s, 1?); dC{H} (75.5
(ArC2), 151.8 (C IV), 147.4 (CIV), 136.2 (CIV), 125.9
(ArC5), 125.6 (ArC6), 123.4 (ArC8), 117.8 (CIV), 99.3
(ArC3), 51.8 (2?), 49.0 (6?), 46.9 (3?), 32.7 (5?), 21.0 (4?),
MHz; CD3OD) 152.7 (CIV), 152.5 (ArC2), 149.7 (CIV),
136.4 (CIV), 127.7 (ArC8), 126.1 (ArC6), 124.3 (ArC5),
119.3 (CIV), 99.8 (ArC3), 85.9 (CIV, Cp), 84.0 (CIV, Cp),
72.3 (Cp), 71.3 (Cp), 70.2 (5C, Cp?), 67.5 (Cp), 58.7 (2?),
44.8 (2C, 1?), 43.3 (5?); dF{H} (376 MHz; CD3OD)
18.9 (1??), 8.2 (1?); dF{H} (376 MHz; CD3OD) ꢂ
to ꢂ117.38 (2F, m, o-F), ꢂ
165.78 (1F, t, 3JFF
F), ꢂ166.80 to ꢂ166.97 (2F, m, m-F); IR (KBr) nmax
3431m (NH), 2972m, 2923m, 2874m, 2852m, 2791m,
1594vs (7-chloroquinoline, n CÄN), 1541m (7-chloro-
quinoline), 1505s (n CÃF), 1455vs (n CÃF), 1442s,
1381m, 1367m, 1341m, 1282m, 1263m, 1219w, 1198m,
1068m, 1017m, 956vs (n CÃF), 866m, 803s, 754m, 647w,
514m and 454m; m/z (FAB) 684[Mꢀ, 23), 332 (19), 320
(Mꢀ ꢂ (Mꢀ ꢂ
AuC6F5, 57), 247 AuC6F5
N(CH2CH3)2, 27), 205 (8), 179 (13), 142 (40), 86
(100) and 58.0 (53); L (C6H5NO2, 20 8C)ꢃ
0.2 Vꢂ1 cm2
molꢂ1
/
117.26
19, p-
/
/
ꢃ
/
/
/
ꢂ
/
117.23 to ꢂ
3JFF
19, p-F), ꢂ
nmax 3411br m (NH), 2955m, 1612w (7-chloroquinoline),
1583s (NÄC, 7-chloroquinoline), 1536m (7-chloroquino-
line), 1499s (n CÃF), 1450vs (n CÃF), 1384m, 1336m,
1278w, 1252w, 1139w, 1105w (ferrocene), 1048m, 1000w
(ferrocene), 952s (n CÃF), 811m (ferrocene), 781m,
489m (ferrocene) and 452w; m/z (FAB) 841 (Mꢀꢀ
H,
1%), 796 (2), 477 (Mꢀ ꢂ
AuC6F4Br, 16), 432 (19), 256
/
117.40 (2F, m, o-F), ꢂ
/
165.86 (1F, t,
ꢃ
/
/
166.86 to ꢂ167.03 (2F, m, m-F);
/
/
/
/
/
/
/
/
/
/
/
/
ꢀ
/
/
/
(HC-Fp-CH2-NMe2, 31), 213 (100), 134 (Fe-Cp-CH2,
4), 91 (CH2-Cp-CH2, 32); E1/2: not found; ferrocene
.
Compound 10 was prepared by an analogous proce-
dure to complex 9 from 2 and (pentafluorophenyl)(te-
trahydrothiophene)gold. The product obtained as an
redox: Epa
ꢃ
/
315 mV and Epcꢃ210 mV; L (C6H5NO2,
/
20 8C)ꢃ
/
0.9 Vꢂ1 cm2 molꢂ1
.
Compound 12 was prepared by an analogous proce-
dure to 9 from 4 and pentafluorophenyl(tetrahydrothio-
phene)gold(I) as a yellow crystalline solid (130 mg,
orange crystalline solid (79 mg, 54%); m.p.: 83ꢁ
/
86 8C;
dH(300 MHz; CD3OD) 8.37 (1H, d, 3JHH
ꢃ
/
6, ArC2-H),
3
7.91 (1H, d, JHH
4
ꢃ
/
9, ArC5-H), 7.76 (1H, d, JHH
ꢃ
/
2,
9, ArC6-
6, ArC3-H), 4.58 (1H, d, 2JHH
60%); m.p.: 102ꢁ
(1H, br s), 8.68 (1H, d, JHH
3JHH 6, ArC2-H), 8.33 (1H, br s), 7.71 (1H, d, 3JHH
9, ArC5-H), 7.17ꢁ7.02 (6H, m, U, ArC6-H), 6.31 (1H, d,
3JHH
6, ArC3-H), 4.50ꢁ4.15 (8H, m, Cp, 1??, 3?a, 4?),
4.11 (5H, s, Cp?), 3.81 (1H, d, 2JHH
13, 2?a), 3.75ꢁ3.66
(1H, m, 3?b), 3.56ꢁ
3.40 (2H, m, 5?), 2.78 (1H, d, 2JHH
/
105 8C; dH (300 MHz; CDCl3) 8.81
4
3
4
ArC8-H), 7.45 (1H, dd, JHH
H), 6.75 (1H, d, 3JHH
ꢃ
/
2 and JHH
ꢃ
/
ꢃ2, ArC8-H), 8.42 (1H,
/
ꢃ
/
ꢃ
/
ꢃ
/
ꢃ
/
2
14, 3?a), 4.55 (1H, d, JHH
4.31ꢁ4.29 (1H, m, Cp) 4.19ꢁ
s, Cp?), 3.92 (1H, d, 2JHH 13, 2?a), 3.29 (1H, d, 2JHH
ꢃ
/
14, 3?b), 4.37 (1H, m, Cp),
/
/
/
4.18 (1H, m, Cp), 4.17 (5H,
ꢃ
/
/
ꢃ
/
ꢃ
/
ꢃ
/
/
13, 2?b), 2.34 (6H, s, 1?); dC{H} (75.5 MHz; CD3OD)
153.3 (ArC2), 150.2 (CIV), 149.5 (CIV), 126.7 (ArC8),
125.7 (ArC6), 124.4 (ArC5), 118.2 (CIV), 100.2 (ArC5),
84.9 (CIV, Cp), 82.9 (CIV, Cp), 72.5 (Cp), 71.5 (Cp), 70.6
(5C, Cp?), 68.2 (Cp), 58.3 (2?), 44.7 (2C, 1?), 42.8 (3?);
/
ꢃ
/
13, 2?b) and 1.99 (6H, s, 1?); dC{H} (75.5 MHz; CDCl3)
160.5 (CIV, CO), 153.3 (ArC2), 152.0 (CIV), 146.9 (CIV),
139.7 (CIV), 136.4 (CIV), 128.2 (2C, U), 126.7 (ArC6),
126.6 (U4), 126.2 (2C, U), 125.7 (ArC5), 123.0 (ArC8),
117.4 (IVC), 98.0 (ArC3), 83.5 (CIV, Cp), 70.6 (Cp), 69.9
(Cp), 69.5 (5C, Cp?), 67.6 (Cp), 57.7 (2?), 46.9 (3?), 45.8
(4?), 44.6 (1??), 44.5 (2C, 1?), 43.8 (5?); dF{H} (376 MHz;
CDCl3) ꢂ
(1F, t, 3JFF
F); IR (KBr) nmax 3409br m (NH), 3091m, 2928m,
2860m, 2823m, 2779m, 1592vs (7-chloroquinoline, n CÄ
dF{H} (376 MHz; CD3OD) ꢂ
/
117.25 to ꢂ
165.88 (1F, t, JFF 19, p-F) ꢂ
167.05 (2F, m, m-F); nmax 3400br m (NH), 3088m,
2945m, 2826m, 2783m, 1591s (7-chloroquinoline, n CÄ
N), 1554m (7-chloroquinoline), 1502s (n CÃF), 1457s (n
CÃF), 1362m, 1325m, 1285w, 1259w, 1226w, 1203w,
1141w, 1105w (ferrocene), 1062m, 1003w (ferrocene),
/
117.45 (2F,
3
m, o-F), ꢂ
/
ꢃ
/
/
166.90 to
ꢂ
/
/
/
120.05 to ꢂ
/
120.25 (2F, m, o-F), ꢂ/164.518
/
ꢃ
/
20, p-F), ꢂ
/
167.38 to ꢂ167.62 (2F, m, m-
/
/
/

148
M.A.L. Blackie et al. / Journal of Organometallic Chemistry 688 (2003) 144ꢁ152
/
N), 1548m (NÄ
1457s (n CÃF), 1361m, 1335m, 1271m, 1204w, 1160w,
1142w, 1104w (ferrocene), 1062m, 1005w (ferrocene),
956s (n CÃF), 858w, 805m, 730w, 698w, 607w, 527w and
487w; m/z (FAB) 974 (Mꢀ, 21), 929 (Mꢂ
HNMe2, 12),
610 (Mꢂ AuC6F5ꢀHNMe2,
AuC6F5, 12) 565 (Mꢀ ꢂ
19), 432 (Mꢀ ꢂ
HNMe2ꢀC6H5CH2NHCO, 5), 409 (7),
304 (5), 213 (89), 134 (Fe-Cp-CH2, 37) 91 (CH2-Cp-
CH2, 100); L (C6H5NO2, 208C)ꢃ
0.7 Vꢂ1 cm2 molꢂ1
When the compounds were purified by preparative
TLC (silica) eluting with CH2Cl2ꢁMeOH 9:1 the
/
C, 7-chloroquinoline), 1502s (n CÃ
/
F),
(54), 359 (15), 303 (15), 256 (HC-Fp-CH2-NMe2, 21),
213 (100), 134 (26), 91 (CH2-Cp-CH2).
Compound 15 was prepared by an analogous proce-
dure to 14 from 3 and dichoro(dicyclooctadiene)dirho-
dium to yield an orange crystalline solid; (130 mg, 57%);
m.p.: 213 8C (dec.); Found: C, 57.37; H, 5.28; N, 7.49.
/
/
/
/
/
/
/
/
Calc. for C33H41Cl2FeN4Rh: C, 57.61; H, 5.36; N,
3
7.26%. dH (300 MHz; CDCl3) 8.50 (1H, d, JHH
ꢃ
ꢃ
/
5,
9,
3
ArC2-H), 8.41 (1H, s, ArC8-H), 7.73 (1H, d, JHH
/
.
/
4
ArC5-H), 7.33 (1H, dd, JHH
3
2 and JHH
ꢃ
/
ꢃ9, ArC6-
/
3
H), 6.27 (1H, d, JHH
COD-CH trans to Cl), 4.14 (1H, m, Cp), 4.10 (2H, m,
/
ꢃ5, ArC3-H), 4.70 (2H, br s,
/
products were found to be spectroscopically consistent
with those obtained by above but in slightly lower
yields.
2
Cp), 4.04 (5H, Cp?), 3.83 (1H, d, JHH
(3H, m, 2?a, COD-CH cis to Cl), 3.38 (1H, d, 2JHH
3?b), 3.48ꢁ3.40 (2H, m, 5?), 2.98ꢁ2.92 (2H, m, 4?), 2.79
13, 2?b), 2.52 (4H, m, COD-CH2), 1.95
ꢃ
/
13, 3?a), 3.67
ꢃ
/13,
/
/
2
(1H, d, JHH
ꢃ
/
2.4. Preparation of complex [RhCl(COD)L]
(6H, s, 1?), 1.76 (4H, m, COD-CH2); dC{H} (75.5 MHz;
CDCl3) 152.0 (ArC2), 149.9 (ArC4), 149.2 (CIV), 134.7
(CIV), 128.6 (ArC8), 125.0 (ArC6), 121.5 (ArC5), 117.4
(CIV), 99.1 (ArC3), 84.5 (2C, CH, COD), 84.2 (2C, CH,
COD), 83.8 (CIV, Cp), 71.1 (Cp), 69.9 (Cp), 68.9 (5C,
Cp?), 65.8 (Cp), 58.2 (2?), 47.3 (4?), 46.4 (3?), 45.0 (2C,
1?), 42.0 (5?) 31.4 (2C, COD, CH2), 30.5 (2C, COD,
CH2); nmax 3311br m (NH), 3093m, 2940m, 2869m,
Synthesis of complex 14: A mixture of dichoro(dicy-
clooctadiene)dirhodium (56 mg, 0.11 mmol) and ferro-
quine (1) (150 mg, 0.34 mmol) in CHx2Cl2 (5 cm3) was
heated under reflux for 4 h. The solvent volume was
reduced to half its original level in vacuo and Et2O was
then added dropwise until the solution became turbid.
The mixture was then cooled to ꢂ
/
15 8C for Â/14 h to
2830m, 1611s (7-chloroquinoline, n CÄ/N), 1584vs (7-
yield a suspension. The mixture was filtered, washed
with Et2O and the orange microcrystalline solid was
dried recrystallised from MeOH and dried in vacuo (156
mg, 60%); m.p.: 212 8C (dec.); Found: C, 55.01; H, 5.19;
N, 6.18. C31H36Cl2FeN3Rh requires C, 54.73; H, 5.33;
N, 6.18%; dH(300 MHz; CDCl3) 9.58 (1H, br s, ArC8-
chloroquinoline), 1541m (7-chloroquinoline), 1451m
(NCH3), 1424m, 1365m, 1331m, 1283w, 1251w, 1200w,
1171w, 1140m, 1105w (ferrocene), 1062w, 1035w, 998w,
879w, 854w, 815m (ferrocene), 766w, 647w and 493w
(ferrocene); m/z (FAB) 723.3 (Mꢀꢀ
687.1436 Cl, C33H41N4ClFeRh
(Mꢀ ꢂ
687.1424), 477 (Mꢀ ꢂ
Rh(COD)Cl, 13), 432 (32), 307
/H), (HRMS)
/
requires
H), 8.61 (1H, d, 3JHH
ꢃ
/
6, ArC2-H) 8.17 (1H, br s, NH),
/
3
4
7.54 (1H, d, JHH
ꢃ
/
9, ArC5-H), 7.30 (1H, d, JHH
6, ArC3-
H), 4.74 (2H, br s, COD-CH trans to Cl), 4.38 (1H, d,
2JHH
13, 3?a), 4.22 (1H, m, Cp), 4.16 (1H, m, Cp), 4.13
(6H, m, Cp?, 3?b), 4.08 (1H, t, JHH
ꢃ
/
2
(2), 213 (100), 179 (5), 107 (91), 89 (23).
and 3JHH
ꢃ
/
9 Hz, ArC6-H), 6.42 (1H, d, 3JHH
ꢃ
/
Compound 16 was prepared by an analogous proce-
dure to 14 from 4 and dichoro(dicyclooctadiene)dirho-
dium to yield an orange crystalline solid; (145 mg, 45%);
m.p.: 210 8C (dec.); Found: C, 56.95; H, 5.60; N, 7.61.
Calc. for C41H48Cl2N5OFeRh: C, 57.49; H, 5.65; N,
ꢃ
/
3
ꢃ
/
2, Cp), 3.79 (1H,
2
d, JHH
2.90 (1H, d, JHH
ꢃ
/
13, 2?a), 3.69 (2H, br s, COD-CH cis to Cl),
2
ꢃ
/
13, 2?b), 2.56 (4H, m, COD-CH2),
8.18%.dH (300 MHz; CDCl3) 9.51 (1H, br s, ArC8-H),
3
8.55 (1H, d, JHH
2.21 (6H, s, 1?), 1.85 (4H, m, COD-CH2); dC{H} (75.5
MHz; CDCl3) 152.7 (ArC2), 150.7 (ArC4), 128.7 (ArC8),
125.6 (ArC6), 122.4 (ArC5), 112.4 (CIV, ArC10), 101.4
(CIV), 99.5 (ArC3), 84.2 (2C, CH, COD), 84.0 (2C, CH,
COD), 71.5 (Cp), 70.5 (Cp), 69.3 (5C, Cp?), 66.1 (Cp),
58.0 (2?), 44.9 (2C, 1?), 42.5 (2?), 31.4 (2C, COD, CH2),
30.5 (2C, COD, CH2); nmax 3442br m (NH), 3230br m,
3091m, 3077m, 2990m, 2932m, 2878m, 2822m, 2776m,
ꢃ6, ArC2-H), 8.02 (1H, br s,
/
3
ArCH2NHCO), 7.57 (1H, d, JHH
7.05 (6H, m, U2, U3, U4, ArC6-H), 6.24 (1H, d, JHH
6, ArC3-H), 4.72 (2H, br s, COD-CH trans to Cl), 4.41ꢁ
4.12 (7H, m, Cp, 1??, 3?a, 4?), 4.08 (5H, s, Cp?), 4.05 (1H,
ꢃ
/
9, ArC5-H), 7.14ꢁ
/
3
ꢃ
/
/
2
m, Cp), 3.77 (1H, d, JHH 13, 2?a), 3.69ꢁ
3?b, 5?, COD-CH cis to Cl), 2.74 (1H, d, 2JHH
ꢃ
/
/
3.25 (5H, m,
13, 2?b),
ꢃ
/
2.50 (4H, m, COD -CH2), 1.94 (6H, s, 1?), 1.77 (4H, m,
COD-CH2); dc{H} (75.5 MHz; CDCl3) 160.5 (CIV, CO),
152.5 (ArC2), 151.2 (CIV), 147.3 (CIV), 140.1 (CIV), 135.5
(CIV), 128.3 (2C, U), 128.2 (ArC6), 126.7 (U4), 126.4
(2C, U), 126.0 (ArC6), 123.0 (ArC8), 119.0 (CIV), 98.7
(ArC3), 84.1 (2C, CH, COD), 83.8 (2C, CH, COD), 82.0
(CIV, Cp), 70.4 (Cp), 69.5 (5C, Cp?), 68.8 (Cp), 67.6
(Cp), 57.9 (2?), 44.7 (2C, 1?), 44.6 (4?), 43.8 (1??), 31.4
(2C, COD, CH2), 30.5 (2C, COD, CH2); nmax 3313m,
3084m, 2988m, 2934m, 2878m, 2828m, 2776m, 1590vs
1590vs (7-chloroquinoline, n CÄ
/
N), 1545m (7-chloro-
quinoline), 1495m (n CÄC, COD), 1451m (NCH3),
/
1427m, 1391w, 1367m, 1350m, 1333m, 1296w, 1282m,
1251m, 1228m, 1201m, 1170m, 1136m, 1105m (ferro-
cene), 1067w, 1029m, 1000m (ferrocene), 962w, 923w,
892w, 861s, 842m, 824s, 807s, 766m, 734m, 701w, 643w,
625w, 615w, 600w, 552w, 523m, 490m (ferrocene), 457w,
and 434w; m/z (FAB) 680 (Mꢀ
/
H, 2%), 644 (Mꢂ
/
Cl,
Rh(COD)Cl, 22), 389
98), 599 (5), 491 (9), 434 (Mꢀ ꢂ
/

M.A.L. Blackie et al. / Journal of Organometallic Chemistry 688 (2003) 144ꢁ
/152
149
(7-chloroquinoline, n CÄ
/
N), 1539s (7-chloroquinoline),
from NMR studies (see Section 3.2) that suggests that
both the gold and rhodium coordinate to the quinoline
nitrogen. In addition, the characteristic CÄN stretch in
the IR spectra shifts by Â20ꢁ
30 cmꢂ1 for most of the
complexes. The exceptions to this rule are complexes 11
and 15 where a second secondary amine is present. The
H8 proton resonance in the 1H-NMR shifts significantly
for complex 15, this indicates that the Rh coordinates to
the quinoline amine (see Section 3.2). However, complex
11 cannot be identified unambiguously.
1491m (n CÄC, COD), 1452m (NCH3), 1400m, 1359m,
/
1331m, 1300m, 1273m, 1256m, 1201m, 1172w, 1139w,
1104w (ferrocene), 1038w, 1005m (ferrocene), 962w,
856m, 810m (ferrocene), 764w, 742m, 695w, 513m,
/
/
/
492m (ferrocene), 462m; m/z (FAB) 856.2 (Mꢀꢀ
/H,
1%), 820 (Mꢀ ꢂ
/
Cl, 3) 694 (3), 610 (Mꢀ ꢂ
63), 565 (29), 409 (9), 307 (12), 237 (38), 213 (45), 150
/Rh(COD)Cl,
(100), 91 (55).
3. Results and discussion
3.2. NMR spectroscopy
3.1. Synthesis
The 1H-NMR spectra of complexes 5ꢁ
8 gave rise to a
/
The reaction of ligands 1ꢁ
/
4
with ionic
15 proton multiplet arising from triphenylphosphine.
Both the H8 and the H2 protons of the quinoline shifted
with respect to the parent ligand, this can be illustrated
by ferroquine (2) where the H8 (d 7.91) and H2 (d 6.46)
quinoline proton resonances shift to 8.26 and 6.97 in 6,
respectively. The second notable change in the spectra
concerns the CH2NMe2 proton resonances, which shift
significantly. This could be interpreted as evidence for
coordination to the NMe2 moiety but the resonances
corresponding to the NMe2 group do not shift signifi-
[Au(PPh3)NO3], and neutral [Au(C6F5)(tht)] were in-
vestigated. The [Au(L)(PPh3)]NO3 complexes are solu-
ble in water and were synthesised under milder
conditions than the corresponding hexafluorophosphate
salts [5]. The complexes 5ꢁ
triphenylphosphinegold(I) and the corresponding ligand
(1ꢁ4) in CH2Cl2 (see Eq.(1)) and isolated as crystalline
solids. The neutral complexes 9ꢁ12 were synthesised
from [Au(C6F5)(tht)] and the corresponding ligand (1ꢁ
/8 were prepared from
/
/
/
4) in CH2Cl2 (see Eq. (2)) and isolated as crystalline
solids.
cantly and
a similar shift is observed for the
HNCH2CH2NH spacer not the CH2NMe2 protons
when the gold is complexed to 3 and 4. The presence
of the triphenylphosphine was observed in the 13C-
NMR spectra and 31P-NMR spectra of these complexes.
Many aspects of the spectroscopic data obtained for the
complex [Au(CQ)(PPh3)]NO3 (5) are similar to the
ð1Þ
data
[Au(CQ)(PPh3)]PF6 [5].
reported
for
the
related
complex
Upon coordination of the Au(C6F5) a similar down-
field shift in the H8 quinoline proton resonance was
observed in the 1H-NMR spectra when compared to the
free ligand. The tetrahydrothiophene was notably ab-
ð2Þ
Complexes of the type [Rh(Cl)(COD)(L)] (13ꢁ
synthesised from [Rh(Cl)(COD)]2 and the correspond-
ing ligands (1ꢁ4) in CH2Cl2 and obtained as crystalline
solids (see Eq. (3)).
/
16) were
1
sent in both H- and 13C-NMR spectra indicating that
/
this had been displaced by the 4-amino-7-chloroquino-
line ligand. The 19F-NMR spectra of 9ꢁ
12 showed
/
small, but consistent changes in the all three pentafluor-
ophenyl resonances compared to the [Au(C6F5)(tht)].
The formation of the rhodium complexes
ð3Þ
1
[Rh(Cl)(COD)(L)] could be clearly observed in the H-
The ligands (1ꢁ
/
4) contain several sites that can
NMR spectra as the chemical environment of the
cyclooctadiene protons changes significantly on com-
plexation, resulting in large changes in the chemical
shifts of these protons. A large change in the chemical
potentially coordinate to a metal. We expected the
metal to coordinate to the quinoline nitrogen since the
4-amino nitrogen donates electrons into the quinoline
ring increasing the electron density at the quinoline
nitrogen and rendering the 4-amino moiety unreactive.
The possibility of the tertiary amine coordinating to the
metal made unambiguous characterisation of these
complexes difficult. Suitable crystals for X-ray diffrac-
tion studies have eluded us but there is strong evidence
shift of the H8 quinoline resonance (ꢀ1 ppm) was
/
observed. Compound 13 [Rh(Cl)(COD)(CQ)] has pre-
viously been synthesized and the spectroscopic data that
we obtained was consistent with that reported in the
literature [4]

150
M.A.L. Blackie et al. / Journal of Organometallic Chemistry 688 (2003) 144ꢁ152
/
3.3. Biological testing
would be expected on the basis of the in vitro
testing.
The data for the in vitro antimalarial activity of the
new derivatives is presented in Table 1. Data for the
3.4. Cyclic voltammetry
ligands 1
/
4 and the previously prepared complex 13 are
ꢁ
included for comparison purposes. The following trends
are consistent with literature reports:
The introduction of a ferrocene moiety into chlor-
oquine may enhance the transport of a 4-aminoquino-
line into the food vacuole or there maybe a toxicity
associated with the metal fragment. One such mechan-
ism is the generation free radicals by ferrocene (see Eq.
(4)) [15].
i) The coordination of gold or rhodium increases the
efficacy of chloroquine (1); this is most notable in
the chloroquine-resistant K1 strain.
ii) The ferrocenyl ligands 2ꢁ4 are more effective than
/
Fe2ꢀ ꢀO2 ꢃFe3ꢀ ꢀO2
;
ꢂ
+
chloroquine in both the chloroquine-sensitive and
the chloroquine-resistant strains of the parasite.
Fe2ꢀ ꢀO2 ꢂ ꢃFe3ꢀ ꢀH2O2;
+
Fe2ꢀ ꢀH2O2 ꢃFe3ꢀ ꢀOHꢂ ꢀOH+
(4)
Several new trends have emerged from these tests:
Previous attempts to find a correlation between the
antimalarial activity and the reduction potential of the
ferrocene have been inconclusive [16]. We have contin-
ued to study the electrochemical properties of these
complexes because recent work on ferroquine analogues
has indicated that there maybe a secondary toxicity
associated with the ferrocene. The ease with which the
ferrocene is oxidised may have a bearing on a minor/
secondary antiplasmodial activity that the primary
chloroquine type action masks.
i) The ferrocenyl ligands are also more efficacious
than the gold or rhodium complexes of chloroquine,
particularly against the resistant strains of the
parasite.
ii) The most active of the three types of coordination
complexes studied are those of the type
[Au(C6F5)(L)]. However, the gold moiety is in
most cases superfluous when coordinated to the
ferrocenyl ligands. In the case of the triphenylpho-
sphine salts 7 and 8, the presence of the gold moiety
has a detrimental effect on the antiplasmodial
activity of the ferrocenyl ligand.
3.5. Cyclic voltammetry
iii) The rhodium complexes are significantly less active
than the gold complexes and exhibit a moderate to
strong antagonistic effect on the efficacy of the
Compounds 2 and 4 both show a fully reversible
redox event whilst the behaviour of 3 is, at best, quasi-
reversible, as it exhibits a greater reversibility with
increasing scan rate (Table 2). The E1/2 value of 7 is
complexes 2ꢁ4. It must be noted that Sa´nchez-
/
Delgado and co-workers [4] reported higher activity
in vivo against P. berghei for the Rh complexes than
not quoted, because the Epa
this compound does not exhibit a full reversible one
ꢂ
/
Epc value indicates that
Table 1
In vitro antiplasmodial activity of metal complexes
Compound
Compound number
D10 (CQ-sensitive)
K1 (CQ-resistant)
IC50 (ng mlꢂ1
)
IC50 (nM)
IC50 (ng mlꢂ1
)
IC50 (nM)
1×
/
H3PO4
1
2
11.83
7.05
5.38
22.93
16.30
11.30
16.54
21.09
10.50
33.27
30.32
18.07
10.08
13.70
23.36
21.50
15.80
202.00
56.10
181.76
2.15
5.98
352.33
4.96
2
3
4
3
12.56
15.54
61.53
5.68
4
10.09
17.74
10.02
33.19
32.14
12.36
8.05
9.48
51.76
5.42
[Au(1)(PPh3)]NO3
[Au(2)(PPh3)]NO3
[Au(3)(PPh3)]NO3
[Au(4)(PPh3)]NO3
[Au(C6F5)(1)]
5
6
7
33.81
32.96
41.78
3.16
33.89
31.09
61.09
3.96
8
9
[Au(C6F5)(2)]
[Au(C6F5)(3)]
[Au(C6F5)(4)]
10
11
12
13
14
15
16
11.53
22.75
12.16
10.57
145.88
47.32
12.33
12.59
46.03
7.05
14.65
12.92
81.31
10.55
597.59
47.70
[Rh(Cl)(COD)(1)]
[Rh(Cl)(COD)(2)]
[Rh(Cl)(COD)(3)]
[Rh(Cl)(COD)(4)]
431.52
40.27

M.A.L. Blackie et al. / Journal of Organometallic Chemistry 688 (2003) 144ꢁ
/152
151
Table 2
Cyclic voltammetry of selected ferrocene containing compounds
Compound
Compound number
Epa (mV) a
Epc (mV) b
E1/2 (mV) c
Epa
ꢂ/Epc (mV)
2
[Au(2)(PPh3)]NO3
2
6
3
7
4
8
181
252
150
294
198
219
113
162
30
147
207
70
90
3
120
108
83
[Au(3)(PPh3)]NO3
4
[Au(4)(PPh3)]NO3
186
115
141
158
180
78
a
Anodic potential.
Cathodic potential.
b
c
Half wave potential (EpaꢀEpc)/2.
/
electron oxidation and therefore it is inappropriate to
quote a E1/2 value (Fig. 2). Coordination of the gold to
the ferrocenyl ligands has an effect on the redox
behaviour of the ferrocenyl moiety. Most notably, in
all cases the incorporation of gold into the molecule
difficult to oxidise in the presence of the coordinated
gold moiety. The effect was most marked when compar-
ing compound 3 with compound 7 [Au(3)(PPh3)]NO3.
There also appeared to be a trend towards reversibility
shown by the lowering in peak separation, Epa
ꢂEpc.
/
resulted in an increase in half wave potentials, E1/2,
which indicates that the ferrocenyl moiety is more
This effect is far more likely to be a ‘through-space’
interaction than a ‘through-bond’ interaction since the
aromatic quinoline and ferrocenyl moieties are not
linked by a conjugated chain.
Here it is observed that as the compounds become
more difficult to oxidise, so they lose efficacy. Unfortu-
nately, it is not possible to draw any conclusion about
this correlation at this stage.
4. Conclusions
The reaction of 7-chloroquinolines 1ꢁ
/4
with
[Au(PPh3)NO3], [Au(C6F5)(tht)] and [Rh(COD)Cl]2
have been investigated. The coordination complexes of
chloroquine show improved efficacy against chloro-
quine-resistant strains of the P. falciparum with respect
to chloroquine. However, there is a threefold drop in
efficacy in moving from the chloroquine sensitive to the
chloroquine resistant strain.
The ferrocenyl 4-aminoquinolines all show improved
efficacy with respect to chloroquine in both sensitive and
resistant strains, ferroquine being the most efficacious.
However, complexation of the second metal to these
compounds at best has little effect on the overall efficacy
of the compounds. At worst, there appears to be a
significant antagonistic effect on complexation of the
second metal. The presence of the second metal centre
makes the ferrocenyl moiety far more difficult to
oxidise.
It should be noted that whilst the gold and rhodium
heterobimetallic compounds do not show additive or
synergistic behaviour, this does not preclude this possi-
bility with other metal combinations.
Fig. 2. Cyclic voltammograms of 2, 3 and 7.

152
M.A.L. Blackie et al. / Journal of Organometallic Chemistry 688 (2003) 144ꢁ152
/
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Acknowledgements
We would like to thank Professor Alan Hutton for
assistance with cyclic voltammetry; UCT, the National
Research Foundation (South Africa), THRIP and the
Claude Harris Leon Foundation for financial support,
Johnson Matthey for the loan of sodium tetrachloroau-
rate and rhodium trichloride, and Siyabonga Ngubane
for help with preparing the final manuscripts.
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