Synthesis, structural characterization and leishmanicidal activity evaluation of ferrocenyl N-heterocyclic compounds

• Ferrocenyl bridge tuning can be obtained with minor changes in the ligands.
• Cytotoxicity of ferrocenyl compounds correlates with oxidation potential.
• Monocyclic aromatic rings show lower toxicity than bicyclic.
• ortho-Substituents next to quinoline N-atom decrease parasite drug susceptibility.
• Leishmania infantum amastigotes are much more sensitive to ferrocenyls than miltefosine.

New ferrocenyl derivatives with the general formula FcC(O)L [Fc = (η5-C5H5)Fe(η5-C5H4)], where L is an aminoquinoline or hydroxyaminoquinoline, have been synthesized for evaluation of their leishmanicidal properties. The compounds were designed with ferrocene coupled to the quinolines by an amide or ester bridge. Ferrocenyl component is intended to act as quinoline carrier and ROS producer after in vivo oxidation to Fe(III), while decreasing normal cell cytotoxicity of coupled quinolines. The bridge was chosen based on its known ability to undergo hydrolysis by the protease/esterase rich media in phagolysosomes, the target of the intracellular form of leishmania parasites.The new compounds include N-(quinolin-3-yl)ferrocenamide (4), N-(quinolin-5-yl)ferrocenamide (5), N-(quinolin-6-yl)ferrocenamide (6), N-(2-methyl-quinolin-4-yl)ferrocenamide (7), N-(2-methylquinolin-6-yl)ferrocenamide (8), N-(6-methoxy-quinolin-8-yl)ferrocenamide (9), 2-amino-quinolin-8-yl ferrocenoate (10) and 2-amino-quinolin-4-yl ferrocenoate (11). They were characterized by NMR, cyclic voltammetry, mass spectrometry, UV/vis, FT-IR and elemental analysis, which confirmed all the proposed molecular structures. Compounds 7 and 8 were also structurally characterized by single crystal X-ray diffraction. In 7, the 4-amino-2-methylquinoline moiety is perpendicular to the substituted cyclopentadienyl ring (Cp), while in 8 the 6-amino-2-methylquinoline component is coplanar to the substituted Cp.The new compounds (4–11), same as four other previously published (1-ferrocenoyl-1H-(2-aminobenzimidazole) (1), 1-ferrocenoyl-1H-benzimidazole (2), 1-ferrocenoyl-1H-imidazole (3) and N-(pyridin-4-yl)ferrocenamide (12)), were evaluated in vitro in cultures of a Leishmania infantum strain, isolated from a human visceral leishmaniasis case, to establish their leishmanicidal activity. The toxicity against the human caucasian histiocytic lymphoma U-937 cell line was analyzed for the same set of compounds. All of them show activity against promastigote forms of L. infantum parasites at relatively high concentration (64–269 μM). Among the complexes that showed a better ratio between the toxic and the therapeutic dose, 3, 9 and 12 were selected for further studies in infected macrophages. Such compounds showed a very significant increase in their activity (17–23 times) giving very similar IC50 values (5.2–5.7 μM). All three compounds gave significantly better therapeutic indexes (88.5, 12; 56.4, 3; 16.6, 9) than the control miltefosine (6.1).2

Organometallic compounds with three structural components (ferrocene + aromatic ligand +biofissionable link) were designed as leishmanicidal agents and show good activity against Leishmania infantum visceral strain amastigotes, with IC50 ≈5 μM and therapeutic indexes as high as 96 in U-937 macrophages, significantly bigger than reference drug miltefosine.Figure optionsDownload as PowerPoint slide