Investigating the antiplasmodial activity of substituted cyclopentadienyl rhodium and iridium complexes of 2-(2-pyridyl)benzimidazole

Abstract

Six cationic half-sandwich Ir(III) and Rh(III) complexes (C1-C6) were synthesised by reaction of 2-(2-pyridyl)benzimidazole with the appropriate chloro-bridged dimers. All complexes were fully characterised using standard spectroscopic techniques and their purity confirmed by RP-HPLC. The molecular structures of these complexes were elucidated using single-crystal X-ray diffraction. Depending on the substituted cyclopentadienyl (Cpx) ligands, the complexes crystallized with an orthorhombic (Cpx = pentamethylcyclopentadienyl), monoclinic (Cpx = tetramethylphenylcyclopentadienyl) or triclinic (Cpx = tetramethylbiphenylcyclopentadienyl) crystal system. All complexes displayed good solubility in PBS and HEPES buffers within the concentration range used for the in vitro inhibitory screening. Using proton NMR experiments, the stability of the complexes in water was monitored at 37 °C and all complexes were resistant to displacement of their chlorido ancillary ligands by water. In vitro screening against the 3D7 chloroquine-sensitive and Dd2 multi-drug-resistant strains of Plasmodium falciparum revealed all complexes exhibited moderate to good potency. Complex C6 emerged as the most promising candidate with IC50 values of 0.75 ± 0.11 and 0.42 ± 0.055 µM against the 3D7 and Dd2 strains, respectively. The newly synthesised complexes were not cytotoxic to Human Embryonic Kidney cells.