In vitro leishmanicidal activity and theoretical insights into biological action of ruthenium(II) organometallic complexes containing anti-inflammatories

• Published in: Biometals Vol. 31; no. 6; pp. 1003 - 1017
• Main Authors: Miranda, Victor M., Costa, Monica S., Guilardi, Silvana, Machado, Antonio E. H., Ellena, Javier A., Tudini, Kelly A. G., Von Poelhsitz, Gustavo
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.12.2018; Springer Nature B.V
• Subjects: Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Biochemistry; Biomedical and Life Sciences; Cell Biology; Computer applications; Coordination compounds; Correlation analysis; Cytotoxicity; Diclofenac; Dose-Response Relationship, Drug; Ibuprofen; Leishmania; Leishmania - cytology; Leishmania - drug effects; Leishmaniasis; Leishmaniasis - drug therapy; Lethality; Life Sciences; Ligands; Medicine/Public Health; Microbiology; Models, Molecular; Naproxen; Organometallic complexes; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; p-Cymene; Parasitic Sensitivity Tests; Pharmacology/Toxicology; Plant Physiology; Promastigotes; Ruthenium; Ruthenium - chemistry; Ruthenium - pharmacology; Ruthenium compounds; Side effects; Structure-Activity Relationship; Toxicity; Tropical diseases; Vector-borne diseases; Anti-inflammatories; Ruthenium(II); Leishmaniasis; Cymene; p-Cymene
• ISSN: 0966-0844; 1572-8773
• DOI: 10.1007/s10534-018-0145-z

Leishmaniasis, a neglected tropical disease caused by protozoans of the genus Leishmania , kills around 20–30 thousand people in Africa, Asia, and Latin America annually and, despite its potential lethality, it can be treated and eventually cured. However, the current treatments are limited owing to severe side effects and resistance development by some Leishmania . These factors make it urgent to develop new leishmanicidal drugs. In the present study, three ruthenium(II) organometallic complexes containing as ligands the commercially available anti-inflammatories diclofenac (dic), ibuprofen (ibu), and naproxen (nap) were synthesized, characterized, and subjected to in vitro leishmanicidal activity. The in vitro cytotoxicity assays against Leishmania (L.) amazonensis and Leishmania (L.) infantum promastigotes have shown that complexes [RuCl(dic)(η 6 - p -cymene)] ( 1 ) and [RuCl(nap)(η 6 - p -cymene)] ( 3 ) were active against both Leishmania species. Complex [RuCl(ibu)(η 6 - p -cymene)] ( 2 ) has exhibited no activity. The IC 50 values for the two active complexes were respectively 7.42 and 23.55 μM, for L. (L.) amazonensis , and 8.57 and 42.25 μM, for L. (L.) infantum . Based on the toxicological results and computational analysis, we proposed a correlation between the complexes and their activity. Our results suggest both complexation to ruthenium(II) and ligands structure are key elements to leishmanicidal activity.