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Toward a novel metal based chemotherapy against tropical diseases 4. Synthesis and characterization of new metal-clotrimazole complexes and evaluation of their activity against Trypanosoma cruzi

Abstract:

The syntheses and characterization of metal imidazole complexes showing activity against Trypanosoma cruzi, the causative agent of Chagas disease, are presented. RuCl<inf>2</inf>(CTZ)<inf>2</inf> (2) and RuCl<inf>2</inf>(BTZ)<inf>2</inf> (4) were prepared by reaction of RuCl<inf>2</inf>(NCCH<inf>3</inf>)<inf>4</inf> (1) with the appropriate ligand (CTZ, clotrimazole = 1-[(2-chlorophenyl)diphenylmethyl]-1H-imidazole; BTZ = 1-[(2-bromophenyl) diphenylmethyl] -1H-imidazole). [Ru(bipy) (CTZ)<inf>2</inf>] (PF<inf>6</inf>)<inf>2</inf> (3) (bipy = 2,2′-bipyridyl) was obtained by reaction of 2 with bipy and NH<inf>4</inf>PF<inf>6</inf> in MeCN. Reaction of [RhCl(COD)]<inf>2</inf> with CTZ yielded RhCl(COD)(CTZ) (5) (COD = 1,5-cyclooctadiene), while AuCl<inf>3</inf>CTZ (6), K<inf>2</inf>[PtCl<inf>4</inf>(CTZ)<inf>2</inf>] (7) and [Cu(CTZ)<inf>2</inf>]PF<inf>6</inf> (8) were obtained by interaction of CTZ with AuCl<inf>3</inf> · HCl, K<inf>2</inf>PtCl<inf>4</inf> and [Cu(CH<inf>3</inf>CN)<inf>4</inf>]PF<inf>6</inf>, respectively. All the new complexes were characterized by NMR and other appropriate techniques. X-ray diffraction studies of 4 · 3H<inf>2</inf>O, 5 and 6 were also carried out. The structure of 4 · 3H<inf>2</inf>O consists of a distorted tetrahedral arrangement of two N atoms from the BTZ ligands and two Cl atoms around the Ru(II) ion; 4 · 3H<inf>2</inf>O crystallizes in the orthorhombic space group Pnma (No. 62) with a = 12.818(5), b = 29.115(5), c = 12.040(5) Å, V = 4493.2(8) Å3 and Z = 4. Complex 5 displayed a square planar structure typical for Rh(I) bound to N from CTZ, Cl, and the two C = C bonds of COD; 5 crystallized in the triclinic space group (P(-1) (No.2) with a = 12.407(3), b = 12.876(4), c = 10.069(3) Å, α = 111.59(2)°, β = 107.80(2)°, γ = 103.28(2)°, V = 1313.4(8) Å3 and Z = 2. Complex 6 also displayed a square arrangement of N from CTZ, plus three Cl atoms around the Au(III) ion; 6 crystallized in the monoclinic space group P2<inf>1</inf>/n (No. 14) with a = 9.507(1), b = 18.280(4), c = 12.877(1) Å, β = 100.59(1)°, V = 2199.7(5) Å3 and Z = 4. All the new compounds were found to be active against in vitro cultures of Trypanosoma cruzi, following the trend 3 = 7<8<CTZ<6<5≪2. More detailed testing and preliminary mechanistic studies were carried out on the most active complex (2), which allowed the proposition of a simple model of action of this compound. © 1998 Elsevier Science S.A. All rights reserved.