Aromatic amine N-oxide organometallic compounds: searching for prospective agents against infectious diseases

• Published in: Dalton transactions : an international journal of inorganic chemistry 2015-08, Vol.44 (32), p.14453-14464
• Main Authors: Rodríguez Arce, Esteban, Mosquillo, M Florencia, Pérez-Díaz, Leticia, Echeverría, Gustavo A, Piro, Oscar E, Merlino, Alicia, Coitiño, E Laura, Maríngolo Ribeiro, Camila, Leite, Clarice Q F, Pavan, Fernando R, Otero, Lucía, Gambino, Dinorah
• Format: Article
• Language: English
• Subjects: Amines - chemistry; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; Enzymes; Ferrous Compounds - chemistry; Infectious diseases; Inhibitors; Ligands; Mathematical models; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Mycobacterium tuberculosis - drug effects; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Oxides - chemistry; Oxidoreductases Acting on CH-CH Group Donors - metabolism; Palladium; Palladium - chemistry; Phosphines - chemistry; Platinum - chemistry; Searching; Selectivity; Structure-Activity Relationship; Trypanosoma cruzi - drug effects
• ISSN: 1477-9226; 1477-9234
• DOI: 10.1039/c5dt00557d

In search of prospective agents against infectious diseases, 1,1'-bis(diphenylphosphino)ferrocene pyridine-2-thiolato-1-oxide M(ii) hexafluorophosphate compounds [M(mpo)(dppf)](PF6), where M = palladium or platinum, were synthesized and fully characterized in the solid state and in solution using experimental and DFT computational techniques. The compounds are isomorphous and the M(ii) transition metal ions are in a nearly planar trapezoidal cis-coordination bound to the pyridine-2-thiolato-1-oxide (mpo) and to the 1,1'-bis(diphenylphosphino)ferrocene molecules, both acting as bidentate ligands. Both compounds showed high cytotoxic activity on Trypanosoma cruzi and Mycobacterium tuberculosis (MTB) and acceptable selectivities towards MTB, but good to excellent selectivity index values as anti-T. cruzi compounds. The inclusion of the ferrocene moiety (dppf ligand) improved the selectivity towards the parasite when compared to the previously reported [M(mpo)2] complexes. Related to the probable mechanism of action of the complexes, molecular docking studies on modelled T. cruzi NADH-fumarate reductase (TcFR) predicted that both be very good inhibitors of the enzyme. The effect of the compounds on the enzyme activity was experimentally confirmed using T. cruzi protein extracts. According to all obtained results, both [M(mpo)(dppf)](PF6) compounds could be considered prospective anti-trypanosomal agents that deserve further research.