Tri-aryl antimony(V) hydroximato and hydroxamato complexes: Combining lipophilic Sb(III/V) and hydroxamic acids in combating Leishmania

Abstract

Six novel tri-aryl antimony(V) hydroximato complexes (3–8) with composition [SbAr₃(O₂NCR)] (3: Ar = Ph, R = o-(OH)Ph, 4: Ar = Ph, R = Me, 5: Ar = Ph, R = Ph; 6: Ar = Mes, R = Me, 7: Ar = Mes, R = Ph, 8: Ar = Mes, R = o-(OH)Ph (where Ph = phenyl, Me = methyl, Mes = mesityl)), were synthesised and evaluated for anti-parasitic activity towards Leishmania major (L. major) promastigotes and amastigotes. Complexes of the form [SbAr₃(O₂NCR)], with the dianionic hydroximato ligand binding O,O′-bidentate to the Sb(V) centre, exist in the solid-state for the mesityl-derived complexes. In contrast, the phenyl-ligated Sb(V) complexes crystallise as the hexacoordinate, hydroxamato species [SbPh₃(O₂NHC(OH))], with the OH ligand derived from entrained H₂O in the crystallisation solvent. It is found that both the aryl and hydroximato ligands are found to influence the bioactivity of the Sb(V) complexes. Complexes 3–8 exhibited varied anti-promastigote activity with IC₅₀ values ranging from 1.53 μM for 6 to 36.0 μM for 3, also reflected in varied anti-amastigote activity with a percentage infection range of 5.50% for 6 to 29.00% for 3 at a concentration of 10 μM. The complexes were relatively non-toxic to human fibroblasts with an IC₅₀ value range of 59.3 μM (7) to ≥100 μM (3–6, 8), and exhibited varied toxicity towards J774.1 A macrophages (IC₅₀: 3.97 (6) to ≥100 (8) μM). All complexes showed enhanced activity compared to the parent hydroxamic acids.