Risedronate metal complexes potentially active against Chagas disease

Area of Science:

• Medicinal Chemistry
• Parasitology
• Coordination Chemistry

Background:

• Chagas disease is a widespread Latin American parasitic disease.
• There is a need for novel metal-based drugs to treat this neglected tropical disease.
• Risedronate (Ris) is a bioactive ligand with potential therapeutic applications.

Purpose of the Study:

• To synthesize and characterize novel metal-risedronate complexes.
• To evaluate the in vitro antiparasitic activity of these complexes against Trypanosoma cruzi.
• To investigate the mechanism of action and protein interactions of the synthesized compounds.

Main Methods:

• Synthesis and characterization of metal-risedronate complexes ([M(II)(Ris)(2)]·4H(2)O and [Ni(II)(Ris)(2)(H(2)O)(2)]·H(2)O).
• Analytical measurements, thermogravimetric analyses, cyclic voltammetry, infrared and Raman spectroscopies.
• Single crystal X-ray diffraction for structural elucidation.
• In vitro evaluation against epimastigotes and intracellular amastigotes of Trypanosoma cruzi.
• Farnesyl diphosphate synthase enzyme inhibition assays.
• Protein interaction studies with albumin.

Main Results:

• Novel copper, cobalt, manganese, and nickel complexes with risedronate were successfully synthesized and characterized.
• Crystal structures of [Cu(II)(Ris)(2)]·4H(2)O and [Ni(II)(Ris)(2)(H(2)O)(2)]·H(2)O were determined.
• The metal-risedronate complexes exhibited improved antiproliferative effects against Trypanosoma cruzi compared to the free ligand.
• Growth inhibition of intracellular amastigotes was observed at low micromolar levels.
• High inhibition of farnesyl diphosphate synthase enzyme was noted.
• All complexes showed strong interaction with albumin, suggesting potential for in vivo transport.

Conclusions:

• Coordination of risedronate to metal ions enhances its antiparasitic activity against Trypanosoma cruzi.
• The synthesized metal complexes represent promising candidates for Chagas disease drug development.
• The observed activity is likely linked to farnesyl diphosphate synthase inhibition.
• Albumin binding indicates favorable pharmacokinetic properties for drug delivery.