Antibacterial and Antiparasitic Activity

Many Rh(I), Rh(II) and Rh(III) complexes are active against malaria, leish-maniasis, trypanosomes, bacteria and algae. The anti-malarial activity of [RhCl(COD)(CQ)] (CQ = chloroquine) is similar to that of chloroquine diphosphate.79,80 However, chloroquine complexes with other metals (ruthenium and gold) are more active.79 Numerous rhodium complexes were investigated for the treatment of leishmaniasis.79,81 83 Rhodium(III) cationic complexes containing 2-hydroxybenzothiazole are very efficient anti-leishmanial agents:81 they totally inhibit the growth of Leishmania donovani. The rhodium(III) complex with mepacrine has an ED50 (effective dose generating 50% inhibition) of less than 1 mM. Ultrastructural studies (investigation of structure by means of electron microscope) suggest that the amastigote kineto-plast-mitochondrion complex is the primary site of action of the rhodium complex.82 The complexes: [RhBr2L4]Br (L = 2-amino-6-ethoxybenzothiazole or 2-bromothiazole) and [RhCl2L4]Cl (L = mefloquine, 2-mepacrine or oxam-niquine) exhibited high cytotoxicity against the macrophage cell line J-774.83 The complex with 2-amino-6-ethoxybenzothiazole exhibited high activity in vivo in parasitized Wistar rats.83 The [Rh2(OOCR)4L2] adducts with anti-malarial drugs (Plasmaquine, Chloroquine, Primaquine, Mepacrine, Penta-quine, Amodiaquine; Figure 20.6) show both anti-tumor and trypanocidal activities. The activity of rhodium complexes against trypanosomes was thoroughly investigated.17,18,84 87 Trypanocidal effects (Trypanosoma evansi, T. equiperdum, T. congolense, T. cruzi) of [RhX(NBD)] (X = alkyl and aryl xanthates) were investigated.17

Of this series, the most active is the complex containing cyclopentyl xanthate. The activities of [Rh2L2(COD)2]X2 (L = anti-parasitic drug 2-hydroxystilbami-dine, COD = 1,3-cyclooctadiene, X" = Cl",NO" ,ClO" ,BPh") and [Rh(COD) L2]X (L = anti-parasitic drug: Benznidazole = 2-nitro-N-(phenylmethyl)-1H-imi-dazole-1-acetamide, Nifurtimox = 3-methyl-N-[(5-nitro-2-furanyl)methylene]-4-thiomorpholine-1,1-dioxide, Niridazole = 1-(5-nitrothiazol-2-yl)-2-imidazolidi-none) were assayed on rats infected with T. evansi, and T. congolense.118 The most active was the complex with benznidazole. Rhodium complexes with diamidine and phenanthridinium trypanocides show higher therapeutic properties than the parent drugs.85 Another group of complexes showing activity against T. cruzi are [RhX2L4]X complexes, where L is a derivative of thiazole.86 It has been found that the rhodium(III) complexes do not interact with native DNA but some of them inhibit the precursor uptake and the

Ol o

Figure 20.6 Chemical structures of anti-malarial drugs used as ligands in syntheses of rhodium complexes: (a) Amodiaquine, (b) Mepacrine, (c) Primaquine, (d) Pentaquine, (e) Plasmaquine and (f) Chloroquine viability of metacyclic forms.86 The rhodium(I) complex with clotrimazole, (1-[(2-chlorophenyl)diphenylmethyl]-1H-imidazole), [RhCl(COD)(CTZ)] efficiently inhibits in vitro cultures of T. cruzi.87 Complexes of Rh(III) and Rh(II) with 2-amino-6-ethoxybenzothiazole, 2-aminonaphtothiazole, 2-chloropyridine and benzimidazole dithiocarbamate were evaluated for their anti-filarial activity against Molinema dessetae and Brugia pahangi.88

The binuclear rhodium(II) complexes [Rh2(RCOO)2(N-N)2(H2O)2](RCOO)2, [Rh2Cl2(RCOO)2(N-N)2] and [Rh2Cl2(MeCOO)(tpy)2](H3O)Cl2-9H2O (R = H, Me, Bu, Ph, PhCHOH; N-N = 2,2'-bipyridine (bpy), 1,10-phenanthroline (phen), 2,9-dimethyl-1,10-phenanthroline (dmp) and 6,7-dimethyl-2,3-di(2-pyridyl)qui-noxaline (dmpq); tpy = 2,20:60,200-terpyridine) are effective anti-bacterial agents against Staphylococcus aureus and Escherichia coli. The most active anti-bacterial

o agents against S. aureus were [Rh2(PhCOO)2(phen)2(H2O)2](PhCOO)2, [Rh2 (PhCOO)2(dmpq)2(H2O)2](PhCOO)2, [Rh2(BuCOO)2(phen)2(H2O)2](BuCOO)2 and [Rh2(BuCOO)2(bpy)2(H2O)2](BuCOO)2. These complexes show rather low activity against E. coli. The most active anti-bacterial agents against E. coli were [Rh2(RCOO)2(N-N)2(H2O)2](RCOO)2 and [Rh2Cl2(RCOO)2(N-N)2] (R = H and Me). These complexes exhibit low activity against S. aureus. The activity of the complexes [Rh2(RCOO)2(N-N)2(H2O)2](RCOO)2 against E. coli decreases in the series: R = H ffi CH3 >C2H5 >C3H7 ffi C4H9. The reverse order was found in the case of S. aureus. The complexes were considerably more active than the uncoordinated nitrogen ligands.43 45 The [Rh2(PhCOO)2(phen)2(H2O)2](PhCOO)2 complex is active against many Staphylococcus strains resistant to commonly used antibiotics.43 The complexes [Rh2(RCOO)2(N-N)2(H2O)2](RCOO)2 are effective cytostatic agents against the synchronously cultivated green alga C. vulgaris. For the [Rh2(MeCOO)2(dpp)2(H2O)2](MeCOO)2 (dpp = 4,7-diphenyl-1,10-phenan-throline) and [Rh2(PhCHOHCOO)2(phen)2(H2O)2](PhCHOHCOO)2 complexes, ED50 values equal to 10~6M and 8 x 10~6M, respectively, were found.46 The complexes inhibited the synthesis of DNA, protein and pigments (chlorophyll a, chlorophyll b, carotenes, luteine and violaxantine). However, the synthesis of RNA at low concentration of the complexes increased. A further well-defined series of metal complexes showing anti-bacterial activity is that of rhodium(III) complexes with pyridine: trans-[RhX2(py)4]Y.89 They are more active against Gram-positive bacteria than against Gram-negative. This perhaps is correlated with penetration because the highest anti-bacterial activity is exhibited by the most lipophilic complexes. The increase in activity corresponded to the increase in the number of C atoms in the alkyl group bound with pyridine ring. The complexes with pyridine derivatives substituted at the 3-, 4- or 5-positions had equal effects. The complex cis-[RhCl2(bpy)2]+ is inactive. Many rhodium(III) complexes, such as RhCl3, (NH4)3[RhCl6], (OC-6-21)-[RhCl3(NH3)3], were effective in the filamentation of bacteria.

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